Application for Inclusion of a Medicine in the WHO Model List of Essential Medicines

Application for inclusion of a medicine in the WHO Model List of Essential Medicines

1. Summary statement of the proposal for inclusion, change or deletion

Inclusion of desmopressin (DDAVP) for the treatment of select patients with von Willebrand disease, Hemophilia A and other rare bleeding disorders.

2. Name of the focal point in WHO submitting or supporting the application (where relevant)

Blood & Transfusion Safety unit. WHO Designated Technical Officer: Junping Yu

3. Name of the organization(s) consulted and/or supporting the application

World Federation of Hemophilia.

4. International Nonproprietary Name (INN, generic name) of the medicine

INN: desmopressin; INN number: 3799

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)

Subcutaneous, intravenous, and intranasal.

6. International availability - sources, of possible manufacturers and trade names

Over 70 products manufactured or available in over 50 countries. See attached list, “Desmopressin NAMES”.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

Therapeutic group.

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

Desmopressin is used in the treatment of select patients with hemophilia A or von Willebrand disease (VWD). Hemophilia A occurs in 1 in 5,000 male births. Ten percent of female carriers of hemophilia are also at risk of bleeding. (Source: National Center for Biotechnology Information, National Institutes of Health, United States.) VWD occurs with equal frequency among men and women, affecting up to 1% of the general population. Women are more likely to experience symptoms of VWD because of the increased bleeding it causes during their menstrual periods, during pregnancy, and after childbirth. (Source: United States Centers for Disease Control and Prevention.)

Desmopressin is currently used in the treatment of both bleeding disorders. It is recommended in the clinical guidelines of many national and international hematological organizations. (See for example, the attached documents “WFH 2013,” “UKHCDO 2014,” NHLBI 2008” and “ESA 2013.”)

Desmopressin may also be indicated in certain situations for patients with other coagulation disorders or platelet disorders. (Source: the attached document, “ESA 2013”)

Desmopressin is a safe and affordable alternative to plasma products and fresh blood components for patients with moderate and mild haemophilia, VWD and other hereditary bleeding disorders in the developed world and particularly in developing countries.

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills)

Desmopressin can be given through intravenous, subcutaneous and intranasal routes. The dose for both intravenous and subcutaneous routes is 0.3 mg/kg. The intranasal dose is 150 mg for patients weighing less than 50 kg and 300 mg for patients weighing more than 50 kg. (The intranasal solution of desmopressin used in the

1 treatment of bleeding disorders is more concentrated than that used in the treatment of nocturnal enuresis or diabetes insipidus.)

See the attached documents, “WFH 2013,” “UKHCDO 2014,” NHLBI 2008,” “PGMJ 2007” and “ESA 2013.”

10. Summary of comparative effectiveness in a variety of clinical settings:

Clinical experience with desmopressin has greatly expanded over the past three decades. A review of the published literature affirms the efficacy and safety of desmopressin for prevention and treatment of bleeding in select patients with hemophilia A, VWD and other congenital bleeding disorders.

See the attached documents, “LEISSINGER 2014,” “MANNUCCI 1997” and “PGMJ 2007”.

11. Summary of comparative evidence on safety:

Most adverse events (AEs) associated with DDAVP are mild and related to the vasomotor effects of the drug (e.g. headache, facial flushing, mild hypotension and tachycardia). Mild to severe hyponatremia and hyponatremia-related seizures are the most serious AEs linked to the use of DDAVP and are caused by its antidiuretic effect, which is ten times greater with IV than with IN or SQ administration.

See the attached documents, “LEISSINGER 2014,” “MANNUCCI 1997” and “PGMJ 2007”.

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group:

Desmopressin is cost effective especially in comparison to blood derivatives and clotting factor concentrates. “Desmopressin is efficacious in mild hemophilia and type 1 VWD and usually permits the avoidance of concentrates, with significant reductions in costs. In the United States, for instance, an average dose of factor VIII concentrate (2,000 IU) costs between US$1,000 and $2,000. An average dose of desmopressin (21 μg) is much cheaper (US$100) and is even less expensive in Europe (the equivalent of US$20-$40).” (See the attached document “TOH 11 2012”)

13. Summary of regulatory status of the medicine (in various countries)

Desmopressin has regulatory approval in many countries including in Africa, Asia, Europe, North America and South America.

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)

See attached document, “Ph EUR Desmopressin”.

15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary

Desmopressin: injection, 4 micrograms (acetate)/ml in 1-ml ampoule; nasal spray 10 micrograms (acetate)/metered dose

2 Desmopressin names and manufacturers

Generic Names

• Desmopressin (OS: BAN) • Desmopressina (OS: DCIT) • Desmopressine (OS: DCF) • Desamino-Cys_-D-Arg_-Vasopressin (IS) • UNII-ENR1LLB0FP (IS) • Desmopressin (PH: BP 2011, Ph. Eur. 7) • Desmopressine (PH: Ph. Eur. 7) • Desmopressinum (PH: Ph. Eur. 7) • Desmopressin Acetate (OS: BANM, USAN, JAN) • DDAVP (IS) • KW-8008 (IS) • Minirin (IS) • Stimate (IS) • UNII-XB13HYU18U (IS) • Desmopressin Acetate (PH: USP 34)

Brand name Manufacturer, country 1. Adiuretin Ferring, Bulgaria 2. D.D.A.V.P. IFET, Greece 3. DDAVP IFET, Greece 4. Desmopresina Mede Alfa Wassermann, Georgia; Reig Jofre, Spain 5. Desmovital Er-Kim, Turkey 6. D-Void Sun, India 7. Emosint Kedrion, Argentina 8. Minirin Ferring, Georgia; Ferring, Luxembourg; Ferring, Oman; Ferring, Peru; Ferring, Tunisia; Ferring, Turkey 9. Minirin Melt Ferring, Georgia 10. Minirinmelt Ferring, Denmark; Ferring, France; Ferring Leciva, Poland 11. Minirin-Melt Ferring, Turkey 12. Minurin Paranova Ferring, Denmark 13. Noctissin Dumex, Oman 14. Octostim Ferring, Turkey 15. Presinex Kemofarmacija, Slovenia 16. Adin N Ferring, Israel 17. Apo-Desmopressin Apotex, Canada; Apotex, Hong Kong 18. DDAVP Desmopressin Ferring, Ireland 19. DDAVP Ferring, Canada; Ferring, United Kingdom; Ferring, South Africa; Gynopharm, Chile; Laboratórios Ferring, Brazil; sanofi-aventis, United States 20. Defirin Ferring, Greece 21. Desmin Dong Kook, South Korea 22. Desmo-C SwedPharm, Chile 23. Desmogalen Galenpharma, Germany

1 24. DesmoMelt Ferring, United Kingdom; Ferring, Malta 25. Desmopresin Ferring, Argentina 26. Desmopresina Swedpharm SwedPharm, Chile 27. Desmopress Ferring Ferring, Hungary 28. Desmopressin Acetate Apotex Apotex, United States 29. Desmopressin Acetate Bausch Bausch & Lomb, United States; Hospira, United States & Lomb 30. Desmopressin Acetate Ferring Ferring, United States 31. Desmopressin Acetate Sun Sun, United States 32. Desmopressin Acetate Teva Teva, United States 33. Desmopressin Acetate Watson Watson, United States 34. Desmopressin Acetate P & D, Malta 35. Desmopressin Actavis Actavis, Denmark; Actavis, Lithuania; Actavis, Latvia; Actavis, Norway; Actavis, Sweden; Inpac, Estonia 36. Desmopressin Ferring Ferring, Sweden 37. Desmopressin TAD TAD, Germany 38. Desmopressin Teva Teva, Germany; Teva, Denmark; Teva, Slovakia 39. Desmopressin Actavis, United Kingdom; AFT, New Zealand; Alpharma, Israel; Biopharm, Georgia; Ferring, United Kingdom; Kyowa Hakko Kirin, Japan 40. Desmopressina Teva Teva Italia, Italy 41. Desmopressine Ferring Ferring, Belgium; Ferring, Luxembourg 42. Desmopressine Teva Teva, Belgium 43. Desmopressine-acetaat Actavis, Netherlands Actavis 44. Desmopressine-acetaat CF Centrafarm, Netherlands 45. Desmopressine-acetaat PCH Pharmachemie, Netherlands 46. Desmopressine-acetaat PHT PH&T, Netherlands 47. Desmopressine-acetaat Sandoz, Netherlands Sandoz 48. Desmopressine-acetaat Teva Teva, Netherlands 49. Desmopressin-Zhonghe Zhonghe Pharmaceutical, China Pharm 50. Desmoprol Proel, Greece 51. Desmospray Ferring, United Kingdom; Ferring, Ireland; Medice, Germany 52. Desmotabs Ferring, United Kingdom; Ferring, Ireland; IFET, Greece; Medice, Germany 53. Dezmopresinijev acetat Teva Teva, Slovenia 54. Dinadom Dominguez, Argentina 55. Emosint Kedrion, Italy; Kedrion, Serbia; Kedrion, Russian Federation 56. Esmon Finixfarm, Greece 57. Minirin dDAVP Ferring, Singapore 58. Minirin DDAVP Ferring, Hong Kong 59. Minirin/Ddavp Ferring, Italy 60. Minirin CSL Behring, Germany; Euro, Netherlands; Ferring, Austria; Ferring, Australia; Ferring, Bosnia & Herzegowina; Ferring, Belgium; Ferring, Bulgaria; Ferring, Canada; Ferring, Switzerland; Ferring, China; 2 Ferring, Germany; Ferring, Denmark; Ferring, Estonia; Ferring, Finland; Ferring, France; Ferring, Greece; Ferring, Hungary; Ferring, Israel; Ferring, Iceland; Ferring, South Korea; Ferring, Lithuania; Ferring, Latvia; Ferring, Malta; Ferring, Mexico; Ferring, Malaysia; Ferring, Norway; Ferring, New Zealand; Ferring, Oman; Ferring, Philippines; Ferring, Portugal; Ferring, Romania; Ferring, Serbia; Ferring, Russian Federation; Ferring, Sweden; Ferring, Slovakia; Ferring, Thailand; Ferring, Taiwan; Ferring, United States; Ferring, Vietnam; Ferring Pharmaceuticals, Poland; Ferring-Leciva, Czech Republic; IFET, Greece; PharmaSwiss, Croatia (Hrvatska); PharmaSwiss, Slovenia 61. Minrin Ferring, Netherlands 62. Minurin Singad Pharma Ferring, Denmark 63. Minurin Ferring, Denmark; Ferring, Spain 64. Miram Teva, Bulgaria 65. Nafiset Pizzard, Mexico 66. Noctissin Actavis, Bulgaria 67. Nocturin Ferring, Germany 68. Nocutil Apogepha, Germany; Gebro, Austria; Gebro, Switzerland; Gebro, Hungary; Gebro Pharma, Denmark; Medac, Sweden 69. Nordurine Ferring, Ireland 70. Novo-Desmopressin Novopharm, Canada 71. Octim Ferring, France; Ferring, United Kingdom 72. Octostim CSL Behring, Germany; Ferring, Argentina; Ferring, Austria; Ferring, Belgium; Ferring, Canada; Ferring, Switzerland; Ferring, Chile; Ferring, Germany; Ferring, Denmark; Ferring, Estonia; Ferring, Spain; Ferring, Finland; Ferring, Hong Kong; Ferring, Hungary; Ferring, South Korea; Ferring, Lithuania; Ferring, Latvia; Ferring, Mexico; Ferring, Netherlands; Ferring, Norway; Ferring, New Zealand; Ferring, Oman; Ferring, Sweden; Rechon Life Science, Israel; Salus, Slovenia 73. PMS-Desmopressin Pharmascience, Canada 74. Presinex Mipharm, Bulgaria; Mipharm, Lithuania; Pfizer, Argentina; Pliva, Georgia; Trima, Israel 75. Stimate CSL Behring, United States 76. Uremin Hyun Dai, South Korea

3 Haemophilia (2013), 19, e1–e47 DOI: 10.1111/j.1365-2516.2012.02909.x

WFH GUIDELINES Guidelines for the management of hemophilia

A. SRIVASTAVA,* A. K. BREWER,† E. P. MAUSER-BUNSCHOTEN,‡ N. S. KEY,§ S. KITCHEN,¶ A. LLINAS,** C. A. LUDLAM,†† J. N. MAHLANGU,‡‡ K. MULDER,§§ M. C. POON¶¶ and A. STREET***; TREATMENT GUIDELINES WORKINGGROUPONBEHALFOFTHEWORLD FEDERATION OF HEMOPHILIA *Department of Hematology, Christian Medical College, Vellore, India; †Department of Oral Surgery, The Royal Infirmary, Glasgow, Scotland; ‡Van Creveldkliniek and Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands; §Department of Medicine, University of North Carolina, Chapel Hill, NC USA; ¶Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK; **Department of Orthopaedics and Traumatology, Fundacio´ n Santa Fe University Hospital Fundacio´ n Cosme y Damiań and Universidad de los Andes and Universidad del Rosario, Bogota´, Colombia; ††Comprehensive Care Haemophilia and Thrombosis Centre, Royal Infirmary, Edinburgh, UK; ‡‡Haemophilia Comprehensive Care Centre, Johannesburg Hospital and Department of Molecular Medicine and Haematology, Faculty of Health Sciences, National Health Laboratory Services and University of the Witwatersrand, Johannesburg, South Africa; §§Bleeding Disorders Clinic, Health Sciences Center, Winnipeg, Canada; ¶¶Departments of Medicine, Pediatrics and Oncology, and Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, University of Calgary, Foothills Hospital and Calgary Health Region, Calgary, Canada; and ***Haematology, Alfred Hospital, Melbourne, Victoria Australia

Summary. Hemophilia is a rare disorder that is healthcare providers seeking to initiate and/or complex to diagnose and to manage. These evidence- maintain hemophilia care programs, encourage based guidelines offer practical recommendations on practice harmonization around the world and, where the diagnosis and general management of hemophilia, recommendations lack adequate evidence, stimulate as well as the management of complications including appropriate studies. musculoskeletal issues, inhibitors, and transfusion- transmitted infections. By compiling these guidelines, Keywords: bleeding disorders, guidelines, hemophilia, the World Federation of Hemophilia aims to assist management, treatment

Correspondence: Dr. Alok Srivastava, Christian Medical College, Vellore 632004, India. Tel.: +91 416 228 2472; fax: +91 416 222 6449; e-mail: [email protected] Accepted after revision 6 June 2012

CONTENTS INTRODUCTION 4 1 GENERAL CARE AND MANAGEMENT OF HEMOPHILIA 5 1.1 WHAT IS HEMOPHILIA? 5 Bleeding manifestations 5 1.2 PRINCIPLES OF CARE 5 1.3 COMPREHENSIVE CARE 6 Comprehensive care team 6 Functions of a comprehensive care program 7 1.4 FITNESS AND PHYSICAL ACTIVITY 8 1.5 ADJUNCTIVE MANAGEMENT 8 1.6 PROPHYLACTIC FACTOR REPLACEMENT THERAPY 8 Administration and dosing schedules 9 1.7 HOME THERAPY 9 1.8 MONITORING HEALTH STATUS AND OUTCOME 10 1.9 PAIN MANAGEMENT 10 Pain caused by venous access 10 Pain caused by joint or muscle bleeding 10 Postoperative pain 10 Pain due to chronic hemophilic arthropathy 10 1.10 SURGERY AND INVASIVE PROCEDURES 11 1.11 DENTAL CARE AND MANAGEMENT 11 REFERENCES 12

2 SPECIAL MANAGEMENT ISSUES 14 2.1 CARRIERS 14 2.2 GENETIC TESTING/COUNSELING AND PRENATAL DIAGNOSIS 14 2.3 DELIVERY OF INFANTS WITH KNOWN OR SUSPECTED HEMOPHILIA 14 2.4 VACCINATIONS 15 2.5 PSYCHOSOCIAL ISSUES 15 2.6 SEXUALITY 15 2.7 AGING HEMOPHILIA PATIENTS 15 Osteoporosis 16 Obesity 16 Hypertension 16 Diabetes Mellitus (DM) 16 Hypercholesterolemia 16 Cardiovascular disease 16 Psychosocial Impact 17 2.8 VON WILLEBRAND DISEASE/RARE BLEEDING DISORDERS 17 REFERENCES 17

3 LABORATORY DIAGNOSIS 19 3.1 KNOWLEDGE AND EXPERTISE IN COAGULATION LABORATORY TESTING 19 Principles of diagnosis 19 Technical aspects 19 3.2 USE OF THE CORRECT EQUIPMENT AND REAGENTS 21 Equipment 21 Reagents 22 3.3 QUALITY ASSURANCE 22 Internal quality control (IQC) 22 External quality assessment (EQA) 22 REFERENCES 23

4 HEMOSTATIC AGENTS 24 4.1 CLOTTING FACTOR CONCENTRATES 24 Product selection 24 FVIII concentrates 25 FIX concentrates 25 4.2 OTHER PLASMA PRODUCTS 26 Fresh frozen plasma (FFP) 26 Cryoprecipitate 27 4.3 OTHER PHARMACOLOGICAL OPTIONS 27 Desmopressin (DDAVP) 27 Tranexamic acid 28 Epsilon aminocaproic acid 28 REFERENCES 29

5 TREATMENT OF SPECIFIC HEMORRHAGES 30 5.1 JOINT HEMORRHAGE (HEMARTHROSIS) 30 Arthrocentesis 31 5.2 MUSCLE HEMORRHAGE 31 Iliopsoas hemorrhage 32 5.3 CENTRAL NERVOUS SYSTEM HEMORRHAGE/HEAD TRAUMA 32

(continued)

5.4 THROAT AND NECK HEMORRHAGE 32 5.5 ACUTE GASTROINTESTINAL (GI) HEMORRHAGE 32 5.6 ACUTE ABDOMINAL HEMORRHAGE 32 5.7 OPHTHALMIC HEMORRHAGE 33 5.8 RENAL HEMORRHAGE 33 5.9 ORAL HEMORRHAGE 33 5.10 EPISTAXIS 33 5.11 SOFT TISSUE HEMORRHAGE 33 5.12 LACERATIONS AND ABRASIONS 34 REFERENCES 34

6 COMPLICATIONS OF HEMOPHILIA 35 6.1 MUSCULOSKELETAL COMPLICATIONS 35 Synovitis 35 Chronic hemophilic arthropathy 36 Principles of physiotherapy/physical medicine in hemophilia 36 Pseudotumors 37 Fractures 37 Principles of orthopedic surgery in hemophilia 37 6.2 INHIBITORS 38 Management of bleeding 39 Allergic reactions in patients with hemophilia B 39 Immune tolerance induction 39 Patients switching to new concentrates 39 6.3 TRANSFUSION-TRANSMITTED AND OTHER INFECTION-RELATED COMPLICATIONS 40 Principles of management of HIV infection in hemophilia 40 Principles of management of HCV infection in hemophilia 40 Principles of management of HBV infection in hemophilia 40 Principles of management of bacterial infection in hemophilia 41 REFERENCES 41

7 PLASMA FACTOR LEVEL AND DURATION OF ADMINISTRATION 44 7.1 CHOICE OF FACTOR REPLACEMENT THERAPY PROTOCOLS 44 REFERENCES 44

Tables 1-1 RELATIONSHIP OF BLEEDING SEVERITY WITH CLOTTING FACTOR LEVEL 5 1-2 SITES OF BLEEDING IN HEMOPHILIA 5 1-3 APPROXIMATE FREQUENCY OF BLEEDING AT DIFFERENT SITES 5 1-4 DEFINITIONS OF FACTOR REPLACEMENT THERAPY PROTOCOLS 8 1-5 STRATEGIES FOR PAIN MANAGEMENT IN PATIENTS WITH HEMOPHILIA 11 1-6 DEFINITION OF ADEQUACY OF HEMOSTASIS FOR SURGICAL PROCEDURES 11 3-1 INTERPRETATION OF SCREENING TESTS 20 5-1 DEFINITION OF RESPONSE TO TREATMENT OF ACUTE HEMARTHROSIS 30 7-1 SUGGESTED PLASMA FACTOR PEAK LEVEL AND DURATION OF ADMINISTRATION (WHEN THERE IS NO SIGNIFICANT RESOURCE 45 CONSTRAINT) 7-2 SUGGESTED PLASMA FACTOR PEAK LEVEL AND DURATION OF ADMINISTRATION (WHEN THERE IS SIGNIFICANT RESOURCE 45 CONSTRAINT)

Introduction given the diversity of health services and economic systems around the world. Our strongly held view is The first edition of these guidelines, published in 2005 that the principles of management of hemophilia are by the World Federation of Hemophilia (WFH), the same all over the world. The differences are served its purpose of being a useful document for mainly in the doses of clotting factor concentrates those looking for basic information on the comprehen- (CFC) used to treat or prevent bleeding, given that the sive management of hemophilia. The need for revision costs of replacement products comprise the major has arisen for several reasons. The most significant of expense of hemophilia care programs. Recognizing these was to incorporate the best existing evidence on this reality, these guidelines continue to include a dual which recommendations were based. There are recent set of dose recommendations for CFC replacement high-quality data from randomized controlled trials therapy. These are based on published literature and establishing the efficacy and superiority of practices in major centers around the world. It should prophylactic factor replacement over episodic treat- be appreciated, however, that the lower doses recom- ment – although the optimal dose and schedule for mended may not achieve the best results possible and prophylaxis continue to be subjects of further should serve as the starting point for care to be initi- research. There is also greater recognition of the need ated in resource-limited situations, with the aim of for better assessment of outcomes of hemophilia care gradually moving toward more optimal doses, based using newly developed, validated, disease-specific clini- on data and greater availability of CFC. metric instruments. This revised version addresses One of the reasons for the wide acceptance of the these issues in addition to updating all sections. first edition of these guidelines was its easy reading for- These guidelines contain several recommendations mat. While enhancing the content and scope of the regarding the clinical management of people with document, we have ensured that the format has hemophilia (practice statements,inbold). All such remained the same. We hope that it will continue to be statements are supported by the best available useful to those initiating and maintaining hemophilia evidence in the literature, which were graded as per care programs. Furthermore, the extensive review of the 2011 Oxford Centre for Evidence-Based Medicine the literature and the wide consensus on which prac- (Appendix I). Where possible, references for tice statements have been made may encourage prac- recommendations that fell outside the selection for tice harmonization around the world. More practice statements were also included. These refer- importantly, in areas where practice recommendations ences have not been graded. lack adequate evidence, we hope that this document A question often raised when developing a guideline will stimulate appropriate studies. document such as this is its universal applicability,

Section 1. General care and management of 3. Patients with mild hemophilia may not bleed excessively until they experience trauma or sur- hemophilia gery. 4. The severity of bleeding in hemophilia is generally 1.1 What is hemophilia? correlated with the clotting factor level, as shown 1. Hemophilia is an X-linked congenital bleeding dis- in Table 1-1. order caused by a deficiency of coagulation factor 5. Most bleeding occurs internally into the joints or VIII (FVIII) (in hemophilia A) or factor IX (FIX) muscles (see Tables 1-2 and 1-3). (in hemophilia B). The deficiency is the result of 6. Some bleeds can be life-threatening and require mutations of the respective clotting factor genes. immediate treatment (see Section 5). 2. Hemophilia has an estimated frequency of approximately one in 10 000 births. 1.2 Principles of care 3. Estimations based on the WFH’s annual global surveys indicate that the number of people with 1. The primary aim of care is to prevent and treat hemophilia in the world is approximately bleeding with the deficient clotting factor. 400 000 [1]. 2. Whenever possible, specific factor deficiency 4. Hemophilia A is more common than hemophilia should be treated with specific factor concen- B, representing 80–85% of the total hemophilia trate. population. 3. People with hemophilia are best managed in a 5. Hemophilia generally affects males on the mater- comprehensive care setting (see ‘Comprehensive nal side. However, both F8 and F9 genes are Care’). prone to new mutations, and as many as 1/3 of 4. Acute bleeds should be treated as quickly as pos- all cases are the result of spontaneous mutation sible, preferably within 2 h. If in doubt, treat. where there is no prior family history. (Level 4) [2] 6. Accurate diagnosis of hemophilia is essential to inform appropriate management. Hemophilia should be suspected in patients presenting with a history of: Table 1-2. Sites of bleeding in hemophilia [63]. • easy bruising in early childhood Serious Life-threatening • “spontaneous” bleeding (bleeding for no Joints (hemarthrosis) Intracranial Muscles, especially deep Neck/throat apparent/known reason), particularly into the compartments (iliopsoas, Gastrointestinal joints, muscles, and soft tissues calf, and forearm) • Excessive bleeding following trauma or sur- Mucous membranes in the gery mouth, gums, nose, and genitourinary tract 7. A family history of bleeding is obtained in about two-thirds of all patients. 8. A definitive diagnosis depends on factor assay to Table 1-3. Approximate frequency of bleeding at different sites. demonstrate deficiency of FVIII or FIX. Site of bleeding Approximate frequency % Bleeding manifestations Hemarthrosis 70–80 More common into hinged joints: 1. The characteristic phenotype in hemophilia is the ankles, knees, and elbows bleeding tendency. Less common into multi-axial joints: shoulders, wrists, hips 2. While the history of bleeding is usually life-long, Muscle 10–20 some children with severe hemophilia may not Other major bleeds 5–10 have bleeding symptoms until later when they Central nervous system <5 begin walking or running.

Table 1-1. Relationship of bleeding severity with clotting factor level [62].

Severity Clotting factor level Bleeding episodes À À Severe <1IUdL 1 (<0.01 IU mL 1)or<1% of normal Spontaneous bleeding into joints or muscles, predominantly in the absence of identiﬁable hemostatic challenge À À Moderate 1–5IUdL 1 (0.01–0.05 IU mL 1)or1–5% of normal Occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery À À Mild 5–40 IU dL 1 (0.05–0.40 IU mL 1)or5to<40% of normal Severe bleeding with major trauma or surgery. Spontaneous bleeding is rare

5. Patients usually recognize early symptoms of 16. Patients should avoid activities likely to cause bleeding even before the manifestation of physi- trauma (see ‘Fitness and Physical Activity’). cal signs. This is often described as a tingling 17. Regular monitoring of health status and assess- sensation or “aura”. ment of outcomes are key components of care 6. During an episode of acute bleeding, an assess- (see ‘Monitoring Health Status and Outcome’). ment should be performed to identify the site of 18. Drugs that affect platelet function, particularly bleeding (if not clinically obvious) and appropri- acetylsalicylic acid (ASA) and non-steroidal anti- ate clotting factor should be administered. inflammatory drugs (NSAIDs), except certain 7. In severe bleeding episodes that are potentially COX-2 inhibitors, should be avoided. Paraceta- life-threatening, especially in the head, neck, mol/acetaminophen is a safe alternative for chest, and gastrointestinal tract, treatment with analgesia (see ‘Pain Management’). factor should be initiated immediately, even 19. Factor levels should be raised to appropriate lev- before diagnostic assessment is completed. els prior to any invasive procedure (see ‘Surgery 8. To facilitate appropriate management in emer- and Invasive Procedures’). gency situations, all patients should carry easily 20. Good oral hygiene is essential to prevent accessible identification, indicating the diagnosis, periodontal disease and dental caries, which severity of the bleeding disorder, inhibitor status, predispose to gum bleeding (see ‘Dental Care type of treatment product used, initial dosage and Management’). for treatment of severe, moderate, and mild bleeding, and contact information of the treating physician/clinic. (Level 5) [3] 1.3 Comprehensive care 9. Administration of desmopressin (DDAVP) can 1. Comprehensive care promotes physical and psy- raise FVIII level adequately (three to six times chosocial health and quality of life while decreas- baseline levels) to control bleeding in patients ing morbidity and mortality. (Level 3) [7–9] with mild, and possibly moderate, hemophilia A. 2. Hemophilia is a rare disorder that is complex to Testing for DDAVP response in individual diagnose and to manage. Optimal care of these – patients is appropriate. (Level 3) [4 6] patients, especially those with severe forms of the 10. Veins must be treated with care. They are the disease, requires more than the treatment of acute lifelines for a person with hemophilia. bleeding. • 23- or 25-gauge butterfly needles are recom- 3. Priorities in the improvement of health and qual- mended. ity of life of people with hemophilia include: • Never cut down into a vein, except in an • prevention of bleeding and joint damage emergency. • prompt management of bleeding – • Apply pressure for 3 5 min after venipuncture. • management of complications including: • Venous access devices should be avoided ○ whenever possible, but may be required in joint and muscle damage and other seque- some children. lae of bleeding ○ 11. Adjunctive therapies can be used to control inhibitor development ○ bleeding, particularly in the absence of clotting viral infection(s) transmitted through blood factor concentrates, and may decrease the need products for them (see ‘Adjunctive Management’). • attention to psychosocial health 12. If bleeding does not resolve despite adequate treatment, clotting factor levels should be mea- Comprehensive care team sured. Inhibitor testing should be performed if 1. The wide ranging needs of people with hemo- the level is unexpectedly low (see ‘Inhibitor Test- philia and their families are best met through ing’, and ‘Inhibitors’). the coordinated delivery of comprehensive care 13. Prevention of bleeding can be achieved by pro- by a multidisciplinary team of healthcare profes- phylactic factor replacement (see ‘Prophylactic sionals, in accordance with accepted protocols Factor Replacement Therapy’). that are practical and national treatment guide- 14. Home therapy can be used to manage mild/mod- lines, if available. (Level 5) [10–12] erate bleeding episodes (see ‘Home therapy’). 2. The comprehensive care team should be multi- 15. Regular exercise and other measures to stimulate disciplinary in nature, with expertise and experi- normal psychomotor development should be ence to attend to the physical and psychosocial encouraged to promote strong muscles, develop health of patients and their families. balance and coordination, and improve fitness 3. The core team should consist of the following (see ‘Fitness and Physical Activity’). members:

• a medical director (preferably a pediatric and/ 9. The comprehensive care team should have the or adult hematologist, or a physician with resources to support family members. This may interest and expertise in hemostasis) include identifying resources and strategies to • a nurse coordinator who: help cope with: ○ coordinates the provision of care • risks and problems of everyday living, particu- ○ educates patients and their families larly with management of bleeding ○ acts as the first contact for patients with an • changes associated with different stages of the acute problem or who require follow-up patient’s growth and development (especially ○ is able to assess patients and institute initial adolescence and aging) care where appropriate • issues regarding schooling and employment • a musculoskeletal expert (physiotherapist, • risk of having another affected child and the occupational therapist, physiatrist, orthope- options available dist, rheumatologist) who can address preven- 10. Establishing a long-term relationship between tion as well as treatment patients/families and members of the compre- • a laboratory specialist hensive care team promotes compliance. • a psychosocial expert (preferably a social worker, or a psychologist) familiar with avail- Functions of a comprehensive care program able community resources 1. To provide or coordinate inpatient (i.e., during 4. The roles assumed by core team members may hospital stays) and outpatient (clinic and other differ, depending on the availability and visits) care and services to patients and their expertise of trained staff and the organization of family. services within the center. 5. All members of the core team should have • Patients should be seen by all core team mem- expertise and experience in treating bleeding dis- bers at least yearly (children every 6 months) orders and should be accessible to patients in a for a complete hematologic, musculoskeletal, timely and convenient manner. Adequate emer- and psychosocial assessment and to develop, gency care should be available at all times. audit, and refine an individual’s comprehensive 6. The following support resources are necessary: management plan. Referrals for other services can also be given during these visits. (Level 5) • Access to a coagulation laboratory capable of [13,14] performing accurate and precise clotting factor • The management plan should be developed assays and inhibitor testing. with the patient and communicated to all treat- • Provision of appropriate clotting factor ers and care facilities. Communication among concentrates, either plasma-derived or recom- treaters is important. binant, as well as other adjunct hemostatic • Smaller centers and personal physicians can agents such as desmopressin (DDAVP) and provide primary care and management of some tranexamic acid where possible. complications, in frequent consultation with • Where clotting factor concentrates are not the comprehensive care center (particularly for available, access to safe blood components patients who live a long distance from the near- such as fresh frozen plasma (FFP) and cryo- est hemophilia treatment center). precipitate. 2. To initiate, provide training for, and supervise • Access to casting and/or splinting for immobi- home therapy with clotting factor concentrates lization and mobility/support aids, as needed. where available. 7. The comprehensive care team should also 3. To educate patients, family members and other include or have access to, among others: caregivers to ensure that the needs of the patient • chronic pain specialist are met. • dentist 4. To collect data on sites of bleeds, types and doses • geneticist of treatment given, assessment of long-term out- • hepatologist comes (particularly with reference to musculoskel- • infectious disease specialist etal function), complications from treatment, and • immunologist surgical procedures. This information is best • gynecologist/obstetrician recorded in a computerized registry and should • vocational counselor be updated regularly by a designated person and 8. Written management protocols are required to maintained in accordance with confidentiality ensure continuity of care despite changes in laws and other national regulations. Systematic clinic personnel. data collection will:

• facilitate the auditing of services provided by 1.5 Adjunctive management the hemophilia treatment center and support 1. Adjunctive therapies are important, particularly improvements to care delivery. where clotting factor concentrates are limited or • help inform allocation of resources. not available, and may lessen the amount of • promote collaboration between centers in shar- treatment product required. ing and publishing data. 2. First aid measures: In addition to increasing 5. Where possible, to conduct basic and clinical factor level with clotting factor concentrates (or research. As the number of patients in each center desmopressin in mild hemophilia A), protection may be limited, clinical research is best conducted (splint), rest, ice, compression, and elevation in collaboration with other hemophilia centers. (PRICE) may be used as adjunctive management for bleeding in muscles and joints. 1.4 Fitness and physical activity 3. Physiotherapy/rehabilitation is particularly important for functional improvement and recovery after 1. Physical activity should be encouraged to promote musculoskeletal bleeds and for those with estab- physical fitness and normal neuromuscular devel- lished hemophilic arthropathy (see ‘Principles of opment, with attention paid to muscle strengthen- Physiotherapy/Physical Medicine in Hemophilia’). ing, coordination, general fitness, physical 4. Antifibrinolytic drugs (e.g., tranexamic acid, functioning, healthy body weight, and self-esteem. epsilon aminocaproic acid) are effective as (Level 2) [15] adjunctive treatment for mucosal bleeds and 2. Bone density may be decreased in people with dental extractions (see ‘Tranexamic Acid’ and hemophilia. [16,17] ‘Aminocaproic Acid’). 3. For patients with significant musculoskeletal dys- 5. Certain COX-2 inhibitors may be used judi- function, weight-bearing activities that promote ciously for joint inflammation after an acute bleed development and maintenance of good bone and in chronic arthritis (see ‘Pain Management’). density should be encouraged, to the extent their joint health permits. (Level 3) [16] 4. The choice of activities should reflect an individ- 1.6 Prophylactic factor replacement therapy ual’s preference/interests, ability, physical 1. Prophylaxis is the treatment by intravenous condition, local customs, and resources. injection of factor concentrate to prevent antici- 5. Non-contact sports such as swimming, walking, pated bleeding (Table 1-4). golf, badminton, archery, cycling, rowing, sail- 2. Prophylaxis was conceived from the observation ing, and table tennis should be encouraged. that moderate hemophilia patients with clotting À 6. High contact and collision sports such as soccer, factor level > 1 IU dL 1 seldom experience hockey, rugby, boxing, and wrestling, as well as high-velocity activities such as motocross racing and skiing, are best avoided because of the potential for life-threatening injuries, unless the Table 1-4. Definitions of factor replacement therapy protocols [64]. individual is on good prophylaxis to cover such Protocol Definition activities. Episodic (on-demand Treatment given at the time of clinically 7. Organized sports programs should be encour- treatment) evident bleeding Continuous prophylaxis aged as opposed to unstructured activities, where Primary prophylaxis Regular continuous* treatment initiated in protective equipment and supervision may be the absence of documented osteochondral lacking. joint disease, determined by physical 8. The patient should consult with a musculoskele- examination and/or imaging studies, and started before the second clinically evident tal professional before engaging in physical large joint bleed and age 3 years** activities to discuss their appropriateness, Secondary prophylaxis Regular continuous* treatment started after protective gear, prophylaxis (factor and other 2 or more bleeds into large joints** and measures), and physical skills required prior to before the onset of joint disease documented by physical examination and imaging studies beginning the activity. This is particularly impor- Tertiary prophylaxis Regular continuous* treatment started after tant if the patient has any problem/target joints the onset of joint disease documented by [18]. physical examination and plain radiographs of the affected joints 9. Target joints can be protected with braces or Intermittent (periodic) Treatment given to prevent bleeding for splints during activity, especially when there is prophylaxis periods not exceeding 45 weeks in a year no clotting factor coverage. (Level 4) [19,20] *Continuous is defined as the intent of treating for 52 weeks per year 10. Activities should be re-initiated gradually after a and receiving a minimum of an a priori defined frequency of infusions for bleed to minimize the chance of a re-bleed. at least 45 weeks (85%) of the year under consideration. **Large joints = ankles, knees, hips, elbows and shoulders.

spontaneous bleeding and have much better 3. The protocol should be individualized as much as preservation of joint function. [21–24] possible based on age, venous access, bleeding 3. Prophylaxis prevents bleeding and joint destruc- phenotype, activity, and availability of clotting tion and should be the goal of therapy to pre- factor concentrates. serve normal musculoskeletal function. (Level 2) 4. One option for the treatment of very young [24–29] children is to start prophylaxis once a week and 4. Prophylactic replacement of clotting factor has escalate depending on bleeding and venous been shown to be useful even when factor levels access. À are not maintained above 1 IU dL 1 at all times 5. Prophylaxis is best given in the morning to cover [26,29,30]. periods of activity. 5. It is unclear whether all patients should remain 6. Prophylactic administration of clotting factor con- on prophylaxis indefinitely as they transition centrates is advisable prior to engaging in activi- into adulthood. Although some data suggest that ties with higher risk of injury. (Level 4) a proportion of young adults can do well off [18,34,35] prophylaxis [31], more studies are needed before a clear recommendation can be made. [32] 1.7 Home therapy 6. In patients with repeated bleeding, particularly into target joints, short-term prophylaxis for 4– 1. Where appropriate and possible, persons with 8 weeks can be used to interrupt the bleeding hemophilia should be managed in a home ther- cycle. This may be combined with intensive apy setting. physiotherapy or synoviorthesis. (Level 3) 2. Home therapy allows immediate access to clot- [33,34] ting factor and hence optimal early treatment, 7. Prophylaxis does not reverse established joint resulting in decreased pain, dysfunction, and damage; however, it decreases frequency of long-term disability and significantly decreased bleeding and may slow progression of joint dis- hospital admissions for complications. (Level 3) ease and improve quality of life. [36,37] 8. Prophylaxis as currently practiced in countries 3. Further improvements in quality of life include where there are no significant resource greater freedom to travel and participate in constraints is an expensive treatment and is only physical activities, less absenteeism, and greater possible if significant resources are allocated to employment stability. [38] hemophilia care. However, it is cost-effective in 4. Home therapy is ideally achieved with clotting the long-term because it eliminates the high factor concentrates or other lyophilized products cost associated with subsequent management of that are safe, can be stored in a domestic fridge, damaged joints and improves quality of life. and are reconstituted easily. 9. In countries with significant resource constraints, 5. Home treatment must be supervised closely by lower doses of prophylaxis given more fre- the comprehensive care team and should only be quently may be an effective option. initiated after adequate education and training. 10. Cost-efficacy studies designed to identify mini- (Level 3) [36,37] mum dosage are necessary to allow access to 6. Teaching should focus on general knowledge of prophylaxis in more of the world. hemophilia; recognition of bleeds and common complications; first aid measures; dosage calculation; preparation, storage, and administration of Administration and dosing schedules clotting factor concentrates; aseptic techniques; performing venipuncture (or access of central 1. There are two prophylaxis protocols currently in venous catheter); record keeping; proper stor- use for which there are long-term data: age and disposal of needles/sharps; and handling À • The Malmo¨ protocol: 25–40 IU kg 1 per dose of blood spills. A certification program is administered three times a week for those with helpful. hemophilia A, and twice a week for those with 7. Patients or parents should keep bleed records hemophilia B. (paper or electronic) that include date and site À • The Utrecht protocol: 15–30 IU kg 1 per dose of bleeding, dosage and lot number of product administered three times a week for those with used, and adverse effects hemophilia A, and twice a week for those with 8. Infusion technique and bleed records should be hemophilia B. reviewed and monitored at follow-up visits. 2. However, many different protocols are followed 9. Home care can be started with young children for prophylaxis, even within the same country, with adequate venous access and motivated fam- and the optimal regimen remains to be defined. ily members who have undergone adequate

training. Older children and teenagers can learn • Health-related quality of life: (HaemoQol, self-infusion with family support. Canadian Hemophilia Outcomes: Kids’ Life 10. An implanted venous access device (Port-A- Assessment Tool [CHO-KLAT]) Cath) can make injections much easier and may For more information on available functional and be required for administering prophylaxis in physical examination scores, see the WFH’s Compen- younger children. (Level 2) [39,40] dium of Assessment Tools at: www.wfh.org/assess- 11. However, the risks of surgery, local infection, ment_tools. and thrombosis associated with such devices need to be weighed against the advantages of starting intensive prophylaxis early. (Level 2) 1.9 Pain management [41,42] Acute and chronic pain are common in patients with 12. The venous access device must be kept hemophilia. Adequate assessment of the cause of pain scrupulously clean and be adequately flushed is essential to guide proper management. after each administration to prevent clot formation. [41] Pain caused by venous access 1. In general, no pain medication is given. 1.8 Monitoring health status and outcome 2. In some children, application of a local anesthetic 1. Regular standardized evaluation at least every spray or cream at the site of venous access may 12 months allows longitudinal assessment for be helpful. individual patients and can identify new or potential problems in their early stages so that treat- Pain caused by joint or muscle bleeding ment plans can be modified. (Level 3) [14,26,43] 1. While clotting factor concentrates should be 2. Patients should be seen by the multidisciplinary administered as quickly as possible to stop bleed- care team after every severe bleeding episode. ing, additional drugs are often needed for pain 3. The following should be evaluated and education control (Table 1-5). should be reviewed and reinforced: 2. Other measures include cold packs, immobiliza- • issues related to venous access tion, splints, and crutches [44]. • issues related to hemostasis (bleed record) • use of products for replacement therapy and Postoperative pain the response to them 1. Intramuscular injection of analgesia should be • musculoskeletal status: impairment and func- avoided. tion through clinical assessment of joints and 2. Postoperative pain should be managed in coordi- muscles, and radiological evaluation annually nation with the anesthesiologist. or as indicated (see ‘Musculoskeletal compli- 3. Initially, intravenous morphine or other narcotic cations’) analgesics can be given, followed by an oral opioid • transfusion-transmitted infections: commonly such as tramadol, codeine, hydrocodone, and oth- HIV, HCV, and HBV, and others if indicated ers. (see ‘Transfusion-transmitted and other infec- 4. When pain is decreasing, paracetamol/acetamino- tion-related complications’) phen may be used. • development of inhibitors (see ‘Inhibitors’) • overall psychosocial status Pain due to chronic hemophilic arthropathy • dental/oral health 4. Several hemophilia-specific scores are available to 1. Chronic hemophilic arthropathy develops in measure joint impairment and function, including patients who have not been adequately treated with activities and participation. These include: clotting factor concentrates for joint bleeding. 2. Treatment includes functional training, adapta- • Impairment: tions, and adequate analgesia as suggested in ○ Clinical: WFH Physical Examination Score Table 1-5. (Level 2) [15,45] (aka Gilbert score), Hemophilia Joint Health 3. COX-2 inhibitors have a greater role in this situa- Score (HJHS) tion. (Level 2) [46,47] ○ Radiological: Pettersson score, MRI, and 4. Other NSAIDs should be avoided. (Level 2) [48] ultrasound scores Activity: Haemophilia 5. When pain is disabling, orthopedic surgery may Activities List (HAL), Paediatric Haemo- be indicated. (Level 5) [49] philia Activities List (PedHAL), Functional 6. Patients with persisting pain should be referred to Independence Score in Hemophilia (FISH) a specialized pain management team.

Table 1-5. Strategies for pain management in patients with hemophilia. 11. Patients with mild hemophilia A, as well as 1 Paracetamol/acetaminophen patients receiving intensive factor replacement If not effective ↓ for the first time, are at particular risk of inhibi- 2 COX-2 inhibitor (e.g., celecoxib, meloxicam, tor development and should be re-screened nimesulide, and others; 4–12 weeks postoperatively. (Level 4) [54] OR 12. Careful monitoring for inihibitors is also advis- Paracetamol/acetaminophen plus codeine able in patients with non-severe hemophilia A (3–4 times per day) OR receiving continuous infusion after surgery [55]. Paracetamol/acetaminophen plus tramadol 13. Infusion of factor concentrates/hemostatic agents (3–4 times per day) is necessary before invasive diagnostic procedures 3 Morphine: use a slow release product with an escape of a rapid release. Increase the slow release product if the rapid release such as lumbar puncture, arterial blood gas deter- product is used more than 4 times per day mination, or any endoscopy with biopsy. Notes: If for any reason medications have been stopped for a period of time, patients who have been taking and tolerating high-dose narcotic drugs should re-start the drug at a lower dose, or use a less powerful 1.11 Dental care and management painkiller, under the supervision of a physician. COX-2 inhibitors should be used with caution in patients with hypertension and renal dysfunction. 1. For persons with hemophilia, good oral hygiene is essential to prevent periodontal disease and dental 1.10 Surgery and invasive procedures caries, which predispose to gum bleeding [56]. 2. Dental examinations should be conducted regularly, Surgery may be required for hemophilia-related com- starting at the time the baby teeth start to erupt. plications or unrelated diseases. The following issues are of prime importance when performing surgery on persons with hemophilia: Table 1-6. Definition of adequacy of hemostasis for sugical procedures 1. Surgery for patients with hemophilia will require [64]. additional planning and interaction with the health- Excellent Intra-operative and postoperative blood loss similar care team than what is required for other patients. (within 10%) to the non-hemophilic patient. 2. A hemophilia patient requiring surgery is best • No extra (unplanned) doses of FVIII/FIX/bypassing agents managed at or in consultation with a comprehen- needed AND • Blood component transfusions required are similar to sive hemophilia treatment center. (Level 3) [50,51] non-hemophilic patient 3. The anesthesiologist should have experience Good Intra-operative and/or postoperative blood loss slightly treating patients with bleeding disorders. increased over expectation for the non-hemophilic patient 4. Adequate laboratory support is required for reli- (between 10 and 25% of expected), but the difference is judged by the involved surgeon/anaesthetist to be clinically able monitoring of clotting factor level and insignificant inhibitor testing. • No extra (unplanned) doses of FVIII/FIX/bypassing agents 5. Preoperative assessment should include inhibitor needed AND • Blood component transfusions required are similar to screening and inhibitor assay, particularly if the non-hemophilic patient recovery of the replaced factor is significantly Fair Intra-operative and/or postoperative blood loss increased less than expected. (Level 4) [52,53] over expectation (25–50%) for the non-hemophilic patient 6. Surgery should be scheduled early in the week and additional treatment is needed • Extra (unplanned) dose of FVIII/FIX/bypassing and early in the day for optimal laboratory and agents factor needed OR blood bank support, if needed. • Increased blood component (within 2 fold) of 7. Adequate quantities of clotting factor concen- the anticipated transfusion requirement trates should be available for the surgery itself Poor/none Significant intra-operative and/or postoperative blood loss that is substantially increased over expectation (>50%) for and to maintain adequate coverage postopera- the non-hemophilic patient, requires intervention, and is tively for the length of time required for healing not explained by a surgical/medical issue other than and/or rehabilitation. hemophilia • Unexpected hypotension or unexpected transfer to ICU 8. If clotting factor concentrates are not available, due to bleeding OR adequate blood bank support for plasma compo- • Substantially increased blood component (>2 fold) of the nents is needed. anticipated transfusion requirement 9. The dosage and duration of clotting factor con- *Apart from estimates of blood loss during surgery, data on pre- and centrate coverage depend on the type of surgery post-operative hemogloblin levels and the number of packed red blood cell units transfused may also be used, if relevant, to estimate surgical performed (Tables 7-1, 7-2). blood loss. 10. Effectiveness of hemostasis for surgical proce- *Surgical hemostasis should be assessed by an involved surgeon and/or dures may be judged as per criteria defined by anaesthetist and records should be completed within 72 hours following the Scientific and Standardization Committee of surgery. *Surgical procedures may be classified as major or minor. A major surgi- the International Society on Thrombosis and cal procedure is defined as one that requires hemostatic support for peri- Haemostasis (Table 1-6). ods exceeding 5 consecutive days.

3. Teeth should be brushed twice a day with a med- reduce the need for replacement therapy. (Level ium texture brush to remove plaque deposits. 4) [59,60] 4. Dental floss or interdental brushes should be 12. Oral antibiotics should only be prescribed if used wherever possible. clinically necessary. 5. Toothpaste containing fluoride should be used in 13. Local hemostatic measures may also be used areas where natural fluoride is not present in the whenever possible following a dental extraction. water supply. Fluoride supplements may also be Typical products include oxidized cellulose and prescribed if appropriate. fibrin glue. 6. An orthodontic assessment should be considered 14. Following a tooth extraction, the patient should for all patients between the ages of 10–14 to be advised to avoid hot food and drinks until determine if there are any problems associated normal feeling has returned. Smoking should be with overcrowding, which can result in peri- avoided as this can cause problems with healing. odontal disease if left untreated. Regular warm salt water mouthwashes (a tea- 7. Close liaison between the dental surgeon and the spoon of salt in a glass of warm water) should hemophilia team is essential to provide good begin the day after treatment and continue for comprehensive dental care. 5–7 days or until the mouth has healed. 8. Treatment can be safely carried out under local anes- 15. Prolonged bleeding and/or difficulty in speaking, thesia using the full range of techniques available to swallowing, or breathing following dental dental surgeons. Infiltration, intra-papillary, and manipulation should be reported to the hematol- intra-ligamentary injections are often done under ogist/dental surgeon immediately. factor cover (20–40%) although it may be possible 16. Non-steroidal anti-inflammatory drugs (NSAIDs) for those with adequate experience to administer and aspirin must be avoided. these injections without it. (Level 4) [57,58] 17. An appropriate dose of paracetamol/acetamino- 9. Treatment from the hemophilia unit may be phen every 6 h for 2–3 days will help prevent required before an inferior alveolar nerve block pain following an extraction. or lingual infiltration. 18. The presence of blood-borne infections should 10. Dental extraction or surgical procedures carried not affect the availability of dental treatment. out within the oral cavity should be performed 19. Prevention of bleeding at the time of dental pro- with a plan for hemostasis management, in con- cedures in patients with inhibitors to FVIII or sultation with the hematologist. (Level 3) [51] FIX requires careful planning [61]. 11. Tranexamic acid or epsilon aminocaproic acid (EACA) is often used after dental procedures to

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Section 2. Special management issues female family members of people with hemophilia to facilitate genetic counseling, and if 2.1 Carriers desired by the family, prenatal diagnosis. (Level 4) [6] 1. Hemophilia is an X-linked disorder that 2. DNA-based mutation analysis to identify the typically affects males, while females are car- specific mutation responsible for hemophilia in a riers. particular family is becoming technically easier 2. Obligate carriers are: and more widely available. This facilitates iden- • daughters of a person with hemophilia tification of carriers and prenatal diagnosis for • mothers of one son with hemophilia and who male fetuses. have at least one other family member with 3. Genetic counseling is key to helping people with hemophilia hemophilia, carriers, and their families make • mothers of one son with hemophilia and who more informed choices. have a family member who is a known carrier 4. Prenatal diagnosis is usually offered when termi- of the hemophilia gene nation of the pregnancy would be considered if • mothers of two or more sons with hemophilia an affected fetus was identified. However, it may 3. The expected mean clotting factor level in carri- also be done to help the family prepare and to ers of hemophilia is 50% of the levels found in plan delivery. Assisted delivery is best avoided in the healthy population [1,2]. an affected fetus. 4. Most carriers are asymptomatic. 5. Fetal gender can be determined using Y chromo- 5. Carriers with clotting factor levels of 40–60% of some-specific PCR in maternal plasma/serum after normal may have an increased bleeding tendency 7–9 weeks of gestation [7,8] or by [3]. ultrasonography beginning week 11 of gestation 6. A few carriers may have clotting factor levels in [9]. the hemophilia range – mostly in the mild cate- 6. Chorionic villus sampling (CVS), or biopsy, is gory – but in rare instances, carriers can be in the main method of prenatal diagnosis and is the moderate or severe range due to extreme best done between 9 and 14 weeks of gestation. lyonization. (Table 1-1) Biopsy carried out earlier may be associated 7. Carriers with clotting factor levels in the hemo- with increased complications including fetal limb philia range may be symptomatic with bleeding abnormalities. (Level 1) [10–13] manifestations commensurate with their degree 7. Amniocentesis can be done at 15–17 weeks of of clotting factor deficiency, particularly during gestation [11]. trauma and surgery [3]. 8. It is important to be aware of and to follow the 8. Menorrhagia and bleeding after medical interven- relevant laws governing such procedures in the tions are the most common manifestations among country where the service is being provided. carriers with significantly low factor levels [3]. 9. For carriers with low factor levels À1 9. Carriers with low clotting factor levels should be (<50 IU dL ), hemostatic support may be categorized as having hemophilia of appropriate required to prevent maternal bleeding during severity and managed accordingly. prenatal diagnosis procedures. 10. Birth control pills and antifibrinolytic agents 10. All invasive methods used for prenatal diagnosis are useful in controlling symptoms of menor- may cause feto-maternal hemorrhage. Anti-D rhagia. immunoglobulin should be given if the mother is 11. Levels of factor VIII increase significantly in RhD negative. (Level 3) [14] pregnancy. Levels of factor IX, however, do not 11. Preimplantation genetic diagnosis allows selec- usually change significantly [4]. tion of embryos without specific mutation to be 12. Immediate female relatives (mother, sisters, and implanted into the uterus. [15] daughters) of a person with hemophilia should have their clotting factor level checked, espe- 2.3 Delivery of infants with known or suspected cially prior to any invasive intervention, child- hemophilia birth, or if any symptoms occur. (Level 3) [3,5] 1. FVIII levels usually rise into the normal range during the second and third trimesters and 2.2 Genetic testing/counseling and prenatal should therefore be measured in carriers during diagnosis the third trimester of pregnancy to inform deci- 1. Where available and possible, genetic testing sions for factor coverage during delivery. (Level for carrier status should be offered to at-risk 3) [4]

2. In carriers with significantly low factor levels economic dimensions of hemophilia, in terms À (<50 IU dL 1), clotting factor replacement is nec- the patient/parents can understand. essary for surgical or invasive procedures includ- • be open and honest about all aspects of care. ing delivery. (Level 3) [4] • allow the patient/parents to work through 3. The need for clotting factor replacement should their emotions and ask questions. Provide care be planned in the prenatal period. and support patiently. 4. Route of delivery in carriers with a normal fetus • talk to affected children, not just their par- should be as per obstetric indications. ents. Children can often understand a good 5. Delivery of infants with known or suspected deal about their illness and can work with hemophilia should be atraumatic, regardless of the physician if properly informed and edu- whether it is vaginal or cesarean, to decrease the cated. risk of bleeding. (Level 3) [4] • remind parents not to ignore siblings that are 6. Forceps and vacuum extraction should be avoided healthy. in vaginal delivery, as well as invasive procedures • be able to recognize warning signs of burnout to the fetus such as fetal scalp blood sampling and depression, which are common with and internal fetal scalp electrodes [16]. chronic illness, and provide suggestions for coping. • recognize that cultural background may affect 2.4 Vaccinations patients’ views of illness. 1. Persons with bleeding disorders should be vacci- • encourage patients to engage in productive nated, but should preferably receive the vaccine and leisure activities at home and in the work- subcutaneously rather than intramuscularly or place. intradermally, unless covered by infusion of clot- • work in partnership with the patient organiza- ting factor concentrates. (Level 4) [17] tion to advocate for hemophilia care and to 2. If intramuscular injection is to be given: provide education to families and members of the community. • It is best done soon after a dose of factor • enlist the assistance of local groups and orga- replacement therapy. nizations where social workers are unavail- • An ice pack can be applied to the injection area able. for 5 min before injection. • The smallest gauge needle available (usually 25–27 gauge) should be used. 2.6 Sexuality • Pressure should be applied to the injection site 1. Patients with hemophilia can have normal sexual for at least 5 min [18]. intercourse [24]. 3. Live virus vaccines (such as oral polio vaccine, 2. Muscle bleedings (e.g., iliopsoas) may sometimes MMR) may be contraindicated in those with HIV be the result of sexual activity. infection. 3. Complications of hemophilia can be accompanied 4. People with hemophilia who have HIV should be by sexual dysfunction, which may include lack of given pneumococcal and annual influenza vac- libido or impotence. cines. 4. Pain or fear of pain may affect sexual desire, and 5. Immunization to hepatitis A and hepatitis B is hemophilic arthropathy may place limitations on important for all persons with hemophilia. These sexual intercourse. immunizations may not be as effective in those 5. Sexuality is also affected by chronic HCV and with HIV infection. (Level 4) [19,20] HIV infection, age-related diseases like hypertension and diabetes mellitus, and certain medications. 2.5 Psychosocial issues 6. In some cases, oral phosphodiesterase-5 inhibi- 1. Patients and their families should be provided tors (sildenafil, tadalafil) may be helpful. These with psychological and social support [21,22]. medications mildly inhibit platelet aggregation in 2. Hemophilia is also a financial burden that places vitro, and may cause epistaxis due to nasal con- restrictions on several aspects of normal living gestion. [23]. 3. The social worker and/or other members of the comprehensive care team should: 2.7 Aging hemophilia patients • provide as much information as possible about 1. Aging patients with hemophilia will inevitably the physical, psychological, emotional, and suffer from age-related diseases [24,25].

2. Comorbidities in aging hemophilia patients Diabetes mellitus (DM) should be managed appropriately as they may 1. The prevalence of DM in hemophilia is not well accentuate problems associated with hemophilia documented, but was observed to be higher in a and impact the patient’s physical and psychoso- cohort of mild hemophilia [35]. cial health, and thus their quality of life. 2. In aging hemophilia patients, especially among those who are overweight, glucose levels should Osteoporosis be checked annually. 1. Bone mineral density (BMD) is decreased in peo- 3. If treatment with insulin is indicated, subcutane- ple with hemophilia [26,27]. ous injections can be administered without bleed- 2. An increased number of arthropathic joints, loss ing complications. (Level 5) [24] of joint movement, and muscle atrophy leading to inactivity are associated with a lower BMD [27]. Hypercholesterolemia 3. Weight-bearing activities (suitable sports) that 1. Mean cholesterol levels in patients with hemo- promote development and maintenance of good philia have been reported to be lower than in the bone density should be encouraged if joint health general population [36]. permits. 2. Cholesterol levels (total cholesterol, HDL, and 4. Calcium and vitamin D supplementation are also LDL fraction) should be measured in aging hemo- important and bisphosphonate therapy may be philia patients at risk of cardiovascular disease. required. A dental evaluation is advisable before 3. Treatment is indicated if cholesterol levels are initiating long-term bisphosphonate therapy high. As a general rule, the total cholesterol/HDL [28,29]. ratio should not be higher than 8.

Obesity Cardiovascular disease 1. The prevalence of overweight (BMI 25–30 À À 1. Hemophilia patients appear to have a reduced kg m 2)andobesity(BMI>30kgm 2)isincreas- risk of mortality from ischemic cardiovascular ing [30]. disease, but the number of deaths from this cause 2. Lack of activity may contribute to an increase in is increasing [34,37,38]. BMI and increased body weight. 2. A possible association between the occurrence of 3. A high BMI has been associated with: myocardial infarction and previous administration • a signiﬁcant limitation in range of motion of clotting factor concentrates has been described (ROM) [31] [39,40]. • increased arthropathic pain 3. Hemophilia patients with cardiovascular disease • increased risk of developing target joints [32] should receive routine care adapted to the indi- • increased risk of diabetes mellitus, atheroscle- vidual situation, in discussion with a cardiologist rosis, and cardiovascular disease, which may [41,42]. further damage arthropathic joints. 4. For acute coronary syndromes requiring percuta- 4. Regular physical activity should be advised. neous cardiac intervention (PCI): 5. If functional limitations restrict daily activities, a • Adequate correction with clotting factor con- physiotherapist familiar with hemophilia may be centrates before PCI and until 48 h after PCI is able to suggest appropriate alternatives. required. (Level 4) [40,41,43] 6. In some cases, referral to a dietician may be indi- • High factor levels should be avoided to prevent cated. occlusive thrombi. During complete correction: ○ Hypertension Heparin can be administered according to standard cardiologic treatment protocols. 1. Hemophilia patients have a higher mean blood ○ Glycoprotein IIb/IIIa inhibitors (abciximab, pressure, are twice as likely to have hypertension, tiroﬁban) used in PCI with stenting can be and use more anti-hypertensive medication com- administered. pared with the general population [33,34]. • Radial artery access site, if technically possible, 2. In view of increased risk of bleeding, hypertensive is preferred over femoral, to minimize retro- patients with hemophilia should be treated adequately peritoneal or groin bleeds. (Level 4) [40,41,43] and have their blood pressure checked regularly. • Factor concentrates should be given for the 3. In the absence of other cardiovascular risk factors, a duration of dual antiplatelet therapy, usually systolic blood pressure 140 mmHg and a dia- about 2 weeks, aiming at trough levels of À stolic pressure 90 mmHg should be maintained. 30 IU dL 1 [41].

• Prolonged use of aspirin is not recommended in such patients are cared for in hemophilia treat- severe hemophilia. Its use in patients on regular ment centers. intensive prophylaxis is possible, although the 2. These guidelines are intended for the treatment of data available are inadequate [41]. hemophilia. Recent publications that address the principles of diagnosis and treatment of von Psychosocial impact Willebrand disease (VWD) and rare bleeding disorders include: 1. In the aging patient, the presence of crippling, painful arthropathy can affect quality of life and • Management of von Willebrand disease: a may lead to loss of independence [44]. guideline from the UK Haemophilia Centre 2. Patients may be confronted with unexpected emo- Doctors’ Organization. Haemophilia 2004;10 tional problems due to memories of negative (3):218.231. experiences related to hemophilia (such as hospi- • The Diagnosis, Evaluation and Management of talization) during their youth. von Willebrand Disease. US Dept of Health 3. Adaptations at home or at work and an adequate and Human Services, National Heart, Lung pain schedule are indicated to improve quality of and Blood Institute NIH Publication no. 08- life and preserve independence. 5832, December 2007. www.nhlbi.nih.gov 4. Active psychosocial support should be provided • von Willebrand Disease: An Introduction for by a social worker, hemophilia nurse, physician the Primary Care Physician. David Lillicrap and/or psychologist. and Paula James, World Federation of Hemo- philia Treatment of Hemophilia monograph No 47, January 2009. www.wfh.org 2.8 von Willebrand disease and rare bleeding • Rare Bleeding Disorders. Peyvandi F, Kaufman disorders R, Selighson U et al. Haemophilia 2006 Jul; 12 – 1. The WFH is committed to providing support and Suppl: 137 42. information to patients, families, and clinicians • The Rare Coagulation Disorders. Paula Bolton- on other hereditary bleeding disorders and many Maggs, World Federation of Hemophilia Treatment of Hemophilia No 39, April 2006. www.wfh.org

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Section 3. Laboratory diagnosis 2. The sample should preferably be collected near the laboratory to ensure quick transport. 1. A correct diagnosis is essential to ensure that a 3. Samples should be tested within 4 h of collec- patient gets the appropriate treatment. Different tion. bleeding disorders may have very similar symp- 4. Results of tests can change according to the sam- toms. ple storage conditions. Higher temperatures 2. Accurate diagnosis can only be made with the sup- (>25°C) lead to loss of FVIII activity over time, port of a comprehensive and accurate laboratory whereas sample storage in the cold (2–8°C) leads service. This is dependent on the laboratory follow- to cold activation. The sample should therefore ing strict protocols and procedures, which require: be maintained at temperatures between 20°C and 25°C where possible, but for no more than • knowledge and expertise in coagulation labora- 4h. tory testing 5. Venipuncture must be clean and the sample col- • use of the correct equipment and reagents lected within 1 min of tourniquet application • quality assurance without prolonged venous stasis. 3. For detailed information on technical aspects and 6. Blood should be withdrawn into a plastic syringe specific instructions on screening tests and factor or an evacuated collection system. The needle assays, please consult the WFH’s Diagnosis of should be 19–21 gauge for adults and 22–23 Hemophilia and Other Bleeding Disorders: A gauge for small children. Collection through Laboratory Manual, Second edition [1]. peripheral venous catheters or non-heparinized central venous catheters can be successful for 3.1 Knowledge and expertise in coagulation many tests of hemostasis. laboratory testing 7. Blood from an indwelling catheter should be Principles of diagnosis avoided for coagulation tests. 8. Frothing of the blood sample should also be 1. Understanding the clinical features of hemophilia avoided. It is often useful to discard the first and the appropriateness of the clinical diagnosis. 2 mL of blood collected. 2. Using screening tests to identify the potential 9. The sample should be collected in citrate tubes cause of bleeding, for example, platelet count, containing 0.105 M–0.109 M (c3.2%) aqueous bleeding time (BT; in select situations), or other trisodium citrate dihydrate, maintaining the pro- platelet function screening tests, prothrombin portion of blood to citrate as 9:1. If the tube time (PT), and activated partial thromboplastin contains less than 80% of the target volume, time (APTT). results may be adversely affected. The higher 3. Confirmation of diagnosis by factor assays and strength concentration of 3.8% trisodium citrate other appropriate specific investigations. is no longer recommended. 10. Prompt and adequate mixing with citrate solu- Technical aspects tion should be done by gentle inversion. Preparation of the patient prior to taking a blood 11. If the sample cannot be processed within 4 h of sample— collection, the platelet poor plasma can be fro- À ° 1. Fasting is not normally necessary before collec- zen at 30 C and stored for a few weeks, or up À ° tion of blood for investigation of possible bleed- to 6 months if stored at 70 C [3]. Storage at À ° ing disorders, although a gross excess of lipids 20 C is usually inadequate. – may affect some automated analyzers. 12. Frozen samples must be thawed rapidly for 4 ° 2. Patients should avoid medications that can affect 5 min at 37 C to avoid formation of cryoprecipi- test results such as aspirin, which can severely tate. affect platelet function and prolong the bleeding/ Preparation of platelet-poor plasma (PPP)— closure time. 3. Patients should avoid strenuous exercise immedi- 1. PPP should be prepared as per standard guidelines ately prior to venipuncture. [2]. 4. If a patient is particularly stressed by the sample 2. PPP is prepared by centrifugation of a sample at collection procedure, the levels of FVIII and von a minimum of 1700 g for at least 10 min at room Willebrand factor may be temporarily elevated. temperature (i.e., not refrigerated). 3. PPP may be kept at room temperature (20°C–25° Sample collection— C) prior to testing. 1. The sample should be collected as per standard 4. Plasma that has been hemolyzed during collection guidelines [2]. and processing should not be analyzed.

End-point detection— Factor assays— 1. Many laboratories now have some form of semi 1. Factor assay is required in the following situa- or fully automated coagulation analyzers. Accu- tions: rately detecting the clotting end-point using a • To determine diagnosis manual technique requires considerable expertise, • To monitor treatment particularly if the clotting time is prolonged or if the fibrinogen concentration is low, and the clot ○ The laboratory monitoring of clotting factor is thin and wispy. concentrates is possible by measuring pre- 2. For manual testing, the tube should be tilted and postinfusion clotting factor levels. three times every five-seconds through an angle ○ Lower than expected recovery and/or of approximately 90° during observation. The reduced half-life of infused clotting factor tube should be immersed in a water bath at may be an early indicator of the presence of 37°C between tilting. inhibitors. • To test the quality of cryoprecipitate Screening tests— ○ It is useful to check the FVIII concentration 1. Platelet count, BT, PT, and APTT may be used to present in cryoprecipitate as part of the screen a patient suspected of having a bleeding quality control of this product. disorder [4]. 2. Phenotypic tests lack sensitivity and specificity 2. Bleeding time lacks sensitivity and specificity and for the detection of carriers. Some obligate car- is also prone to performance-related errors. riers may have a normal FVIII:C/VWF:Ag Therefore other tests of platelet function such as ratio. Genotypic testing is a more precise platelet aggregometry are preferred when avail- method of carrier detection and is therefore able [5,6]. recommended. 3. Based on the results of these tests, the category of 3. One-stage assays based on APTT are the most bleeding disorder may be partially characterized commonly used techniques. The following assay to guide subsequent analysis. (Table 3-1). features are important: 4. These screening tests may not detect abnormalities in patients with mild bleeding disorders • FVIII- and FIX-deficient plasma must com- including some defects of platelet function, FXIII pletely lack FVIII and FIX respectively, i.e., À1 deficiency, and those rare defects of fibrinolysis, contain <1 IU dL , and have normal levels of which may be associated with a bleeding ten- other clotting factors. dency. • The reference/calibration plasma, whether commercial or locally prepared, must be calibrated Correction studies— in international units (i.e., against an appropriate WHO international standard). 1. Correction or mixing studies using pooled normal • At least three different dilutions of the refer- plasma (PNP) will help define whether prolonged ence plasma and the test sample under analysis coagulation times are due to factor deficiency or are needed for a valid assay. circulating anticoagulants of inhibitors. Correc- • Use of a single dilution of test sample substan- tion studies with FVIII/FIX-deficient plasma may tially reduces the precision of the test and may be used to identify the particular deficiency if a lead to completely inaccurate results in the factor assay is not available. presence of some inhibitors. • When assaying test samples from subjects with moderate or severe hemophilia, an Table 3-1. Interpretation of screening tests. extended or separate calibration curve may

Possible diagnosis PT APTT* BT Platelet count be needed. It is not acceptable to simply extend the calibration curve by extrapolation Normal Normal Normal Normal Normal Hemophilia A or Normal Prolonged* Normal Normal without analyzing additional dilutions of the B** calibration plasma. VWD Normal Normal or Normal or Normal or • Some cases of genetically conﬁrmed mild hemo- prolonged* prolonged reduced Platelet defect Normal Normal Normal or Normal or philia A have normal FVIII activity when the prolonged Reduced one-stage assay is used for diagnosis, but *Results of APTT measurements are highly dependent on the laboratory reduced activity in chromogenic and two-stage method used for analysis. clotting assays. The reverse can also occur. This **The same pattern can occur in the presence of FXI, FXII, prekallikrein, means that more than one type of FVIII assay or high molecular weight kininogen deﬁciencies.

is needed to detect all forms of mild hemophilia 2. A laboratory scientist/technologist with an A [7,8]. interest in coagulation must have an in-depth understanding of the tests to achieve accurate Inhibitor testing— results. 3. In some cases, it may be beneficial to have a labo- 1. The presence of some form of inhibitor is sus- ratory scientist/technologist who has had further pected when there is a prolonged APTT that is training in a specialist center. not fully corrected by mixing patient plasma with PNP. 2. The most frequently encountered functional 3.2 Use of the correct equipment and reagents inhibitors of hemostasis are lupus anticoagulants (LA), which are not directed against specific clot- 1. Equipment and reagents are the tools of the trade ting factors and which should be excluded. of any laboratory. The following requirements 3. Results of APTT testing on mixtures of test and are necessary for accurate laboratory testing. normal plasma can be difficult to interpret, particularly as in acquired hemophilia there may ini- Equipment tially be a full correction of APTT in the presence 1. A 37°C ± 0.5°C water bath. of a potent specific anti-FVIII antibody. 2. A good light source placed near the water bath to 4. Most FVIII inhibitors that occur secondary to accurately observe clot formation. replacement therapy in subjects with hemophilia A 3. Stopwatches. show a characteristic pattern: the APTT of a 4. Automated pipettes (either fixed or variable vol- patient/PNP mixture is intermediate, i.e., between ume) capable of delivering 0.1 mL and 0.2 mL the APTTs of the two materials, and is further accurately and precisely. ° prolonged when the mixture is incubated at 37 C 5. Clean soda glass test tubes (7.5 cm 9 1.2 cm) for – for 1 2h. clotting tests. Reuse of any glassware consum- 5. Confirmation that an inhibitor is directed against ables should be avoided whenever possible, unless a specific clotting factor requires a specific inhibi- it can be demonstrated that test results are unaf- tor assay. fected by the process used. Plasticware used in 6. The Nijmegen modification of the FVIII inhibitor coagulation analyzers should not be re-used. assay offers improved specificity and sensitivity 6. An increasingly large number of semi-automated over the original Bethesda assay. (Level 1) [9,10] and fully automated coagulometers are now avail- 7. It is performed as follows: able. In many cases, this equipment has the fol- • Buffered PNP (providing FVIII) is mixed with lowing advantages: ° test plasma and incubated at 37 C • Accuracy of end-point reading. • After 2 h, the residual FVIII is measured by com- • Improved precision of test results. parison against the FVIII in a control mixture • Ability to perform multiple clot-based assays. comprised of buffered PNP and FVIII-deficient • Reduction of observation errors (the end-point plasma, which has been incubated alongside the of the reaction is typically measured electro- test mixture. mechanically or photoelectrically). • Residual FVIII is converted into inhibitor units • Use of polystyrene (clear) cuvettes instead of using a semi-log plot of the residual FVIII glass tubes. against inhibitor convention, which has been 7. All equipment requires maintenance to be kept in constructed using the assumption that 100% À good working order. residual = 0 BU mL 1 inhibitor, and 50% resid- À ual = 1.0 BU mL 1 (the latter being the interna- • When equipment is purchased, consideration tionally agreed convention for defining inhibitor should be given to, and resources put aside, for activity). regular maintenance by a product specialist. • When residual FVIII activity is <25%, the • Pipettes should be checked for accurate sam- patient plasma must be retested after dilution ple/reagent delivery. to avoid underestimation of the inhibitor • Water baths, refrigerators, and freezers should potency. undergo regular temperature checks. À • An inhibitor titer of 0.6 BU mL 1 is to be 8. Good results can be obtained using basic equip- taken as clinically significant [11]. ment and technology provided that good laboratory practice is observed. These skills can then be Trained personnel— adapted to more automated technology. 1. Even the simplest coagulation screening tests are complex by nature.

Selection of coagulometers— 3. Instructions supplied with the reagent should be followed. 1. Many coagulation analyzers are provided as a 4. Particular attention should be paid to reagent stabil- package of instrument and reagent, and both ity. Once a reagent is reconstituted or thawed for components can influence the results obtained. daily use, there is potential for deterioration over This needs to be taken into account when evalu- time depending on the conditions of storage and use. ating and selecting a system. Other important 5. Once an appropriate test and reagents have been issues to consider are: decided upon, normal/reference ranges should ide- • type of tests to be performed and the work- ally be defined, and must take account of the con- load, as well as workflow, in the laboratory ditions used locally. • operational requirements (power, space, humidity, temperature, etc.) 3.3 Quality assurance • service requirements and breakdown response • throughput and test repertoire 1. Quality assurance (QA) is an umbrella term used • costs to describe all measures taken to ensure the reli- • ability to combine with reagents from other ability of laboratory testing and reporting. manufacturers 2. QA covers all aspects of the diagnosis process from • user-programmable testing sample-taking, separation and analysis, and internal • comparability between results on primary ana- quality control through to reporting of the result and lyzer and any back-up methods ensuring that it reaches the clinician. • compatibility with blood sample tubes and 3. It is the responsibility of everyone involved to plasma storage containers in local use make sure that the procedures are followed in the • safety assessment (mechanical, electrical, correct manner. microbiological) • availability of suitable training Internal quality control (IQC) 2. Information is required in relation to the perfor- 1. IQC is used to establish whether a series of tech- mance characteristics of the system. This can be niques and procedures are being performed con- obtained from a variety of sources including the sistently over a period of time. published literature and manufacturers’ data, but 2. IQC measures are taken to ensure that the results may also require some form of local assessment. of laboratory investigations are reliable enough to Aspects to consider include: assist clinical decision making, monitor therapy, • precision of testing with a target of <3% of CV and diagnose hemostatic abnormalities. for screening tests and <5% for factor assays 3. IQC is particularly useful to identify the degree of • carry-over precision of a particular technique. • interfering substances 4. For screening tests of hemostasis, normal and • reagent stability on board analyzer abnormal plasma samples should be included reg- • comparability with other methods ularly. At least one level of IQC sample should be • sample identification included with all batches of tests. • data handling, software, and quality control • training required External quality assessment (EQA) • reliability 1. Laboratories are strongly advised to participate in 3. A number of published guidelines and recommen- an external quality assessment scheme (EQAS) to dations describe the evaluation of coagulation audit the effectiveness of the IQC systems in analyzers [12,13]. place. 2. EQAS helps to identify the degree of agreement Reagents between the laboratory results and those obtained 1. It is good practice to ensure continuity of supply by other laboratories. of a chosen reagent, with attention paid to conti- 3. Participation in such a scheme helps build con- nuity of batches and long shelf-life. This may be fidence between a laboratory and its users. achieved by asking the supplier to batch hold for 4. The WFH IEQAS is specifically designed to meet the laboratory, if possible. the needs of hemophilia treatment centers world- 2. Changing to a different source of material is not wide. The scheme includes analyses relevant to recommended unless there are supply problems or the diagnosis and management of bleeding. because of questionable results. Different brands Details of this scheme, which is operated in con- may have completely different sensitivities and junction with the U.K. National External Quality should not be run side by side. Assessment Service for Blood Coagulation in

Shefﬁeld, U.K., can be obtained from the WFH 6. For a laboratory to attain a high level of [14]. testing reliability and to participate successfully in 5. Other national and international quality assess- EQAS, it must have access to appropriate ment schemes are also available. reagents and techniques and an appropriate number of adequately trained staff.

References 5 Bick RL. Laboratory evaluation of platelet jmegen. Semin Thromb Hemost 2009; 35: dysfunction. Clin Lab Med 1995; 15:1–38. 752–9. 1 Kitchen S, McCraw A, Echenagucia M. 6 Rodgers RP, Levin J. Bleeding time revis- 11 Verbruggen B, Novakova I, Wessels H, Diagnosis of Hemophilia and Other Bleed- ited. Blood 1992; 1: 79. Boezeman J, van den Berg M, Mauser-Bun- ing Disorders: A Laboratory Manual, 2nd 7 Duncan EM, Duncan BM, Tunbridge LJ schoten E. The Nijmegen modiﬁcation of edn. Montreal: World Federation of Hemo- et al. Familial discrepancy between one the Bethesda assay for factor VIII:C inhibi- philia, 2010. stage and 2 stage factor VIII assay methods tors: improved speciﬁcity and reliability. – 2 Clinical and Laboratory Standards Institute. in a subgroup of patients with haemophilia Thromb Haemos 1995; 73: 247 51. – Collection, Transport, and Processing of A. Br J Haematol 1994; 87: 846 8. 12 Clinical and Laboratory Standards Institute. Blood Specimens for Testing Plasma-Based 8 Oldenburg J, Pavlova A. Discrepancy Protocol for the Evaluation, Validation, Coagulation Assays and Molecular Hemo- between one-stage and chromogenic FVIII and Implementation of Coagulometers: stasis Assays: Approved Guideline, 5th edn. activity assay results can lead to misdiagno- Approved Guideline. CLSI document H57- CLSI H21-A5, Wayne, PA; Clinical and sis of haemophilia A phenotype. Haemosta- A, Vol.28 No.4. Wayne, PA; Clinical and – Laboratory Standards Institute, 2008. seologie 2010; 30: 207 11. Laboratory Standards Institute, 2008. 3 Woodhams B, Girardot O, Blanco MJ et al. 9 Meijer P, Verbruggen B. The between-labo- 13 Gardiner C, Kitchen S, Dauer RJ et al. Stability of coagulation proteins in frozen ratory variation of factor VIII inhibitor Recommendations for evaluation of coagu- plasma. Blood Coagul Fibrinolysis 2001; testing: the experience of the external qual- lation analyzers. Lab Hematol 2006; 12: – 12: 229–36. ity assessment program of the ECAT foun- 32 8. 4 Clinical and Laboratory Standards Institute. dation. Semin Thromb Hemost 2009; 35: 14 Jennings I, Kitchen DP, Woods TA et al. – One Stage Prothrombin Time (PT) Test and 786 93. Laboratory performance in the World Fed- Activated Partial Thromboplastin Time 10 Verbruggen B, van Heerde WL, Laros-van eration of Hemophilia EQA programme, – (APTT) Test: Approved Guideline–Second Gorkom BA. Improvements in factor VIII 2003 2008. Haemophilia 2009; 15: – edition. CLSI H47-A2. Wayne, PA; Clinical inhibitor detection: from Bethesda to Ni- 571 7. and Laboratory Standards Institute, 2008.

Section 4. Hemostatic agents 1. Purity of product 2. Viral inactivation/elimination 4.1 Clotting factor concentrates Purity— 1. The WFH strongly recommends the use of viral- inactivated plasma-derived or recombinant 1. Purity of concentrates refers to the percentage of concentrates in preference to cryoprecipitate or the desired ingredient (e.g., FVIII), relative to fresh frozen plasma for the treatment of hemo- other ingredients present. philia and other inherited bleeding disorders. 2. There is no universally agreed classification of (Level 5) [1,2] products based on purity. 2. The comprehensive WFH Guide for the Assess- 3. Concentrates on the market vary widely in their ment of Clotting Factor Concentrates reviews fac- purity. tors affecting the quality, safety, licensing, and 4. Some products have high or very high purity at assessment of plasma-derived products and the one stage of the production process, but are sub- important principles involved in selecting suitable sequently stabilized by albumin, which lowers products for the treatment of hemophilia [2]. their final purity. Generally speaking, products 3. The WFH also publishes and regularly updates a with higher purity tend to be associated with low Registry of Clotting Factor Concentrates, which manufacturing yields. These concentrates are, lists all currently available products and their therefore, costlier. manufacturing details [3]. 5. Concentrates of lower purity may give rise to 4. The WFH does not express a preference for allergic reactions [4,5]. Patients who experience recombinant over plasma-derived concentrates these repeatedly with a particular product may and the choice between these classes of product benefit from the administration of an antihista- must be made according to local criteria. mine immediately prior to infusion or from use of 5. Currently manufactured plasma-derived concen- a higher purity concentrate. trates produced to Good Manufacturing Practice 6. Plasma-derived FVIII concentrates may contain (GMP) standards have an exemplary safety record variable amounts of von Willebrand factor with respect to lipid-coated viruses, such as HIV (VWF). It is therefore important to ascertain a and HCV. product’s VWF content (as measured by ristocetin 6. Product safety is the result of efforts in several cofactor activity) if it is used for the treatment of areas: VWD [6]. 7. For treatment of FIX deficiency, a product con- • improved donor selection (exclusion of at-risk taining only FIX is more appropriate than pro- donors) thrombin complex concentrates, which also • improved screening tests of donations, includ- contain other clotting factors such as factors II, ing nucleic acid testing (NAT) VII, and X, some of which may become activated • type and number of in-process viral inactiva- during manufacture. Products containing acti- tion and/or removal steps vated clotting factors may predispose to thrombo- 7. The risk of prion-mediated disease through embolism. (Level 2) [7,8] plasma-derived products exists. In the absence 8. The viral safety of products is not related to pur- of a reliable screening test for variant Creutz- ity, as long as adequate viral elimination mea- feldt-Jakob disease (vCJD), and with no estab- sures are in place. lished manufacturing steps to inactivate the vCJD prion, this problem is currently being Viral inactivation/elimination— handled by excluding plasma from all donors perceived to be at risk. As new information 1. In-process viral inactivation is the single largest evolves in this field, constant awareness of cur- contributor to the safety of plasma-derived con- rent scientific recommendations is needed for centrates [9]. those involved in making decisions regarding 2. There is a growing tendency to incorporate two choice of clotting factor concentrate for people specific viral-reducing steps in the manufacturing with hemophilia. process of concentrates. • Heat treatment is generally effective against a Product selection broad range of viruses, both with and without When selecting plasma-derived concentrates, consider- a lipid envelope, including HIV, HAV, HBV, ation needs to be given to both the plasma quality and HCV. and the manufacturing process. Two issues deserve special consideration:

• Solvent/detergent treatment is effective against 8. It is best to use the entire vial of FVIII once HBV, HCV, and HIV, but does not inactivate reconstituted, although many products have been non-enveloped viruses such as HAV. shown to have extended stability after reconsti- 3. Some viruses (such as human parvovirus B19) tution. are relatively resistant to both types of process. 9. Continuous infusion avoids peaks and troughs None of the current methods can inactivate and is considered by some to be advantageous prions. and more convenient. However, patients must 4. Nano (ultra) filtration can be used to remove be monitored frequently for pump failure. (Level small viruses such as parvovirus, but filtration 3) [13,14] techniques currently in use do not eliminate the 10. Continuous infusion may lead to a reduction in risk of transmission [10]. the total quantity of clotting factor concentrates 5. A product created by a process that used and can be more cost-effective in patients incorporates two viral reduction steps should with severe hemophilia [15]. However, this cost- not automatically be considered better than effectiveness comparison can depend on the one that only has one specific viral inactivation doses used for continuous and intermittent bolus step. infusions [16]. 6. If only one step is used, this step should prefera- 11. Dose for continuous infusion is adjusted bly inactivate viruses with and without lipid enve- based on frequent factor assays and calcula- lopes. tion of clearance. As FVIII concentrates of very high purity are stable in IV solutions for FVIII concentrates at least 24–48 h at room temperature with less than 10% loss of potency, continuous 1. FVIII concentrates are the treatment of choice for infusion for a similar number of hours is hemophilia A. possible. 2. All plasma-derived products currently in the market are listed in the WFH Registry of Clotting FIX concentrates Factor Concentrates [3]. Consult the product insert for specific details. 1. FIX concentrates are the treatment of choice for hemophilia B. Dosage/administration— 2. All plasma-derived products currently in the market are listed in the WFH Registry of Clotting 1. Vials of factor concentrates are available in dos- Factor Concentrates [3]. Consult the product ages ranging from approximately 250–3000 information guide for specific details. units each. 3. FIX concentrates fall into two classes: 2. In the absence of an inhibitor, each unit of FVIII per kilogram of body weight infused intrave- • Pure FIX concentrates, which may be plasma- nously will raise the plasma FVIII level approxi- derived or recombinant. À mately 2 IU dL 1. (Level 4) [11] • FIX concentrates that also contain factors II, 3. The half-life of FVIII is approximately 8–12 h. VII, IX, and X, also known as prothrombin 4. The patient’s factor level should be measured complex concentrates (PCCs), are only rarely 15 min after the infusion to verify the calculated used. dose. (Level 4) [11] 4. Whenever possible, the use of pure FIX concen- 5. The dose is calculated by multiplying the trates is preferable for the treatment of hemo- patient’s weight in kilograms by the factor level philia B as opposed to PCC (Level 2) [7,8], À in IU dL 1 desired, multiplied by 0.5. particularly in the following instances: À Example: 50 kg 9 40 (IU dL 1 level desired) 9 • Surgery 0.5 = 1,000 units of FVIII. Refer to Tables 7-1 • Liver disease and 7-2 for suggested factor level and duration • Prolonged therapy at high doses of replacement required based on type of hemor- • Previous thrombosis or known thrombotic rhage. tendency 6. FVIII should be infused by slow IV injection at a • Concomitant use of drugs known to have rate not to exceed 3 mL per min in adults and thrombogenic potential, including antifibrino- 100 units per min in young children, or as speci- lytic agents fied in the product information leaflet. (Level 5) 5. Pure FIX products are free of the risks of throm- [12] bosis or disseminated intravascular coagulation 7. Subsequent doses should ideally be based on the (DIC), which may occur with large doses of half-life of FVIII and on the recovery in an indi- PCCs. vidual patient for a particular product.

Dosage/administration— available or affordable treatment option. (Level 5) [1,2] 1. Vials of FIX concentrates are available in doses 2. Cryoprecipitate and FFP are not subjected to viral ranging from approximately 250–2000 units inactivation procedures (such as heat or solvent/ each. detergent treatment), leading to an increased risk 2. In absence of an inhibitor, each unit of FIX per of transmission of viral pathogens, which is sig- kilogram of body weight infused intravenously nificant with repeated infusions [1]. will raise the plasma FIX level approximately À 3. Certain steps can be taken to minimize the risk of 1IUdL 1. (Level 4) [11] transmission of viral pathogens. These include: 3. The half-life is approximately 18–24 h. 4. The patient’s FIX level should be measured • Quarantining plasma until the donor has been approximately 15 min after infusion to verify tested or even retested for antibodies to HIV, calculated doses. (Level 4) [11] hepatitis C, and HBsAg – a practice that is dif- 5. Recombinant FIX (rFIX) has a lower recovery ficult to implement in countries where the pro- than plasma-derived products, such that each portion of repeat donors is low. unit of FIX per kg body weight infused will raise • Nucleic acid testing (NAT) to detect viruses À the FIX activity by approximately 0.8 IU dL 1 – a technology that has a potentially much À in adults and 0.7 IU dL 1 in children under greater relevance for the production of cryo- 15 years of age. The reason for the lower recov- precipitate than for factor concentrates, as ery of rFIX is not entirely clear [17]. the latter are subjected to viral inactivation 6. To calculate dosage, multiply the patient’s weight steps [20]. in kilograms by the factor level desired. Example: 4. Allergic reactions are more common following À 50 kg 9 40 (IU dL 1 level desired) = 2000 units infusion of cryoprecipitate than concentrate [21]. of plasma-derived FIX. For rFIX, the dosage will Ä 9 be 2000 0.8 (or 2000 1.25) = 2500 units for Fresh frozen plasma (FFP) adults, and 2000 Ä 0.7 (or 2000 9 1.43) = 2860 units for children. Refer to Tables 7-1 and 7-2 for 1. As FFP contains all the coagulation factors, it is suggested factor level and duration of replacement sometimes used to treat coagulation factor therapy based on type of hemorrhage. deficiencies. 7. FIX concentrates should be infused by slow IV 2. Cryoprecipitate is preferable to FFP for the treat- injection at a rate not to exceed a volume of ment of hemophilia A and VWD. (Level 4) [22] 3 mL per min in adults and 100 units per min in 3. Due to concerns about the safety and quality of young children, or as recommended in the prod- FFP, its use is not recommended, if avoidable uct information leaflet. (Level 5) [12] (Level 4) [23]. However, as FFP and cryo-poor 8. If used, PCCs should generally be infused at half plasma contain FIX, they can be used for the this rate. Consult the product information leaflet treatment of hemophilia B in countries unable to for instructions. (Level 2) [18] afford plasma-derived FIX concentrates. 9. Purified FIX concentrates may also be adminis- 4. It is possible to apply some forms of virucidal tered by continuous infusion (as with FVIII con- treatment to packs of FFP (including solvent/ centrates). detergent treatment) and the use of treated packs 10. Allergic reactions may occur with infusions of is recommended. However, virucidal treatment FIX concentrates in patients with anti-FIX inhib- may have some impact on coagulation factors. itors. In such patients, infusions may need to be The large scale preparation of pooled solvent/ covered with hydrocortisone [19]. Changing the detergent-treated plasma has also been shown to brand of clotting factor concentrate sometimes reduce the proportion of the largest multimers of reduces symptoms. VWF [24,25].

Dosage/administration— 4.2 Other plasma products 1. One ml of fresh frozen plasma contains 1 unit of 1. The WFH supports the use of coagulation factor factor activity. concentrates in preference to cryoprecipitate or 2. It is generally difﬁcult to achieve FVIII levels À fresh frozen plasma (FFP) due to concerns about higher than 30 IU dL 1 with FFP alone. À their quality and safety. However, the WFH rec- 3. FIX levels above 25 IU dL 1 are difﬁcult to ognizes the reality that they are still widely used achieve. An acceptable starting dose is 15– À in countries around the world where it is the only 20 mL kg 1. (Level 4) [22]

Cryoprecipitate desmopressin is more variable and therefore less predictable. (Level 3) [28,29] 1. Cryoprecipitate is prepared by slow thawing of 5. DDAVP is particularly useful in the treatment or fresh frozen plasma (FFP) at 4°C for 10–24 h. It prevention of bleeding in carriers of hemophilia. appears as an insoluble precipitate and is sepa- (Level 3) [30] rated by centrifugation. 6. Although DDAVP is not licensed for use in preg- 2. Cryoprecipitate contains significant quantities of À nancy, there is evidence that it can be safely used FVIII (about 3–5IUmL 1), VWF, fibrinogen, during delivery and in the postpartum period in and FXIII, but not FIX or FXI. The resultant an otherwise normal pregnancy. Its use should be supernatant is called cryo-poor plasma and con- avoided in pre-eclampsia and eclampsia because tains other coagulation factors such as factors of the already high levels of VWF. (Level 3) VII, IX, X, and XI. [31,32] 3. Due to concerns about the safety and quality of 7. Obvious advantages of DDAVP over plasma cryoprecipitate, its use in the treatment of con- products are the much lower cost and the absence genital bleeding disorders is not recommended of any risk of transmission of viral infections. and can only be justified in situations where clot- 8. DDAVP may also be useful to control bleeding ting factor concentrates are not available. (Level and reduce the prolongation of bleeding time 4) [1,22,26] associated with disorders of hemostasis, including 4. Although the manufacture of small pool, viral- some congenital platelet disorders. inactivated cryoprecipitate has been described, it 9. The decision to use DDAVP must be based on is uncertain whether it offers any advantage with both the baseline concentration of FVIII, the respect to overall viral safety or cost benefit over increment achieved, and the duration of treatment conventionally manufactured large pool concen- required. trates [27].

Dosage/administration— Dosage/administration— 1. A bag of cryoprecipitate made from one unit of 1. Although desmopressin is given subcutaneously FFP (200–250 mL) may contain 70–80 units of in most patients, it can also be administered by FVIII in a volume of 30–40 mL. intravenous infusion or by nasal spray. It is important to choose the correct preparation of desmopressin because some lower dose prepara- 4.3 Other pharmacological options tions are used for other medical purposes. In addition to conventional coagulation factor concen- 2. Appropriate preparations include: trates, other agents can be of great value in a signifi- À • 4 lgmL 1 for intravenous use cant proportion of cases. These include: À • 15 lgmL 1 for intravenous and subcutaneous 1. desmopressin use 2. tranexamic acid • 150 lg per metered dose as nasal spray À 3. epsilon aminocaproic acid 3. A single dose of 0.3 lgkg 1 body weight, either by intravenous or subcutaneous route, can be Desmopressin (DDAVP) expected to boost the level of FVIII three- to six- fold. (Level 4) [28,33] 1. Desmopressin (1-deamino-8-D-arginine vasopres- 4. For intravenous use, DDAVP is usually diluted sin, also known as DDAVP) is a synthetic analog in at least 50–100 mL of physiological saline of vasopressin that boosts plasma levels of FVIII and given by slow intravenous infusion over 20– and VWF [28]. 30 min. 2. DDAVP may be the treatment of choice for 5. The peak response is seen approximately 60 min patients with mild or moderate hemophilia A after administration either intravenously or sub- when FVIII can be raised to an appropriate thera- cutaneously. peutic level because it avoids the expense and 6. Closely spaced repetitive use of DDAVP over potential hazards of using a clotting factor con- several days may result in decreased response centrate. (Level 3) [28,29] (tachyphylaxis). Factor concentrates may be 3. Desmopressin does not affect FIX levels and is of needed when higher factor levels are required no value in hemophilia B. for a prolonged period. (Level 3) [34] 4. Each patient’s response should be tested prior to 7. Rapid infusion may result in tachycardia, flush- therapeutic use, as there are significant differences ing, tremor, and abdominal discomfort. between individuals. The response to intranasal

8. A single metered intranasal spray of 3. A syrup formulation is also available for pediat- À 1.5 mg mL 1 in each nostril is appropriate for ric use. If this is not available, a tablet can be an adult. For an individual with a body weight crushed and dissolved in clean water for topical of less than 40 kg, a single dose in one nostril is use on bleeding mucosal lesions. sufficient. (Level 4) [35,36] 4. Tranexamic acid is commonly prescribed for 9. Although the intranasal preparation is available, 7 days following dental extractions to prevent some patients find it difficult to use and it may postoperative bleeding. be less efficacious than when given subcutane- 5. Tranexamic acid is excreted by the kidneys and ously. the dose must be reduced if there is renal impair- 10. As a result of its antidiuretic activity, water ment to avoid toxic accumulation. retention and hyponatremia can be a problem. 6. The use of tranexamic acid is contraindicated When repeated doses are given, the plasma for the treatment of hematuria as its use may osmolality or sodium concentration should be prevent dissolution of clots in the ureters, lead- measured. (Level 4) [28,37] ing to serious obstructive uropathy and potential 11. In most adults, hyponatremia is uncommon. permanent loss of renal function. 12. Due to water retention, DDVAP should be used 7. Similarly, the drug is contraindicated in the set- with caution in young children and is contrain- ting of thoracic surgery, where it may result in dicated in children under 2 years of age who the development of insoluble hematomas. are at particular risk of seizures secondary to 8. Tranexamic acid may be given alone or together cerebral edema due to water retention. (Level with standard doses of coagulation factor con- 4) [38,39] centrates. (Level 4) [45] 13. There are case reports of thrombosis (including 9. Tranexamic acid should not be given to patients myocardial infarction) after infusion of DDAVP. with FIX deficiency receiving prothrombin com- It should be used with caution in patients with a plex concentrates, as this will exacerbate the risk history, or who are at risk, of cardiovascular of thromboembolism. (Level 5) [46] disease. (Level 4) [33] 10. If treatment with both agents is deemed necessary, it is recommended that at least 12 h Tranexamic acid elapse between the last dose of APCC and the administration of tranexamic acid. (Level 5) [46] 1. Tranexamic acid is an antifibrinolytic agent that 11. In contrast, thromboembolism is less likely when competitively inhibits the activation of plasmino- tranexamic acid is used in combination with gen to plasmin. rFVIIa to enhance hemostasis. (Level 4) [47] 2. It promotes clot stability and is useful as adjunctive therapy in hemophilia and some other bleed- Epsilon aminocaproic acid ing disorders [40]. 3. Regular treatment with tranexamic acid alone is 1. Epsilon aminocaproic acid (EACA) is similar to of no value in the prevention of hemarthroses in tranexamic acid, but is less widely used as it has hemophilia. (Level 4) [40] a shorter plasma half-life, is less potent, and is 4. It is valuable, however, in controlling bleeding more toxic [40]. from skin and mucosal surfaces (e.g., oral bleeding, epistaxis, menorrhagia). (Level 2) [41–43] Dosage/administration— 5. Tranexamic acid is particularly valuable in the 1. EACA is typically administered to adults orally or setting of dental surgery and may be used to con- intravenously every 4–6 h up to a maximum of trol oral bleeding associated with eruption or À 24 g day 1 in an adult. shedding of teeth. (Level 4) [42,44] À 2. A 250 mg mL 1 syrup formulation is also available. 3. Gastrointestinal upset is a common complication; Dosage/administration— reducing the dose often helps. 1. Tranexamic acid is usually given as an oral tab- 4. Myopathy is a rare adverse reaction specifically let three to four times daily. It can also be given reported in association with aminocaproic acid by intravenous infusion two to three times daily, therapy (but not tranexamic acid), typically and is also available as a mouthwash. occurring after administration of high doses for 2. Gastrointestinal upset (nausea, vomiting, or diar- several weeks. rhea) may rarely occur as a side effect, but these 5. The myopathy is often painful and associated symptoms usually resolve if the dosage is with elevated levels of creatine kinase and even reduced. When administered intravenously, it myoglobinuria. must be infused slowly as rapid injection may 6. Full resolution may be expected once drug treat- result in dizziness and hypotension. ment is stopped.

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Section 5. Treatment of specific hemorrhages 13. Instruct the patient to avoid weight-bearing, apply compression, and elevate the affected 1. Bleeding in patients with hemophilia can occur joint. (Level 3) [4] at different sites (Tables 1-2 and 1-3), each of 14. Consider immobilizing the joint with a splint which requires specific management. until pain resolves. 2. As a general principle in case of large internal 15. Ice/cold packs may be applied around the joint hemorrhage, hemoglobin should be checked and for 10–15 min every 2-4 h for pain relief, if corrected while other measures are being planned. found beneficial. Do not apply ice in direct con- Measures of hemodynamic stability, such as pulse tact with skin. [39] and blood pressure, should be monitored as indi- 16. If bleeding does not stop, a second infusion may cated. be required. If so, repeat half the initial loading dose in 12 h (hemophilia A) or 24 h (hemophilia B). (Level 3) [4] 5.1 Joint hemorrhage (hemarthrosis) 17. Further evaluation is necessary if the patient’s 1. A joint bleed is defined as an episode charac- symptoms continue longer than 3 days. The terized by rapid loss of range of motion as presence of inhibitors, septic arthritis, or frac- compared with baseline that is associated ture should be considered if symptoms and find- with any combination of the following: pain ings persist. or an unusual sensation in the joint, palpable 18. Rehabilitation must be stressed as an active part swelling and warmth of the skin over the joint of the management of acute joint bleeding epi- [1]. sodes. (Level 2) [4,6,7] 2. The onset of bleeding in joints is frequently • As soon as the pain and swelling begin to sub- described by patients as a tingling sensation and side, the patient should be encouraged to tightness within the joint. This “aura” precedes change the position of the affected joint from the appearance of clinical signs. a position of comfort to a position of func- 3. The earliest clinical signs of a joint bleed are tion, gradually decreasing the flexion of the increased warmth over the area and discomfort joint and striving for complete extension. with movement, particularly at the ends of range. • This should be done as much as possible with 4. Later symptoms and signs include pain at rest, active muscle contractions. Gentle passive swelling, tenderness, and extreme loss of assistance may be used initially and with cau- motion. tion if muscle inhibition is present. 5. A re-bleed is defined as worsening of the condi- • Early active muscle control must be encour- tion either on treatment or within 72 h after aged to minimize muscle atrophy and prevent stopping treatment [1]. chronic loss of joint motion. 6. A target joint is a joint in which 3 or more spon- • Active exercises and proprioceptive training taneous bleeds have occurred within a consecu- must be continued until complete prebleed tive 6-month period. 7. Following a joint bleed, flexion is usually the most comfortable position, and any attempt to Table 5-1. Definition of response to treatment of acute hemarthrosis [1]. change this position causes more pain. Excellent Complete pain relief within 8 hours and/or 8. Secondary muscle spasm follows as the patient complete resolution of signs of bleeding after tries to prevent motion and the joint appears the initial injection and not requiring any “frozen”. further replacement therapy within 72 hours Good Significant pain relief and/or improvement in 9. The goal of treatment of acute hemarthrosis is signs of bleeding within approximately 8 to stop the bleeding as soon as possible. This hours after a single injection, but requiring should ideally occur as soon as the patient rec- more than one dose of replacement therapy within 72 hours for complete resolution ognizes the “aura”, rather than after the onset Moderate Modest pain relief and/or improvement in of overt swelling and pain. signs of bleeding within approximately 8 10. Evaluate the patient clinically. Usually, X-rays hours after the initial injection and requiring and ultrasounds are not indicated. more than one injection within 72 hours but without complete resolution 11. Administer the appropriate dose of factor None None or minimal improvement, or condition concentrate to raise the patient’s factor level worsens, within approximately 8 h after the suitably (refer to Tables 7-1 and 7-2). (Level 2) initial injection. [2–5] The above definitions of response to treatment of an acute hemarthrosis 12. The definitions listed in Table 5-1 are recom- relate to inhibitor negative individuals with hemophilia. These definitions may require modification for inhibitor positive patients receiving bypass- mended for the assessment of response to treating agents as hemostatic cover or patients who receive factor concentrates ment of an acute hemarthrosis. [1] with extended half-lives.

joint range of motion and functioning are nent contracture, re-bleeding, and formation of restored and signs of acute synovitis have dis- pseudotumors. sipated [8]. 4. Sites of muscle bleeding that are associated with • If exercises are progressed judiciously, factor neurovascular compromise, such as the deep replacement is not necessarily required before flexor muscle groups of the limbs, require imme- exercising. diate management to prevent permanent damage and loss of function. These groups include: Arthrocentesis • the iliopsoas muscle (risk of femorocutaneous, 1. Arthrocentesis (removal of blood from a joint) crural, and femoral nerve palsy) may be considered in the following situations: • the superior-posterior and deep posterior compartments of the lower leg (risk of posterior • a bleeding, tense, and painful joint, which tibial and deep peroneal nerve injury) shows no improvement 24 h after conservative • the flexor group of forearm muscles (risk of treatment Volkmann’s ischemic contracture) • joint pain that cannot be alleviated 5. Bleeding can also occur in more superficial mus- • evidence of neurovascular compromise of the cles such as the biceps brachii, hamstrings (tri- limb ceps surae), gastrocnemius, quadriceps, and the • unusual increase in local or systemic tempera- gluteal muscles. ture and other evidence of infection (septic 6. Symptoms of muscle bleeds are: arthritis) (Level 3) [4,9,10] 2. Inhibitors should be considered as a reason for • aching in the muscle persistent bleeding despite adequate factor • maintenance of the limb in a position of com- replacement. The presence of inhibitors must be fort ruled out before arthrocentesis is attempted. • severe pain if the muscle is stretched 3. The early removal of blood should theoretically • pain if the muscle is made to actively contract reduce its damaging effects on the articular carti- • tension and tenderness upon palpation and lage [10]. If there is a large accumulation of possible swelling blood, it will also decrease pain. 7. Raise the patient’s factor level as soon as possi- 4. Arthrocentesis is best performed soon after a ble, ideally when the patient recognizes the first bleed under strictly aseptic conditions. signs of discomfort or after trauma. If there is 5. When necessary, arthrocentesis should be per- neurovascular compromise, maintain the levels formed under factor levels of at least 30– for 5–7 days or longer, as symptoms indicate À 50 IU dL 1 for 48–72 h. Arthrocentesis should (refer to Tables 7-1 and 7-2). (Level 3) [11–13] not be performed in circumstances where such 8. Rest the injured part and elevate the limb. factor replacement is not available. In the pres- 9. Splint the muscle in a position of comfort and ence of inhibitors, other appropriate hemostatic adjust to a position of function as pain allows. agents should be used for the procedure, as 10. Ice/cold packs may be applied around the mus- needed. (Level 3) [4] cle for 15–20 min every four to 6 h for pain 6. A large bore needle, at least 16-gauge, should be relief if found beneficial. Do not apply ice in used. direct contact with skin. 7. The joint should be immobilized with mild com- 11. Repeat infusions are often required for 2–3 days pression. or much longer in case of bleeds at critical sites 8. Weight-bearing should be avoided for 24–48 h. causing compartment syndromes and if extensive 9. Physiotherapy should be initiated as described rehabilitation is required. (Level 5) [14,15] above. 12. The patient should be monitored continuously for neurovascular compromise; fasciotomy may be required in some such cases. (Level 5) [16,17] 5.2 Muscle hemorrhage 13. Hemoglobin level should be checked and cor- 1. Muscle bleeds can occur in any muscle of the body, rected if needed as muscle bleeds can result in usually from a direct blow or a sudden stretch. significant blood loss. 2. A muscle bleed is defined as an episode of bleed- 14. Physiotherapy should begin as soon as pain sub- ing into a muscle, determined clinically and/or sides and should be progressed gradually to by imaging studies, generally associated with restore full muscle length, strength, and func- pain and/or swelling and functional impairment tion. (Level 4) [12,18] e.g., a limp associated with a calf bleed [1]. 15. Factor coverage during this process is prudent, 3. Early identification and proper management of unless the physiotherapist is experienced with muscle bleeds are important to prevent perma- hemophilia management. Serial casting or splint-

ing may be required. Supportive bracing will be tor level for 10–14 days (refer to Tables 7-1 and required if there has been nerve damage. 7-2). (Level 4) [23,24] 16. Increasing pain during physical therapy can sug- 4. Intracranial hemorrhage may be an indication for gest re-bleeding and should be regularly evalu- prolonged secondary prophylaxis (3–6 months), ated [19]. especially where a relatively high risk of recurrence has been observed (e.g., in the presence of Iliopsoas hemorrhage HIV infection). (Level 3) [23,25,26] 5. Immediate medical evaluation and hospitalization 1. This type of muscle hemorrhage has a unique are required. A CT scan or MRI of the brain presentation. Signs may include pain in the should be performed. Neurological consultation lower abdomen, groin, and/or lower back and should be sought early. (Level 4) [27,28] pain on extension, but not on rotation, of the 6. Severe headache may also be a manifestation hip joint. There may be paresthesia in the med- of meningitis in immunocompromised patients. ialaspectofthethighorothersignsoffemoral nerve compression such as loss of patellar reflex and quadriceps weakness. The symptoms 5.4 Throat and neck hemorrhage may mimic acute appendicitis, including a 1. This is a medical emergency because it can lead positive Blumberg′ssign. to airway obstruction. Treat first before evaluat- 2. Immediately raise the patient’s factor level. Main- ing. tain the levels for 5–7 days or longer, as symp- 2. Immediately raise the patient’s factor level when toms indicate (refer to Tables 7-1 and 7-2). significant trauma or symptoms occur. Maintain (Level 4) [20–22] the factor levels until symptoms resolve (refer to 3. Hospitalize the patient for observation and con- Tables 7-1 and 7-2). (Level 4) [15,29,30] trol of pain. Maintain strict bed rest. Ambulation 3. Hospitalization and evaluation by a specialist are with crutches is not permitted, as ambulation essential. (Level 5) [15] requires contraction of the muscle. (Level 4) [20– 4. To prevent hemorrhage in patients with severe 22] tonsillitis, treatment with factor may be indicated, 4. It is useful to confirm the diagnosis and monitor in addition to bacterial culture and treatment recovery with an imaging study (ultrasonography, with appropriate antibiotics. CT scan, or MRI). (Level 4) [20–22] 5. Limit the patient’s activity until pain resolves and hip extension improves. A carefully supervised 5.5 Acute gastrointestinal (GI) hemorrhage program of physiotherapy is key to restoring full 1. Immediately raise the patient’s factor levels. activity and function and preventing re-bleeding. Maintain the factor level until hemorrhage Restoration of complete hip extension before has stopped and etiology is defined (refer to returning to full activity is recommended. (Level Tables 7-1 and 7-2). (Level 4) [31,32] 4) [20–22] 2. Acute gastrointestinal hemorrhage may present as 6. If residual neuromuscular deficits persist, further hematemesis, hematochezia, or malena. orthotic support may be necessary. 3. For signs of GI bleeding and/or acute hemorrhage in the abdomen, medical evaluation and possibly 5.3 Central nervous system hemorrhage/head hospitalization are required. trauma 4. Hemoglobin levels should be regularly monitored. Treat anemia or shock, as needed. 1. This is a medical emergency. Treat first before 5. Treat origin of hemorrhage as indicated. evaluating. 6. EACA or tranexamic acid may be used as adjunc- 2. All posttraumatic head injuries, confirmed or sus- tive therapy for patients with FVIII deficiency and pected, and significant headaches must be treated those with FIX deficiency who are not being trea- as intracranial bleeds. Sudden severe pain in the ted with prothrombin complex concentrates. back may be associated with bleeding around the spinal cord. Do not wait for further symptoms to develop or for laboratory or radiologic evalua- 5.6 Acute abdominal hemorrhage tion. 1. An acute abdominal, including retroperitoneal, 3. Immediately raise the patient’s factor level when hemorrhage can present with abdominal pain and significant trauma or early symptoms occur. Fur- distension and can be mistaken for a number of ther doses will depend on imaging results. Main- infectious or surgical conditions. It may also pres- tain factor level until etiology is defined. If a ent as a paralytic ileus. Appropriate radiologic bleed is confirmed, maintain the appropriate fac- studies may be necessary.

2. Immediately raise the patient’s factor levels. are being treated with large doses of pro- Maintain the factor levels (refer to Tables 7-1 thrombin complex concentrates or in patients and 7-2) until the etiology can be defined, then with inhibitors being treated with activated treat appropriately in consultation with a special- prothrombin complex concentrates (APCC). ist. (Level 4) [15,29,30] (Level 4) [35,36] 5. Factor replacement may be required as directed by the hemophilia center. 5.7 Ophthalmic hemorrhage 6. Oral EACA or tranexamic acid should be used if 1. This is uncommon unless associated with trauma appropriate. (Level 4) [37,38] or infection. 7. Advise the patient to avoid swallowing blood. 2. Immediately raise the patient’s factor level. Main- 8. Advise the patient to avoid using mouthwashes tain the factor level as indicated (refer to Tables until the day after the bleeding has stopped. 7-1 and 7-2). (Level 4) [15,29,30] 9. Advise the patient to eat a soft diet for a few days. 3. Have the patient evaluated by an ophthalmologist 10. Evaluate and treat for anemia as indicated. as soon as possible. 5.10 Epistaxis 5.8 Renal hemorrhage 1. Place the patient’s head in a forward position to avoid swallowing blood and ask him to gently 1. Treat painless hematuria with complete bed rest À blow out weak clots. Firm pressure with gauze and vigorous hydration (3 L m 2 body surface soaked in ice water should be applied to the ante- area) for 48 h. Avoid DDAVP when hydrating rior softer part of the nose for 10–20 min. intensively. (Level 4) [33] 2. Factor replacement therapy is often not necessary 2. Raise the patient’s factor levels (refer to Tables unless bleeding is severe or recurrent [15,29]. 7-1 and 7-2) if there is pain or persistent gross 3. Antihistamines and decongestant drugs are useful hematuria and watch for clots and urinary for bleeds specifically related to allergies, upper obstruction. (Level 4) [33,34] respiratory infections, or seasonal changes. 3. Do not use antifibrinolytic agents. (Level 4) [33] 4. If bleeding is prolonged or occurs frequently, 4. Evaluation by an urologist is essential for eval- evaluate for anemia and treat appropriately. uation of a local cause if hematuria (gross or 5. EACA or tranexamic acid applied locally in a microscopic) persists or if there are repeated soaked gauze is helpful. episodes. 6. Consult with an otolaryngologist if the bleed is persistent or recurrent. Anterior or posterior nasal 5.9 Oral hemorrhage packing may be needed to control bleeding. 1. Early consultation with a dentist or oral and 7. Epistaxis can often be prevented by increasing the maxillofacial surgeon is essential to determine humidity of the environment, applying gels (e.g., the source of bleeding. The most common causes petroleum jelly or saline drops/gel) to the nasal are: mucosa to preserve moisture, or administering saline spray. • dental extraction • gingival bleeding often due to poor oral hygiene 5.11 Soft tissue hemorrhage • trauma 1. Symptoms will depend on the site of hemorrhage. 2. Local treatments must be considered treat the 2. Factor replacement therapy is not necessary for hemorrhage. These may include: most superficial soft tissue bleeding. The applica- • direct pressure on the area using a damp tion of firm pressure and ice may be helpful gauze swab, maintained for at least 15 min [15,29]. • sutures to close the wound 3. Evaluate the patient for severity of hemorrhage • application of local hemostatic agents and possible muscular or neurovascular involve- • antibiotics, especially in gingival bleeding due ment. Rule out possible trauma to spaces con- to poor oral hygiene taining vital organs, such as the head or • use of EACA or tranexamic acid as a mouth- abdomen. wash 4. Open compartmental hemorrhage, such as in the 3. An appropriate dose of regular paracetamol/acet- retroperitoneal space, scrotum, buttocks, or aminophen will help control the pain. thighs, can result in extensive blood loss. Treat 4. Antifibrinolytic agents should not be used sys- with factor immediately if this situation is sus- temically in patients with FIX deficiency that pected.

5. Hemoglobin levels and vital signs should be regu- 2. For deep lacerations, raise the factor level (refer larly monitored. to Tables 7-1 and 7-2), and then suture. (Level 4) [15,29,30] 3. Sutures may be removed under cover of factor 5.12 Lacerations and abrasions concentrate. 1. Treat superﬁcial lacerations by cleaning the wound, then applying pressure and steri-strips.

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The clinical features of early bleed- haemophilia with inhibitors: an analysis of Dent Assoc 2008; 54:24–8. ing into the muscles of the lower limb in the Hemophilia and Thrombosis Research 39 d’Young AI. Domiciliary application of severe haemophiliacs. J Bone Joint Surgery Society Registry (2004–2008). Haemophilia CryoCuff in severe haemophilia: qualitative 1983; 65-B:19–23. 2010; 16: 625–31. questionnaire and clinical audit. Haemo- 12 Beyer R, Ingerslev J, Sørensen B. Current 25 Patiroglu T, Ozdemir MA, Unal E et al. philia 2008; 14: 823–7. practice in the management of muscle hae- Intracranial hemorrhage in children with

Section 6. Complications of hemophilia of secondary prophylaxis with intensive physiotherapy are beneficial. • physiotherapy (Level 2) [9,10], including: 6.1 Musculoskeletal complications ○ daily exercise to improve muscle strength 1. The most common sites of bleeding are the joints and maintain joint motion and muscles of the extremities. ○ modalities to reduce secondary inflamma- 2. Depending on the severity of the disease, bleeding tion, if available [11] episodes may be frequent and without apparent ○ functional training [12] cause (see Table 1-1). • a course of NSAIDs (COX-2 inhibitors), 3. In the child with severe hemophilia, the first hem- which may reduce inflammation (Level 2) arthrosis typically occurs when the child begins to [13,14] crawl and walk: usually before 2 years of age, • functional bracing, which allows the joint to but occasionally later. move but limits movement at the ends of 4. If inadequately treated, repeated bleeding will range where the synovium can be pinched and lead to progressive deterioration of the joints and which may prevent new bleeding. [15] muscles, severe loss of function due to loss of • synovectomy motion, muscle atrophy, pain, joint deformity, and contractures within the first one to two dec- Synovectomy— ades of life [1,2]. 1. Synovectomy should be considered if chronic Synovitis synovitis persists with frequent recurrent bleeding not controlled by other means. Options for syno- 1. Following acute hemarthrosis, the synovium vectomy include chemical or radioisotopic synovi- becomes inflamed, is hyperemic and extremely orthesis, and arthroscopic or open surgical friable. synovectomy. (Level 4) [16,17] 2. Failure to manage acute synovitis can result in 2. Non-surgical synovectomy is the procedure of repeated hemarthroses [1,2]. choice. 3. During this stage, the joint requires protection 3. Radioisotopic synovectomy using a pure beta with a removal splint or compressive bandaging. emitter (phosphorus-32 or yttrium-90) is highly 4. Activities should be restricted until swelling and effective, has few side effects, and can be accom- temperature of the joint return to baseline. plished in an outpatient setting. (Level 4) [18,19] 5. In some cases, COX-2 inhibitors may be useful. 6. Range of motion is preserved in the early stages. • A single dose of clotting factor is often suffi- Differentiation between hemarthrosis and syno- cient for a single injection of the isotope. vitis is made by performing a detailed physical • Rehabilitation is less intense than after surgical examination of the joint. synovectomy, but is still required to help the 7. The presence of synovial hypertrophy may be patient regain strength, proprioception, and confirmed by ultrasonography or MRI. Plain normal functional use of the joint. radiographs and particularly MRI will assist in 4. If a radioisotope is not available, chemical synovi- defining the extent of osteochondral changes. orthesis with either rifampicin or oxytetracycline 8. With repeated bleeding, the synovium becomes chlorhydrate is an appropriate alternative [20,21]. chronically inflamed and hypertrophied, and the • Chemical synoviorthesis involves weekly injec- joint appears swollen (this swelling is usually tions until the synovitis is controlled. not tense, nor is it particularly painful): this is • These painful injections require the administra- chronic synovitis. tion of intra-articular xilocaine a few minutes 9. As the swelling continues to increase, articular before injection of the sclerosing agent, oral damage, muscle atrophy, and loss of motion will analgesics (a combination of acetaminophen/ progress to chronic hemophilic arthropathy. paracetamol and an opioid), and a dose of clot- 10. The goal of treatment is to deactivate the syno- ting factor concentrate prior to each injection. vium as quickly as possible and preserve joint • The low cost of the chemical agent is offset by function (Level 5) [3,4]. Options include: the need for multiple injections of factor con- • factor concentrate replacement, ideally given centrate. with the frequency and at dose levels sufficient • Rehabilitation, as described for radioactive syn- to prevent recurrent bleeding (Level 2) [5–8] ovectomy, is recommended. 5. Surgical synovectomy, whether open or arthro- ○ If concentrates are available in sufficient scopic, requires a large supply of clotting factor doses, short treatment courses (6–8 weeks) for both surgery and the lengthy period of reha-

bilitation. The procedure must be performed by 12. Pain should be controlled with appropriate anal- an experienced team at a dedicated hemophilia gesics. Certain COX-2 inhibitors may be used to treatment center. It is only considered when other relieve arthritic pain (see ‘Pain Management’). less invasive and equally effective procedures fail. (Level 2) [13,14] 13. Supervised physiotherapy aiming to preserve Chronic hemophilic arthropathy muscle strength and functional ability is a very important part of management at this stage. Sec- 1. Chronic hemophilic arthropathy can develop any ondary prophylaxis may be necessary if recur- time from the second decade of life (and some- rent bleeding occurs as a result of times earlier), depending on the severity of physiotherapy. (Level 2) [9,10] bleeding and its treatment. 14. Other conservative management techniques 2. The process is set in motion by the immediate include: effects of blood on the articular cartilage during hemarthrosis [1,2] and reinforced by persistent • serial casting to assist in correcting deformi- chronic synovitis and recurrent hemarthroses, ties. [28,29] resulting in irreversible damage. • bracing and orthotics to support painful and 3. With advancing cartilage loss, a progressive unstable joints. [15] arthritic condition develops that includes: • walking aids or mobility aids to decrease stress on weight-bearing joints. • secondary soft tissue contractures • adaptations to the home, school, or work • muscle atrophy environment to allow participation in commu- • angular deformities nity activities and employment and to facili- 4. Deformity can also be enhanced by contracture tate activities of daily living. [30] following muscle bleeds or neuropathy. 15. If these conservative measures fail to provide 5. Loss of motion is common, with flexion contrac- satisfactory relief of pain and improved func- tures causing the most significant functional loss. tioning, surgical intervention may be considered. 6. Joint motion and weight bearing can be extre- Surgical procedures, depending on the specific mely painful. condition needing correction, may include: 7. As the joint deteriorates, swelling subsides due to progressive fibrosis of the synovium and the • extra-articular soft tissue release to treat con- capsule. tractures. 8. If the joint becomes ankylosed, pain may dimin- • arthroscopy to release intra-articular adhe- ish or disappear. sions and correct impingement. [31] 9. The radiographic features of chronic hemophilic • osteotomy to correct angular deformity. arthropathy depend on the stage of involvement. • prosthetic joint replacement for severe disease involving a major joint (knee, hip, shoulder, • Radiographs will only show late osteochon- elbow). [32] dral changes. [22,23] • elbow synovectomy with radial head excision. • Ultrasound or MRI examination will show [33] early soft tissue and osteochondral changes. • arthrodesis of the ankle, which provides excel- [24–26] lent pain relief and correction of deformity • Cartilage space narrowing will vary from min- with marked improvement in function. Recent imal to complete loss. improvements in ankle replacement surgery • Bony erosions and subchondral bone cysts will may pose an alternative for persons with develop, causing collapse of articular surfaces hemophilia in the future. [34,35]. that can lead to angular deformities. 16. Adequate resources, including sufficient factor • Fibrous/bony ankylosis may be present. [27] concentrates and postoperative rehabilitation, 10. The goals of treatment are to improve joint must be available to proceed with any surgical function, relieve pain, and assist the patient to procedure. (Level 3) [36–38] continue/resume normal activities of daily living. Principles of physiotherapy/physical medicine in 11. Treatment options for chronic hemophilic hemophilia arthropathy depend on: 1. Physiotherapists and occupational therapists and/ • the stage of the condition or physiatrists should be part of the core hemo- • the patient’s symptoms philia team. Their involvement with patients and • the impact on the patient’s lifestyle and func- their families should begin at the time of diagno- tional abilities • the resources available

sis, and they remain important to the patient or radiotherapy may heal some lesions. Sur- throughout their lifespan. gery may be needed for others. (Level 4) 2. Their role in the management of the patient with [44,45] hemophilia includes the following [9,39–41]: • Surgical excisions, including limb amputa- tions, may be necessary for large pseudotu- • Assessment mors, particularly if they erode long bones. ○ Determining the site of an acute bleed Large abdominal pseudotumors present a spe- ○ Regular assessment throughout life cial challenge in surgical management of ○ Preoperative assessment hemophilia; surgery must only be performed • Education by teams with experience in hemophilia. ○ Of the patient and family regarding muscu- Fractures loskeletal complications and their treatment ○ Of school personnel regarding suitable activ- 1. Fractures are not frequent in people with hemo- ities for the child, immediate care in case of philia, possibly due to lower levels of ambulation a bleed, and modifications in activities that and intensity of activities [46]. However, a person may be needed after bleeds. with hemophilic arthropathy may be at risk for • Treatment of acute bleeds, chronic synovitis, fractures around joints that have significant loss and chronic arthropathy using a variety of tech- of motion and in bones that are osteoporotic. niques including hydrotherapy, heat, ice, elec- 2. Treatment of a fracture requires immediate factor trical nerve stimulation, pulsed diathermy, concentrate replacement. (Level 4) [46–48] ultrasound as well as various orthoses for pain 3. Clotting factor levels should be raised to at least relief and restoration of function. 50% and maintained for 3–5 days. (Level 4) [3,46–48] Pseudotumors 4. Lower levels may be maintained for 10–14 days while the fracture becomes stabilized and to pre- 1. The pseudotumor is a potentially limb and life- vent soft tissue bleeding. threatening condition unique to hemophilia that 5. The management plan should be appropriate for occurs as a result of inadequately treated soft the specific fracture, including operative treatment tissue bleeds, usually in muscle adjacent to under appropriate coverage of clotting factor con- bone, which can be secondarily involved. It is centrates. most commonly seen in a long bone or the 6. Circumferential plaster should be avoided; splints pelvis. are preferred. (Level 4) [46] 2. If not treated, the pseudotumor can reach enor- 7. Compound/infected fractures may require exter- mous size, causing pressure on the adjacent neu- nal fixators. [49] rovascular structures and pathologic fractures. A 8. Prolonged immobilization, which can lead to sig- fistula can develop through the overlying skin. nificant limitation of range of movement in the 3. Diagnosis is made by the physical finding of a adjacent joints, should be avoided. (Level 4) localized mass. [46,47] 4. Radiographic findings include a soft tissue mass 9. Physiotherapy should be started as soon as the with adjacent bone destruction. fracture is stabilized to restore range of motion, 5. A more detailed and accurate evaluation of a muscle strength, and function. [39] pseudotumor can be obtained with CT scan and MRI. Principles of orthopedic surgery in hemophilia 6. Management depends on the site, size, rate of For important considerations related to performing growth, and effect on adjoining structures. surgical procedures in persons with hemophilia, please Options include factor replacement and monitor- see “Surgery and Invasive Procedures”. Specific issues ing, aspiration, and surgical ablation. in relation to orthopedic surgery include: • A 6-week course of treatment with factor is 1. Orthopedic surgeons should have had specific recommended, followed by repeat MRI. If training in surgical management of persons with the tumor is decreasing, continue with factor hemophilia. [3] and repeat MRI for three cycles. (Level 4) 2. Performing multiple site elective surgery in a [42,43] simultaneous or staggered fashion to use clotting • Proceed to surgery if necessary, which will be factor concentrates judiciously should be consid- much easier if the tumor has shrunk. ered. (Level 3) [50] • Aspiration of the pseudotumor followed by injections of fibrin glue, arterial embolization,

3. Local coagulation enhancers may be used. Fibrin 8. Bleeding manifestations in moderate/mild hemo- glue is useful to control oozing when operating in philia complicated by an inhibitor are more fre- extensive surgical fields. (Level 3) [36,51,52] quently reminiscent of those seen in patients 4. Postoperative care in patients with hemophilia with acquired hemophilia A (due to auto-anti- requires closer monitoring of pain and often bodies to FVIII), with a greater predominance of higher doses of analgesics in the immediate post- mucocutaneous, urogenital, and gastrointestinal operative period. (Level 5) [36] bleeding sites [57]. Consequently, the risk of 5. Good communication with the postoperative severe complications or even death from bleed- rehabilitation team is essential [39]. Knowledge ing may be significant in these patients. of the details of the surgery performed and intra- 9. Inhibitors are much less frequently encountered operative joint status will facilitate planning of an in hemophilia B, occurring in less than 5% of appropriate rehabilitation program. affected individuals. [58] 6. Postoperative rehabilitation should be carried out 10. In all cases, inhibitors render treatment with by a physiotherapist experienced in hemophilia replacement factor concentrates difficult. management. Patients on clotting factor therapy should there- 7. Rehabilitation may have to progress more slowly fore be screened for inhibitor development. in persons with hemophilia. 11. Confirmation of the presence of an inhibitor and 8. Adequate pain control is essential to allow appro- quantification of the titer is performed in the priate exercise and mobilization. laboratory, preferably using the Nijmegen-modi- 9. These principles also apply to fixation of fractures fied Bethesda assay (see ‘Inhibitor testing’). and excision of pseudotumors. (Level 1) [59,60] 12. For children, inhibitors should be screened once every 5 exposure days until 20 exposure days, 6.2 Inhibitors every 10 exposure days between 21 and 50 exposure days, and at least two times a year 1. “Inhibitors” in hemophilia refer to IgG antibod- until 150 exposure days. (Level 5) [61] ies that neutralize clotting factors. 13. For adults with more than 150 exposure days, 2. In the current era in which clotting factor con- apart from a 6–12 monthly review, any failure centrates have been subjected to appropriate to respond to adequate factor concentrate viral inactivation, inhibitors to FVIII or FIX are replacement therapy in a previously responsive considered the most severe treatment-related patient is an indication to assess for an inhibitor. complication in hemophilia. (Level 3) [56,62–64] 3. The presence of a new inhibitor should be sus- 14. Inhibitor measurement should also be done in pected in any patient who fails to respond clini- all patients who have been intensively treated cally to clotting factors, particularly if he has for more than 5 days, within 4 weeks of the last been previously responsive. In this situation, the infusion. (Level 4) [63,65] expected recovery and half-life of the transfused 15. Inhibitors should also be assessed prior to sur- clotting factor are severely diminished. gery or if recovery assays are not as expected, 4. Inhibitors are more frequently encountered in and when clinical response to treatment of persons with severe hemophilia compared with bleeding is sub-optimal in the postoperative per- those with moderate or mild hemophilia. iod. (Level 2) [53,63,66] 5. The cumulative incidence (i.e., lifetime risk) of 16. A low responding inhibitor is defined as an inhibitor development in severe hemophilia A is À inhibitor level that is persistently <5 BU mL 1, in the range of 20–30% and approximately 5– whereas a high responding inhibitor is defined 10% in moderate or mild disease. [53,54] À by a level 5BUmL 1. 6. In severe hemophilia A, the median age of inhib- 17. High responding inhibitors tend to be persistent. itor development is 3 years or less in developed If not treated for a long period, titer levels may countries. In moderate/mild hemophilia A, it is fall or even become undetectable, but there will is closer to 30 years of age, and is often seen in be a recurrent anamnestic response in 3–5 days conjunction with intensive FVIII exposure with when challenged again with specific factor prod- surgery. [55,56] ucts. 7. In severe hemophilia, inhibitors do not change 18. Some low titer inhibitors may be transient, dis- the site, frequency, or severity of bleeding. In appearing within 6 months of initial documenta- moderate or mild hemophilia, the inhibitor may tion, despite recent antigenic challenge with neutralize endogenously synthesized FVIII, factor concentrate. thereby effectively converting the patient’s phe- 19. Very low titer inhibitors may not be detected by notype to severe. the Bethesda inhibitor assay, but by a poor

recovery and/or shortened half-life (T-1/2) fol- 12. Although there has been interest in the use of lowing clotting factor infusions. immunosuppressive therapies in patients with inhibitors, their role is not yet defined, and Management of bleeding there is no consensus as to whether they have a place in the management of these patients. 1. Management of bleeding in patients with inhibitors must be in consultation with a center experienced in their management. (Level 5) [63,67] Allergic reactions in patients with hemophilia B 2. Choice of treatment product should be based on 1. Up to 50% of hemophilia B patients with inhibi- titer of inhibitor, records of clinical response to tors may have severe allergic reactions, including product, and site and nature of bleed. (Level 4) anaphylaxis, to FIX administration. Such [63,68] reactions can be the first symptom of inhibitor 3. Patients with a low-responding inhibitor may be development. treated with specific factor replacement at a 2. Newly diagnosed hemophilia B patients, particu- much higher dose, if possible, to neutralize the larly those with a family history and/or with inhibitor with excess factor activity and stop genetic defects predisposed to inhibitor develop- bleeding. (Level 4) [63,68] ment, should be treated in a clinic or hospital set- 4. Patients with a history of a high responding inhibiting capable of treating severe allergic reactions tor but with low titers may be treated similarly in during the initial 10–20 treatments with FIX con- an emergency until an anamnestic response occurs, centrates. Reactions can occur later, but may be – usually in 3 5 days, precluding further treatment less severe. (Level 4) [71,72] with concentrates that only contain the missing factor. (Level 4) [63,68] Immune tolerance induction 5. Porcine factor VIII prepared from the plasma of pigs has been effective in halting bleeding 1. In patients with severe hemophilia A, eradica- in some patients. The plasma-derived preparation of inhibitors is often possible by immune tion is being superceded by a recombinant por- tolerance induction (ITI) therapy. (Level 2) cine factor VIII concentrate currently in [73,74] clinical trials. 2. Before ITI therapy, high-responding patients 6. With an inhibitor level 5 BU, the likelihood is should avoid FVIII products to allow inhibitor low that specific factor replacement will be effec- titers to fall and to avoid persistent anamnestic tive in overwhelming the inhibitor without ultra rise. As noted, some patients may develop an high dose continuous infusion therapy. anamnestic response to the inactive FVIII mole- 7. Alternative agents include bypassing agents such cules in APCC as well. (Level 2) [75] as recombinant factor VIIa (rFVIIa) and pro- 3. Optimal regimen (product or dose) for ITI thrombin complex concentrates (PCC), including remains to be defined. An international trial com- À1 the activated forms (APCC). paring 50 IU kg three times a week to À1 8. The efficacy of two doses of rFVIIa and one dose 200 IU kg daily was recently stopped due to of APCC for management of joint bleeding has safety concerns (higher number of intercurrent been shown to be essentially equivalent. (Level 2) bleeds) in the low-dose arm pending detailed [69] analysis and interpretation of the data. [76] 9. Notably, however, some patients respond better 4. Response to ITI may be less favorable in patients to one agent than the other, highlighting the with moderate/mild hemophilia. [63] need to individualize therapy. (Level 2) [69,70] 5. Experience with ITI for hemophilia B inhibitor 10. An anamnestic immune response should be patients is limited. The principles of treatment expected in patients with hemophilia B and a in these patients are similar, but the success rate FIX inhibitor treated with prothrombin complex is much lower, especially in persons whose inhib- concentrates––whether activated or not––since itor is associated with an allergic diathesis. these concentrates all contain FIX. 6. Hemophilia B inhibitor patients with a history of 11. On the other hand, the risk of anamnesis in severe allergic reactions to FIX may develop patients with hemophilia A and an inhibitor nephrotic syndrome during ITI, which is not treated with a(n) (activated) prothrombin com- always reversible upon cessation of ITI therapy. plex concentrate will vary depending on the con- Alternative treatment schedules, including immu- centrate and its content of FVIII, which is nosuppressive therapies, are reported to be suc- generally minimal. It is estimated that APCC cessful. [77] leads to an anamnestic response in approximately 30% of FVIII inhibitor patients.

Patients switching to new concentrates 2. As part of the hemovigilance program, all people with hemophilia treated with plasma-derived 1. For the vast majority of patients, switching products that are not adequately virus-inactivated products does not lead to inhibitor develop- should be tested for HIV at least every 6– ment. 12 months and whenever clinically indicated. 2. However in rare instances, inhibitors in previ- (Level 4) [85] ously treated patients have occurred with the 3. The diagnosis, counseling, initiation of treat- introduction of new FVIII concentrates. ment, and monitoring of HIV, as well as the 3. In those patients, the inhibitor usually disappears treatment of HIV-associated complications in after withdrawal of the new product. infected people with hemophilia, should be the 4. Patients switching to a new factor concentrate same as in the non-hemophilic population. should be monitored for inhibitor development. (Level 2) [86,87] (Level 2) [53] 4. None of the currently available classes of anti- HIV drugs are contraindicated in people with 6.3 Transfusion-transmitted and other infection- hemophilia. (Level 5) [88–90] related complications Principles of management of HCV infection in hemo- 1. The emergence and transmission of HIV, HBV philia and HCV through clotting factor products resulted in high mortality of people with hemo- 1. Assessment of HCV in people with hemophilia philia in the 1980s and early 1990s. [78,79] should include: 2. Many studies conducted all over the world indi- • anti-HCV serology to determine exposure cate that HIV, HBV, and HCV transmission • HCV polymerase chain reaction (PCR) in those through factor concentrate has been almost com- who are anti-HCV positive pletely eliminated. [80,81] • HCV genotyping in those who are HCV PCR 3. This is a result of the implementation of several positive risk-mitigating steps, which include careful selec- • liver function tests and non-invasive assessment tion of donors and screening of plasma, effec- of fibrosis and liver architecture tive virucidal steps in the manufacturing 2. The current standard of treatment for HCV is process, and advances in sensitive diagnostic pegylated interferon (PEG-INF) and ribavirin, technologies for detection of various pathogens. which give sustained virological response in 61% [82] of people with hemophilia. (Level 1) [91–96] 4. Recombinant factor concentrates have been 3. New antiviral therapies, in combination with adopted over the past two decades, particularly in these drugs, may improve sustained virologic developed countries. Recombinant products have response rates. [97] contributed significantly to infection risk reduc- 4. HCV genotype 1 and HIV coinfection predict tion. poorer response to anti-HCV therapy. 5. The new challenge remains emerging and re- 5. Where HCV eradication cannot be achieved, reg- emerging infections, many of which are not ame- ular monitoring (every 6–12 months) for end- nable to current risk reduction measures. These stage liver complication is recommended. (Level include the non-lipid enveloped viruses and pri- 3) [98] ons, for which diagnosis and elimination methods are still a challenge. [81,83,84] Principles of management of HBV infection in hemo- 6. As new treatments are continually emerging in philia this rapidly changing field, transfusion-transmitted infections in people with hemophilia are best 1. All people with hemophilia treated with plasma- managed by a specialist. derived products that are not adequately virus- inactivated should be screened for hepatitis B – Principles of management of HIV infection in hemo- antigen and anti-hepatitis B at least every 6 philia 12 months and whenever clinically indicated. (Level 4) [99] 1. Knowledge and expertise in the treatment of 2. Active HBV infection should be managed as per HIV-infected people with hemophilia are cur- local infectious disease guidelines and protocols. rently limited to case series and reports. HIV 3. Those without HBV immunity should be given treatment in people with hemophilia is therefore the anti-HBV vaccine. Protective seroconversion largely informed by guidelines used in the non- should be rechecked following vaccination. (Level hemophilia population. 4) [99–101]

4. People with hemophilia who do not seroconvert 2. In general, joint aspiration to treat hemarthrosis should be revaccinated with double the hepatitis should be avoided, unless done early under B vaccine dose. (Level 4) [99,102] appropriate cover of factor replacement and with strict aseptic precautions to prevent infection. Principles of management of bacterial infection in [106,107] hemophilia 3. Bleeding is likely to delay healing and worsen infection and should therefore be well contolled. [108] 1. The risk factors for bacterial infections in people 4. Control of the source of infection is of para- with hemophilia are venous access catheter inser- mount importance in people with hemophilia. tion, surgical arthroplasty, and other surgical [109,110] interventions. [103–105]

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Haemophilia 2004; Haemophilia 2008; 14: 303 14. mophilia. Haemophilia 2008; 14: 989 10: 157–60. 25 Keshava S, Gibikote S, Mohanta A, Do- 98. 13 Rattray B, Nugent DJ, Young G. Celec- ria AS. Refinement of a sonographic pro- 38 Mathews V, Viswabandya A, Baidya S oxib in the treatment of haemophilic tocol for assessment of haemophilic et al. Surgery for hemophilia in develop-

ing countries. Semin Thromb Hemost and consensus report. Haemophilia problem bleeds in patients with severe 2005; 31: 538–43. 2010; 16: 747–66. congenital haemophilia A and high-titre 39 De Kleijn P, Blamey G, Zourikian N, 54 Wight J, Paisley S. The epidemiology of inhibitors. Haemophilia 2007; 13: Dalzell R, Lobet S. Physiotherapy follow- inhibitors in haemophilia A: a systematic 256–63. ing elective orthopaedic procedures. Hae- review. Haemophilia 2003; 9: 418–35. 69 Astermark J, Donfield SM, DiMichele mophilia 2006; 12(Suppl. 3): 108–12. 55 Eckhardt CL, Menke LA, Van Ommen DM et al. A randomized comparison of 40 Heijnen L, Buzzard BB. The role of phys- CH et al. Intensive peri-operative use of bypassing agents in hemophilia compli- ical therapy and rehabilitation in the factor VIII and the Arg593 ->Cys muta- cated by an inhibitor: the FEIBA Novo- management of hemophilia in developing tion are risk factors for inhibitor devel- seven Comparative (FENOC) Study. countries. Semin Thromb Hemost 2005; opment in mild/moderate hemophilia A. Blood 2007; 109:546–51. 31: 513–7. J Thromb Haemost 2009; 7: 930–7. 70 Berntorp E, Shapiro A, Astermark J et al. 41 Hermans C, de Moerloose P, Fischer K 56 Kempton CL, Soucie JM et al. In non- Inhibitor treatment in haemophilias A et al. European Haemophilia Therapy severe hemophilia A the risk of inhibitor and B: summary statement for the 2006 Standardisation Board. Management of after intensive factor treatment is greater international consensus conference. Hae- acute haemarthrosis in haemophilia A in older patients: a case-control study. mophilia 2006; 12(Suppl. 6): 1–7. without inhibitors: literature review, JTH 2010; 8: 2224–31. 71 Chitlur M, Warrier I, Rajpurkar M, European survey and recommendations. 57 Hay CR. Factor VIII inhibitors in mild Lusher JM. Inhibitors in factor IX Haemophilia 2011; 17: 383–92. and moderate-severity haemophilia A. deficiency a report of the ISTH-SSC 42 D’Young AI. 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A purified factor VIII concentrate during in haemophilia: a comprehensive review systematic approach to controlling

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Stavudine or zidovudine in three-drug

Section 7. Plasma factor level and duration of cant resource constraint (Table 7-1) and countries where treatment products are limited administration (Table 7-2). 5. With the lower doses for treating musculoskele- 7.1 Choice of factor replacement therapy protocols tal bleeds listed in Table 7-2, it may only be 1. The correlation shown between possible factor possible to avoid major target joints and crip- replacement therapy protocols and overall out- pling deformities. come in Fig. 7-1 depicts the choices that one 6. Higher doses listed in Table 7-1 have been shown needs to make when selecting doses and regimen to avoid joint damage, but the optimal dose needed of clotting factor concentrates. to achieve this remains to be defined. 2. While enabling a completely normal life should 7. Observational studies documenting the musculo- remain the ultimate goal of factor replacement skeletal outcome of doses and protocols of fac- therapy, this cannot be achieved immediately in tor replacement are extremely important in people with hemophilia in all situations. defining these issues. 3. The availability of treatment products varies 8. Doses for prophylactic replacement of factor significantly around the world and there will concentrates vary between different countries therefore always be a range of doses with and also among centers in the same country. which people with hemophilia are treated. 9. Commonly used dosage for prophylactic factor À Lower doses may increase as the global avail- replacement is 25–40 IU kg 1 2–3 times weekly ability of treatment products improves incre- in countries with less resource constraints (see mentally over time. Section 1 for details) [1–3]. 4. Tables 7-1 and 7-2 present commonly followed 10. In situations where there are greater constraints guidelines on plasma factor peak levels and on supply of factor concentrates, prophylaxis duration of replacement that reflect the different may be initiated with lower doses of 10– À practices in countries where there is no signifi- 20 IU kg 1 2–3 times per week. (Level 2) [4,5]

Fig. 7-1. Strategies for clotting factor replacement at different ages and impact on outcomes.

Table 7-1. Suggested plasma factor peak level and duration of administration (when there is no signiﬁcant resource constraint) [6].

Hemophilia A Hemophilia B

Desired level Desired level Type of hemorrhage (IU dLÀ1) Duration (days) (IU dLÀ1) Duration (days) Joint 40–60 1–2, may be longer 40–60 1–2, may be longer if if response is inadequate response is inadequate Superﬁcial muscle/no NV 40–60 2–3, sometimes longer if 40–60 2–3, sometimes longer if compromise (except iliopsoas) response is inadequate response is inadequate Iliopsoas and deep muscle with NV injury, or substantial blood loss Initial 80–100 1–260–80 1–2 Maintenance 30–60 3–5, sometimes longer as 30–60 3–5, sometimes longer as secondary prophylaxis secondary prophylaxis during physiotherapy during physiotherapy CNS/head Initial 80–100 1–760–80 1–7 Maintenance 50 8–21 30 8–21 Throat and neck Initial 80–100 1–760–80 1–7 Maintenance 50 8–14 30 8–14 Gastrointestinal Initial 80–100 7–14 60–80 7–14 Maintenance 50 30 Renal 50 3–5403–5 Deep laceration 50 5–7405–7 Surgery (major) Pre-op 80–100 60–80 Post-op 60–80 1–340–60 1–3 40–60 4–630–50 4–6 30–50 7–14 20–40 7–14 Surgery (minor) Pre-op 50–80 50–80 Post-op 30–80 1–5, depending on type 30–80 1–5, depending on type of procedure of procedure NV, neurovascular.

Table 7-2. Suggested plasma factor peak level and duration of administration (when there is signiﬁcant resource constraint).

Hemophilia A Hemophilia B

Desired level Desired level À À Type of hemorrhage (IU dL 1) Duration (days) (IU dL 1) Duration (days) Joint 10–20 1–2 may be longer if response 10–20 1–2, may be longer if response is inadequate is inadequate Superﬁcial muscle, no NV injury 10–20 2–3, sometimes longer if response 10–20 2–3, sometimes longer if response is (except iliopsoas) is inadequate inadequate Iliopsoas, and deep muscle with NV injury or substantial bloodloss Initial 20–40 15–30 Maintenance 10–20 3–5, sometimes longer as secondary 10–20 3–5, sometimes longer as secondary prophylaxis during physiotherapy prophylaxis during physiotherapy CNS/head Initial 50–80 1–350–80 1–3 Maintenance 30–50 4–730–50 4–7 20–40 8–14 20–40 8–14 Throat and neck Initial 30–50 1–330–50 1–3 Maintenance 10–20 4–710–20 4–7 Gastrointestinal Initial 30–50 1–330–50 1–3 Maintenance 10–20 4–710–20 4–7 Renal 20–40 3–515–30 3–5 Deep laceration 20–40 5–715–30 5–7 Surgery (major) Pre-op 60–80 50–70 Post-op 30–40 1–330–40 1–3 20–30 4–620–30 4–6 10–20 7–14 10–20 7–14 Surgery (minor) Pre-op 40–80 40–80 Post-op 20–50 1–5, depending on type of procedure 20–50 1–5, depending on type of procedure NV, neurovascular.

References

1 Astermark J, Petrini P, Tengborn L, Schul- Group. A randomized clinical trial of pro- 5 Wu R, Luke KH, Poon MC et al. Low dose man S, Ljung R, Berntorp E. Primary prophylaxis in children with hemophilia A (the secondary prophylaxis reduces joint bleeding phylaxis in severe haemophilia should be ESPRIT Study). J Thromb Haemost 2011c; in severe and moderate haemophilic chil- – started at an early age but can be individual- 9: 700 10. dren: a pilot study in China. Haemophilia – ized. Br J Haematol 1999; 105: 1109–13. 4 Fischer K, van der Bom JG, Mauser-Bunscho- 2011; 17:70 4. 2 Blanchette VS. Prophylaxis in the haemo- ten EP et al. Changes in treatment strategies 6 Rickard KA. Guidelines for therapy and philia population. Haemophilia 2010; 16 for severe haemophilia over the last 3 decades: optimal dosages of coagulation factors for (Suppl. 5): 181–8. effects on clotting factor consumption and treatment of bleeding and surgery in haemo- – – 3 Gringeri A, Lundin B, von Mackensen S, arthropathy. Haemophilia 2001c; 7: 446 52. philia. Haemophilia 1995; 1(Suppl. 1): 8 13. Mantovani L, Mannucci PM, ESPRIT Study

Acknowledgement Disclosures

A professional agency was engaged to assist with the literature search and Dr. Srivastava has received grant support from the Bayer Hemophilia to grade the evidence. In addition, given the fact that many recommenda- Awards Program and also serves on their Grants Review and Awards Com- tions are based on expert opinion, we circulated a draft version of these mittee. Dr. Key has acted as a paid consultant to Novo Nordisk and has guidelines to many others involved in hemophilia care outside of the writ- received grant funding from Baxter. Dr. Kitchen has acted as a paid consul- ing group. The authors are grateful to those who provided detailed com- tant to Novo Nordisk, Pfizer, and Bayer. Dr. Llinas has lectured for Baxter, ments. Finally, we would like to acknowledge the extraordinary effort Novo Nordisk, Pfizer, and Bayer and has performed clinical trials for Bayer from WFH staff, Jennifer Laliberte´, and also Elizabeth Myles, in complet- and Baxter. Dr. Ludlam has received an educational grant from Novo Nor- ing this work. disk, has acted as medical advisor for Ipsen, a consultant for Biogen Idec and Baxter as well as Bayer, from which he has also received funding to attend medical conferences. Dr. Mauser-Bunschoten has received unre- Disclaimer stricted research funding from CSL Behring, is a speaker for Bayer, Sanquin Bloedvoorziening, and Novo Nordisk, and has received funding for post- The World Federation of Hemophilia does not endorse particular treat- marketing surveillance by Wyeth and Baxter. Dr. Poon has attended advi- ment products or manufacturers; any reference to a product name is sory board meetings of CSL Behring, Novo Nordisk, Octapharma, and not an endorsement by the WFH. The World Federation of Hemo- Pfizer. He has attended sponsored meetings on behalf of Baxter and Bayer, philia does not engage in the practice of medicine and under no cir- is a speaker for Pfizer, and acted as chair of Novo Nordisk’s expert panel cumstances recommends particular treatment for specific individuals. on Glanzmann’s Thrombasthenia registry. The other authors have no com- Dose schedules and other treatment regimes are continually revised and peting interests to declare. new side-effects recognized. These guidelines are intended to help develop basic standards of care for the management of hemophilia and do not replace the advice of a medical advisor and/or product insert information. Any treatment must be designed according to the needs of the individual and the resources available.

Appendix I. Oxford Centre for Evidence-Based Medicine 2011 Levels Of Evidence

Question Step 1 (Level 1*) Step 2 (Level 2*) Step 3 (Level 3*) Step 4 (Level 4*) Step 5 (Level 5) How common is the Local and current random sample Systematic review of surveys that Local non-random sample** Case-series** n/a problem? surveys (or censuses) allow matching to local circumstances** Is this diagnostic or Systematic review of cross-sectional Individual cross-sectional studies Non-consecutive studies, Case-control studies, Mechanism-based monitoring test accurate? studies with consistently applied with consistently applied reference or studies without consistently or “poor or non- reasoning (Diagnosis) reference standard and blinding standard and blinding applied reference standards** independent reference MANAG THE FOR GUIDELINES standard** What will happen if we do Systematic review of inception cohort Inception cohort studies Cohort study or control arm of Case-series or case control n/a not add a therapy? (Prognosis) studies randomized trial* studies, or poor quality prognostic cohort study** Does this intervention help? Systematic review of randomized trials Randomized trial or observational study Non-randomized controlled Case-series, case-control Mechanism-based (Treatment Benefits) or n-of-1 trials with dramatic effect cohort/follow-up study** studies, or historically reasoning controlled studies** What are the COMMON harms? Systematic review of randomized Individual randomized trial or Non-randomized controlled Case-series, case-control, Mechanism-based (Treatment Harms) trials, systematic review of nested (exceptionally) observational study cohort/follow-up study or historically controlled reasoning case-control studies, n of-1 trial with with dramatic effect (postmarketing surveillance) studies** the patient you are raising the question provided there are sufficient about, or observational study with numbers to rule out a common dramatic effect harm. (For long-term harms What are the RARE harms? Systematic review of randomized trials Randomized trial or (exceptionally) the duration of follow-up must (Treatment Harms) or n-of-1 trial observational study with dramatic be sufficient.)** effect

Is this (early detection) test Systematic review of randomized trials Randomized trial Non -randomized controlled Case-series, case-control, Mechanism-based HEMOPHILIA OF EMENT worthwhile? (Screening) cohort/follow-up study** or historically controlled reasoning studies** OCEBM Levels of Evidence Working Group. “The Oxford 2011 Levels of Evidence”. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o = 5653.

Haemophilia *Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size. **As always, a systematic review is generally better than an individual study. (2013), 19 e1–e47 , e47 guideline

The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology

Mike A. Laffan,1 Will Lester,2 James S. O’Donnell,3 Andrew Will,4 Robert Campbell Tait,5 Anne Goodeve,6 Carolyn M. Millar1and David M. Keeling7

1Centre for Haematology, Imperial College London, London, 2Department of Haematology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK, 3National Centre for Coagulation Disorders, St James’s Hospital, Dublin, Ireland, 4Royal Manchester Children’s Hospital, Manchester, 5Department of Haematology, Royal Infirmary, Glasgow, 6Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust & Department of Cardiovascular Science, University of Sheffield, Sheffield, and 7Oxford University Hospitals, Oxford, UK

Keywords: diagnosis, management, guideline, United King- Major changes since last guideline dom Haemophilia Centre Doctors Organization, von Wille- brand. The principal changes have been increased understanding of the genetic basis of von Willebrand disease, a relaxation of The guideline group was selected to be representative of UK- definition and a focus on how laboratory tests can guide based medical experts. MEDLINE and EMBASE were searched management. systematically for publications in English from 2002 using the key word Willebrand. The writing group produced the What is von Willebrand disease? draft guideline, which was subsequently reviewed by the A United Kingdom Haemophilia Centre Doctors Organization Von Willebrand factor (VWF) is a large and complex plasma (UKHCDO) advisory committee, a British Committee for glycoprotein that is essential for normal haemostasis. It is Standards in Haematology (BCSH) sounding board of well recognized that deficiency of VWF results in a bleeding approximately 50 UK haematologists, and the BCSH execu- disorder that varies in severity according to the degree of tive; comments were incorporated where appropriate. The deficiency and the specific characteristics of the molecule and ‘GRADE’ system was used to quote levels and grades of which may have features of both primary and secondary hae- evidence, details of which can be found in at http://www.bcsh- mostatic defects. The complex structure of the protein and guidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_ the wide range of plasma levels encountered in the popula- GRADES_OF_RECOMMENDATION/43_GRADE.html. The tion make laboratory assessment and diagnosis a challenging objective of this guideline is to provide healthcare profession- proposition. Since the last guidelines by this group (Laffan als with clear guidance on the diagnosis and management of et al, 2004; Pasi et al, 2004), there have been considerable patients with von Willebrand disease. advances in understanding the genetics, function and clinical correlates of VWF, which have been incorporated into this Guideline update revised and unified document. Here we define von Wille- brand disease (VWD) as a bleeding disorder that is predomi- This is a single guideline replacing two separate guidelines nantly attributable to reduced levels of VWF activity. We on diagnosis and management respectively, published in recognize that this is frequently, but not always, attributable 2004 (Laffan et al, 2004; Pasi et al, 2004). Where there has to a defect in the VWF gene (VWF). Our emphasis remains been no significant change in understanding or practice, the on practical guidance rather than taxonomic purity. reader is referred to the earlier guidelines. When patients present with mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is a possible Correspondence: Dr G Dolan, UKHCDO Chairman, UKHCDO cause or contributory factor. During the initial assessment it Secretariat, City View House, Union Street, Ardwick, Manchester is important to remember that bleeding histories can be M12 4JD, UK. subjective and the disease characteristics can take time to E-mail: [email protected]

ª 2014 John Wiley & Sons Ltd First published online 12 August 2014 British Journal of Haematology, 2014, 167, 453–465 doi:10.1111/bjh.13064 Guideline evolve; there is also overlap between symptoms suffered by symptoms: this is likely to reflect interaction with additional people with VWD and the normal population (Sadler, 2003; abnormalities in the haemostatic pathway, including mild Tosetto et al, 2013). Figure 1 shows the bleeding symptoms platelet defects (Millar et al, 2008a; Daly et al, 2009). in an international study of type 1 VWD patients in compar- A study of 280 patients with hereditary mucocutaneous ison with unaffected family members (Tosetto et al, 2006). bleeding found abnormalities of VWF and/or platelets in To improve decisions regarding the significance of bleeding approximately one-third, whilst the majority had no identifi- symptoms, attempts have been made to develop a standard- able laboratory abnormality. (Quiroga et al, 2007). Therefore, ized bleeding assessment tool (BAT), with the Scientific and while identification of laboratory abnormalities may guide Standardization Committee of the International Society on management, the primary diagnosis remains ‘abnormal Thrombosis and Haemostasis (ISTH/SSC) BAT being the bleeding’; for which risk factors may or may not be identi- most recent iteration (Rodeghiero et al, 2010; Rydz & James, fied. Because VWF levels are relatively easy to measure (in 2012). These tools can help predict the likelihood of a bleed- comparison to platelet function) VWD has often been diag- ing disorder being present and have good negative predictive nosed in patients with bleeding symptoms and VWF levels value but studies evaluating their ability to predict future that are only slightly reduced (0Á3–0Á5 iu/ml), giving the bleeding episodes are lacking (Tosetto et al, 2013). potentially misleading impression that this is the sole respon- The plasma level of VWF in normal individuals varies sible factor. over a six-fold range, from 0Á40 to 2Á40 iu/ml (Abildgaard A Bayesian approach to diagnosis of VWD combining lab- et al, 1980), and VWF levels are approximately 25% lower in oratory data, personal bleeding history and family data has blood group O individuals than in non-O (Gill et al, 1987). been evaluated: however an area of uncertainty remained A VWF activity <0Á30 iu/ml is usually associated with bleed- (Tosetto et al, 2008). Thus, caution should be exercised in ing symptoms and is more likely to be associated with a diagnosing VWD in patients with borderline VWF levels in mutation in VWF, however these associations are less strong the range 0Á3–0Á5 iu/ml in order to avoid the burden of an for VWF levels between 0Á30 and 0Á50 iu/ml (Eikenboom unnecessary diagnosis and the hazard of failing to complete et al, 2006; James et al, 2006). In patients recruited to the further necessary investigations. MCMDM-1 VWD study, VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity (VWF:RCo) values below 0Á40 iu/ Recommendations ml significantly increased the likelihood of type 1 VWD (Tosetto et al, 2006). Amongst 117 obligate carriers of type 3 • We recommend against the use of reference ranges or VWD (type 3 OC) with VWF <0Á5 iu/ml, only 26% had blood group-specific ranges for the diagnosis of von bleeding symptoms (Sadler, 2003) and a more recent study Willebrand disease (VWD) (2C). (Castaman et al, 2006) did not demonstrate an independent • When investigating a patient with mucocutaneous bleed- correlation between bleeding score and VWF:Ag in 70 type 3 ing a diagnosis of VWD can be made when von Wille- OC. These patients are also likely to have a normal physio- brand factor (VWF) activity is <0Á30 iu/ml (1B). logical rise in VWF in response to stress. Therefore, mildly • Patients with an appropriate bleeding history and VWF reduced VWF activity in isolation may be insufficient to activity 0Á3–0Á5 iu/ml should be regarded as having pri- result in significant bleeding. Nonetheless, some patients with mary haemostatic bleeding with reduced VWF as a risk only mildly reduced VWF levels do have significant bleeding factor rather than VWD. We suggest referring to this as ‘Low VWF’ (2C). • We recommend use of a bleeding score (e.g. Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis bleeding assessment tool) to standardize history taking (2C). • When reviewing patients and families with an historical diagnosis of VWD, we suggest confirming the accuracy of that diagnosis (2A). • The incidental finding of VWF activity <0Á30 iu/ml should be taken to indicate VWD or acquired von Wille- brand syndrome (AVWS).

Classification of VWD The simplified classification of VWD proposed by the ISTH Fig 1. Predictive value of bleeding symptoms in diagnosis of type 1 (Sadler, 1994) is still in common use. Despite the potential VWD. Reproduced with permission, from Tosetto et al (2006). for reclassification based on molecular defects, there has been

454 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 167, 453–465 Guideline a reluctance to move to a more complex taxonomy; only overall sensitivity of the Platelet Function Analyser (PFA) minor qualifications were introduced when last reviewed for detecting VWD is reported to be 90%, it is close to (Sadler et al, 2006). Table I summarizes how the classifica- 100% in type 2 (excluding 2N) and type 3 VWD but lower tion is currently applied. in type 1 VWD and may be normal when VWF activity is In contrast to type 1 VWD, type 2 variants are usually 0Á3–0Á5 iu/ml. Factor VIII (FVIII), VWF:Ag and measure- linked to VWF and usually have a predictable laboratory and ments of VWF activity are the initial laboratory tests clinical phenotype. Misclassification remains an issue, typi- required to make a diagnosis of VWD and must be per- cally between type 1 and type 2M (Nitu-Whalley et al, 2000). formed if VWD is suspected. A diagnostic algorithm is In the MCMDM-1 VWD study a third of the families shown in Fig 2. Factors that can affect VWF levels (such as recruited with an historical diagnosis of type 1 VWD had anxiety and needle phobia, the combined contraceptive pill, minor multimer abnormalities and a proportion of these pregnancy and strenuous exercise) were discussed fully in were subsequently classified as type 2 VWD (Goodeve et al, our previous guideline (Laffan et al, 2004). Misdiagnosis can 2007; Budde et al, 2008). However the relevance of subtle be minimized by ensuring at least two concordant sets of abnormalities in VWF multimer patterns remains controver- results are obtained. Samples should not be put on ice sial and they lack clear clinical significance (Budde et al, (Bohm et al, 2006). 2008; Castaman et al, 2008; James & Lillicrap, 2012). Classification remains an artificial exercise and although it Factor VIII assay is of great use for study and research, it does not completely define or predict response to therapy and also has a variable Factor VIII is measured using an APTT-based one stage clot- relationship to genetics. From a clinical perspective, any fur- ting assay or chromogenic assay. Although FVIII half-life is ther reclassification of VWD subtypes should focus on clini- regulated by VWF and is frequently reduced in VWD, FVIII cal utility and, ideally, correlate with responses to therapy. levels may be normal in VWD.

Tests used for the primary diagnosis of VWD Von Willebrand factor antigen von Willebrand disease cannot be excluded by a normal Plasma VWF:Ag levels are measured by immunological activated partial thromboplastin time (APTT). Although the methods, usually by enzyme-linked immunosorbent assay

Table I. Classiﬁcation of VWD.

Type Description Comments Inheritance

1 Partial quantitative deficiency of Includes VWF mutations causing rapid VWF Mostly autosomal dominant inheritance when VWF clearance (e.g. VWF Vicenza) and requires VWF <0Á3 iu/ml. Mutations of VWF in function:antigen ratio >0Á6 kindred with levels >0Á3 iu/ml show variable penetrance 2 Qualitative VWF defects 2A Decreased VWF-dependent platelet Some controversy exists regarding classification Mostly autosomal dominant adhesion with selective deficiency of VWF mutations associated with subtle of high-molecular-weight reductions in HMW multimers multimers 2B Increased affinity for platelet GPIb Should be distinguished from PT-VWD, using Autosomal dominant either platelet agglutination tests or genetic testing. Cases with normal VWF multimer and platelet count have been described 2M Decreased VWF-dependent platelet This also includes defects of VWF collagen Autosomal dominant adhesion without selective binding. May be combined quantitative/ deficiency of HMW multimers qualitative defect 2N Markedly decreased binding affinity Should be distinguished from mild haemophilia Reduced VWF:FVIII binding defects are more for FVIII A commonly identified in a compound heterozygote state with a VWF null allele rather than the classical homozygous form 3 Virtually complete deficiency of Equivalent to <0Á03 iu/ml in most assays Autosomal recessive, frequent null VWF alleles. VWF Bleeding symptoms in 26–48% of obligate carriers

VWD, von Willebrand disease; PT-VWD, platelet type pseudo-VWD; VWF, von Willebrand factor; VWF, VWF gene; FVII, factor VIIIGPIb, glycoprotein Ib; HMW, high molecular weight.

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INITIAL TESTS

If only low FVIII:C, differential diagnosis is type 2N or mild VWF:Ag haemophilia A VWF:RCo

VWF:CB

VWF:RCo and/or FVIII:C Undetectable VWF:Ag VWF:CB reduced

RCo/Ag and CB/Ag RCo/Ag or CB/Ag < 0·6 Type 3 > 0·6

Type 1 Type 2

Response to low concentration Normal/reduced RIPA ristocetin

Type 2B, or Loss of HMW Preservation of HMW multimers, Fig 2. An algorithm for the investigation of platelet-type multimers, RCo/Ag RCo/Ag low but CB/Ag normal suspected von Willebrand disease. VWF, von and CB/Ag both low (rarely RCo/Ag normal, CB/Ag low) Willebrand factor; VWF:Ag, VWF antigen; VWF:RCo, ristocetin cofactor activity; VWFCB, collagen binding activity; FVIII, factor VIII; FVIII:C, Factor VIII coagulant activity; GPIb, glycoprotein Ib; HMW, high molecular weight; Type 2A Type 2M RIPA, ristocetin-induced platelet agglutination.

(ELISA) or by automated immunoturbidimetric methods The platelet agglutination method has been automated, relying on latex particle agglutination. The latter may give with improvement in sensitivity and reproducibility (Lawrie falsely high results in the presence of rheumatoid factor. et al, 2011). Other approaches to automation have used a monoclonal antibody to link recombinant GPIb to latex beads (Lawrie et al, 2011, 2013) or magnetic particles (Cab- Von Willebrand factor activity rera et al, 2013). The use of a recombinant GPIb with gain- Assessment of the ability of VWF to bind FVIII is discussed of-function mutations can remove the requirement for rist- below. Here we examine the ability of VWF to support plate- ocetin (Flood et al, 2011; Lawrie et al, 2013). let adhesion by binding to platelet glycoprotein Ib (GPIb) It must be recognized that using ristocetin rather than shear and collagen. to induce VWF binding to GPIb is unphysiological. Thus sequence variations affecting the ristocetin binding sites on Binding of VWF to platelet GPIb. Binding of VWF to platelet VWF can result in low VWF:RCo estimation in the absence of GPIb has traditionally been assessed by ristocetin cofactor a physiological defect of VWF (Flood et al, 2009, 2010). activity (VWF:RCo). Ristocetin dimers bind to VWF and Assays based on monoclonal antibodies directed against induce a conformational change facilitating VWF binding to the VWF GPIb-binding site, sometimes called ‘VWF activity platelet GPIb and thus cross-linking of platelets. Putative assays’ have previously failed to detect type 2 VWD (Preston, ristocetin binding sites flank the A1 domain, which contains 1998) and although more recent versions have improved pre- the GPIb binding region. In the traditional assay the aggluti- cision and sensitivity, they are not yet sufficiently reliable to nation of normal fixed platelets is measured in dilutions of replace VWF:RCo (Chen et al, 2011; Favaloro et al, 2012). test plasma containing an excess of ristocetin and the Pending further data we recommend they are not relied on patient’s VWF:RCo is determined by reference to a plasma for diagnosis. standard. The agglutination is dependent on the presence of high molecular weight (HMW) multimers and an intact Binding of VWF to collagen (collagen binding activity, VWF: GPIb binding site. CB). The primary collagen binding site of VWF is in the A3

456 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 167, 453–465 Guideline domain. ELISAs are available to measure binding of patient type 2 VWD, but if not available, similar information can be VWF to immobilized collagen. VWF:CB is dependent on cautiously inferred from the VWF:CB/VWF:Ag ratio (Fav- the presence of HMW multimers and an intact collagen aloro, 2007). binding site: assays using type III and type I/III mixtures of collagen have been found to give the best sensitivity to Ristocetin-induced platelet agglutination (RIPA) these factors (Favaloro, 2000). Although VWF:RCo and VWF:CB assess different aspects of VWF function, both are In normal individuals, low concentrations of ristocetin are sensitive to the loss of HMW multimers and both the not sufficient to initiate VWF-dependent platelet agglutina- VWF:RCo to VWF:Ag ratio and the VWF:CB to VWF:Ag tion. Platelet agglutination at low ristocetin concentrations ratio will be reduced in type 2A disease, though the latter (<0Á5–0Á7 mg/ml) suggests a pathological enhancement of ratio is better at differentiating type 2A from type 1 disease the VWF – GPIb interaction, which is characteristic of type (Favaloro et al, 2000). 2B VWD and platelet-type pseudo-VWD (PT). Type 2B comprises a wide spectrum of severity overlapping with normality and in some patients the only abnormal feature pres- Recommendations ent is RIPA positivity. If it is not practical to perform RIPA • In the initial investigation for VWD, FVIII, VWF:Ag and on all cases then it should always be performed when the VWF activity should be measured(1A). VWF:RCo/VWF:Ag or VWF:CB/VWF:Ag ratio is reduced or • VWF activity should be assessed by its ability to bind if thrombocytopenia is present, bearing in mind that this both GPIb and collagen (2B). may miss some mild forms of type 2B VWD (Federici et al, • We recommend against using assays based on monoclo- 2009). nal antibodies directed against the VWF GPIb-binding site (1B). VWF-FVIII binding assay (VWF:FVIIIB) Mutations of the FVIII binding site within the D’ and D3 Secondary classification of VWD domains of VWF can impair FVIII binding. If present in the homozygous state or in trans with a null allele this gives rise Types 2A and 2M are qualitative disorders in which VWF to type 2N VWD in which plasma VWF:Ag, VWF:RCo and function is significantly more reduced than VWF:Ag. Conse- VWF:CB are often normal but FVIII coagulant (FVIII:C) lev- quently, the VWF:RCo/VWF:Ag and the VWF:CB/VWF:Ag els are markedly reduced. These mutations may also compli- ratios are critically important in their differentiation from cate a type 1 phenotype causing a disproportionate reduction type 1. In the MCMDM-1 VWD study the median VWF: in FVIII level. The ability of patient VWF to bind added RCo/VWF:Ag ratio for 1166 healthy controls was 1Á00 with a exogenous normal FVIII can be assessed using an immuno- range of 0Á59–1Á62 (2Á5th–97Á5th centiles) (Goodeve et al, sorbent plate-binding assay (Zhukov et al, 2009) but these 2007). In a comparison of collagen-binding assays in 232 assays are technically difficult and genetic analysis provides a healthy controls, the lower limit of normal for VWF:CB/ practical alternative. VWF:Ag was >0Á76 for all types of collagen (Flood et al, 2012) and >0Á6 for VWF:RCo/VWF:Ag. Thus patients with a function:antigen ratio <0Á6 should be considered to have Making a diagnosis in neonates and children type 2 VWD and further tests should be performed for The diagnosis of VWD in neonates and infants is compli- classification. cated by pre-analytical variation due to the difficulty in obtaining an unactivated and uncontaminated venous or Multimer analysis cord sample and the prolonged physiological increase of Plasma VWF multimer distribution can be analysed using VWF following delivery. In a study of full term normal non-reducing sodium dodecyl sulphate agarose gel electro- infants the mean VWF level was 1Á53 iu/ml at day 1 of life, phoresis. Following electrophoresis, a number of different reducing to 1Á07 iu/ml at day 180 (Andrew et al, 1987). methodologies have been described for VWF multimer Thus the diagnosis of VWD should not normally be visualization (Krizek & Rick, 2000; Ott et al, 2010; Pruthi attempted before 6 months of age. However when testing is et al, 2010). The gel agarose concentration can be modified clinically necessary, a severe deficiency or function-antigen in order to examine either the presence of HMW VWF discrepancy indicating type 2 disease should be apparent. multimers (c. 1%) or abnormalities of VWF satellite bands Samples from children are particularly prone to the eleva- (1Á5–3%). tion by stress and if borderline results are obtained they Von Willebrand factor multimer analysis should not be may need to be repeated when the child is older. Modified performed until a diagnosis of VWD has been established. bleeding scores for use in children are available (Marcus Multimer analysis is essential for the strict classification of et al, 2011).

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Recommendations phenotype with reduced VWF-FVIII binding in addition to reduced VWF-GPIba binding (Hampshire et al, 2010). Simi- • A function:antigen ratio of <0Á6 should be used to iden- larly, for some affected individuals without a clear family his- tify patients with type 2 VWD (1B). tory of bleeding, VWD inheritance risks for family members • RIPA should be performed on all patients with reduced are unclear and genetic analysis may help provide clarity VWF:RCo/VWF:Ag or VWF:CB/VWF:Ag ratios or when through identification of mutation(s) that suggest either thrombocytopenia is present (1B). dominant or recessive inheritance. • Multimer analysis should be used to distinguish between types 2A and 2M (1B). • If multimer analysis is not available then the ratios of Family testing VWF:RCo and VWF:CB to VWF:Ag should be used to When a diagnosis of VWD is made it is appropriate to test distinguish types 2A and 2M (1B). first degree relatives with or without a positive bleeding history. In this circumstance, a presumptive diagnosis of VWD may be made on the basis of laboratory findings alone. For Genetic analysis and family testing patients with ‘low VWF’ (0Á3–0Á5 iu/ml), family testing may be justifiable depending on bleeding and family history. Genetic testing For many patients, phenotypic analysis yields sufficient infor- Recommendations mation for VWD classification and thus appropriate treatment. However, certain circumstances, indicated below, may • Type 1 VWD should not be excluded in children before warrant VWF analysis to help clarify disease type or risk of the age of 6 months (1B). disease inheritance, or to facilitate prenatal diagnosis. • Family testing in VWD is appropriate prior to develop- Mild or moderate haemophilia A and 2N VWD can be ment of bleeding symptoms (2B). challenging to discriminate, especially in the absence of a • Genetic analysis should be used where beneficial to clar- family history. The VWF:FVIIIB assay can discriminate ify diagnosis and aid management (1B). between the two disorders, but is not widely available. Analy- – sis of VWF exons 17 25 can identify missense VWF:FVIIIB Management mutations in patients that have type 2N VWD; individuals lacking these mutations should be investigated for sequence Haemostatic therapies variation in the F8 gene. Type 2B VWD and PT-VWD patients present with simi- Available therapies to correct haemostasis in VWD comprise lar phenotypes and can be discriminated by plasma/platelet the non-concentrate therapies tranexamic acid and desmo- mixing studies or by genetic analysis. All 2B VWD muta- pressin or concentrates containing either high purity VWF tions have been identified between amino acid residues alone or intermediate purity concentrates containing FVIII- 1266–1461 encoded by exon 28 of VWF whilst PT-VWD VWF. mutations affect either the beta hairpin or macroglycopep- tide regions of GPIba encoded by the central region of Desmopressin. The pharmacology and clinical use of desmo- GP1BA exon 2 (Hamilton et al, 2011). Discrimination using pressin to temporarily elevate FVIII and VWF levels by genetic analysis is straightforward and can help guide appro- releasing endothelial stores have been extensively reviewed priate therapy. and were discussed in the previous version of this guideline Prenatal diagnosis is occasionally requested by families (Mannucci, 1997; Pasi et al, 2004). Intravenous, subcutane- with type 3 VWD, particularly where the parents already ous and intranasal desmopressin all have a UK product have one affected child. Mutation analysis of the index case license for the treatment of VWD. can identify the familial mutation(s), which should be con- Desmopressin frequently causes flushing and sometimes firmed to be present in each parent and can subsequently hypotension, which are not harmful. Excessive fluid retention be sought in a fetus using chorionic villus or amniocentesis should be avoided by limiting fluid intake to 1 l in the sub- samples. Both sequence and gene dosage analyses may be sequent 24 h. Serum sodium should be monitored if desmo- required to identify the two VWF mutations although pressin is used in children <2 years old or whenever repeated mutations are not yet identified in all cases (Keeney et al, doses are given. Desmopressin use has rarely been followed 2008). by occlusive arterial events and should not be used in For those patients where phenotypic analysis does not patients who are likely to have atherosclerosis (Federici, clarify VWD type, genetic analysis can be used to try and 2008). identify explanatory mutation(s), e.g. some patients with D3 Because of its clinical utility, and the wide variation in domain missense mutations may present with a pleiotropic response, a trial of desmopressin should be considered in all

458 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 167, 453–465 Guideline patients with type 1, type 2A, 2M and 2N VWD who do • Adults should be warned to limit fluid intake to 1 l in not have a contraindication to its use. It is also useful in the 24 h after desmopressin (2C). patients with bleeding and low VWF as a risk factor (‘low • Desmopressin should be avoided in those with known VWF’). In type 2B a transient thrombocytopenia frequently atherosclerosis (1C). follows desmopressin administration (Casonato et al, 1999). This has been regarded as a reason for contraindication and VWF-containing concentrates. A number of plasma-derived although no harmful effects have been reported, the thera- concentrates containing VWF are available for replacement peutic response is usually poor and desmopressin is not rec- therapy in patients whose desmopressin response is inade- ommended for type 2B VWD (Mannucci, 1988; Federici, quate for the relevant bleeding episode or surgical procedure 2008). (Batlle et al, 2009). In choosing which concentrate to use, Doses, routes of administration and responses are given the plasma source, purification and viral inactivation mea- in Table II. The magnitude of response will depend on the sures should first be considered although all currently avail- underlying defect and there are several VWF mutations able concentrates have an excellent safety record. For (including R1205H Vicenza) that have been associated with haemostatic activity, the relevant characteristics of these con- rapid VWF clearance (Casari et al, 2013): it is therefore centrates are the multimeric composition of the VWF, important to measure both the peak response at 30–60 min reflected in the VWF:RCo/VWF:Ag ratio, and the amount of and the maintenance of response at 4–6 h (Millar et al, FVIII contained per unit of VWF. A VWF:RCo/VWF:Ag 2008b; Castaman et al, 2013). However, even when the ratio close to 1 is desirable because it indicates the VWF has VWF or FVIII response is shortened, most dental extrac- normal multimeric structure and adhesive function, but the tions, minor surgeries and deliveries may be successfully appropriate amount of FVIII is debatable and will vary managed with desmopressin (Castaman et al, 2011; Trigg according to the circumstance. Some high purity concen- et al, 2012). trates contain virtually no FVIII and if given alone to a Desmopressin is relatively contraindicated in children patient with type 3 VWD it will be >12 h before the FVIII <2 years old. If, after careful consideration, it is to be used in level has risen to normal (Goudemand et al, 1998; Borel- this age group then fluid restriction, avoidance of hyponatrae- Derlon et al, 2007). mic solutions and close monitoring of serum electrolytes and Comparison of different concentrates yields a uniform urine output for at least 24 h after administration is advised. VWF:RCo recovery of 0Á021–0Á024 (iu/ml)/(U/kg) (Mann- ucci et al, 1992a) but reveals significant differences in specific Tranexamic acid. Tranexamic acid administered topically, as activity (function:antigen) and in their content of HMW a mouthwash, orally or parenterally remains a useful therapy multimers (Budde et al, 2006; Batlle et al, 2009). for minor bleeding or surgery (beginning prior to the proce- Initial (primary) haemostasis is dependent upon elevation dure) either on its own or as an adjunctive therapy to des- of the plasma VWF:RCo activity to normal, but longer term mopressin or concentrates. (Pasi et al, 2004). secure haemostasis is dependent on a normal level of Factor VIII (Mannucci et al, 1987; Sakurai et al, 2006). Because Recommendations endogenous FVIII production is normal, continued administration of large amounts of FVIII may result in an undesir- • A trial of desmopressin should be carried out in patients ably high plasma FVIII level. with type 1, type 2A, 2M and 2N VWD with VWF antigen, activity and FVIII measured at baseline, 30–60 min and 4–6 h (1B). Recommendations • When shown to be effective, desmopressin should be • For replacement therapy a VWF-containing concentrate used in preference to blood-derived products where pos- manufactured from a safe plasma source with adequate sible (1B).

Table II. Desmopressin doses and response for VWD.

Route of administration Suggested formulation Dose Peak levels achieved

Intravenous infusion over 30– 4 lg/ml diluted in 100 ml 0Á9% NaCl for 0Á3 lg/kg 15 min after infusion 60 min infusion completed Subcutaneous 15 lg/ml 0Á3 lg/kg 60–90 min after injection Intranasal 150 lg per metered spray >50 kg: 150 lg spray to each 1–4 h after administration nostril ≤50 kg: single 150 lg spray

ª 2014 John Wiley & Sons Ltd 459 British Journal of Haematology, 2014, 167, 453–465 Guideline

viral testing and inactivation procedures should be cho- effective (Windyga et al, 2011) and was common practice sen (1A). before rapid VWF:RCo measurement became available • For treatment of acute bleeding or emergency surgery, a (Lusher, 1998; Mannucci, 2001). It does not appear necessary VWF-FVIII concentrate or a combination of high purity to correct the bleeding time or PFA100 time and these need FVIII and high purity VWF concentrates should be used not be measured. Surgery should therefore be carried out (1A). only in centres with the ability to perform these measurements with the required frequency. Tranexamic acid remains a useful adjunctive therapy. Treatment of bleeding episodes When bleeding persists despite apparently normal plasma levels of VWF activity, platelet transfusion may be Treatment of acute bleeding episodes. Typical bleeding prob- helpful. lems in VWD are epistaxes, gum bleeding and menorrhagia. Platelet transfusion is also the treatment of choice in Post-traumatic bleeding can also occur and type 3 patients platelet-type VWD pseudo (PT-VWD) and may be supple- can develop spontaneous joint or muscle bleeding. When any mented by FVIII-VWF concentrate (O’Connor et al, 2011; of these are frequent, self-administration of desmopressin Othman, 2011). and tranexamic acid can be helpful (Leissinger et al, 2001). If the patient is non-desmopressin responsive, then acute treatment and secondary prophylaxis using concentrates should Recommendations be considered. Hormonal management of menorrhagia • Factor VIII levels should be monitored regularly in all should also be considered, including use of the Mirena coil major and most minor surgical procedures (1B). The (Laffan et al, 2004). FVIII plasma concentration should be ≥1Á0 iu/ml to cover major surgery and sustained above 0Á5 iu/ml in Surgery including dentistry. Management of surgery in the postoperative period (1B). patients with VWD may be straightforward in those with • The VWF:RCo should be monitored in major surgical mild forms of the disease. However, type 3 and type 2 vari- procedures, particularly in the perioperative period ants may be extremely difficult to manage and there is no (grade C, level IV). The VWF:RCo should be maintained guarantee that haemostasis will be achieved even when above 0Á5 iu/ml in the perioperative period (1B). plasma concentrations have apparently been corrected into the normal range. In these patients, surgery should be carried out in a centre where experienced haematology and labora- Prophylactic therapy tory support is available and after careful consultation between responsible teams. Because most cases of VWD are relatively mild and patients Minor surgery including dental work using an inferior do not suffer from serious spontaneous bleeding, prophylaxis dental block in patients with type 1 disease or ‘low VWF’ is rarely indicated. Exceptions include patients with type 3 (and a minority of 2A and 2M) can often be carried out disease plus haemarthroses, severe epistaxis, women with using desmopressin with or without tranexamic acid. The menorrhagia, and those with VWD in conjunction with an level of VWF:RCo and FVIII required will vary with the par- on-going risk factor for bleeding, such as angiodysplasia. In ticular procedure but is likely to be satisfactory if >0Á5 iu/ml. 2006 an international survey reported that 74Á5% type 3, The response to desmopressin should be measured unless it 17Á6% type 2 and 7Á8% type 1 patients were receiving pro- is well known and also when repeated doses are given. The phylaxis (Berntorp et al, 2006). The most frequent indica- response to a second dose of desmopressin is, on average, tions were epistaxis/oral bleeding (23Á6%), gastrointestinal 30% lower than the first but tends not to fall further thereaf- (GI) bleeding (23Á6%), joint bleeding (21Á8%), and menor- ter (Mannucci et al, 1992b). Particular care is required when rhagia (7Á3%) (Berntorp et al, 2006). Prophylaxis was able to the endogenous VWF has a shortened half-life and in almost abolish joint bleeding but was less effective against patients with type 2N VWD. When desmopressin is contra- mucosal bleeding (50–60% reduction). A German cohort indicated or the response is inadequate, a VWF-FVIII con- study also reported that prophylaxis was almost completely centrate should be used. The recovery of both VWF and effective in abolishing bleeding (Halimeh et al, 2011). Typical FVIII is approximately 0Á02 iu/ml per iu/kg given. doses were 20–50 iu/kg VWF:RCo given 2–3 times per week. For major surgery in all types of VWD the VWF:RCo and In these studies a variety of VWF concentrates were used, FVIII should be corrected to ≥1Á0 iu/ml preoperatively with but notably, for prophylaxis, a FVIII-containing concentrate either desmopressin or concentrate(s). In the postoperative may not be necessary. There are no data to indicate the period, recent studies have shown efficacy by measuring and appropriate trough level of FVIII or VWF but analogy with maintaining VWF:RCo >0Á5 iu/ml for 6 d (Mannucci et al, experience in haemophilia seems appropriate. Prophylaxis 2013). However, maintaining FVIII >0Á5 iu/ml for 7–10 d beginning at age <5 years is reported to prevent arthropathy using a suitable VWF-FVIII concentrate has also proved (Berntorp et al, 2010).

460 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 167, 453–465 Guideline

Recommendations Tranexamic acid is not contraindicated during pregnancy or the puerperium; a limited quantity (c. 1%) may be • Prophylaxis should be considered for recurrent bleeding secreted in breast milk http://www.medicines.org.uk/emc/ in all types of VWD (1A). medicine/27753, although is unlikely to produce an antiﬁ- • In children with type 3 VWD, consider prophylaxis 2–3 brinolytic effect in the infant. times per week at 30–50 iu VWF:RCo/kg when joint Where a fetus is at risk of having signiﬁcantly reduced bleeding develops (as for haemophilia). (1A). plasma VWF activity levels, invasive monitoring procedures, • Intermediate purity FVIII-VWF or high purity VWF mid-cavity rotational forceps and Ventouse delivery should concentrates are both appropriate for prophylaxis (1B). be avoided with early recourse to Caesarean section. Admin- istration of intramuscular vitamin K therapy can be considered safe, unless the infant is at risk of type 3 VWD. Pregnancy

Levels of VWF and FVIII rise from early in the first tri- Recommendations mester of pregnancy and increase with gestational stage, • reaching two to three times those of the non-pregnant All women with type 2 and type 3 VWD, and women state at term. Levels start to fall soon after delivery, with type 1 VWD in whom VWF levels are unlikely to returning to non-pregnant values within a few weeks (Stir- normalize should be delivered in a obstetric unit with ling et al, 1984; Sanchez-Luceros et al, 2003; Mahieu et al, close collaboration between haematology, obstetric, 2007). anaesthetic and neonatal teams and access to 24-h moni- Women with VWD whose VWF activity does not rise to toring of FVIII-VWF (2C). • normal levels during pregnancy should be delivered in an The delivery of women with type 1 VWD can be man- Á obstetric unit that can easily and quickly access Haemophilia aged as normal when VWF:RCo activity is >0 5 iu/ml by – Centre and comprehensive neonatal care facilities. A plan for 34 36 weeks gestation (1C). • management of delivery and the puerperium should be Vaginal delivery or Caesarean section can be performed Á drawn up jointly between the obstetrician and Haemophilia when VWF:RCo activity is maintained >0 5 iu/ml and 3 9 Centre and agreed with the patient. The increase in VWF is platelet count maintained >50 10 /l (2C). • often sufficient to correct the VWF deficiency in women with Neuraxial anaesthesia is not recommended in women type 1 VWD, but not in qualitative or severe VWF deficiency with type 2 and type 3 VWD, or in women with type 1 (Walker et al, 1994; Lee et al, 2006). Pregnancy may exacer- VWD in whom plasma VWF levels have failed to nor- bate the thrombocytopenia and bleeding tendency in women malize (1B). • with type 2B VWD (Ranger et al, 2012). Intermediate or high purity VWF concentrates, desmo- Von Willebrand factor parameters should be checked at pressin and tranexamic acid can be used to support haemo- booking and at around 34 weeks gestation unless levels have stasis during pregnancy, delivery and the puerperium (1B). already been shown to have risen to normal. Neuraxial anaesthesia, vaginal delivery and Caesarean section can all be regarded as safe in type 1 when VWF:RCo >0Á5 iu/ml. In VWF inhibitors type 2 and 3 VWD, restoration of normal haemostasis is not Von Willebrand factor inhibitors have been described in reliably achievable even following replacement therapy. multi-transfused patients with type 3 VWD at a frequency of Therefore, neuraxial anaesthesia is not recommended for use 5–10% (James et al, 2013) but not in other VWD subgroups. in types 2 or 3 VWD irrespective of whether VWF activity Patients who develop inhibitors may present with loss of has been restored to apparently normal levels. Patients may response to VWF concentrate, sometimes with an associated require several days’ treatment, especially after Caesarean sec- anaphylactic reaction (Mannucci et al, 1987). tion. Even if VWF parameters are satisfactory at the time of Inhibitors to VWF cannot be reliably detected by either delivery, abnormal bleeding may ensue following discharge conventional mixing tests or ELISA-based assays (James et al, from hospital. It is important that women are made aware of 2013). Poor VWF recovery and/or rapid clearance after infu- this and advised to seek appropriate medical help should sion of VWF concentrate may therefore be the only indica- they develop persistent heavy postpartum bleeding. Throm- tion of an inhibitor. boprophylaxis may be given to patients with adequate cor- Treatment options for type 3 VWD patients with inhibi- rection of VWF parameters. tors include recombinant FVIII administered by continuous Desmopressin is safe both in pregnancy and at delivery intravenous infusion at very large doses sufficient to main- (Ray, 1998; Trigg et al, 2012) but should be avoided in pre- tain FVIII levels >0Á50 iu/ml (Mannucci et al, 1987), recom- eclampsia. Repeated administration should be avoided in binant activated FVII (rVIIa) (Ciavarella et al, 1996; view of the sensitivity of the fetus to the effects of hyponatra- Mannucci, 2001; Boadas et al, 2011), platelet transfusions emia. (James et al, 2013) and tranexamic acid. Patients with low-

ª 2014 John Wiley & Sons Ltd 461 British Journal of Haematology, 2014, 167, 453–465 Guideline level inhibitors may still respond to infusions of VWF-con- Disclaimer taining concentrate but anamnestic responses may be seen. A case of successful immune tolerance in a 9-year-old boy with While the advice and information in these guidelines is type 3 VWD and inhibitors has been described (Pergantou believed to be true and accurate at the time of going to et al, 2012). press, neither the authors, the UKHCDO, the British Society for Haematology nor the publishers accept any legal responsibility for the content of these guidelines. Recommendations • Traditional mixing studies are an unreliable method for Acknowledgements inhibitor screening in type 3 VWD and measurement of in vivo recovery and survival should be considered if an J.S.O’D is supported by a Science Foundation Ireland Princi- inhibitor is suspected (2A). pal Investigator Award (11/PI/1066). ACG is funded through • If there is no response to VWF concentrate or when the NIH Program Project Grant, Zimmerman Program anaphylaxis occurs, high dose rVIII infusion, rVIIa, for the Molecular and Clinical Biology of VWD study platelet transfusion and tranexamic acid should be con- (HL-081588). ML and CM acknowledge support from the sidered (2A). Imperial College BRC.

Author contributions Acquired von Willebrand syndrome (AVWS) All authors took an active role in drafting, reviewing and Acquired von Willebrand syndrome is the term used to approving the guideline in a series of round table meetings describe an acquired loss of VWF function. It can arise via a and subsequent correspondence. ML assembled the final wide range of mechanisms and should be suspected when a draft. patient’s current symptoms or laboratory results do not match their clinical history. The AVWS will respond to removal of the cause where this is possible, such as aortic Conflict of interests valve replacement, treatment of Wilms tumour or correction ML has received speaker fees from Bayer, Octapharma and of hypothyroidism. Paraproteins causing AVWS are not eas- Pfizer, advisory board fees from CSL-Behring, Pfizer, Bayer ily removed but AVWS associated with IgG paraproteins fre- and Grifols and research support from Bayer and CSL Beh- quently responds to intravenous immunoglobulin (Federici ring. WL has received speaker fees and travel support from et al, 1998). Other treatment options include VWF concen- CSL and advisory board fees from Octapharma. JSOD has trates, desmopressin, plasma exchange and immunoadsorp- served on the speakers bureau for Baxter, Bayer, Novo Nor- tion (Tiede et al, 2011). disk, Leo Pharma and Octapharma; served on the advisory boards of Baxter, Bayer, Octapharma and Pfizer and received Topics for audit research grant funding awards from Baxter, Bayer and Novo Nordisk. AW has no declarations of interest relating to this Registration for those patients who fulfil diagnostic criteria guideline. AG has received speaker fees from Octapharma for VWD. and VWF mutation database support from CSL Behring. Patient registrations with appropriate classification of type CMM has received research grant funding award and speaker entered. fees from CSL Behring, Pfizer and Baxter and served on advi- Proportion of eligible patients who have had test dose of sory boards for CSL and NovoNordisk. DMK has served on desmopressin administered. advisory boards for Baxter, CSL, Bayer, Pfizer and NovoNor- Proportion of desmopressin test doses that include a mea- disk. RCT has received speaker and/or consultancy fees from surement of fall-off at 4–6h. Baxter, Pfizer and Bayer. Proportion of patients registered with mild haemophilia who have had possible 2N VWD excluded.

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ª 2014 John Wiley & Sons Ltd 465 British Journal of Haematology, 2014, 167, 453–465 Haemophilia (2008), 14, 171–232 DOI: 10.1111/j.1365-2516.2007.01643.x

GUIDELINES von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)1

W. L. NICHOLS,* M. B. HULTIN, A. H. JAMES,à M. J. MANCO-JOHNSON,§ R. R. MONTGOMERY,– T. L. ORTEL,** M. E. RICK, J. E. SADLER,àà M. WEINSTEIN§§ and B. P. YAWN–– *Special Coagulation Laboratory, Division of Hematopathology, Department of Laboratory Medicine and Pathology, and Coagulation Clinic and Comprehensive Hemophilia Center, Division of Hematology and Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN; Department of Medicine, Stony Brook University, Stony Brook, NY; àDepartment of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC; §Department of Pediatrics, University of Colorado Denver, Aurora, CO, and Center for Cancer and Blood Disorders, Children’s Hospital of Denver, Denver,CO; –Blood Research Institute, BloodCenter of Wisconsin, and Section of Pediatric Hematology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI; **Division of Hematology, Department of Medicine, and Clinical Coagulation Laboratory, Department of Pathology, Duke University Medical Center, Durham, NC; Hematology Service, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD; ààDepartment of Medicine, Washington University, St. Louis, MO; §§Ofﬁce of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Rockville, MD; and ––Department of Research, Olmsted Medical Center, Rochester, MN, and Department of Family and Community Medicine, University of Minnesota, Minneapolis, MN, USA

Summary. von Willebrand disease (VWD) is a com- understanding them is important for proper diagno- monly encountered inherited bleeding disorder sis and management of patients with VWD. These affecting both males and females, causing mucous evidence-based guidelines for diagnosis and manage- membrane and skin bleeding symptoms, and bleed- ment of VWD from the National Heart, Lung, and ing with surgical or other haemostatic challenges. Blood Institute (NHLBI) Expert Panel (USA) review VWD may be disproportionately symptomatic in relevant publications, summarize current under- women of child-bearing age. It may also occur less standing of VWD pathophysiology and classification, frequently as an acquired disorder (acquired von and present consensus diagnostic and management Willebrand syndrome). VWD is caused by deficiency recommendations based on analysis of the literature or dysfunction of von Willebrand factor (VWF), and expert opinion. They also suggest an approach a plasma protein that mediates platelet haemostatic for clinical and laboratory evaluation of individuals function and stabilizes blood coagulation factor VIII. with bleeding symptoms, history of bleeding or The pathophysiology, classification, diagnosis and conditions associated with increased bleeding risk. management of VWD are relatively complex, but This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective 1From The Diagnosis, Evaluation and Management of von Wille- information about bleeding symptoms, advance- brand Disease, National Heart, Lung, and Blood Institute, National ments in diagnostic and therapeutic tools, and Institutes of Health (GPO #08-5832), which is available at http:// enhancement in the education and training of clini- www.nhlbi.nih.gov/guidelines/vwd and from the NHLBI Health Information Center, Bethesda, MD (telephone no. 301-592-8573). cians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi. Correspondence: William L. Nichols, MD, Hilton 200 SCL, Mayo nih.gov/guidelines/vwd) has a more detailed docu- Clinic, 200 First Street SW, Rochester, MN 55905, USA. e-mail: [email protected] ment, a synopsis of these recommendations, and patient education information. Accepted 7 October 2007

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd 171 172 W. L. NICHOLS et al.

Keywords: acquired von Willebrand syndrome, menorrhagia, platelet disorder, von Willebrand bleeding disorder, clotting factor concentrate, coag- disease, von Willebrand factor ulation factor VIII, desmopressin, haemorrhage,

needed are better knowledge of and treatment Introduction options for management of VWD and bleeding or von Willebrand disease (VWD) is an inherited bleeding risk. As documented in this VWD guidelines bleeding disorder that is caused by deﬁciency or publication, published studies are lacking to support dysfunction of von Willebrand factor (VWF), some of the recommendations that, therefore, are a plasma protein that mediates the initial adhesion based mainly on Expert Panel opinion. of platelets at sites of vascular injury and also binds Guidelines for VWD diagnosis and management, and stabilizes blood clotting factor VIII (FVIII) in the based on the evidence from published studies, the circulation. Therefore, defects in VWF can cause opinions of experts, or both, have been published for bleeding by impairing platelet adhesion or by reduc- practitioners in Canada [6], Italy [7] and the United ing the concentration of FVIII. Kingdom [8,9], but not in the United States. The VWD is a relatively common cause of bleeding, VWD guidelines from the US Expert Panel are based but the prevalence varies considerably among on review of published evidence as well as expert studies and depends strongly on the case deﬁnition opinion. Users of these guidelines should be aware that is used. VWD prevalence has been estimated that individual professional judgment is not abro- in several countries on the basis of the number of gated by recommendations in these guidelines. symptomatic patients seen at haemostasis centres, These guidelines for diagnosis and management and the values range from roughly 23 to 110 per of VWD were developed for practicing primary million population (0.0023–0.01%) [1]. care and specialist clinicians — including family The prevalence of VWD has also been estimated physicians, internists, obstetrician–gynaecologists, by screening populations to identify persons with paediatricians, and nurse practitioners — as well as bleeding symptoms, low VWF levels, and similarly haematologists and laboratory medicine specialists. affected family members. This population-based The National Heart, Lung, and Blood Institute approach has yielded estimates for VWD prevalence (NHLBI) Web site [10] has a synopsis of these of 0.6% [2], 0.8% [3] and 1.3% [4] – more than two recommendations, patient education information, orders of magnitude higher than the values arrived at and a more detailed document that includes addi- by surveys of haemostasis centres. tional background information. Also on the Web site The discrepancies between the methods for esti- are 13 evidence tables that summarize published mating VWD prevalence illustrate the need for better information supporting recommendations that are information concerning the relationship between graded as B or higher and have two or more VWF levels and bleeding. Many bleeding symptoms references. are exacerbated by defects in VWF, but the magnitude of the effect is not known. For example, Project history and methods approximately 12% of women who have menstrual periods have excessive menstrual bleeding [5]. This During spring 2004, the NHLBI began planning for fraction is much higher among women with VWD, the development of clinical practice guidelines for but it also appears to be increased for women who VWD. In consultation with the American Society of have VWF levels at the lower end of the normal Hematology, the institute convened an Expert Panel range. Quantitative data on these issues would allow on VWD, chaired by William L. Nichols MD. The a more informed approach to the diagnosis and Expert Panel members were selected to provide management of VWD and could have important expertise in basic sciences, clinical and laboratory implications for medical practice and for public diagnosis, evidence-based medicine, and the clinical health. management of VWD, including specialists in In addition to the need for better information haematology as well as family medicine, obstetrics about VWD prevalence and the relationship of low and gynaecology, paediatrics, internal medicine and VWF levels to bleeding symptoms or risk, there are laboratory sciences. The Expert Panel comprised one needs for enhancing knowledge and improving clin- basic scientist and nine physicians — including one ical and laboratory diagnostic tools for VWD. Also family physician, one obstetrician–gynaecologist and

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 173 seven haematologists with expertise in VWD (two 1 date restriction: 1990–2004; were paediatric haematologists). Ad hoc members of 2 language: English; and the Panel represented the Division of Blood Diseases 3 study/publication types: randomized-controlled and Resources of the NHLBI. The Panel was trial; meta-analysis; controlled clinical trial; epi- coordinated by the Office of Prevention, Education, demiological studies; prospective studies; multi- and Control of the NHLBI. Panel members disclosed, centre study; clinical trial; evaluation studies; verbally and in writing, any financial conflicts. practice guideline; review, academic; review, mul- Barbara M. Alving MD, then acting director of the ticase; technical report; validation studies; review NHLBI, gave the charge to the Expert Panel to of reported cases; case reports; journal article (to examine the current science in the area of VWD and exclude letters, editorials, news, etc.). to come to consensus regarding clinical recommen- The search strategies were constructed and exe- dations for diagnosis, treatment and management of cuted in the MEDLINE database as well as in the this common inherited bleeding disorder. The Panel Cochrane Database of Systematic Reviews to com- was also charged to base each recommendation on pile a set of citations and abstracts for each section. current science and to indicate the strength of the Initial searches on specific key word combinations relevant literature for each recommendation. and date and language limits were further refined by The development of this report was funded using the publication type limits to produce results entirely by the NHLBI, National Institutes of that more closely matched the section outlines. Once Health (NIH). Panel members and reviewers partic- the section results were compiled, the results were ipated as volunteers and were compensated only for put in priority order by study type as follows: travel expenses related to three in-person Expert 1 randomized-controlled trial; Panel meetings. 2 meta-analysis (quantitative summary combin- After the Expert Panel finalized a basic outline for ing results of independent studies); the guidelines, members were assigned to the three 3 controlled clinical trial; main sections: (i) Introduction and Background, (ii) 4 multicentre study; Diagnosis and Evaluation, and (iii) Management of 5 clinical trial (includes all types and phases of VWD. Three members were assigned lead responsi- clinical trials); bility for each section. The section groups were 6 evaluation studies; responsible for developing detailed outlines for the 7 practice guideline (for specific healthcare guide- sections, reviewing the pertinent literature, writing lines); the sections and drafting recommendations with the 8 epidemiological studies; supporting evidence for the full Panel to review. 9 prospective studies; After internal NHLBI/NIH review of the draft 10 review, academic (comprehensive, critical, or document, it was posted on the NHLBI Web site for analytical review); public review and comments. The draft was then 11 review, multicase (review with epidemiologi- revised by the Expert Panel in response to external cal applications); review comments. The final document underwent 12 technical report; NHLBI/NIH review before posting on the NHLBI 13 validation studies; Web site as well as finalization of a modified version 14 review of reported cases (review of known for scientific journal publication. cases of a disease); and 15 case reports. On examination of the yield of the initial liter- Literature searches ature search, it was determined that important areas Three section outlines, approved by the Expert in the section outlines were not addressed by the Panel chair, were used as the basis for compiling citations, possibly because of the date delimiters. In relevant search terms, using the Medical Subject addition, Panel members identified pertinent refer- Headings (MeSH terms) of the MEDLINE data- ences from their own searches and databases, base. If appropriate terms were not available in including landmark references predating the 1990 MeSH, then relevant non-MeSH key words were date restriction, and 2005 and 2006 references (to used. In addition to the search terms, inclusion and October 2006). Therefore, additional follow-up exclusion criteria were defined on the basis of database searching was done using the same search feedback from the Panel about specific limits to strategies from the initial round, but covering dates include in the search strategies, specifically the before 1990 and during 2005 and 2006 to double- following: check for key studies appearing in the literature

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 174 W. L. NICHOLS et al. outside the limits of the original range of dates. Scientific overview Also, refined searches in the 1990–2006 date range were conducted to analyse the references used by Discovery and identification of VWD/VWF Panel members that had not appeared in the original search results. These revised searches The patient who led to the discovery of a hereditary helped round out the database search to provide bleeding disorder that we now call Ôvon Willebrand the most comprehensive approach possible. As a diseaseÕ was a 5-year-old girl who lived on the A˚ land result, the references used in the guidelines included Islands and was brought to Deaconess Hospital in those retrieved from the two literature searches Helsinki, Finland, in 1924 to be seen by Dr Erik von combined with the references suggested by the Panel Willebrand [11]. He ultimately assessed 66 members members. These references inform the guidelines of her family and reported in 1926 that this was a and clinical recommendations, on the basis of the previously undescribed bleeding disorder that dif- best available evidence in combination with the fered from haemophilia and exhibited (i) mucocuta- PanelÕs expertise and consensus. neous bleeding, (ii) autosomal inheritance rather than being linked to the X chromosome, (iii) prolonged bleeding times (BT) by the Duke method Clinical recommendations – grading and levels of (earlobe BT) and (iv) normal clotting time. Not only evidence did he recognize the autosomal inheritance pattern, Recommendations made in this document are he also recognized that bleeding symptoms were based on the levels of evidence described in greater in children and in women of child-bearing Table 1, with a priority grading system of A, B age. He subsequently found that blood transfusions or C. Grade A is reserved for recommendations were useful not only to correct the anaemia, but also based on evidence levels Ia and Ib. Grade B is to control bleeding. given for recommendations having evidence levels In the 1950s, it became clear that a Ôplasma factorÕ, of IIa, IIb and III. Grade C is for recommendations antihaemophilic factor (factor VIII [FVIII]), was based on evidence level IV [8]. None of the decreased in these persons and that Cohn fraction recommendations merited a grade of A. Evidence I-0 could correct both the plasma deficiency of FVIII tables are available on the NHLBI Web site for and the prolonged BT. For the first time, the factor those recommendations graded as B with two or causing the long BT was called Ôvon Willebrand more references [10]. factorÕ. As cryoprecipitate and commercial FVIII concentrates were developed, it was recognized that both VWF and antihaemophilic factor (FVIII) purified together. When immunoassays were developed, persons who Table 1. Levels of evidence. had VWD (in contrast to those who had haemophilia Level Type of evidence A) were found to have reduced factor VIII-related Ia Evidence obtained from meta-analysis of antigen (FVIIIR:Ag), which we now refer to as von randomized-controlled trials Willebrand factor antigen (VWF:Ag). Characteriza- Ib Evidence obtained from at least one tion of the proteins revealed that FVIII was the randomized-controlled trial clotting protein deficient in haemophilia A, and VWF IIa Evidence obtained from at least one well-designed was a separate FVIII carrier protein that resulted in controlled study without randomization IIb Evidence obtained from at least one other type of the cofractionation of both proteins in commercial well-designed quasi-experimental study concentrates. Furthermore, a deficiency of VWF III Evidence obtained from well-designed non-experimental resulted in increased FVIII clearance because of the descriptive studies, such as comparative studies, reduced carrier protein, VWF. correlation studies and case–control studies Since the 1980s, molecular and cellular studies IV Evidence obtained from expert committee reports or have defined haemophilia A and VWD more pre- opinions and/or clinical experiences of respected cisely. Persons who had VWD had a normal FVIII authorities gene on the X chromosome, but some were found to From Agency for Health Care Policy and Research. Acute pain have an abnormal VWF gene on chromosome 12. management: operative or medical procedures and trauma. AHCPR Archived Clinical Practice Guidelines [Monograph on the Variant forms of VWF were recognized in the 1970s, Internet]. Rockville, MD: Agency for Health Care Policy and and these variations are now recognized as the result Research. Available at: http://www.ncbi.nlm.nih.gov/books/bv. of synthesis of an abnormal protein. Gene sequenc- fcgi?rid=hstat6.chapter.8991 ing identified many of these persons as having a VWF

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Table 2. Synopsis of VWF designations, properties and assays. Designation Property Assay VWF Multimeric glycoprotein that promotes platelet See specific VWF assays below adhesion and aggregation and is a carrier for FVIII in plasma VWF:RCo Binding activity of VWF that causes binding of VWF to Ristocetin cofactor activity: quantitates platelet platelets in the presence of ristocetin with consequent agglutination after addition of ristocetin and VWF agglutination VWF:Ag VWF protein as measured by protein assays; does not Immunological assays such as ELISA, LIA, RIA, Laurell imply functional ability electroimmunoassay VWF:CB Ability of VWF to bind to collagen Collagen-binding activity: quantitates binding of VWF to collagen-coated ELISA plates VWF multimers Size distribution of VWF multimers as assessed by VWF multimer assay: electrophoresis in agarose gel and agarose gel electrophoresis visualization by monospecific antibody to VWF FVIII Circulating coagulation protein that is protected FVIII activity: plasma clotting test based on PTT assay from clearance by VWF and is important in thrombin using FVIII-deficient substrate; quantitates activity generation RIPA Test that measures the ability of a personÕs VWF to bind RIPA: aggregation of a personÕs PRP to various to platelets in the presence of various concentrations concentrations of ristocetin of ristocetin ELISA, enzyme-linked immunosorbent assay; FVIII, factor VIII; LIA, latex immunoassay (automated); PRP, platelet-rich plasma; PTT, activated partial thromboplastin time; RIA, radioimmunoassay; RIPA, ristocetin-induced platelet aggregation; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen-binding activity; VWF:RCo, von Willebrand factor ristocetin cofactor activity. gene mutation. The genetic causes of milder forms of ing into storage granules. The latter two processes low VWF are still under investigation, and these are under the control of the VWF propeptide forms may not always be caused by an abnormal (VWFpp), which is cleaved from VWF at the time VWF gene. In addition, acquired disorders may of storage. VWF that is released acutely into the result in reduced or dysfunctional VWF (discussed circulation is accompanied by a parallel rise in FVIII, in a later section, Acquired von Willebrand Syn- but it is still not entirely clear whether this protein– drome). Table 2 summarizes VWF designations, protein association first occurs within the endothelial functions and assays. Table 3 lists and defines cell [12,13]. abbreviations used in the text of this document. In plasma, the FVIII–VWF complex circulates as a loosely coiled protein complex that does not interact strongly with platelets or endothelial cells under The VWF protein and its functions in vivo basal conditions. When vascular injury occurs, VWF VWF is synthesized in two cell types. In the vascular becomes tethered to the exposed subendothelium endothelium, VWF is synthesized and subsequently (collagen, etc.). The high fluid shear rates that occur stored in secretory granules (Weibel-Palade bodies) in the microcirculation appear to induce a confor- from which it can be released by stress or drugs such mational change in multimeric VWF that causes as desmopressin (1-desamino-8-D-arginine, DDAVP; platelets to adhere, become activated, and then Sanofi-Aventis US, Bridgewater, NJ, USA), a syn- aggregate so as to present an activated platelet thetic analogue of vasopressin. VWF is also synthe- phospholipid surface. This facilitates clotting that is sized in bone marrow megakaryocytes where it is regulated in part by FVIII. Because of the specific stored in platelet alpha-granules from which it is characteristics of haemostasis and fibrinolysis on released after platelet activation. Desmopressin does mucosal surfaces, symptoms in VWD are often not release platelet VWF. greater in these tissues. VWF is a protein that is assembled from identical Plasma VWF is primarily derived from endothelial subunits into linear strings of varying size referred to synthesis. Platelet and endothelial cell VWF are as multimers. These multimers can be larger than released locally after cellular activation where this 20 million daltons in mass and more than 2 lm long. VWF participates in the developing haemostatic plug The complex cellular processing consists of dimer- or thrombus (Fig. 1). ization in the endoplasmic reticulum, glycosylation Plasma VWF has a half-life of approximately 12 h in the endoplasmic reticulum and Golgi complex, (range: 9–15). VWF is present as very large multi- multimerization in the Golgi complex, and packag- mers that are subjected to physiological degradation

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Table 3. Nomenclature and abbreviations*. bocytopenic purpura (TTP). The most common Designation Definition variant forms of type 2A VWD are characterized ADAMTS13 A Disintegrin-like And Metalloprotease domain by increased VWF susceptibility to ADAMTS13. (reprolysin type) with ThromboSpondin type 1 motif, member 13: a plasma Factors affecting VWF levels Factors that affect levels metalloprotease that cleaves multimeric VWF of plasma VWF include age, race, ABO and Lewis AVWS Acquired von Willebrand (disease) syndrome blood groups, epinephrine, inflammatory mediators, BT Bleeding time and endocrine hormones (particularly those associ- CBC Complete blood cell count ated with the menstrual cycle and pregnancy). VWF CV Coefficient of variation D&C Dilation and curettage is increased during pregnancy (a three- to fivefold DDAVP 1-Desamino-8-d-arginine; desmopressin elevation over a womanÕs baseline by the third DVT Deep vein thrombosis trimester) with ageing and with acute stress or ELISA Enzyme-linked immunosorbent assay inflammation. Africans and African-Americans have FDA Food and Drug Administration higher average levels of VWF than the White or

FVIII [Blood clotting] factor VIII caucasian populations [14,15]. VWF is reduced by

FVIIIR:Ag Factor VIII-related antigen (see VWF:Ag) hypothyroidism and rarely by autoantibodies to GPIb Glycoprotein Ib (platelet) VWF. The rate of VWF synthesis probably is not IGIV Immune globulin intravenous (also known as IVIG) affected by blood group; however, the survival of ISTH International Society on Thrombosis VWF appears to be reduced in individuals who have and Haemostasis type O blood. In fact, ABO blood group substance IU International Unit has been identified on VWF. i.v. intravenous(ly) LIA Latex immunoassay (automated) MeSH Medical Subject Headings (in MEDLINE) The genetics of VWD MGUS Monoclonal gammopathy of uncertain significance Since the 1980s, molecular and cellular studies have NHLBI National Heart, Lung, and Blood Institute defined haemophilia A and VWD more precisely. NIH National Institutes of Health Persons with severe VWD have a normal FVIII gene NSAID Non-steroidal anti-inflammatory drug on the X chromosome, and some are found to have PCR Polymerase chain reaction an abnormal VWF gene on chromosome 12. The PFA-100 Platelet function analyzer VWF gene is located near the tip of the short arm of PLT-VWD Platelet-type von Willebrand disease PTT Partial thromboplastin time (activated partial chromosome 12, at 12p13.3 [16]. It spans approx- thromboplastin time) imately 178 kb of DNA and contains 52 exons [17]. RIPA Ristocetin-induced platelet aggregation Intron–exon boundaries tend to delimit structural s.c. subcutaneous(ly) domains in the protein, and introns often occur at TTP Thrombotic thrombocytopenic purpura similar positions within the gene segments that tPA Tissue plasminogen activator encode homologous domains. Thus, the structure of VWD von Willebrand disease the VWF gene reflects the mosaic nature of the VWF von Willebrand factor (FVIII carrier protein) VWF:Ag von Willebrand factor antigen protein (Fig. 2). VWF:CB von Willebrand factor collagen-binding activity A partial, unprocessed VWF pseudogene is located VWF:FVIIIB von Willebrand factor: factor VIII-binding assay at chromosome 22q11.2 [18]. This pseudogene spans VWF:PB assay von Willebrand factor platelet-binding assay approximately 25 kb of DNA and corresponds to VWFpp von Willebrand factor propeptide exons 23–34 and part of the adjacent introns of the

VWF:RCo von Willebrand factor ristocetin cofactor activity VWF gene [19]. This segment of the gene encodes WHO World Health Organization domains A1A2A3, which contain binding sites for *Abbreviations listed appear in the text. Abbreviations in the platelet glycoprotein Ib (GPIb) and collagen, as well tables are expanded in each tableÕs footnotes. as the site cleaved by ADAMTS13. The VWF These abbreviations (for FVIII and VWF and all their properties) pseudogene and gene have diverged 3.1% in DNA are deﬁned in Marder et al. [397] and Mazurier and Rodeghiero [398]. sequence, consistent with a relatively recent origin of the pseudogene by partial gene duplication [19]. This by the metalloprotease ADAMTS13 [A Disintegrin- pseudogene is found in humans and great apes like And Metalloprotease domain (reprolysin type) (bonobo, chimpanzee, gorilla and orangutan) but with ThromboSpondin type 1 motif, member 13]. not in more distantly related primates [20]. The VWF Deﬁciency of ADAMTS13 is associated with the pseudogene complicates the detection of VWF gene pathological microangiopathy of thrombotic throm- mutations because polymerase chain reactions

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Fig. 1. von Willebrand factor (VWF) and normal haemostasis. A blood vessel cross-section shows stages of normal haemostasis. Top, VWF is the carrier protein for blood clotting factor VIII (FVIII). Under normal conditions VWF does not interact with platelets or the blood vessel wall that is covered with endothelial cells. Middle left, After vascular injury, VWF adheres to the exposed subendothelial matrix. Middle right, After VWF is uncoiled by local shear forces, platelets adhere to the altered VWF, and these platelets undergo activation and recruit other platelets to this injury site. Bottom left, The activated and aggregated platelets alter their membrane phospholipids exposing phosphatidylserine, and this activated platelet surface binds clotting factors from circulating blood and initiates blood clotting on this surface where fibrin is locally deposited. Bottom right, The combination of clotting and platelet aggregation and adhesion forms a platelet- fibrin plug, which results in the cessation of bleeding. The extent of the clotting is carefully regulated by natural anticoagulants. Subse- quently, thrombolysis initiates tissue repair, and ultimately the vessel may be re-endothelialized and blood flow maintained. (Courtesy of R. R. Montgomery, the BloodCenter of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin; used with permission).

Fig. 2. Structure and domains of von Willebrand factor (VWF). The VWF protein sequence [amino acid (aa) 1–2813] is aligned with the cDNA sequence (nucleic acid 1–8439). The VWF signal peptide is the first 22 aa, the propeptide (VWFpp) is aa 23–763 and mature VWF is aa 764–2800. Type 2 mutations are primarily located in specific domains (regions) along the VWF protein. Types 2A, 2B and 2M VWF mutations are primarily located within exon 28 that encodes for the A1 and A2 domains of VWF. The two different types of 2A are those that have increased proteolysis (2A2) and those with abnormal multimer synthesis (2A1). Type 2N mutations are located within the D¢ and D3 domains. Ligands that bind to certain VWF domains are identified, including factor VIII (FVIII), heparin, platelet glycoprotein Ib complex (GPIb), collagen and platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) that binds to the RGD (arginine-glycine-aspartate) amino acid sequence in VWF. (Courtesy of R. R. Montgomery, the BloodCenter of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin; used with permission.)

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(PCRs) can inadvertently amplify segments from Table 4. Classification of von Willebrand disease*. either or both loci, but this difficulty can be Type Description overcome by careful design of gene-specific PCR 1 Partial quantitative deficiency of VWF primers [19]. 2 Qualitative VWF defect The VWF pseudogene may occasionally serve as a 2A Decreased VWF-dependent platelet adhesion with reservoir of mutations that can be introduced into selective deficiency of high-molecular-weight the VWF locus. For example, some silent and some multimers potentially pathogenic mutations have been identi- 2B Increased affinity for platelet GPIb fied in exons 27 and 28 of the VWF gene of persons 2M Decreased VWF-dependent platelet adhesion without selective deficiency of high-molecular-weight who have VWD. These same sequence variations multimers occur consecutively in the VWF pseudogene and 2N Markedly decreased binding affinity for FVIII might have been transferred to the VWF by gene 3 Virtually complete deficiency of VWF conversion [21–23]. The segments involved in the FVIII, factor VIII; GPIb, glycoprotein Ib (platelet); VWF, von potential gene conversion events are relatively short, Willebrand factor. from a minimum of seven nucleotides [21] to a *Disease types are defined as described in Sadler et al. [27]. maximum of 385 nucleotides [23]. The frequency of these potential interchromosomal exchanges is testing procedures, although most of the VWD unknown. subtypes could be assigned by using tests that were The spectrum of VWF gene mutations that cause widely available. The 1994 classification reserved the VWD is similar to that of many other human genetic designation of VWD for disorders caused by muta- diseases and includes large deletions, frameshifts tions within the VWF gene [28], but this criterion has from small insertions or deletions, splice-site muta- been dropped from the 2006 classification [27] tions, nonsense mutations causing premature termi- because, in practice, it is verifiable for only a small nation of translation, and missense mutations fraction of patients. affecting single amino acid residues. A database of VWD is classified into three major categories: VWF mutations and polymorphisms has been com- partial quantitative deficiency (type 1), qualitative piled for the International Society on Thrombosis deficiency (type 2) and total deficiency (type 3). Type and Haemostasis (ISTH) [24,25] and is maintained 2 VWD is divided further into four variants (2A, 2B, for online access at the University of Sheffield [26]. 2M and 2N) on the basis of details of the phenotype. Mutations causing VWD have been identified Before publication of the 1994 revised classification throughout the VWF gene. In contrast to haemo- of VWD [28], VWD subtypes were classified using philia A, in which a single major gene rearrangement roman numerals (types I, II, and III), generally causes a large fraction of severe disease, no such corresponding to types 1, 2 and 3 in the 1994 recurring mutation is common in VWD. There is a classification, and within type II several subtypes good correlation between the location of mutations existed (designated by adding sequential letters of the in the VWF gene and the subtype of VWD, as alphabet, i.e. II-A through II-I). Most of the latter discussed in more detail in the next section, Classi- VWD variants were amalgamated as type 2A in the fication of VWD Subtypes. In selected families, this 1994 classification, with the exception of type 2B information can facilitate the search for VWF muta- (formerly II-B), for which a separate new classifica- tions by DNA sequencing. tion was created. In addition, a new subtype (2M, with ÔMÕ representing ÔmultimerÕ) was created to include variants with decreased platelet-dependent Classification of VWD subtypes function [VWF ristocetin cofactor activity VWD is classified on the basis of criteria developed (VWF:RCo)] but no significant decrease of higher by the VWF Subcommittee of the ISTH, first molecular weight VWF multimers (which may or published in 1994 and revised in 2006 (Table 4) may not have other aberrant structure). Subtype 2N [27,28]. VWD was defined, with ÔNÕ representing ÔNor- The classification was intended to be clinically mandyÕ, where the first individuals were identified, relevant to the treatment of VWD. Diagnostic with decreased FVIII because of VWF defects of categories were defined that encompassed distinct FVIII binding. pathophysiological mechanisms and correlated with Type 1 VWD affects approximately 75% of the response to treatment with desmopressin or symptomatic persons who have VWD (see Castaman blood products. The classification was designed to et al. [29] for a review). Almost all the remaining be conceptually independent of specific laboratory persons are divided among the four type 2 variants,

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Table 5. Inheritance, prevalence and bleeding propensity in patients with von Willebrand disease. Type Inheritance Prevalence Bleeding propensity 1 Autosomal dominant Up to 1% Mild to moderate 2A Autosomal dominant (or recessive) Uncommon Variable, usually moderate 2B Autosomal dominant Uncommon Variable, usually moderate 2M Autosomal dominant (or recessive) Uncommon Variable, usually moderate 2N Autosomal recessive Uncommon Variable, usually moderate 3 (severe) Autosomal recessive Rare (1:250 000–1:1 000 000) High (severe bleeding) and the partitioning among them varies considerably associated with rapid clearance has been reported in among centres. In France, for example, patientsÕ domain D4 [40]. distribution has been reported to be 30% type 2A, Increased clearance of VWF from the circulation in 28% type 2B, 8% type 2M (or unclassified) and 34% type 1 VWD may account for the exaggerated but type 2N [30]. In Bonn, Germany, the distribution has unexpectedly brief responses to desmopressin been reported to be 74% type 2A, 10% type 2B, observed in some patients. Consequently, better data 13% type 2M and 3.5% type 2N [31]. Table 5 on the prevalence of increased clearance could affect summarizes information about inheritance, preva- the approach to diagnosing type 1 VWD and the lence and bleeding propensity in persons who have choice of treatment for bleeding. different types of VWD. A diagnosis of type 1 VWD is harder to establish The prevalence of type 3 VWD in the population is when the VWF level is not markedly low but instead not known precisely but has been estimated (per is near the lower end of the normal range. Type 1 million population) as 0.55 for Italy [32], 1.38 for VWD lacks a qualitative criterion by which it can be North America [33], 3.12 for Sweden [32] and 3.2 recognized and instead relies only on quantitative for Israel [34]. The prevalence may be as high as 6 decrements of protein concentration and function. per million where consanguinity is common [1]. VWF levels in the healthy population span a wide range of values. The mean level of plasma VWF is ) Type 1 VWD Type 1 VWD is found in persons who 100 IU dL 1, and approximately 95% of plasma ) have partial quantitative deficiency of VWF. The VWF levels lie between 50 and 200 IU dL 1 [45,46]. level of VWF in plasma is low, and the remaining Because mild bleeding symptoms are common in the VWF mediates platelet adhesion normally and binds healthy population, the association of bleeding FVIII normally. Laboratory evaluation shows con- symptoms with a moderately low VWF level may cordant decreases in VWF protein concentration be coincidental [47]. The conceptual and practical (VWF:Ag) and assays of VWF function (VWF:RCo). issues associated with the evaluation of moderately Levels of blood clotting FVIII usually parallel VWF low VWF levels are discussed more completely later and may be reduced secondary to reduced VWF. in this section. (See section Type 1 VWD vs. Low Usually, in type 1 VWD, the FVIII/VWF:Ag ratio is VWF: VWF Level as a Risk Factor for Bleeding.) 1.5–2.0. In most persons with type 1 VWD, this results in normal or mildly decreased FVIII, not Type 2 VWD The clinical features of several type 2 reduced as much as the VWF. VWF multimer gels VWD variants are distinct from those of type 1 show no significant decrease in large VWF multimers VWD, and they can have strikingly distinct and [28]. The laboratory evaluation of VWD is discussed specific therapeutic needs. As a consequence, the in the Diagnosis and Evaluation section. medical care of patients with type 2 VWD benefits The spectrum of mutations occurring in VWD type from the participation of a haematologist who has 1 has been described extensively in two major studies expertise in haemostasis. Bleeding symptoms in type [35,36]. Particularly severe, highly penetrant forms 2 VWD are often thought to be more severe than of type 1 VWD may be caused by dominant VWF those in type 1 VWD, although this impression needs mutations that interfere with the intracellular trans- to be evaluated in suitable clinical studies. port of dimeric proVWF [37–41] or that promote the Type 2A VWD. Type 2A VWD refers to qualita- rapid clearance of VWF from the circulation tive variants in which VWF-dependent platelet [40,42,43]. Persons who have such mutations usually adhesion is decreased because the proportion of ) have plasma VWF levels <20 IU dL 1 (International large VWF multimers is decreased. Levels of Units per deciliter) [35,36]. Most of the mutations VWF:Ag and FVIII may be normal or modestly characterized to date cause single amino acid substi- decreased, but VWF function is abnormal, as shown tutions in domain D3 [37–39,41,44]. One mutation by markedly decreased VWF:RCo [48]. Type 2A

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VWD may be caused by mutations that interfere with binding, which leads to the proteolytic degradation the assembly or secretion of large multimers or by and depletion of large, functional VWF multimers mutations that increase the susceptibility of VWF [58,60]. Circulating platelets are also coated with multimers to proteolytic degradation in the circula- mutant VWF, which may prevent the platelets from tion [49–51]. The deficit of large multimers predis- adhering at sites of injury [61]. poses persons to bleed. Although laboratory results for type 2B VWD The location of type 2A VWD mutations some- may be similar to those in type 2A or type 2M times can be inferred from high-resolution VWF VWD, patients with type 2B VWD typically have multimer gels. For example, mutations that primar- thrombocytopenia that is exacerbated by surgery, ily reduce multimer assembly lead to the secretion pregnancy or other stress [62–64]. The thrombocy- of multimers that are too small to engage platelets topenia probably is caused by reversible sequestra- effectively and therefore are relatively resistant to tion of VWF-platelet aggregates in the proteolysis by ADAMTS13. Homozygous mutations microcirculation. These aggregates are dissolved by in the propeptide impair multimer assembly in the the action of ADAMTS13 on VWF, causing the Golgi complex and give rise to a characteristic characteristic decrease of large VWF multimers and ÔcleanÕ pattern of small multimers that lack the the prominent satellite banding pattern that indi- satellite bands usually associated with proteolysis cates increased proteolytic degradation [65,66]. The (see Diagnosis and Evaluation section); this pattern diagnosis of type 2B VWD depends on finding was initially described as Ôtype IICÕ VWD [52–54]. abnormally increased ristocetin-induced platelet Heterozygous mutations in the cystine knot domain aggregation (RIPA) at low concentrations of can impair dimerization of proVWF in the endo- ristocetin. plasmic reticulum and cause a recognizable multi- Type 2B VWD mutations occur within or adjacent mer pattern originally referred to as Ôtype IIDÕ to VWF domain A1 [24,57,67–70], which changes [55,56]. A mixture of monomers and dimers arrives conformation when it binds to platelet GPIb [71]. in the Golgi complex, where the incorporation of The mutations appear to enhance platelet binding by monomers at the end of a multimer prevents further stabilizing the bound conformation of domain A1. elongation. As a result, the secreted small multimers Type 2M VWD. Type 2M VWD includes variants contain minor species with an odd number of subunits with decreased VWF-dependent platelet adhesion that appear as faint bands between the usual species that is not caused by the absence of high-molecular- that contain an even number of subunits. Hetero- weight VWF multimers. Instead, type 2M VWD zygous mutations in cysteine residues of the D3 mutations reduce the interaction of VWF with domain can also impair multimer assembly, but these platelet GPIb or with connective tissue and do not mutations often also produce an indistinct or ÔsmearyÕ substantially impair multimer assembly. Screening multimer pattern referred to as Ôtype IIEÕ [57,58]. laboratory results in type 2M VWD and type 2A In contrast to mutations that primarily affect VWD are similar, and the distinction between them multimer assembly, mutations within or near the depends on multimer gel electrophoresis [69]. A2 domain of VWF cause type 2A VWD, which is Mutations in type 2M VWD have been identified associated with markedly increased proteolysis of the in domain A1 (Fig. 2), where they interfere with VWF subunits [58] (Fig. 2). These mutations appar- binding to platelet GPIb [24,57,69,72–74]. One ently interfere with the folding of the A2 domain and family has been reported in which a mutation in make the Tyr1605–Met1606 bond accessible to VWF domain A3 reduces VWF binding to collagen, ADAMTS13 even in the absence of increased fluid thereby reducing platelet adhesion and possibly shear stress. Two subgroups of this pattern have been causing type 2M VWD [75]. distinguished: group I mutations enhance proteolysis Type 2N VWD. Type 2N VWD is caused by VWF by ADAMTS13 and also impair multimer assembly, mutations that impair binding to FVIII, lowering whereas group II mutations enhance proteolysis FVIII levels so that type 2N VWD masquerades as an without decreasing the assembly of large VWF autosomal recessive form of haemophilia A [76–78]. ) multimers [51]. Computer modelling of domain A2 In typical cases, the FVIII level is <10% (IU dL 1), suggests that group I mutations affect both assembly with a normal VWF:Ag and VWF:RCo. Discrimina- and proteolysis, because group I mutations have a tion from haemophilia A may require assays of more disruptive effect on the folding of domain A2 FVIII-VWF binding [79,80]. than do group II mutations [59]. Most mutations that cause type 2N VWD occur Type 2B VWD. Type 2B VWD is caused by within the FVIII binding site of VWF (Fig. 2), which mutations that pathologically increase platelet-VWF lies between residues Ser764 and Arg1035 and spans

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 181 domain D¢ and part of domain D3 [24,81,82]. The The example of Vicenza VWD illustrates some of most common mutation, Arg854Gln, has a relatively these problems. Vicenza VWD was first described mild effect on FVIII binding and tends to cause a less as a variant of VWD in which the level of plasma ) severe type 2N VWD phenotype [79]. Some muta- VWF is usually <15 IU dL 1 and the VWF multi- tions in the D3 domain C-terminal of Arg1035 can mers are even larger than normal, like the ultra- reduce FVIII binding [83–85], presumably through large multimers characteristic of platelet VWF [94]. an indirect effect on the structure or accessibility of The low level of VWF in plasma in Vicenza VWD the binding site. appears to be explained by the effect of a specific mutation, Arg1205His, that promotes clearance of Type 3 VWD Type 3 VWD is characterized by VWF from the circulation about five times more undetectable VWF protein and activity, and FVIII rapidly than normal [43]. Because the newly ) levels usually are very low (1–9 IU dL 1) [86–88]. synthesized multimers have less opportunity to be Nonsense and frameshift mutations commonly cause cleaved by ADAMTS13 before they are cleared, type 3 VWD, although large deletions, splice-site accelerated clearance alone may account for the mutations and missense mutations can also do so. increased multimer size in Vicenza VWD [95]. Mutations are distributed throughout the VWF gene, Whether Vicenza VWD is classified under type 1 and most are unique to the family in which they were VWD or type 2M VWD depends on the interpre- first identified [24,89,90]. tation of laboratory test results. The abnormally A small fraction of patients with type 3 VWD large multimers and low RIPA values have led develop alloantibodies to VWF in response to the some investigators to prefer the designation of type transfusion of plasma products. These antibodies 2M VWD [96]. However, the VWF:RCo/VWF:Ag have been reported in 2.6–9.5% of patients with type ratio typically is normal, and large VWF multimers 3 VWD, as determined by physician surveys or are not decreased relative to smaller multimers, so screening [87,91]. The true incidence is uncertain, that other investigators have classified Vicenza however, because of unavoidable selection bias in VWD under type 1 VWD [43]. Regardless of these studies. Anti-VWF alloantibodies can inhibit how this variant is classified, the markedly short- the haemostatic effect of blood product therapy and ened half-life of plasma VWF in Vicenza VWD is a also may cause life-threatening allergic reactions key fact that, depending on the clinical circum- [87,92]. Large deletions in the VWF gene may stance, may dictate whether the patient should predispose patients to this complication [91]. receive treatment with desmopressin or FVIII/VWF concentrates. VWD classification, general issues The principal dif- ficulties in using the current VWD classification Type 1 VWD vs. low VWF: VWF level as a risk concern how to define the boundaries between the factor for bleeding various subtypes through laboratory testing. In addition, some mutations have pleiotropic effects Persons who have very low VWF levels, i.e. ) on VWF structure and function, and some persons <20 IU dL 1, are likely to have VWF gene mutations, are compound heterozygous for mutations that significant bleeding symptoms and a strongly positive cause VWD by different mechanisms. This hetero- family history [35,36,39,97–101]. Diagnosing type 1 geneity can produce complex phenotypes that are VWD in these persons seems appropriate because difficult to categorize. Clinical studies of the rela- they may benefit from changes in lifestyle and from tionship between VWD genotype and clinical phe- specific treatments to prevent or control bleeding. notype would be helpful to improve the Identification of affected family members may also management of patients with the different subtypes be useful, and genetic counselling is simplified when of VWD. the pattern of inheritance is straightforward. The distinction between quantitative (type 1) and In contrast, persons with VWF levels of ) qualitative (type 2) defects depends on the ability to 30–50 IU dL 1, just below the usual normal range ) recognize discrepancies among VWF assay results (50–200 IU dL 1), pose problems for diagnosis and [82,93], as discussed in the section Diagnosis and treatment. Among the total US population of ) Evaluation. Similarly, distinguishing between type approximately 300 million, VWF levels <50 IU dL 1 2A and type 2M VWD requires multimer gel are expected in about 7.5 million persons, who analysis. Standards need to be established for using therefore would be at risk for a diagnosis of type 1 laboratory tests to make these important distinc- VWD. Because of the strong influence of ABO blood tions. group on VWF level [45], about 80% of US residents

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 182 W. L. NICHOLS et al. who have low VWF have also blood type O. slightly lower than those who have the Secretor locus Furthermore, moderately low VWF levels and bleed- [111]. An effect of the VWF locus has been difficult ing symptoms generally are not coinherited within to discern by linkage analysis. One study suggested families and are not strongly associated with intra- that 20% of the variance in VWF levels is attribut- genic VWF mutations [102–104]. In a recent Cana- able to the VWF gene [110], whereas another study dian study of 155 families who had type 1 VWD, the could not demonstrate such a relationship [112]. proportion showing linkage to the VWF locus was In sum, known genetic factors account for a just 41% [100]. In a similar European study, linkage minority of the heritable variation in VWF level, ) to the VWF locus depended on the severity of the and moderately low VWF levels (30–50 IU dL 1)do phenotype. If plasma levels of VWF were not show consistent linkage to the VWF locus ) <30 IU dL 1, linkage was consistently observed, but [99,100,102,103]. The diagnosis and management ) if levels of VWF were higher than 30 IU dL 1, the of VWD would be facilitated by better knowledge of proportion of linkage was only 51% [99]. Further- how inherited and environmental factors influence more, bleeding symptoms were not significantly the plasma concentration of VWF. linked to the VWF gene in these families [99]. The attribution of bleeding to a low VWF level can Family studies suggest that 25–32% of the vari- be difficult because mild bleeding symptoms are very ance in plasma VWF is heritable [105,106]. Twin common, as discussed in the section Diagnosis and studies have reported greater heritability of 66–75% Evaluation, and the risk of bleeding is only modestly [107,108], although these values may be overesti- increased for persons who have moderately mates because of shared environmental factors decreased VWF levels [47]. For example, in the [106,109]. Therefore, it appears that, at least in the course of investigating patients with type 3 VWD, healthy population, a substantial fraction of the approximately 190 obligate heterozygous relatives variation in VWF level is not heritable. have had bleeding histories obtained and VWF levels Few genes have been identified that contribute to measured (Table 6). The geometric mean VWF level ) the limited heritability of VWF level. The major was 47 IU dL 1 [47], with a range (±2 SD) of ) genetic influence on VWF level is the ABO blood 16–140 IU dL 1. Among 117 persons who had ) group, which is thought to account for 20–30% of its VWF <50 IU dL 1, 31 (26%) had bleeding symp- heritable variance [14,108,110]. The mean VWF toms. Among 74 persons who had VWF higher than ) ) level for blood type O is 75 U dL 1, which is 25–35 50 IU dL 1, 10 (14%) had bleeding symptoms. ) UdL 1 lower than other ABO types, and 95% of Therefore, the relative risk of bleeding was 1.9 VWF levels for type O blood donors are between 36 (P = 0.046, FisherÕs exact test) for persons who had ) and 157 U dL 1 [45]. The Secretor locus has a low VWF. There was a trend for an increased smaller effect. Secretor-null persons have VWF levels frequency of bleeding symptoms at the lowest VWF

Table 6. Bleeding and VWF level in type 3 VWD heterozygotes. Source Setting Population Results ) Castaman et al. [399] 1 family with type 3 proband 11 heterozygous None with bleeding; 6 with VWF <50 IU dL 1 Eikenboom et al. [22] 8 families with type 3 probands 22 heterozygous 2 who had mild bleeding among 9 ) with VWF <50 IU dL 1 Zhang et al. [400] 13 families with type 3 probands 55 heterozygous 22 who had mild bleeding among 38 with ) VWF <50 IU dL 1; 9 who had mild bleeding ) among 17 with VWF >50 IU dL 1 Schneppenheim 22 families with type 3 probands 44 heterozygous 5 who had epistaxis, bruising or menorrhagia ) et al. [113] among 24 with VWF <50 IU dL 1; 1 who had postoperative bleeding among 20 ) with VWF >50 IU dL 1 Eikenboom 1 family with type 3 proband 4 heterozygous 2 who had mild bleeding among ) et al. [199] 4 with VWF <50 IU dL 1 Inbal et al. [401] 4 families with type 3 probands 20 heterozygous None who had bleeding; 15 with ) VWF <50 IU dL 1 Nichols et al. [402] 1 family with type 3 proband 6 heterozygous None with bleeding; 2 with ) VWF <50 IU dL 1 Mannucci et al. [46] 15 families with type 3 probands 28 heterozygous None who had bleeding; 19 with ) VWF <50 IU dL 1 VWD, von Willebrand disease; VWF, von Willebrand factor.

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 183 levels: among 31 persons who had VWF levels An inverse relationship exists between the platelet ) <30 IU dL 1, 12 (39%) had symptoms. Bleeding count and VWF multimer size, probably because was mild and consisted of epistaxis, bruising, men- increased encounters with platelets promote orrhagia and bleeding after tooth extraction. The one increased cleavage of VWF by ADAMTS13. person who experienced postoperative bleeding had This mechanism probably accounts for AVWS asso- ) a VWF level higher than 50 IU dL 1 [113]. ciated with myeloproliferative disorders; reduction The management of bleeding associated with VWF of the platelet count can restore a normal VWF deficiency would be facilitated by better understand- multimer distribution [120–122]. In rare instances, ing of the heritability of low VWF levels (in the range VWF has been reported to bind GPIb that was ) of 20–50 IU dL 1), their association with intragenic expressed ectopically on tumour cells [115,123]. VWF mutations, and their interactions with other Acquired von Willebrand syndrome has been modifiers of bleeding risk. Such data could provide a described in hypothyroidism caused by non-immune foundation for treating VWF level as a biomarker for mechanism [124]. Several drugs have been associated a moderate risk of bleeding, much as high blood with AVWS; those most commonly reported include pressure and high cholesterol are treated as biomar- valproic acid, ciprofloxacin, griseofulvin and kers for cardiovascular disease risk. hydroxyethyl starch [114,115]. Acquired von Willebrand syndrome occurs in various conditions, but other clinical features may Acquired von Willebrand syndrome direct attention away from this potential cause of Acquired von Willebrand syndrome (AVWS) refers bleeding. More studies are needed to determine the to defects in VWF concentration, structure or func- incidence of AVWS and to define its contribution to tion that are not inherited directly but are conse- bleeding in the many diseases and conditions with quences of other medical disorders. Laboratory which it is associated. findings in AVWS are similar to those in VWD and may include decreased values for VWF:Ag, Prothrombotic clinical issues and VWF in persons VWF:RCo or FVIII. The VWF multimer distribution who do not have VWD may be normal, but the distribution often shows a decrease in large multimers similar to that seen in Whether elevation of VWF is prothrombotic has type 2A VWD [114,115]. AVWS usually is caused by been the subject of several investigations. Both one of three mechanisms: autoimmune clearance or arterial and venous thrombotic disorders have been inhibition of VWF, increased shear-induced proteo- studied. lysis of VWF, or increased binding of VWF to platelets or other cell surfaces. Autoimmune Open heart surgery Haemostatic activation after mechanisms may cause AVWS in association with open heart surgery has been suggested as a mech- lymphoproliferative diseases, monoclonal gammop- anism of increased risk of postoperative thrombosis athies, systemic lupus erythematosus, other autoim- in this setting. A randomized trial comparing mune disorders and some cancers. Autoantibodies to coronary artery surgery with or without cardiopul- VWF have been detected in <20% of patients in monary bypass (Ôoff-pumpÕ) found a consistent and whom they have been sought, suggesting that the equivalent rise in VWF:Ag levels at 1–4 postopera- methods for antibody detection may not be suffi- tive days in the two groups [125], suggesting that ciently sensitive or that AVWS in these settings may the surgery itself, rather than cardiopulmonary not always have an autoimmune basis. bypass, was responsible for the rise in VWF. There Pathological increases in fluid shear stress can is no direct evidence that the postoperative rise in occur with cardiovascular lesions, such as ventricular VWF contributes to the risk of thrombosis after septal defect and aortic stenosis, or with primary cardiac surgery. pulmonary hypertension. The increased shear stress can increase the proteolysis of VWF by ADAMTS13 Coronary artery disease Three large prospective stud- enough to deplete large VWF multimers and thereby ies of subjects without evidence of ischaemic heart produce a bleeding diathesis that resembles type 2A disease at entry have shown, by univariate analysis, VWD. The VWF multimer distribution improves if a significant association of VWF:Ag level at entry the underlying cardiovascular condition is treated with subsequent ischaemic coronary events successfully [114–119]. [126–128]. However, the association remained sig- Increased binding to cell surfaces, particularly nificant by multivariate analysis in only one subset of platelets, can also consume large VWF multimers. subjects in these studies [126], a finding that could

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 184 W. L. NICHOLS et al. have occurred by chance. These findings suggest that about bleeding issues or for evaluation before the association of VWF with the incidence of procedures that may increase their risk of bleeding. coronary ischaemic events is relatively weak and Using the answers to the initial assessment, the may not be directly causal. second part focuses on a strategy for optimal laboratory assessment of persons who potentially Thrombosis associated with atrial fibrillation A pro- have bleeding disorders and suggests guidelines for spective study of vascular events in subjects with interpretation of laboratory results. atrial fibrillation found, by univariate analysis, a significant association of VWF:Ag level with Evaluation of the patient subsequent stroke or vascular events. The association with vascular events remained significant with mul- History, signs and symptoms The initial clinical tivariate analysis [129]. assessment of a person who is being evaluated for VWD should focus on a personal history of excessive Thrombotic thrombocytopenic purpura The heredi- bleeding throughout the personÕs life and any family tary deficiency or acquired inhibition of a VWF- history of a bleeding disorder. The history of cleaving protease, ADAMTS13, is associated with bleeding should identify the spontaneity and severity, the survival in plasma of ultralarge VWF multimers, sites of bleeding, duration of bleeding, type of insult which are involved in the propensity to development or injury associated with bleeding, ease with which of platelet-rich thrombi in the microvasculature of bleeding can be stopped and concurrent medica- individuals who have TTP [130,131]. tions — such as aspirin or other non-steroidal anti- inflammatory drugs (NSAIDs), clopidogrel (Plavix), Deep vein thrombosis In a case–control study of 301 warfarin or heparin — at the onset of bleeding. patients, evaluated at least 3 months after cessation Particularly when an invasive procedure is antici- of anticoagulation treatment for a first episode of pated, the person should be asked whether he or she deep vein thrombosis (DVT), plasma levels of is currently taking any of these medications and also VWF:Ag and FVIII activity were related to risk of whether he or she has any history of liver or kidney DVT, according to univariate analysis. In multivar- disease, blood or bone marrow disease or high or iate analysis, the relation of VWF level with risk of low-platelet counts. If a history of any of these DVT was not significant after adjustment for FVIII disorders is present, further appropriate evaluation levels [132]. or referral should be undertaken.

Clinical manifestations The most common presenting Diagnosis and evaluation symptoms in persons who receive a diagnosis of VWD are summarized in Table 7. Symptoms usually Introduction involve mucous membranes and skin sites, and The evaluation of a person for possible VWD or bleeding is of mild-to-moderate severity (bleeding other bleeding disorders may be initiated because of that does not require blood transfusions and usually various clinical indications (Fig. 3). These indica- does not require visits to the physician) for most tions and situations may include evaluation of (i) an persons with VWD, reflecting the predominance of asymptomatic person who will undergo a surgical type 1 VWD. However, life-threatening bleeding or interventional procedure; (ii) persons who pres- (central nervous system and gastrointestinal tract) ent with current symptoms of or a history of can occur in persons with type 3 VWD, in some increased bleeding, abnormal laboratory studies, a persons with type 2 VWD, and rarely in persons with positive family history of a bleeding disorder or a type 1 VWD. Uncommon bleeding manifestations, combination of these factors; or (iii) persons who such as haemarthrosis, are more common in persons present with a prior diagnosis of VWD but do not who have a more severe deficiency, especially those have supporting laboratory documentation. In all with type 3 VWD [87,133]. Clinical symptoms may cases, the initial step in assessment should focus on also be modified by coexisting illnesses or other key aspects of the personÕs clinical history to medications. For example, use of aspirin or NSAIDs determine whether the person may benefit from can exacerbate the bleeding tendency, whereas use of further diagnostic evaluation. This section is divided oral contraceptives can decrease bleeding in women into two parts. The first part uses a summary of the with VWD. medical literature to suggest questions for an initial The clinical evaluation of bleeding symptoms is a assessment of persons presenting with concerns challenge, because mild bleeding symptoms are also

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 185

Fig. 3. Initial evaluation of patients to determine whether laboratory testing is indicated. The initial strategy is to determine which patients would benefit most from further diagnostic evaluation for von Willebrand disease (VWD) or other bleeding disorders. Left upper box, Individuals (for example, an asymptomatic person who will undergo a surgical or other invasive procedure) would be asked three questions about their personal and family bleeding history, which, if any responses are positive, would lead to a second set of questions selected for sensitivity and specificity for VWD (lower right, Box 1). Those patients answering positively to one or more of the second set of questions would benefit from laboratory evaluation. Right upper boxes, Patients presenting with specific information or a concern about bleeding would be asked the additional questions (Box 1) and the initial questions (left upper box) if not already asked and would also undergo laboratory evaluation. The three initial questions and the nine additional questions (Box 1) also appear in Table 9 and in Diagnostic Recommendations I. DDAVP, desmopressin; NSAID, non-steroidal anti-inflammatory drug. common in healthy populations (Table 7, ÔNormalsÕ definition of menorrhagia is not clearly specified in column). Responses to questionnaires used to survey most of these studies and the diagnostic criteria for healthy controls indicate that they identify them- VWD are not uniform. The sensitivity of menorrha- selves as having specific bleeding manifestations as gia as a predictor of VWD may be estimated as frequently as persons with VWD, particularly type 1 32–100%. However, menorrhagia is a common VWD (Table 7) [134–137]. In addition, a family symptom, occurring with a similar frequency in history of bleeding was reported in 44% of healthy healthy controls and women with VWD; therefore, it children undergoing tonsillectomy [137] and by 35% is not a specific marker for VWD (Table 7). In a [135] or 60% [138] of persons referred because of survey of 102 women who had VWD and were bleeding. Because bleeding symptoms are so pre- registered at haemophilia treatment centres in the valent, it may be impossible to establish a causal United States, 95% reported a history of menorrha- relationship between bleeding and low VWF. gia, but 61% of controls also reported a history of Some of the most important clinical issues in VWD menorrhagia [139]. Studies have reported a preva- apply specifically to women, particularly menorrha- lence of VWD of between 5% and 20% among gia. Studies of women with VWD report a high women who have menorrhagia [140–146]. There- prevalence of menorrhagia (Table 7), although the fore, the specificity of menorrhagia as a predictor of

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 186 W. L. NICHOLS et al.

Table 7. Common bleeding symptoms of healthy individuals and patients with VWD. Normals (n = 500 [134]; n = 341 All types of Type 1 VWD Type 3 VWD [135]*; n =88 VWD (n = 264 [ (n =42 Type 2 VWD (n = 66 [133]; [148] ; n =60 134]; n = 1885 [395]à; n = 671 (n = 497 n = 385 Symptoms [136] ), % [394]), % [133]), % [133]), % [87]), % Epistaxis 4.6–22.7 38.1–62.5 53–61 63 66–77 Menorrhagia§ 23–68.4 47–60 32 32 56–69 Bleeding after dental 4.8–41.9 28.6–51.5 17–31 39 53–70 extraction Ecchymoses 11.8–50 49.2–50.4 50 NR NR Bleeding from minor 0.2–33.3 36 36 40 50 cuts or abrasions Gingival bleeding 7.4–47.1 26.1–34.8 29–31 35 56 Postoperative bleeding 1.4–28.2 19.5–28 20–47 23 41 Haemarthrosis 0–14.9 6.3–8.3 2–3 4 37–45 Gastrointestinal bleeding 0.6–27.7 14 5 8 20 NR, not reported; VWD, von Willebrand disease. *A total of 341 individuals were sent a questionnaire, but the precise number responding was not provided. Study included women only. àStudy included males only. §Calculated for females older than 13–15 years.

VWD can be estimated as 5–20%. Three findings that selection of those with bleeding disorders had predict abnormal menstrual blood loss of more than already been made by the referring doctor [135]. 80 mL are (i) clots larger than approximately 1 inch Drews et al. [148] attempted to develop a ques- in diameter; (ii) low serum ferritin and (iii) the need to tionnaire-based screening tool to identify women change a pad or tampon more than hourly [147]. who might benefit from a diagnostic work-up for VWD. They conducted a telephone survey of 102 Further evaluation for inherited bleeding disorders women who had a diagnosis of type 1 VWD and Because Ôbleeding symptomsÕ other than menorrhagia were treated at a haemophilia treatment centre; 88 of are reported frequently by persons who have appar- their friends served as controls. With the exception of ently normal haemostasis, it is important to ask postpartum transfusions, all study variables were questions that can best identify persons who have a reported more frequently by women who had VWD true bleeding disorder. Sramek and colleagues [135] than by their friends (Table 8, columns 6 and 7). In used a written questionnaire with patients who had a addition, positive responses to multiple questions proven bleeding disorder. When the responses were were more likely to be obtained from patients who compared with those of a group of healthy volun- have an inherited bleeding disorder [148]. An teers, the most informative questions were related to important limitation of this study is that these (i) prolonged bleeding after surgery, including after women were more symptomatic than most women dental extractions and (ii) identification of family who have a diagnosis of type 1 VWD, indicating a members who have an established bleeding disorder more severe phenotype of the disease; this fact might (Table 8, columns 2–5). A history of muscle or joint decrease the sensitivity of the questions in persons bleeding (haematomas or haemarthroses) may also who have milder type 1 VWD and fewer symptoms. be helpful when associated with the above symp- More recently, Rodeghiero and colleagues [149] toms. compared responses to a standardized questionnaire General questions that relate to isolated bleeding obtained from 42 obligatory carriers of VWD (from symptoms — such as frequent gingival bleeding, well-characterized families) to responses from 215 profuse menstrual blood loss, bleeding after delivery controls. The questionnaire covered 10 common and epistaxis in the absence of other bleeding bleeding symptoms (including all symptoms in symptoms — were not informative [135]. The study Table 7 and postpartum haemorrhage), with also found that an elaborate interview after referral assigned scores for each ranging from 0 (no symp- to a haematologist was not particularly helpful toms) to 3 (severe symptoms, usually including when attempting to distinguish persons who have hospitalization, transfusion support or both). With a true bleeding disorder from persons who have a this instrument, the researchers found that having a ÔsuspectedÕ bleeding disorder, implying that the cumulative total bleeding score of 3 in men or 5 in

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Table 8. Prevalences of characteristics in patients with diagnosed bleeding disorders vs. healthy controls. Univariate Multivariate Women who Type 1 VWD analysis* analysis* have VWD familiesà

Symptom OR 95% CI OR 95% CI Sensitivity 95% CI OR 95% CI Family members have an 97.5 38.3–248 50.5 12.5–202.9 ………… established bleeding disorder Profuse bleeding from 67.2 28.4–159 30.0 8.1–111.1 ……16.7 2.0–137.7 small wounds Profuse bleeding at site of 27.7 8.0–96.1 11.5 1.2–111.9 ………… tonsillectomy/adenoidectomy Easy bruising 12.7 8.0–20.2 9.9 3.0–32.3 9.8 4.8–17.3 8.1 2.1–30.5 Profuse bleeding after surgery 23.0 10.6–50.1 5.8 1.3–26.4 52.9 42.8–62.9 8.9 3.6–21.8 Muscle bleeding (ever) 13.3 6.4–27.7 4.8 0.7–31.4 9.8 4.8–17.3 …… Frequent nosebleeds 3.5 2.0–6.2 3.8 0.9–15.7 61.8 51.6–71.2 4.9 2.4–10.0 Profuse bleeding at site of 39.4 20.6–75.5 3.2 0.9–11.3 54.9 44.7–64.8 4.6 2.5–8.4 dental extraction Blood in stool (ever) 2.8 1.7–4.6 2.8 0.7–11.7 13.7 7.7–22.0 1.6 0.6–4.3 Family members with 28.6 15.0–54.6 2.5 0.7–9.4 ………… bleeding symptoms Joint bleeding (ever) 8.6 4.8–15.2 2.5 0.6–10.2 20.6 13.2–29.7 …… Menorrhagia 5.4 3.0–9.8 2.5 0.6–9.9 …… 5.1 2.6–10.1 Haemorrhage at time of delivery 5.3 2.3–12.0 2.1 0.3–13.5 50.0 39.9–60.1 0.9 0.3–3.2 Frequent gingival bleeding 2.8 1.9–4.2 0.7 0.3–2.0 76.5 67.0–84.3 1.3 0.3–6.7 Haematuria (ever) 3.2 1.8–5.6 0.5 0.1–2.3 ………… CI, conﬁdence interval; OR, odds ratio; VWD, von Willebrand disease. Ellipses indicate data were not reported. *Univariate and multivariate analyses from Sramek et al. [135] comparing 222 patients who had a known bleeding disorder (43% mild VWD) and 341 healthy volunteers. Compiled from responses to a questionnaire sent to 102 women, who had type 1 VWD, in a haemophilia treatment centre, from Drews et al. [148]. àCompiled from interviews comparing affected and unaffected family members of patients who had type 1 VWD, from Tosetto et al. [150] and F. Rodeghiero (personal communication). The index cases (patients who had VWD) were not included in the analysis.

women was very specific (98.6%) but not as sensitive data for comparison, the severity of bleeding dimin- (69.1%) for type 1 VWD. Limitations of this study ished with increasing plasma VWF, not only for include its retrospective design and awareness of the subjects who had low VWF levels, but throughout respondentÕs diagnosis by the person administering the normal range as well. Although the mean the questionnaire. This questionnaire is available bleeding score was significantly different among online [149]. several groups, the distribution was sufficiently A similar retrospective case–control study [150] broad that the bleeding score could not predict the used a standardized questionnaire like that of affected or unaffected status of individuals. Rodeghiero et al. [149] to compare bleeding symp- In a related study, bleeding symptoms were toms of 144 index cases who had type 1 VWD with assessed with the same questionnaire in 70 persons those in 273 affected relatives, 295 unaffected who were obligatory carriers of type 3 VWD, 42 relatives and 195 healthy controls. The interviewers persons who were obligate carriers of type 1 VWD were not blinded to subjectÕs status. At least one (meaning affected family members of index cases bleeding symptom was reported by approximately who had type 1 VWD) and 215 persons who were 98% of index cases, 89% of affected relatives, 32% healthy controls [151]. Carriers of type 3 VWD were of unaffected relatives and 12% of healthy controls. compared with carriers of type 1 VWD to address the The major symptoms of affected persons (excluding question of whether the distinct types of VWF index cases) included bleeding after tooth extraction, mutations associated with these conditions predis- nosebleeds, menorrhagia, bleeding into the skin, posed to the same or different severity of bleeding. postoperative bleeding and bleeding from minor Approximately 40% of carriers of type 3 VWD, 82% wounds. Using a bleeding score calculated from the of carriers of type 1 VWD and 23% of healthy

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 188 W. L. NICHOLS et al. controls had at least one bleeding symptom. The Table 9. Suggested questions for screening persons for a bleeding major bleeding symptoms in carriers of type 3 VWD disorder. were bleeding into skin and postsurgical bleeding. Initial Questions* The results suggest that carriers of type 3 VWD are 1. Have you or a blood relative ever needed medical attention somewhat distinct, because they have bleeding for a bleeding problem, or have you been told you have a symptoms more frequently than healthy controls bleeding disorder or problem? but less frequently than persons who have or are During or after surgery? With dental procedures or extractions? carriers of type 1 VWD. Usually, carriers of type 1 With trauma? VWD have lower VWF levels than carriers of type 3 During childbirth or for heavy menses? VWD. Ever had bruises with lumps? 2. Do you have or have you ever had Family history Although a family history that is Liver or kidney disease? positive for an established bleeding disorder is useful A blood or bone marrow disorder? in identifying persons who are likely to have VWD, A high- or low-platelet count? 3. Are you currently taking or have you recently taken such a history is frequently not present. This is most anticoagulation or antiplatelet medications (warfarin, commonly the case for persons with milder forms of heparin, aspirin, NSAIDs, clopidogrel – provide VWD and whose family members may have minimal, common names)? if any, symptoms. As shown in Table 8, the presence If answers to any of the questions above are positive, obtain of a documented bleeding disorder in a family relevant specific information including treatment history member is extremely helpful in deciding which (e.g. blood transfusions), and ask the following additional persons to evaluate further, whereas a family history questions. Additional Questions à of bleeding symptoms is less helpful. 1. Do you have a blood relative who has a bleeding disorder, such as von Willebrand disease or haemophilia? Summary of medical history evaluation Table 9 sum- 2. Have you ever had prolonged bleeding from trivial wounds, marizes suggested questions that can be used to lasting more than 15 min or recurring spontaneously during the 7 identify persons who should be considered for days after the wound? further evaluation for VWD with laboratory studies. 3. Have you ever had heavy, prolonged, or recurrent bleeding after surgical procedures, such as tonsillectomy? 4. Have you ever had bruising, with minimal or no apparent Physical examination The physical examination trauma, especially if you could feel a lump under the bruise? should be directed to confirm evidence for a bleeding 5. Have you ever had a spontaneous nosebleed that required disorder, including size, location and distribution of more than 10 min to stop or needed medical attention? ecchymoses (e.g. truncal), haematomas, petechiae 6. Have you ever had heavy, prolonged, or recurrent and other evidence of recent bleeding. The examina- bleeding after dental extractions that required medical tion should also focus on findings that may suggest attention? other causes of increased bleeding, such as evidence 7. Have you ever had blood in your stool, unexplained by a specific anatomic lesion (such as an ulcer in the stomach or a of liver disease (e.g. jaundice), splenomegaly, polyp in the colon), that required medical attention? arthropathy, joint and skin laxity (e.g. Ehlers-Danlos 8. Have you ever had anaemia requiring treatment or received a syndrome), telangiectasia (e.g. hereditary haemor- blood transfusion? rhagic telangiectasia), signs of anaemia or anatomic 9. For women, have you ever had heavy menses, lesions on gynaecological examination. characterized by the presence of clots greater than an inch in diameter or changing a pad or tampon more than hourly or by resulting in anaemia or Acquired von Willebrand Syndrome Persons with low iron level? AVWS present with bleeding symptoms similar to those described above, except that the past personal NSAIDs, non-steroidal anti-inflammatory drugs. *Initial questions, such as for an asymptomatic person who will history and family history are negative for bleeding undergo a surgical or interventional procedure. symptoms. AVWS may occur spontaneously or in Additional questions such as for persons answering positively to association with other diseases, such as monoclonal the initial questions or for persons presenting with specific issues, gammopathies, other plasma cell dyscrasias, lym- including (i) current bleeding symptoms or a history of increased phoproliferative diseases, myeloproliferative disor- bleeding; (ii) abnormal laboratory test results; (iii) family history ders (e.g. essential thrombocythemia), autoimmune of a bleeding disorder; or (iv) previous diagnosis of a bleeding disorders, valvular and congenital heart disease, disorder, including von Willebrand disease. The initial questions should also be asked, if not already done. certain tumours and hypothyroidism [114,152]. à Sources: Laffan et al. [8], Drews et al. [148] and Dean et al. The evaluation should be tailored to finding condi- [158]. tions associated with AVWS.

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 189

Fig. 4. Laboratory assessment for von Willebrand disease (VWD) or other bleeding disorders. If the clinical evaluation suggests a bleeding disorder, the initial haemostasis tests should be ordered, followed by or along with the initial VWD assays indicated in the algorithm. Referral to a haemostasis specialist is appropriate for help in interpretation, repeated testing and specialized tests. CBC, complete blood cell count; FVIII, factor VIII; PT, prothrombin time; PTT, partial thromboplastin time; RIPA, ristocetin-induced platelet aggregation; TT, thrombin time; VWF, von Willebrand factor; VWF:Ag, von Wille- brand factor antigen; VWF:RCo, von Willebrand factor ristocetin cofactor activity. *Correction of the PTT mixing study immediately and after 2-h incubation re- moves a FVIII inhibitor from consideration. Investigation of other intrinsic factors and lupus anticoagulant may also be indicated. Isolated decreased platelets may occur in VWD type 2B.

VWF:RCo and FVIII) should be considered at the Laboratory diagnosis and monitoring first visit. An algorithm for using clinical laboratory studies to Some centres add a BT or a platelet function make the diagnosis of VWD is summarized in analyzer (PFA-100) assay to their initial laboratory Fig. 4. tests. The BT test is a non-specific test and subject to Ideally, a simple, single laboratory test could operational variation. It has been argued that the BT screen for the presence of VWD. Such a screening test is a population-based test that was never test would need to be sensitive to the presence of intended to test individuals [153]. Variables that most types of VWD and would have a low false- may affect results include a crying or wiggling child, positive rate. However, no such test is available. In differences in the application of the blood pressure the past, the activated partial thromboplastin time cuff, and the location, direction and depth of the cut (PTT) and BT were recommended as diagnostic tests. made by the device. This test also has a potential for These tests were probably satisfactory for detecting causing keloid formation and scarring, particularly severe type 3 VWD, but as variant VWD and milder in non-White individuals. forms of VWD were characterized, it became appar- The PFA-100 test result has been demonstrated to ent that many of the persons who have these be abnormal in the majority of persons with VWD, conditions had normal PTT and BT results. other than those with type 2N, but its use for population screening for VWD has not been estab- Initial haemostasis laboratory evaluation An initial lished [154–157]. Persons with severe type 1 VWD haemostasis laboratory evaluation usually includes or type 3 VWD usually have abnormal PFA-100 (i) a platelet count and complete blood cell count; (ii) values, whereas persons with mild or moderate type PTT; (iii) prothrombin time; and (iv) optionally 1 VWD and some with type 2 VWD may not have either a fibrinogen level or a thrombin time (Fig. 4). abnormal results [158–160]. When persons are This testing neither rules in nor rules out VWD, but it studied by using both the BT and PFA-100, the can suggest whether coagulation factor deficiency or results are not always concordant [157,159,161]. thrombocytopenia might be the potential cause of When using the PTT in the diagnosis of VWD, clinical bleeding. If the mucocutaneous bleeding results of this test are abnormal only if the FVIII is history is strong, initial VWD assays (VWF:Ag, sufficiently reduced. Because the FVIII gene is normal

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 190 W. L. NICHOLS et al. in VWD, the FVIII deficiency is secondary to the into a laboratory test that is still the most widely deficiency of VWF, its carrier protein. In normal accepted functional test for VWF. (In vivo, however, individuals, the levels of FVIII and VWF:RCo it is the high shear in the microcirculation, and not a are approximately equal, with both averaging ristocetin-like molecule, that causes the structural ) 100 IU dL 1. In type 3 VWD, the plasma FVIII level changes in VWF that lead to VWF binding to ) is usually <10 IU dL 1 and represents the steady platelets.) state of FVIII in the absence of its carrier protein. In Several methods are used to assess the platelet persons with type 1 VWD, the FVIII level is often agglutination and aggregation that result from the slightly higher than the VWF level and may fall binding of VWF to platelet GPIb induced by ristoce- within the normal range. In persons with type 2 tin (VWF:RCo). The methods include (1) time to VWD (except for type 2N VWD in which it is visible platelet clumping using ristocetin, washed decreased), the FVIII is often two to three times normal platelets (fresh or formalinized) and dilutions higher than the VWF activity (VWF:RCo) [162,163]. of patient plasma; (2) slope of aggregation during Therefore, the PTT is often within the normal platelet aggregometry using ristocetin, washed nor- range. If VWF clearance is the cause of low VWF, mal platelets and dilutions of the personÕs plasma; (3) the FVIII reduction parallels that of VWF, probably automated turbidometric tests that detect platelet because both proteins are cleared together as a clumping, using the same reagents noted above; (4) complex. ELISAs that assess direct binding of the personÕs plasma VWF to platelet GPIb (the GPIb may be Initial tests for VWD The initial tests commonly used derived from plasma glycocalicin) in the presence of to detect VWD or low VWF are determinations of ristocetin [164–166] and (5) the binding of a mono- plasma levels of (i) VWF:Ag; (ii) VWF:RCo; and (iii) clonal antibody to a conformation epitope of the FVIII (Fig. 4). These three tests, readily available in VWF A1 loop [167]. Method (5) can be performed in most larger hospitals, measure the amount of VWF an ELISA or LIA format. It is not based on ristocetin protein present in plasma (VWF:Ag), the function of binding. The first three assays above may use platelet the VWF protein that is present as VWF:RCo, and membrane fragments containing GPIb rather than the ability of the VWF to serve as the carrier protein whole platelets. The sensitivity varies for each to maintain normal FVIII survival. If any of the laboratory and each assay; in general, however, above tests is abnormally low, the next steps should methods 1 and 2, which measure platelet clumping be discussed with a coagulation specialist, who may by using several dilutions of the personÕs plasma, are ) recommend referral to a specialized centre and quantitative to approximately 6–12 IU dL 1 levels. ) repeating the initial VWD laboratory tests in addi- Method 3 is quantitative to about 10–20 IU dL 1. ) tion to performing other tests. Method 4 can measure VWF:RCo to <1 IU dL 1, VWF:Ag assay. VWF:Ag is an immunoassay that and a variation of it can detect the increased VWF measures the concentration of VWF protein in binding to GPIb seen in type 2B VWD [168]. Some plasma. Commonly used methods are based on automated methods are less sensitive and require enzyme-linked immunosorbent assay (ELISA) or modification of the assay to detect levels ) automated latex immunoassay (LIA). As discussed <10 IU dL 1. Each laboratory should define the below, the standard reference plasma is critical and linearity and limits of its assay. Several monoclonal should be keyed to the World Health Organization ELISAs (method 5) that use antibodies directed to the (WHO) standard. The personÕs test results should be VWF epitope containing the GPIb-binding site have reported in international units (IU), either as inter- been debated because the increased function of the ) national units per decilitre (IU dL 1) or as interna- largest VWF multimers is not directly assessed [169]. ) tional units per millilitre (IU mL 1). Most The VWF:RCo assay has high intralaboratory and ) laboratories choose IU dL 1, because it is similar to interlaboratory variation, and it does not actually the conventional manner of reporting clotting factor measure physiological function. The coefficient of assays as a percentage of normal. variation (CV) has been measured in laboratory VWF:RCo assay. VWF:RCo is a functional assay surveys at 30% or greater, and the CV is still higher ) of VWF that measures its ability to interact with when the VWF:RCo is lower than 12–15 IU dL 1 normal platelets. The antibiotic ristocetin causes [170–174]. This becomes important not only for the VWF to bind to platelets, resulting in platelet clumps initial diagnosis of VWD, but also for determining and their removal from the circulation. Ristocetin whether the patient has type 1 vs. type 2 VWD (see was removed from clinical trials because it caused additional discussion in the section below, Ratio of thrombocytopenia. This interaction was developed VWF:RCo to VWF:Ag). Despite these limitations, it

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 191 is still the most widely accepted laboratory measure specimen collection, transport or processing is sub- of VWF function. Results for VWF:RCo should be optimal. Like the tests discussed above, it should be ) ) expressed in IU dL 1 on the basis of the WHO expressed in IU dL 1 on the basis of the WHO plasma standard. plasma standard. FVIII assay. FVIII coagulant assay is a measure of the cofactor function of the clotting factor, FVIII, in Laboratory results in different VWD sub- plasma. In the context of VWD, FVIII activity types Expected patterns of laboratory results in measures the ability of VWF to bind and maintain different subtypes of VWD, depicted in Fig. 5, the level of FVIII in the circulation. In the United include results of the three initial VWD tests States, the assay is usually performed as a 1-stage (VWF:Ag, VWF:RCo and FVIII) and results of other clotting assay based on the PTT, although some assays for defining and classifying VWD subtypes. laboratories use a chromogenic assay. The clotting The three initial tests (or at least the VWF:RCo and assay, commonly done using an automated or FVIII assays) are also used for monitoring therapy. semiautomated instrument, measures the ability of plasma FVIII to shorten the clotting time of FVIII- Other assays to measure VWF, define and diagnose deficient plasma. Because this test is important in the VWD and classify subtypes diagnosis of haemophilia, the efforts to standardize this assay have been greater than those applied to VWF multimer analysis. The VWF multimer test, an other haemostasis assays. FVIII activity is labile, with assay that is available in some larger centres and in the potential for spuriously low assay results if blood commercial laboratories, is usually performed after

Fig. 5. Expected laboratory values in von Willebrand disease (VWD). The symbols and values represent prototypical cases. In practice, ) laboratory studies in certain patients may deviate slightly from these expectations. L, 30–50 IU dL 1; fl, flfl, flflfl, relative decrease; ›, ››, ›››, relative increase; BT, bleeding time; FVIII, factor VIII activity; GPIb, platelet glycoprotein Ib complex; LD-RIPA, low-dose ristocetin- ) induced platelet aggregation (concentration of ristocetin £0.6 mg mL 1); N, normal; PFA-100-CT, platelet function analyzer closure time; PLT-VWD, platelet-type VWD; RIPA, ristocetin-induced platelet aggregation; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von Willebrand factor ristocetin cofactor activity. (Courtesy of R. R. Montgomery, the BloodCenter of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin; adapted from and used with permission.) *Persons with PLT-VWD have a defect in their platelet GPIb. Laboratory test results resemble type 2B VWD, and both have a defect in their LD-RIPA. In the VWF platelet-binding assay, persons with type 2B VWD have abnormally increased platelet binding. Normal persons and those with PLT-VWD have no binding of their VWF to normal platelets at low ristocetin concentrations.

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 192 W. L. NICHOLS et al. the initial VWD testing indicates an abnormality, intermediate and small multimers) or Ôhigh resolu- preferably using a previously unthawed portion of tionÕ (which differentiate each multimer band of the the same sample or in association with a repeated smaller multimers into 3–8 satellite bands). For VWD test panel (VWF:Ag, VWF:RCo and FVIII) diagnostic purposes, the low-resolution gel systems using a fresh plasma sample. VWF multimer analysis are used primarily; these systems help to differen- is a qualitative assay that depicts the variable tiate the type 2 VWD variants from types 1 or 3 concentrations of the different-sized VWF multimers VWD. Figure 6 illustrates the differences between by using sodium dodecyl sulphate–protein electro- these two techniques with regard to the resolution phoresis followed by detection of the VWF multi- of high- and low-molecular-weight multimers. It mers in the gel, using a radiolabelled polyclonal should be noted that multimer appearance alone antibody or a combination of monoclonal antibod- does not define the variant subtype and that only ies. Alternatively, the protein is transferred to a types 2A, 2B and platelet-type VWD (PLT-VWD) membrane (Western blot), and the multimers are have abnormal multimer distributions with relative identified by immunofluorescence or other staining deficiency of the largest multimers. An exception is techniques [101,175,176]. Vicenza variant VWD with ultralarge VWF multi- Multimer assays are designated as Ôlow resolutionÕ mers and low VWF. For more information about (which differentiate the largest multimers from the VWF multimer findings in type 2 VWD variants, see

Fig. 6. Analysis of von Willebrand factor (VWF) multimers. The distribution of VWF multimers can be analysed using sodium dodecyl sulphate (SDS)–agarose electrophoresis followed by immunostaining. Low-resolution gels (0.65% agarose, left side) can demonstrate the change in multimer distribution of the larger multimers (top of the gel), while high-resolution gels (2–3% agarose, right side) can separate each multimer into several bands that may be distinctive. For example, the lowest band in the 0.65% gel can be resolved into ﬁve bands in the 3% agarose gel, but the 3% gel fails to demonstrate the loss of high-molecular-weight multimers seen at the top in the 0.65% gel. The dotted line indicates the resolution of the smallest band into several bands in the 3% agarose gel. In each gel, normal plasma (NP) is run as a control. Type 1 von Willebrand disease (VWD) plasma has all sizes of multimers, but they are reduced in concentration. Type 2A VWD plasma is missing the largest and intermediate multimers, while type 2B VWD plasma is usually missing just the largest VWF multimers. No multimers are identiﬁed in type 3 VWD plasma. Patients with thrombotic thrombocytopenic purpura (TTP) may have larger than normal multimers when studied with low-resolution gels. (Courtesy of R. R. Montgomery, the BloodCenter of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin; used with permission).

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 193 the section above (Type 2 VWD) and associated a few patients have been identified who have specific references. collagen-binding defects that are independent of Low-dose RIPA. RIPA and the VWF platelet- multimer size, and the defects have been associated binding (VWF:PB) assay are two tests that are with a mutation of VWF in the A3 domain [75]. The performed to aid in diagnosing type 2B VWD. RIPA prevalence of such defects is unknown. The place of may be done as part of routine platelet aggregation VWF:CB in the evaluation of VWD has not been testing. Low-dose RIPA is carried out in platelet-rich established. In principle, however, patients who have plasma, using a low concentration of ristocetin defects in collagen binding may have a normal ) (usually <0.6 mg mL 1, although ristocetin lots vary, VWF:RCo and thus escape clinical diagnosis unless resulting in the use of slightly different ristocetin a VWF:CB assay is performed. Limited studies concentrations). This low concentration of ristocetin suggest that supplementary VWF:CB testing, com- does not cause VWF binding and aggregation of plementing assays of VWF:RCo and VWF:Ag, can platelets in samples from normal persons, but it does improve the differentiation of type 1 VWD from cause VWF binding and aggregation of platelets in types 2A, 2B or 2M VWD [170,180,181]. samples from patients with either type 2B VWD or VWF FVIII-binding assay. The VWF FVIII-bind- mutations in the platelet VWF receptor. The latter ing (VWF:FVIIIB) assay measures the ability of a defects have been termed pseudo-VWD or PLT- personÕs VWF to bind added exogenous FVIII and is VWD, and they can be differentiated from type 2B used to diagnose type 2N VWD [77,79,80,182,183]. VWD by VWF:PB assay. At higher concentrations of The assay is performed by capturing the personÕs ) ristocetin (1.1–1.3 mg mL 1), RIPA is reduced in VWF on an ELISA plate, removing the bound persons with type 3 VWD. However, the test is not endogenous FVIII, and then adding back a defined sufficiently sensitive to reliably diagnose other types concentration of exogenous recombinant FVIII. The of VWD. amount of FVIII bound is determined by chromo- VWF:PB assay. The VWF:PB assay measures the genic or immunological FVIII assay. The level of this binding of VWF to normal paraformaldehyde-fixed bound FVIII is then related to the amount of the platelets using low concentrations of ristocetin (usu- personÕs VWF initially bound in the same well. In ) ally 0.3–0.6 mg mL 1) [177]. The amount of VWF clinical experience, type 2N VWD is usually reces- bound to the fixed platelets is determined by using a sive; the person is either homozygous or compound labelled antibody. Clinically normal individuals or heterozygous (one allele is type 2N and the other is a those with types 1, 2A, 2M, 2N and 3 VWD exhibit type 1 or null allele). In either case, the VWF in the minimal or no binding to platelets at the concentra- circulation does not bind FVIII normally, and the tion of ristocetin used, but patients with type 2B concentration of FVIII is thus decreased. VWD exhibit extensive binding that causes their Ratio of VWF:RCo to VWF:Ag. The VWF:RCo/ variant phenotype (a loss of high-molecular-weight VWF:Ag ratio can aid in the diagnosis of types 2A, multimers, decreased ristocetin cofactor activity, and 2B and 2M VWD and help differentiate them from thrombocytopenia). Both type 2B VWD and PLT- type 1 VWD. For example, a VWF:RCo/VWF:Ag VWD have agglutination of platelet-rich plasma to ratio of <0.6 [184] or 0.7 has been used as a criterion low-dose ristocetin, but the VWF:PB assay can for dysfunctional VWF [8,185]. A similar approach differentiate type 2B VWD from PLT-VWD. Only has been proposed for the use of the VWF:CB/ VWF from persons with type 2B VWD has increased VWF:Ag ratio [8,185]. In type 2A VWD, the ratio is VWF:PB, while VWF from persons with PLT-VWD usually low, and in type 2B VWD, the VWF:RCo/ has normal VWF:PB with low doses of ristocetin. VWF:Ag ratio is usually low but may be normal. In VWF collagen-binding assay. The VWF collagen- type 2M VWD, the VWF:Ag concentration may be binding (VWF:CB) assay measures binding of VWF reduced or normal, but the VWF:RCo/VWF:Ag ratio to collagen. The primary site of fibrillar collagen is <0.7. One study [72] determined the VWF:RCo/ binding is in the A3 domain of VWF. Like the VWF:Ag ratio in nearly 600 individuals with VWF ) ristocetin cofactor assay, the VWF:CB assay is levels lower than 55 IU dL 1 who had normal VWF dependent on VWF multimeric size, with the largest multimers. The study used this ratio to identify multimers binding more avidly than the smaller families who had type 2 VWD, but most centres do forms. The VWF:CB assay performance and sensi- not have the ability to establish normal ranges for tivity to VWD detection or discrimination among patients who have low VWF. Additionally, the VWD subtypes is highly dependent on the source of VWF:RCo assay has a CV as high as 30% or more, collagen, as well as on whether type 1 collagen or a depending on the methods used, whereas the CV for mixture of type 1/3 collagen is used [178,179]. Only the VWF:Ag assay is somewhat lower. The high

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 194 W. L. NICHOLS et al. intrinsic variability of the VWF:RCo assay, especially Platelet VWF assays. Platelet VWF studies are at low levels of VWF, can make the VWF:RCo/ performed by some laboratories, including VWF:Ag ratio an unreliable criterion for the diag- VWF:RCo, VWF:Ag and VWF multimers, using nosis of type 2 VWD [170,172–174]. VWF extracted from washed platelets. The methods It is important that the same plasma standard used and interpretations of these studies, however, are not in both the VWF:RCo and VWF:Ag assays and that a well standardized. reference range for the VWF:RCo/VWF:Ag ratio and DNA sequencing analysis. DNA sequencing of its sensitivity to types 2A and 2M VWD be patient DNA has been used to make a molecular determined in each laboratory. Because no large diagnosis of variants of type 2 VWD [192–194], but multicentre studies have evaluated the precise ratio DNA sequencing is not widely available. Most of the that should be considered abnormal, a ratio in the mutations found in types 2B, 2M and 2N VWD range of less than 0.5–0.7 should raise the suspicion cluster in the cDNA that directs the synthesis of of types 2A, 2B or 2M VWD. Further confirmation specific regions of VWF (Fig. 2) [195]. In the com- should be sought by additional testing (e.g. repeated mon forms of type 2A VWD, in which the VWF is VWD test panel and VWF multimer study or spontaneously cleaved by ADAMTS13, mutations sequencing of the A1 region of the VWF gene) cluster in the A2 domain (which contains the cleavage [186]. Subsequent sections provide more information site). In the less common type 2A variants of VWD, in about the VWF:RCo/VWF:Ag ratio (Diagnostic which multimer formation is inhibited, the mutations Recommendations II.C.1.a and III.B and Evidence may be scattered throughout the gene. In most Table 3 [10]). persons with type 1 VWD, the genetic mutations ABO blood type. ABO blood types have a notable have not been established, although several studies effect on plasma VWF (and FVIII) concentrations are under way to characterize these mutations. [45,187]. Individuals who have blood type O have Assays for detecting VWF antibody. Assays for concentrations approximately 25% lower than per- detecting anti-VWF antibodies are not as well sons who have other ABO blood types. The diagnosis established as the assays for detecting antibodies to of type 1 VWD occurs more frequently in individuals FVIII in patients with haemophilia A. Some patients who have blood group type O [45]. Table 10 with AVWS do appear to have anti-VWF antibodies illustrates the effect of blood type on VWF:Ag level. that decrease the half-life of infused VWF. Although Although stratification of reference ranges for a few antibodies do inhibit VWF function and can be VWF:Ag and VWF:RCo with respect to blood demonstrated in 1:1 mixing studies with normal group O and non-group O has been recommended plasma using the VWF:RCo assay, most anti-VWF [188,189], limited evolving information supports the antibodies are not inhibitors of VWF function. The concept that, despite the ABO blood grouping and presence of these antibodies, however, promotes associated VWF reference ranges, the major deter- rapid clearance of VWF. The plasma level of the minant of bleeding symptoms or risk is low VWF VWFpp is normally proportionate to the level of [184,190,191]. Therefore, referencing VWF testing VWF:Ag, and the VWFpp level can be measured to results to the population reference range, rather than aid in the detection of the rapid clearance of VWF. to ABO-stratified reference ranges, may be more Accelerated plasma clearance of VWF:Ag — as useful clinically. occurs in some patients with AVWS, in those who have certain type 1 VWD variants, or in those who have type 3 VWD and have alloantibodies to VWF — is associated with an increase in the ratio of Table 10. Influence of ABO blood groups on VWF:Ag. VWFpp to VWF:Ag [196,197]. Persons with type 3 )1 ABO VWF:Ag Range, U dL VWD, with large deletions of the VWF gene, are )1 )1 type Number mean (U dL ) (IU dL ) prone to develop alloantibodies to transfused VWF O 456 74.8 35.6–157.0 (41–179) [198]. Patients who have AVWS, VWF antibodies or A 340 105.9 48.0–233.9 (55–267) mutations that affect VWF clearance can be studied B 196 116.9 56.8–241.0 (65–275) using VWF-survival testing after administration of AB 109 123.3 63.8–238.2 (73–271) desmopressin or VWF concentrate. VWF:Ag, von Willebrand factor antigen. Modified from Gill et al. [45]. Used with permission. In this ) publication, VWF:Ag was expressed as U dL 1 (units per deciliter), Making the diagnosis of VWD ) but the range in IU dL 1 (WHO) is higher for all blood groups, as noted in the values in parentheses (R. R. Montgomery, J. L. Endres Scoring systems and criteria for assessing the bleed- and K. D. Friedman, personal communication). ing history and the probability of having VWD,

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 195 especially type 1 VWD, are evolving and have not yet testing with respect to the menstrual cycle is not been subjected to prospective studies outside defined clear. Family studies may be helpful to diagnose populations [149,189]. Establishing the diagnosis of hereditary decreases in VWF levels. VWD in persons with type 2 VWD variants and type Blood sample collection and processing. Problems 3 VWD is usually straightforward, based on the may occur in preparing samples for testing. As noted initial VWD tests (VWF:Ag, VWF:RCo and FVIII). above, anxiety may falsely elevate the VWF and Treatment depends on the specific subtype (e.g. type FVIII levels, and the setting for phlebotomy should 2A, 2B, 2M or 2N), which is determined by be as calm as possible. It is important that the sample additional tests, including VWF multimer analysis. be obtained by atraumatic collection of blood, drawn In contrast, the diagnosis of type 1 VWD is often into the appropriate amount of citrate anticoagulant. more difficult [22,46,95,199,200], partly because not The College of American Pathologists, as well as the all persons who have decreased levels of VWF have a Clinical Laboratory Standards Institute (formerly the molecular defect in the VWF gene. Whether individ- National Committee for Clinical Laboratory Stan- uals who do not have an abnormality in the VWF dards, commonly known as NCCLS), recommends gene should be diagnosed as having VWD or should collecting blood into 3.2% citrate, although some be given another designation is currently under laboratories still use 3.8% citrate. Fasting or non- consideration (see Type 1 VWD vs. Low VWF). lipaemic samples should be used for testing, and The reasons for reduced VWF levels in many of these icteric or haemolysed samples may also compromise persons who have a normal VWF gene sequence are the quality of testing results [188,201]. If a person not understood. A ÔlowÕ VWF level is believed to has polycythemia or profound anaemia, the amount confer some bleeding risk, despite the presence of a of anticoagulant should be adjusted on the basis of normal VWF gene, and those persons who have nomograms designed for this purpose. Blood should clinical bleeding and low VWF concentrations may be centrifuged promptly to obtain plasma, and the benefit from treatment to raise the VWF level. Most plasma should remain at room temperature if assays clinicians would agree that persons having VWF are to be completed within 2 h. Whole blood should ) levels <30 IU dL 1 probably have VWD. It is likely not be transported on wet ice (or frozen) [202,203]. that most of these persons have a mutation in the If plasma samples are frozen, they should be thawed VWF gene. Currently, several large European Union, at 37C to avoid formation of a cryoprecipitate. Canadian and US studies are trying to define that Plasma assays should be performed on platelet-poor frequency. Persons whose plasma VWF levels are or platelet-free plasma [188]. Although a small below the lower limit of the laboratory reference number of platelets may not greatly affect studies ) range, but higher than 30 IU dL 1, may have VWD done on fresh plasma, freezing these samples may but are sometimes referred to as having Ôpossible type result in the release of proteases or platelet mem- 1 VWDÕ or Ôlow VWFÕ. There is no generally brane particles that affect plasma assays for VWF. accepted designation for these persons. Although Thus, plasmas should be centrifuged carefully. Some type 3 VWD is usually the result of inheriting two laboratories perform double centrifugation to ensure null alleles, the heterozygous carriers in these families platelet removal. The integrity of samples may suffer do not universally have a history of serious bleeding; during transport to an outside laboratory, and steps therefore, type 3 VWD has been called a recessive should be taken that can best ensure prompt delivery disorder [22,46,103]. of frozen samples. Table 11 provides additional information about collection and processing of blood and plasma samples for laboratory testing. Special considerations for laboratory diagnosis of VWF reference standards. The VWF reference VWD standard is critical to the laboratory diagnosis of Repeated laboratory testing. Repeated testing for VWD. When possible, all laboratory assays of VWF VWD is sometimes needed to identify low levels of should use the same standard to avoid artifactual VWF. Stress — including surgery, exercise, anxiety, discrepancies. Results of VWF assays can be reported crying in a frightened child, as well as systemic in IUs only if they have been referenced to the WHO inflammation, pregnancy or administration of oes- standard for that analyte. If a reference plasma pool trogen or oral contraceptives — can increase plasma is used, it is usually reported as a percentage of levels of VWF and mask lower baseline values. VWF normal, as it cannot be called an IU. To assist the ) levels vary with the menstrual cycle, and lowest comparison, IUs are usually expressed as IU dL 1 so values are detected on days 1–4 of the menstrual that the reported values have the same range as cycle. However, the importance of timing of the values reporting a percentage of normal plasma.

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Table 11. Collection and handling of plasma samples for Diagnostic recommendations laboratory testing. The recommendations are graded according to crite- Phlebotomy conditions – An atraumatic blood draw limits the ria described in Table 1. Diagnostic Recommenda- exposure of tissue factor from the site and the activation of clotting factors, minimizing falsely high or low values tions I–III summarize the PanelÕs patient diagnostic Patient stress level – Undue stress, such as struggling or crying in recommendations. Evidence Tables 1–5 are provided children or anxiety in adults, may falsely elevate VWF and FVIII in the full online document [10] for recommenda- levels. Very recent exercise can also elevate VWF levels. tions given a grade of B and having two or more Additional conditions in the person – The presence of an acute or references. chronic inflammatory illness may elevate VWF and FVIII levels, The recommendations that follow (Diagnostic as may pregnancy or administration of oestrogen or oral Recommendations I, II and III) include specific contraceptives Sample processing – To prevent cryoprecipitation of VWF and clinical history, physical findings, laboratory assays, other proteins, blood samples for VWF assays should be and diagnostic criteria that this Panel suggests will transported to the laboratory at room temperature. Plasma provide the most definitive diagnosis of VWD. should be separated from blood cells promptly at room In addition, the Panel suggests the following with temperature, and the plasma should be centrifuged thoroughly to regard to laboratory testing (Diagnostic Recommen- remove platelets. If plasma samples will be assayed within 2 h, dations II). (i) Tests such as the BT, PFA-100 or other they should be kept at room temperature. Frozen plasma samples automated functional platelet assays have been used, should be carefully thawed at 37C and kept at room temperature for <2 h before assay. but there are conflicting data with regard to sensi- Sample storage – Plasma samples that will be stored or transported tivity and specificity for VWD [157,159,161]. There- to a reference laboratory must be frozen promptly at or fore, the Panel believes current evidence does not below )40C and remain frozen until assayed. A control sample support their routine use as screening tests for VWD. that is drawn, processed, stored and transported under the same (ii) The Panel believes that platelet-based assays conditions as the tested personÕs sample may be helpful in should be used for the ristocetin cofactor method indicating problems in the handling of important test samples. (VWF:RCo assay). (iii) The Panel emphasizes the FVIII, factor VIII; VWF, von Willebrand factor. importance of the timing of the phlebotomy for Laboratory testing variables. Laboratory variables assays, with the patient at his or her optimal baseline also occur. The variability (CV) of the VWF:RCo as far as possible. (For example, VWF levels may be assay is high (‡20–30%), and the CV of the VWF:Ag elevated above baseline during the second and third assay is also relatively high (‡10–20%), as is the CV trimesters of pregnancy or during oestrogen therapy, for the FVIII assay [170,172–174,178,204–206]. The during acute inflammation such as the perioperative quality of laboratory testing also varies considerably period, during infections and during acute stress.) among laboratories (high interlaboratory CV). Cou- The careful handling and processing of the sample pled with variability of VWF and FVIII contributed are also critical, particularly if the sample will be sent by conditions of the patient and the blood sample, for testing at a remote location. the high variability of these three diagnostic tests can Laboratory testing should be guided by the contribute to difficulty in diagnosing VWD or history and physical findings (Diagnostic Recom- classifying the VWD subtype (e.g. type 1 vs. type 2 mendations I) and the initial laboratory evaluation variant, using the VWF:RCo/VWF:Ag ratio). Some (Diagnostic Recommendations II). For example, of the more specialized tests, such as VWF multimer findings of liver disease may lead to a different or analysis likely also have high variability of test additional laboratory evaluation rather than an performance and interpretation [175,176], and they evaluation for VWD. Diagnostic Recommendations are often not available at local testing laboratories. III detail recommendations for synthesis of clinical findings and laboratory test results to make the Summary of the laboratory diagnosis of VWD The diagnosis of VWD. diagnosis of VWD can be complex, and no single diagnostic approach is suitable for all patients. Diagnostic Recommendations I Improvements in laboratory testing and quality, along with further research into the frequency of I. Evaluation of Bleeding Symptoms and Bleeding mutations of the VWF gene, alterations of other Risk by History and Physical Examination* proteins that result in reduced VWF levels, and the correlation of clinical symptoms with laboratory test A. Ask the following broad questions: levels are necessary to place the diagnosis of VWD on 1. Have you or a blood relative ever needed a more secure foundation. medical attention for a bleeding problem, or have

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you been told you had a bleeding problem? See Evidence Table 1 [10] for additional detail and Grade B, level IIb [135] information. If the answer is ÔYesÕ to either of the broad questions above, ask the additional probes: C. Perform a physical examination to include eval- a. Have you needed medical attention for uation for bleeding? After surgery? After dental work? 1. Evidence for bleeding disorder, including size, With trauma? location, and distribution of ecchymoses (e.g. b. Have you ever had bruises so large they truncal), haematomas, petechiae, and other evi- had lumps? dence of recent bleeding and/or anaemia. Grade B, level IIb [135] Grade C, level IV 2. Do you have or have you ever had: 2. Evidence that suggests other causes or risks of a. Liver or kidney disease? increased bleeding, such as jaundice or spider b. A blood or bone marrow disorder? A high angiomas (liver disease), splenomegaly, arthropa- or low platelet count? thy, joint and skin laxity (e.g. Ehlers-Danlos If the answer is ÔYesÕ to any of these questions, syndrome), telangiectasia (e.g. hereditary haem- obtain relevant details. orraghic telangiectasia), or evidence of anatomic Grade C, level IV lesion on gynaecologic examination. 3. Are you currently taking, or have you recently Grade C, level IV taken anticoagulation or antiplatelet medications *Summarized in Fig. 3 and Table 9. (warfarin, heparin, aspirin, nonsteroidal anti- inflammatory drugs, clopidogrel)? Diagnostic Recommendations II If the answer is ÔYesÕ, obtain relevant details. Grade C, level IV II. Evaluation by Laboratory Testing* B. If answers to questions I.A.1 are positive, ask if A. Initial laboratory evaluation for the aetiology of a the patient or any blood relatives have had the bleeding disorder should include the following: following: 1. A complete blood cell count (including plate- 1. A bleeding disorder, such as von Willebrand let count), prothrombin time, activated partial disease or haemophilia? thromboplastin time (PTT), and optionally either 2. Prolonged, heavy, or recurrent bleeding from thrombin time or fibrinogen level. a. Trivial wounds, lasting more than 15 min 2. If laboratory abnormalities besides the PTT or recurring spontaneously during the 7 days are present (the platelet count may also be after the wound? decreased in type 2B von Willebrand disease b. Surgical procedures, such as tonsillectomy? [VWD]), in conjunction with the history and 3. Bruising with minimal or no apparent trauma, physical examination findings, consider bleeding especially if you could feel a lump? disorders other than VWD or additional underly- 4. Spontaneous nosebleeds that required more ing diseases. than 10 min to stop or needed medical attention? 3. If the mucocutaneous bleeding history is 5. Dental extractions leading to heavy, pro- strong, consider performing initial VWD assays longed, or recurrent bleeding? at the first visit (see II.B, below). 6. Blood in your stool, unexplained by a specific 4. If there are no abnormalities on initial blood anatomic lesion (such as an ulcer in the stomach testing or if there is an isolated prolonged PTT or a polyp in the colon), that required medical that corrects in the 1:1 mixing study, the follow- attention? ing 3 tests for VWD should be performed (II.B, 7. Anaemia requiring treatment or received a below), unless another cause for bleeding has been blood transfusion? identified and VWD is not likely (see Fig. 4). For 8. For women, heavy menses, characterized by further laboratory evaluation, physicians may the presence of clots larger than 1 inch and/or consider referral to a haemostasis center because changing a pad or tampon more than hourly or of the special sample handling and testing require- resulting in anaemia or low iron level? ments (see Table 11). If answers to questions I.B.1–8 are positive, Grade C, level IV obtain relevant specific information, including B. Initial tests for diagnosing or excluding VWD history of treatment (e.g. blood transfusion). include the following three tests: Grade B, level IIb [135,148]

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1. Von Willebrand factor ristocetin cofactor See Evidence Table 5 [10] for additional informa- activity (VWF:RCo). tion and detail. 2. Von Willebrand factor antigen (VWF:Ag). 3. Additional studies in selected persons may 3. Factor VIII activity (FVIII). include the following: Grade B, level III [3,45,170,171] a. Gene sequencing. See Evidence Table 2 [10] for additional detail and Grade C, level IV information. b. Assays for antibodies to VWF. Grade C, level IV C. If any of the above test results is abnormally c. Platelet-binding studies. low, a discussion with or a referral to a haemo- Grade B, level III [177] stasis expert is appropriate. In addition to repeat- *Laboratory testing should be guided by the ing the initial three tests (in most cases), the history and physical findings (Diagnostic Recom- specialist may recommend appropriate studies from mendations I) and results of the initial laboratory the following: evaluation (II.A, above). For example, findings of 1. The first set of additional tests may include liver disease may lead to a different or additional a. Evaluation of the ratio of VWF activity laboratory evaluation rather than an evaluation for (VWF:RCo and/or von Willebrand factor colla- VWD (II.B, above). gen-binding activity [VWF:CB]) to VWF:Ag (only in laboratories that have defined reference ranges for the ratio[s]). Diagnostic Recommendations III Grade B, level III [72,73,93,158,170,185] See Evidence Table 3 [10] for additional informa- III. Making the Diagnosis tion and detail. A. Clinical criteria. These criteria include personal b. VWF multimer study. and/or family history and/or physical evidence of Grade B, level III [176] mucocutaneous bleeding. Until further validation of c. Ristocetin-induced platelet aggregation scoring systems and criteria for assessing bleeding (RIPA). history and the probability of von Willebrand Grade B, level III [48] disease (VWD), especially type 1 VWD, the Expert d. VWF:CB. Panel suggests that an increasing number of positive Grade B, level IIb [170,180,181] responses to the questions about bleeding (Diagnos- See Evidence Table 4 [10] for additional informa- tic Recommendations I; Fig. 3; Table 9) and abnor- tion and detail. mal findings on physical examination increase the 2. Studies in selected patients, especially those likelihood that an individual has a bleeding disorder, who have discordantly low FVIII activity com- including possible VWD. pared to von Willebrand factor (VWF) levels and who are suspected of having type 2N VWD, AND should include a FVIII binding assay (VWF:FVIIIB). B. Laboratory criteria. The values in the following Grade B, level IIb [79,80,183] table represent prototypical cases without additional

) ) Condition VWF:RCo (IU dL 1) VWF:Ag (IU dL 1) FVIII Ratio of VWF:RCo/VWF:Ag Type 1 <30* <30* fl or normal >0.5 to 0.7 Type 2A <30* <30–200* fl or normal <0.5 to 0.7 Type 2B <30* <30–200* fl or normal Usually <0.5 to 0.7 Type 2M <30* <30–200* fl or normal <0.5 to 0.7 Type 2N 30–200 30–200 flfl >0.5 to 0.7 ) Type 3 <3 <3 flflfl (<10 IU dL 1) Not applicable ÔLow VWFÕ 30–50 30–50 Normal >0.5 to 0.7 Normal 50–200 50–200 Normal >0.5 to 0.7 FVIII, factor VIII; VWD, von Willebrand disease; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von Willebrand factor ristocetin cofactor activity. fl refers to a decrease in the test result compared to the laboratory reference range. ) *Less than 30 IU dL 1 is designated as the level for a definitive diagnosis of VWD; some patients with type 1 or type 2 VWD have levels of ) VWF:RCo and/or VWF:Ag of 30-50 IU dL 1. ) The VWF:Ag in the majority of individuals with type 2A, 2B or 2M VWD is <50 IU dL 1.

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 199 von Willebrand factor (VWF) (or other disease) of VWD, the severity of the haemostatic challenge, abnormalities in the patient. In practice, exceptions and the nature of the actual or potential bleeding. occur, and repeated testing and clinical experience Because some persons who have a VWF:RCo level ) are important and may be necessary for interpreta- higher than 30 IU dL 1 manifest clinical bleeding, tion of laboratory results. persons not having a definite diagnosis of VWD but 1. Although published evidence is limited, for who have low VWF and a bleeding phenotype may defining the ratio of VWF:RCo/VWF:Ag to use for merit treatment or prophylaxis of bleeding in certain distinguishing type 1 VWD versus type 2 VWD clinical situations [191]. variants (A, B, or M), the Expert Panel recom- Infusions of VWF to prevent bleeding episodes — mends a ratio of less than 0.5–0.7 until more known as prophylaxis — are less frequently required in laboratories clearly define a reference range using patients with severe VWD in contrast to patients with large numbers of normal subjects and persons severe haemophilia. The Centers for Disease Control with type 1 VWD and type 2 VWD variants. and Prevention Universal Data Collection Project Web Grade C, level IV [72,73,93,158,184,185] site [207] reports that 45% of patients with severe 2. The Panel currently recommends that haemophilia A use some type of prophylaxis, either ) 30 IU dL 1 be used as the cutoff level for sup- continuous or intermittent, compared with 10% of porting the definite diagnosis of VWD for the patients with severe VWD. Risks and benefits of following reasons: prophylaxis should be carefully weighed when con- • There is a high frequency of blood type O in sidering long-term therapy for VWD [208,209]. the United States, and it is associated with ÔlowÕ Treatment of VWD in the United States varies VWF levels [45]. widely and frequently is based on local experience • Bleeding symptoms are reported by a signifi- and physician preference. Few standard recommen- cant proportion of normal individuals [134– dations exist to guide therapy for VWD [6,7,9]. This 136,148]. guideline document presents recommendations • No abnormality in the VWF gene has been regarding the management and prevention of bleed- identified in many individuals who have mildly to ing in persons with VWD and reviews the strength of moderately low VWF:RCo levels. evidence supporting those recommendations. Grade C, level IV [102–104] This recommendation does not preclude the diag- Non-replacement therapy with desmopressin to nosis of VWD in individuals who have VWF:RCo of ) elevate VWF 30–50 IU dL 1 if there is supporting clinical and/or family evidence for VWD. This recommendation also Mechanism of action of desmopressin Desmopressin does not preclude the use of agents to increase VWF (DDAVP) is a synthetic derivative of the antidiuretic ) levels in those who have VWF:RCo of 30–50 IU dL 1 hormone, vasopressin. Desmopressin has been used and may be at risk for bleeding. to treat VWD for more than 25 years, and its pharmacology, mechanism of action and indications have been reviewed extensively [210–212]. Desmo- Management of VWD pressin stimulates the release of VWF from endothelial cells through its agonist effect on vasopressin V2 Introduction receptors [210,211,213]. The mechanism by which Therapies to prevent or control bleeding in persons desmopressin increases plasma concentration of with VWD follow three general strategies. The first VWF is probably through cyclic adenosine mono- strategy is to increase the plasma concentration of phosphate (cAMP)-mediated release of VWF from VWF by releasing endogenous VWF stores through endothelial cell Weibel-Palade bodies [213,214]. stimulation of endothelial cells with desmopressin. FVIII levels also increase acutely after administration The second approach is to replace VWF by using of desmopressin, although the FVIII storage com- human plasma-derived, viral-inactivated concen- partment and the mechanism of release by desmo- trates. The third strategy uses agents that promote pressin have not been fully elucidated [12,215]. haemostasis and wound healing but do not substan- Desmopressin induces the release of tissue plasmin- tially alter the plasma concentration of VWF. The ogen activator (tPA) [216,217]. However, the three treatment options are not mutually exclusive, secreted tPA is rapidly inactivated by plasminogen and patients may receive any one or all three classes activator inhibitor type 1 (PAI-1) and does not of agents at the same time. The appropriateness of appear to promote fibrinolysis or bleeding after therapeutic choice depends on the type and severity desmopressin treatment.

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 200 W. L. NICHOLS et al.

Table 12. Intravenous desmopressin effect on plasma concentrations of FVIII and VWF in normal persons and persons with VWD. Mean increase (fold)*

Group/source Number VWF:RCo VWF:Ag FVIII Type of evidence Normals Mannucci et al. [218] 10 NA 3.3 4.5 Case series Lethagen et al. [219] 10 NA 2.7 3.7 Case series VWD Type 1 Mannucci et al. [218] 15 NA 3.6 5.5 Case series de la Fuente et al. [220] 13 5.0 4.5 5.7 Case series Mannucci et al. [94] 7 9.5 9.0 10.3 Case series Rodeghiero et al. [221] 14 NA NA 7.8 Case series Mannucci et al. [222] 15 5.1 4.8 4.3 Case series Revel-Vilk et al. [223] – 91% response rate 56 NA NA NA Retrospective review Federici et al. [224] – 27% response rate 26 3.1 NA 3.3 Case series Type 1, Vicenza (ultralarge multimers) Mannucci et al. [94] 6 9.1 8.3 10.2 Case series Rodeghiero et al. [221] 5 NA NA 10 Case series Type 1, severeà Revel-Vilk et al. [223] – 36% response rate 14 NA NA NA Retrospective review Federici et al. [224] – 27% response rate 26 3.1 NA 1.4 Case series Type 1, severe with normal platelet VWF Rodeghiero et al. [225] 14 NA NA 7.8 Case series Mannucci et al. [101] – 6/6 with increase 6 NA NA NA Case series in FVIII, VWF:RCo and VWF:Ag Type 1, Ôplatelet lowÕ Mannucci et al. [101] – 7/7 with increase in 7 NA NA NA Case series FVIII; 0/7 with increase in VWF:RCo or VWF:Ag Rodeghiero et al. [221] – 2/2 with increase 2 NA NA 2.1 Case series in FVIII; VWF response not reported Type 2A de la Fuente et al. [220] – 86% response rate 7 6.4 4.9 4.9 Case series Revel-Vilk et al. [223] – 40% response rate, 5 4.2 NA 2.9 Retrospective review results given for responders only Federici et al. [224] – 7% response rate 15 2.6 NA 3.4 Case series Type 2B Casonato et al. [66] 4 2.3 3.5 3.0 Case series McKeown et al. [226] 3 3.2 3.2 3.6 Case series Castaman and Rodeghiero [227] 33 Normalized Normalized Normalized in 18/33 in 33/33 in 33/33 Type 2M Federici et al. [224] – 14% response rate 21 3.3 NA 3.0 Case series Type 2N Mazurier et al. [228] 8 1.4 2.2 9.7 Case series Federici et al. [224] – 75% response rate 4 3.8 NA 6.6 Case series Type 3 Castaman et al. [229] – 0% response rate 6 1.8 8.6 2.5 Case series FVIII, factor VIII; NA, not available; VWD, von Willebrand disease; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von Willebrand factor ristocetin cofactor. *Data are given as mean fold increase in plasma factor compared to baseline after a single administration of desmopressin. Mean fold increases were calculated from original data, where possible, if not included in the manuscript. ) Response deﬁned as twofold increase AND to at least 30 IU dL 1 VWF:RCo and FVIII. ) ) àVWF:RCo <10 IU dL 1 OR bleeding time >15 min OR FVIII <20 IU dL 1.

Desmopressin dosing and administration Table 12 VWD [66,94,101,218–229]. When administered displays published reports of desmopressin effects intravenously (i.v.) to normal persons as well as to on laboratory assays of VWF and FVIII in normal patients with VWD or mild haemophilia, desmo- persons and persons who have various subtypes of pressin consistently increases plasma VWF and FVIII

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 201 from twofold to more than fivefold over baseline traemia may complicate repeated desmopressin dos- levels [94,215,218–223]. Children younger than ing, and fluid restriction and serum sodium 2 years have a lower response rate than older monitoring are recommended. children [223]. Two controlled prospective studies Desmopressin can also be administered subcuta- in healthy volunteers form the basis for desmopressin neously (s.c.) or intranasally [218,219,230]. The dosing recommendations [218,219]. Maximal FVIII effective s.c. dose is identical to the i.v. dose, but ) response was determined at 0.3 lgkg 1 in both the s.c. preparation is not available in the United studies, while maximal VWF release data were States. The preparation of desmopressin for nasal ) determined at 0.2 and 0.3 lgkg 1 in the same two instillation (Stimate) contains 150 lg of desmo- studies. On the basis of these data, standard dosing pressin per metered nasal puff (0.1 mL of a ) ) of desmopressin is 0.3 lgkg 1 given i.v. in 30– 1.5 mg mL 1 solution). The dose is one puff for 50 mL of normal saline over 30 min, with peak persons who weigh <50 kg and two puffs (one puff increments of FVIII and VWF 30–90 min after the to each nostril) for persons weighing 50 kg or infusion [215,219,220,230]. Nasal administration of more. Although the intrasubject and intersubject high-dose desmopressin acetate (Stimate; CSL Beh- CV for reproducibility of nasal spray effect is ring, King of Prussia, PA, USA) is often effective for good, nasal absorption is variable and all patients minor bleeding, but i.v. administration is the pre- with VWD and who are responsive to i.v. desmo- ferred route for prophylaxis of surgical bleeding and pressin should undergo a trial of nasal desmopres- for treatment of major haemorrhage. sin (Stimate) to measure FVIII and VWF response A retrospective review of desmopressin adminis- before using it [219]. When used for epistaxis, tration to 56 children who had non-severe type 1 intranasal desmopressin ideally is delivered into the VWD found a 91% response rate, defined as a non-bleeding nostril. Persons who have inadequate twofold increase in FVIII and VWF activity, to at plasma responses to i.v. desmopressin will not ) least 30 IU dL 1 [223]. In a small case series of VWD respond to intranasal desmopressin. patients, the consistency of FVIII increments and the Another nasal formulation of desmopressin for responses of the BT after a second test dose of enuresis contains 10 lg per puff (about 7% of the desmopressin were within 10–20% of the initial Stimate concentration); however, this preparation is values [221]. Evidence shows that response to not suitable for treatment of VWD. Patients and desmopressin diminishes with repeated doses, prob- parents must be carefully instructed regarding the ably because of depletion of the VWF storage two concentrations of nasal desmopressin — the one ) compartment [215,218]. However, when desmopres- used for bleeding (1.5 mg mL 1) and the one used sin was given in four daily doses to 15 patients who for antidiuretic hormone replacement (diabetes in- ) had type 1 VWD, an increase in FVIII activity of at sipidus) and bedwetting (0.1 mg mL 1) — to avoid least twofold was found in 100% of the patients after accidental underdosing for VWD. the first administration, in 80% after the second, in 87% after the third and in 74% after the fourth Monitoring of VWD patients receiving administration [222]. desmopressin Treatment of patients who have Consistency of response to desmopressin has been VWD with desmopressin should be based on results studied using three to four once-daily doses of a therapeutic trial, ideally one performed in [218,222]. A series of 15 type 1 VWD patients patients in a non-bleeding state and before general showed a mean increase of VWF:RCo to fivefold clinical use. Although the pattern of desmopressin above baseline after the first dose of desmopressin, responsiveness is fairly consistent within VWF sub- significantly decreased response to fourfold after the types, population results should not be used to plan second daily dose, and no significant change in treatment of individual patients (Table 12). response between the second and third and third and VWF:RCo and FVIII activities should be measured fourth doses [222]. The proportion of VWD patients in all VWD patients at baseline and within 1 h after attaining at least a twofold increase in FVIII activity administering desmopressin. Additional assay of after the second to fourth daily doses – 80% after the VWF:RCo and FVIII, done 2–4 h after desmopressin second daily dose of desmopressin to 74% after the administration, will evaluate for shortened survival fourth dose – was substantially higher than that for and should be considered for patients who have a haemophilia A patients (55% vs. 37%). There is no history of poor response to treatment [43]. published evidence regarding response to desmopres- According to conservative definitions of laboratory sin given every 12 h to compare with daily dosing of response, the majority of patients with type 1 VWD desmopressin. In addition to tachyphylaxis, hypona- respond adequately to desmopressin (Table 12).

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 202 W. L. NICHOLS et al.

Single infusions of desmopressin for common bleed- released FVIII may be severely decreased, with an ing episodes — such as epistaxis, simple dental apparent plasma half-life as low as 2 h, depending on extraction or menorrhagia — do not usually require the mutation [163,228]. Emerging information sug- laboratory monitoring. Patients should be monitored gests that some individuals with type 1 VWD have for VWF:RCo activity as well as FVIII activity accelerated plasma clearance of VWF and may around major surgical procedures or major bleeding beneﬁt from trial testing of VWF:RCo 2–4 h after a events. For major surgical procedures or bleeding dose of desmopressin [42,235]. events, patients with VWD should be referred to After infusion of desmopressin into patients with hospitals with in-house or daily laboratory availabil- type 2B VWD, VWF multimers of larger but still ity of FVIII and VWF:RCo activity assays. Care somewhat less than normal molecular weight can be should be taken to monitor serum electrolytes, detected in plasma after 15–30 min, with persistence especially after surgery or multiple doses of desmo- throughout 4 h of study [65,163,234,236]. Although pressin. Adult patients, especially those who are formal pharmacokinetic studies have not been elderly, should be evaluated for cardiovascular dis- reported for type 2B VWD, VWF:RCo activity ease before using desmopressin because myocardial increases were less than that seen in type 1 VWD infarction rarely has been precipitated by desmo- with an apparent half-life of approximately 4 h pressin therapy in patients with haemophilia or [65,226]. Bleeding time response to desmopressin in uraemia [231–233]. type 2B VWD is inconsistent [226,227].

Pharmacokinetics of VWF and FVIII after Clinical response to desmopressin in VWD The clinical desmopressin After stimulation with desmopressin, effectiveness of desmopressin to prevent or control released VWF and FVIII circulate with an apparent bleeding depends, in large part, on the plasma half-life characteristic of the patientÕs own proteins, VWF:RCo or FVIII activity achieved after drug or approximately 8–10 h for both proteins in normal administration, which in turn depends primarily on individuals [215]. Type 2 VWF proteins that are the basal levels of plasma FVIII and VWF:RCo and released by desmopressin increase in concentration to a lesser extent on the underlying qualitative VWF but retain their intrinsic molecular dysfunction defect [66,94,101,218–229]. Table 13 and Evidence [234]. For this reason, desmopressin has been efﬁca- Tables 7–11 [10] summarize published data on the cious in only a minority of patients with types 2A or clinical response when using desmopressin in con- 2M VWD. Therefore, monitoring is necessary to junction with common surgical procedures document adequate correction of VWF:RCo. Type [133,215,220,223,225,227,229,237–247]. All data 2N VWF lacks FVIII stabilization; consequently, were derived from retrospective studies and small patients with 2N VWF release FVIII and the abnor- case series; there are no randomized-clinical trials of mal VWF protein as expected, but the survival of the use of desmopressin in persons with VWD.

Table 13. Clinical results of desmopressin treatment in patients with von Willebrand disease*. Surgical prophylaxis Number Frequency Duration Other treatment Bleeding outcome Adults Dental procedures 113 Once Once or Antifibrinolytics Excellent/good in 109/113 [65,66,220,225,227,229,237–241,380,396] twice Gynaecological [215,220,238,239] 9 Daily 1–7 days Antifibrinolytics 2/7 Delayed bleeding in 2/9 requiring extended desmopressin treatment for 3 and 6 days Surgery [215,220,229,239,242,255,380] 26 Daily 1–5 days Excellent/good in 25/26 Haemorrhage after 1 rhinoplasty Children Primarily tonsillectomy and 146 Once or 1–7 days Antifibrinolytics Excellent/good in 125/146 adenoidectomy [241–247] twice daily in most for 7 days Primarily tonsillectomy/adenoidectomy [261] 119 NA NA NA Excellent/good in 105/119 Otologic surgery [242] 6 Daily 2 days Excellent/good in 6/6 NA, not available. *For additional detail and information, see Evidence Tables 7–11 [10].

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Whether desmopressin will be adequate for pro- desmopressin complicates the management of fluids phylaxis around surgery or for treatment of bleeding and electrolytes for surgery or during childbirth. events in persons with type 1 VWD depends on the Seizures have been associated with hyponatraemia severity of the haemostatic challenge and the time after desmopressin administration, primarily in young required for healing. Major surgery requires children [257,260]. Most paediatric haematologists haemostasis for 7–14 days [239,248–253], whereas do not use desmopressin in children <2 years old minor surgical procedures can be treated adequately [223,260,261]. in 1–5 days [239,245,246,253]. If treatment is nec- Myocardial infarction after treatment with desmo- essary for more than 3 days, VWF concentrate is pressin has been reported, although rarely, in usually given to supplement therapy with desmopres- patients with mild haemophilia A [231,233,262]. sin [239,246]. Currently, however, expert opinions Desmopressin should be avoided in patients who are are divided regarding the risk of delayed haemor- at very high risk for cardiovascular or cerebrovascu- rhage 5–10 days after a bleeding challenge in VWD lar disease, especially the elderly, as underlying patients, e.g. those who have had tonsillectomy or inhibition of plasminogen activation with desmo- given birth. In small case series, persons with type 1 pressin-related vasoconstriction contributes addi- VWD Vicenza manifested an exaggerated response to tional prothrombotic effects in these patients [263]. desmopressin [43,94,221]. Individuals with type 2N Because of reported complications in other patient VWD exhibit a brisk rise in plasma FVIII after populations, desmopressin should be used with receiving desmopressin, but they have a mean FVIII caution for brain, ocular and coronary artery sur- half-life of only 3 h because of deficient FVIII geries [232,264,265], and VWF concentrate replace- stabilization by the defective VWF [228]. Persons ment generally is used in these settings. with low-platelet VWF or type 2A VWD have a low Desmopressin does not appear to increase myome- likelihood of having a clinically relevant desmopres- trial contractility greatly; consequently, pregnancy is sin response, but they may warrant a desmopressin not an absolute contraindication [266–269] but use trial [221,224]. Type 2B VWD previously was a of desmopressin is rarely indicated (see Pregnancy). contraindication to desmopressin therapy because platelet counts usually fell after desmopressin stimu- Replacement therapies to elevate VWF concentration: lation [254]. However, thrombocytopenia after des- VWF concentrates mopressin in type 2B VWD is usually transient and often is not associated with bleeding or thrombosis As of January 2007, Humate-P (CSL Behring) and [255]. In patients with type 2B VWD, decrease in Alphanate SD/HT (Grifols USA, Los Angeles, CA, platelet count after desmopressin administration has USA) are plasma-derived concentrates licensed in been considered ÔpseudothrombocytopeniaÕ by some the United States to replace VWF in persons who authors because it is related to platelet agglutination have VWD. One other plasma derivative — Koate in vitro rather than in vivo agglutination and clear- DVI (Talecris Biotherapeutics USA, Research ance [65,236]. Therefore, desmopressin may be Triangle Park, NC, USA) — is licensed in the cautiously considered for patients with type 2B United States to treat haemophilia and has been VWD. Patients with type 3 VWD almost never used off-label for VWD. These products are not experience a clinically relevant rise in VWF:RCo or identical, having differing ratios of FVIII to VWF, FVIII activities, and desmopressin is not considered and should not be considered as interchangeable clinically useful in these patients [223,224]. [270–272]. All these products are manufactured at US-licensed facilities from pooled plasma collected Complications and toxic effects of desmopressin Minor from paid donors. adverse effects of desmopressin are common and Products that contain FVIII and little or no VWF include facial flushing, transient hypertension or are generally not useful to treat VWD, but in rare hypotension, headache or gastrointestinal upset circumstances these products may be used to treat [211,212,256], but these effects rarely limit clinical patients who have antibody-mediated AVWS [273]. use. Water retention after a dose of desmopressin, with These products include the plasma-derived concen- an increase in urinary osmolality, is universal; how- trates Monoclate P (CSL Behring), Monarc-M ever, decreased serum sodium in otherwise healthy (Blood Diagnostics, Inc., Irmo, SC, USA) and adults is variable and is related to multiple doses Hemofil M (Baxter Healthcare Corp., Deerfield, IL, [256,257]. In the case of repeated dosing, all patients USA) and recombinant products Helixate FS (CSL should be instructed to limit fluid intake to mainte- Behring), Kogenate FS (Bayer HealthCare, Berkeley, nance levels for 24 h [258–260]. Prophylactic use of CA, USA), Recombinate (Baxter Healthcare), Advate

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(Baxter Healthcare) and ReFacto (Wyeth Pharma- VWF:RCo to FVIII [249,279], and the dose or ceuticals, Philadelphia, PA, USA). frequency of dosing should not be assumed to be Humate-P, a lyophilized concentrate of purified the same for all. The ratio of VWF:RCo to FVIII for VWF and FVIII, contains other plasma proteins, Humate-P in various reports is 2.7, 2 and 1.6; for including fibrinogen and albumin. In Humate-P, the Koate-DVI, the ratio is 1.2 and 0.8 and for Alpha- quantity of the large, most haemostatically active nate, the ratio is 0.5. These products also differ in multimers of VWF is decreased compared to their relative levels of high-molecular-weight multi- fresh plasma [274]. When reconstituted at the mers. Koate-DVI, in particular, has fewer large VWF recommended volume, each millilitre of the prod- multimers compared to Alphanate SD/HT, which has ) uct contains 50–100 IU mL 1 VWF:RCo and fewer than Humate-P or normal plasma ) 20–40 IU mL 1 FVIII activity [275]. The median [272,281,282]. Recombinant VWF has been pre- half-life of VWF:RCo activity was 10.3 h (range: pared and evaluated in animal models [283] but is 6.4–13.3) in one study [275] and 11.3 h in another not available for use in humans. study [248]. The product is indicated for use in adult Cryoprecipitate, derived from plasma, historically and paediatric patients for treatment of spontaneous has been used to treat haemophilia A and VWD. and trauma-induced bleeding when use of DDAVP is Although cryoprecipitate is not required to have a thought or known to be inadequate or contraindi- specified level of VWF, the final product must have cated. Humate-P has received FDA approval for use on average at least 80 units of FVIII per standard in prophylactic management of surgery and invasive donor unit [284]. Currently, cryoprecipitate is used procedures in patients with VWD. under rare circumstances to treat VWD, such as Alphanate SD/HT is a lyophilized concentrate of when potential exposure to infectious agents can be VWF and FVIII and other plasma proteins. It is limited by using directed donations to prepare the prepared from pooled human plasma by cryoprecip- product [285]. However, the use of cryoprecipitate is itation of FVIII, fractional solubilization and further strongly discouraged by the National Hemophilia purification using heparin-coupled, cross-linked Foundation, except in life- or limb-threatening situ- agarose. Upon reconstitution to the recom- ations when no VWF concentrate is available, mended volume, each millilitre of product contains because cryoprecipitate is not virally inactivated ) 40–180 IU mL 1 FVIII activity and not less than [286]. In developing countries, patients with VWD ) 16 IU mL 1 VWF:RCo activity [276]. The median may have no other options, because virally inacti- half-life for VWF:RCo activity was 6.91 h (mean, vated plasma concentrates are not available or are 7.46 ± 3.20 h; range: 3.68–16.22) [276]. The prod- too expensive [280], but use of cryoprecipitate poses uct is indicated for bleeding prophylaxis in patients a serious risk of disease transmission [287]. with VWD, except type 3, who are undergoing VWF concentrates are dosed primarily on the basis surgical or invasive procedures and in whom desmo- of labelled VWF:RCo units and secondarily on the pressin (DDAVP) is either ineffective or contraindi- basis of labelled FVIII units. A dosing trial with cated. pharmacokinetic laboratory monitoring should be Adverse reactions to VWF concentrates are rare considered before major surgery for selected patients but include allergic and anaphylactic symptoms, with type 3 VWD or AVWS who are at risk for poor urticaria, chest tightness, rash, pruritus and oedema VWF recovery because of inhibitors. Use of VWF [250]. If these reactions occur, the infusion should be concentrates to prevent or control bleeding has been stopped, and appropriate treatment should be given clinically efficacious, as shown in Table 14. The as required. These products should be used with ultimate goal of surgical prophylaxis is to achieve a ) caution in patients who have known risk factors for therapeutic level of 100 IU dL 1 of VWF:RCo and, thrombosis, as there have been a few reports of at least for the first 3 days of treatment, a nadir of ) venous thromboembolism associated with high levels 50 IU dL 1 of VWF:RCo, as well as similar targets of FVIII [277,278]. Risk factors include old age, for FVIII [248,250–253,288]. Successful surgical previous thrombosis, obesity, surgery, immobility, haemostasis was reported with the use of continuous oestrogen therapy and use of antifibrinolytic therapy. infusion after initial bolus infusion at rates of ) If patients receive VWF replacement therapy contin- 1–2 U kg 1 per hour of VWF:RCo [249]. uously for several days, it has been recommended Replacement therapy, using a VWF concentrate, is that FVIII levels be monitored to avoid unacceptably indicated for severe bleeding events or major surgery high levels [212,278]. in patients with types 2 and 3 VWD as well as in Each of the products that contains VWF:RCo patients with type 1 VWD and who are unresponsive activity differs significantly in their ratios of to desmopressin or require protracted therapy, or

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Table 14. Efﬁcacy of VWF replacement concentrate for surgery and major bleeding events*. ) Source Number Uses Loading dose (U kg 1) Outcome Michiels et al. [252] 5 Surgery 60–80 100% Excellent–good Thompson et al. [253] 42 Surgery 82.3 100% Excellent–good Gill et al. [403] 53 Bleeding events 67 98% Excellent–good Lillicrap et al. [250] 344/73 Bleeding events/surgery 55.3/69.1 99% Excellent–good Nitu-Whalley et al. [239] 10 Surgery 54 100% Excellent–good Lubetsky et al. [251] 3/9 Bleeding events/surgery 39.5 92.5% Excellent–good Dobrkovska et al. [248] 73 Surgery 80 99% Excellent–good Hanna et al. [249] 5 Surgery 25–100à§ 100% Excellent–good Kreuz et al. [246] 26/41 Bleeding events/surgery 10–50§ 100% Excellent–good Scharrer et al. [288] 66/70 Bleeding events/surgery 20–80§ 100% Excellent–good FVIII, factor VIII; VWF, von Willebrand factor; VWF:RCo, von Willebrand factor ristocetin cofactor activity. *For additional details and information, see Evidence Table 12 [10]. ) Loading dose (VWF:RCo IU dL 1) reported as median except for Lubetsky et al. [251] (mean). àContinuous infusion was used after the loading dose. ) §Loading dose (FVIII IU dL 1).

Table 15. Suggested durations of VWF replacement for different Table 16. Initial dosing recommendations for VWF concentrate types of surgical procedures. replacement for prevention or management of bleeding. Major surgery, 7–14 days* Major surgery/bleeding ) Cardiothoracic Loading dose* 40–60 U kg 1 ) Caesarean delivery Maintenance dose 20–40 U kg 1 every 8–24 h Craniotomy Monitoring VWF:RCo and FVIII trough and peak, Hysterectomy at least daily ) Open cholecystectomy Therapeutic goal Trough VWF:RCo and FVIII >50 IU dL 1 Prostatectomy for 7–14 days ) Minor surgery, 1–5 days* Safety parameter Do not exceed VWF:RCo 200 IU dL 1 ) Biopsy: breast, cervical or FVIII 250–300 IU dL 1 Complicated dental extractions May alternate with desmopressin for latter part of treatment Gingival surgery Minor surgery/bleeding ) Central line placement Loading dose* 30–60 U kg 1 ) Laparoscopic procedures Maintenance dose 20–40 U kg 1 every 12– Other procedures, if uncomplicated, single VWF treatment 48 h Cardiac catherization Monitoring VWF:RCo and FVIII trough and peak, Cataract surgery at least once ) Endoscopy (without biopsy) Therapeutic goal Trough VWF:RCo and FVIII >50 IU dL 1 Liver biopsy for 3–5 days ) Lacerations Safety parameter Do not exceed VWF:RCo 200 IU dL 1 ) Simple dental extractions or FVIII 250–300 IU dL 1 VWD, von Willebrand disease; VWF, von Willebrand factor. May alternate with desmopressin for latter part of treatment *Individual cases may need a longer or shorter duration FVIII, factor VIII; VWF, von Willebrand factor; VWF:RCo, von depending on the severity of VWD and the type of procedure. Willebrand factor ristocetin cofactor activity. ) *Loading dose is in VWF:RCo IU dL 1. where desmopressin is contraindicated. The dose and duration of therapy depend on the haemostatic are based on published results (Table 14) as well as challenge and expected duration required for hae- consensus expert opinion. mostasis and wound healing. Major surgery requires The adequacy of courses of VWF replacement haemostasis for 7–14 days [239,248–253], whereas usually should be conﬁrmed by laboratory assessment minor surgical procedures can be treated adequately of VWF:RCo and FVIII levels, although monitoring of in 1–5 days [239,245,246,253]. Certain procedures single infusions for treatment of outpatients may not can be managed adequately by using a single infusion be necessary. Duration of VWF elevation after ) of 20–40 U kg 1 of VWF:RCo before the procedure. replacement therapy is highly variable in the surgical Table 15 lists examples of major and minor surgical setting. Thromboembolic events have been reported procedures. Table 16 lists initial dosing recommen- in patients with VWD and who are in situations of dations for use of VWF replacement therapy to high thrombotic risk and receiving VWF:RCo/FVIII prevent or treat bleeding. These recommendations complex replacement therapy, especially in the setting

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 206 W. L. NICHOLS et al. of known risk factors for thrombosis [277–279]. In all currently available in the United States, and use of patients who have VWD and are receiving VWF the i.v. form as an oral rinse (Ôswish and swallowÕ concentrate, attention should be given to avoid approach) is not an FDA-approved indication. The exceeding maximal recommended levels of VWF:RCo package insert for each drug should be consulted for and FVIII, perform proper thrombotic-risk assess- more detailed guidance and for a full list of risks and ment, and institute appropriate preventive strategies. contraindications. Both drugs can cause nausea and Human platelets contain 10–15% of total blood vomiting; less frequent but serious adverse effects VWF, and platelet transfusions have been used include thrombotic complications. Both drugs are successfully to treat bleeding in VWD patients excreted renally, and dose adjustment or avoidance is [289,290]. Platelet transfusion therapy should be advisable when significant renal insufficiency is considered as an adjunctive source of VWF, espe- present. Disseminated intravascular coagulation cially in patients with type 3 or platelet-low VWD and bleeding from the renal parenchyma or upper and PLT-VWD, to control bleeding that is non- urinary tract are relative contraindications to anti- responsive or poorly responsive to replacement fibrinolytic agents. Renovascular thrombi have fol- therapy with VWF concentrate. lowed use of antifibrinolytic agents in patients with disseminated intravascular coagulation and have caused renal failure. Patients have also experienced Other therapies for VWD urinary tract obstruction with upper urinary tract Antifibrinolytics The antifibrinolytic drugs amino- bleeding, related to large clots in the renal pelvis or caproic acid and tranexamic acid are agents that lower urinary tract. Changes in colour vision during inhibit the conversion of plasminogen to plasmin, therapy with tranexamic acid require cessation of the inhibiting fibrinolysis and thereby helping to stabilize drug and ophthalmologic examination. clots that have formed. Studies in haemophilia and in prostatectomy provided the basis for initial trials of Topical agents Topical bovine thrombin (Thrombin- antifibrinolytic agents in VWD [291]. The drugs can JMI; King Pharmaceuticals, Bristol, TN, USA) is be used orally or i.v. to treat mild mucocutaneous marketed in the United States as an aid to haemostasis bleeding in patients with VWD. In patients with for topical therapy of accessible minor bleeding from mild-to-moderate VWD, tranexamic acid given top- capillaries and small venules. Fibrin sealant [Tisseel ically in the oral cavity (Ôswish and swallow or spitÕ) VH (Baxter), consisting of human thrombin, fibrino- every 6 h has been used for prophylaxis in dental gen concentrate and bovine aprotinin] is indicated as surgery, in combination with applied pressure, other an adjunct to haemostasis in certain surgical situa- topical agents and suturing of surgical sites [237]. tions, but it is not effective for the treatment of massive The evidence for the effectiveness of local application and brisk arterial bleeding. Fibrin sealants have been of these agents is based on clinical case series [292], used with good results as adjunctive therapy for dental but this route of administration is not currently FDA surgery in persons with haemophilia or VWD approved. When desmopressin or VWF/FVIII con- [237,293]. Topical collagen sponges are also ap- centrates are indicated, the use of antifibrinolytic proved for control of bleeding wounds [294]. Other agents as adjuncts to desmopressin or VWF concen- topical agents approved for limited indications trates has been helpful in controlling bleeding, such include Coseal (Baxter), BioGlue (CryoLife, Inc., as in the oral cavity [133,220,225,229,237–240] and Kennesaw, GA, USA) and QuikClot (Z-Medica Cor- in the gastrointestinal and genitourinary tracts. poration, Wallingford, CT, USA); however, no The usual adult dose of aminocaproic acid is 4–5 g reports of their use in treating VWD could be found. as a loading dose orally or i.v. (1 h before invasive QuikClot, containing the mineral zeolite, was ap- ) procedures), and then 1 g h 1, i.v. or orally, or 4–6 g proved recently by the FDA for use with compression every 4–6 h orally, until bleeding is controlled, or for dressings for control of external traumatic bleeding in 5–7 days postoperatively [212]. Total daily dose of the prehospital setting (e.g. on the battlefield). The aminocaproic acid is limited to 24 g per 24 h to added benefit of topical agents – when used with single minimize potential adverse effects. Weight-based or combination therapies, including antifibrinolytic dosing is required in children and can also be used drugs, desmopressin and VWF/FVIII concentrate – is ) in adults (50–60 mg kg 1) [212,292]. Lower doses unproven. The topical use of plasma-derived bovine or ) (25 mg kg 1) may be effective and can be used when human proteins imparts a theoretical risk of disease gastrointestinal tract adverse effects interfere with transmission and of potential allergic and other therapy. Tranexamic acid is given i.v. at a dose of immune reactions. The use of fibrin sealants in ) 10 mg kg 1 every 8 h [212]. The oral form is not addition to drugs, concentrates or both may be viewed

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 207 as optional adjunctive therapy for dental surgery and immunosuppressive agents [114]. Because many for cases in which surface wound bleeding continues patients in the international registry series received despite combined therapy with drugs and concen- multiple therapeutic modalities, the independent trates. The safety of these topical agents in therapy for contribution of each therapy to clinical improve- VWD remains to be demonstrated. ment was unclear. When all other therapeutic modalities fail to control bleeding adequately, the infusion of recom- Other issues in medical management binant activated factor VII (FVIIa) may be consid- All persons with signiﬁcant bleeding symptoms ered, but this agent should be used with caution. related to VWD are likely to require human blood Little experience has been reported for its use in product administration and should receive immuni- treating VWD. A recent report described acute zations for hepatitis A and B as recommended for myocardial infarction immediately after the second ) individuals with haemophilia [295]. Persons with dose of 90 lgkg 1 in a 50-year-old man who had VWD should be counselled to avoid aspirin, NSAIDs hereditary type 2A VWD, gastrointestinal tract and other platelet-inhibiting drugs [296–298]. bleeding and several risk factors for, but no history of, coronary artery disease [303]. Treatment of AVWS Cardiac valvular diseases Congenital or acquired In an international registry of 189 cases of AVWS, heart disease has been associated with AVWS desmopressin produced clinical and laboratory [114,116,304]. Elevated shear stress around a ste- improvement in one-third of cases, although this notic valve or septal defect may promote the prote- effect was often short lived [114]. If FVIII activity olysis and depletion of high-molecular-weight VWF and the PTT were abnormal, a good desmopressin multimers [131]. Patients who had associated aortic response was less common than in hereditary VWD stenosis or other cardiac valvular disorders infre- and was often brief. In the international registry quently responded to any of the therapies described series, most patients who had AVWS also received above [114,119]. After surgical correction of the VWF/FVIII concentrates; the extent and duration of cardiac defect, the multimer pattern has improved at response varied. Therefore, VWF:RCo and FVIII least transiently in most patients studied levels must be measured preinfusion and postinfusion [116,119,304]. Administration of VWF/FVIII con- of desmopressin or VWF/FVIII concentrates in centrate immediately preoperatively should be con- patients with AVWS to determine the extent and sidered for patients who demonstrate transient duration of response and to guide subsequent dosage improvement in VWF activity with a test dose. and dosing intervals [114,152]. In patients who had a previous inadequate Angiodysplasia Bleeding from gastrointestinal angio- response to desmopressin and VWF/FVIII concen- dysplasia has been reported in persons with AVWS ) trates, i.v. immunoglobulin G (IGIV), 1 g kg 1 daily [305] as well as in persons with various types of for 2 days, given alone was effective in controlling congenital VWD. For example, bleeding from angio- bleeding and raising VWF:RCo activity for 3 weeks dysplasia is a classic presentation of AVWS associ- in all eight patients who had excessive bleeding and ated with aortic stenosis [119,306] and is often an IgG monoclonal gammopathy of uncertain sig- resistant to medical therapy, requiring surgical cor- niﬁcance (MGUS) [299]. In the international regis- rection of the valve defect to ameliorate bleeding try series, one-third of the 63 patients treated with symptoms. In the absence of a correctable underlying high-dose IGIV had a good response [114]. The aetiology of angiodysplasia and bleeding associated underlying diagnoses of the responders were lym- with AVWS or congenital VWD, management of the phoproliferative disorders (including MGUS), solid condition can be challenging, as no single treatment tumours and autoimmune diseases. An anti-VWF modality is successful in all cases [307]. antibody could be demonstrated in vitro in about two-thirds of those responders. High-dose IGIV Thrombocytosis Thrombocytosis, especially in per- therapy in the setting of AVWS is an off-label use sons with essential thrombocythemia, is associated but should be considered when desmopressin and with a relative reduction in the proportion of high- VWF/FVIII concentrate therapy fail to control molecular-weight multimers [122]. Although the bleeding symptoms adequately [300–302]. Some relation of this abnormality to bleeding is inconsis- patients with immune-mediated AVWS have re- tent, treatment is aimed at reduction of the platelet sponded to plasmapheresis, corticosteroids and count.

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Hypothyroidism In contrast to the above syndromes, AVWS that occurs in hypothyroidism is caused by decreased synthesis, and the VWF multimer patterns are normal [308,309]. A minority of patients with hypothyroidism have VWF levels below normal, and not all who have low VWF levels have bleeding symptoms. The decrease in VWF is corrected by thyroid hormone replacement [124,309].

Management of menorrhagia in women with VWD Menorrhagia is often the primary bleeding symptom in haemophilia treatment centre haemophilia treatment centre Case series Retrospective review, single Prospective, open label Prospective, open label Prospective, open label Survey of haemophilia treatment centres Retrospective review, single women with VWD [87,310,311]. Menorrhagia, how- Patient survey ever, may be a sign of a gynaecological disorder rather than VWD [312]. Therefore, a full gynaecological

evaluation is required before therapy is initiated [312]. Õ Õ in

Medical therapies that have been described to Õ ;21% good Õ Ô control menorrhagia in women with VWD include Õ Õ or Õ Õ combined oral contraceptives, tranexamic acid, des- Õ mopressin and, most recently, the levonorgestrel- Õ much better releasing intrauterine system (Table 17). Data regard- Ô very effective excellent effective ineffective Ô Ô Ô ing the effectiveness of these therapies are limited. The Ô no effect well-controlled good effect slight improvement Ô Ô Ô Ô effective; 14% not effective 100%; 50% developed amenorrhea; increased haemoglobin concentrations only published randomized-clinical trial of desmo- 3 pressin for menorrhagia was small and failed to demonstrate efﬁcacy compared with placebo [313]. The available data show no evidence that desmopres-

sin is more effective than other therapies used to treat No Periods menorrhagia [314]. Depending on the womanÕs age, underlying gynaecological condition and reproductive plans, any of the therapies demonstrated to be effective for the treatment of menorrhagia in women without VWD may be suitable, with the exception of NSAIDs, which decrease platelet function and systemic haemostasis [315]. In one retrospective review intrauterine system DesmopressinDesmopressin Placebo No No significant difference 92% Prospective, double-blind, randomized trial of 36 adolescent girls with VWD and menorrhagia, Oral contraceptives No 76% treatment using oral contraceptive pills or intranasal desmopressin were equally efficacious [316]. In adolescent or adult women who do not desire pregnancy, but may desire future child-bearing, the first choice of therapy should be combined oral contraceptives. Combined oral contraceptives contain a synthetic oestrogen (ethinyl estradiol) and a progestin [317]. The progestin prevents ovulation, and the synthetic oestrogen prevents breakthrough bleeding [318]. A majority of studies have found that have VWD bleeding disorders type 1 VWD combined oral contraceptives increase fibrinogen, prothrombin, FVII, FVIII and/or VWF [319–321] and, consequently, promote haemostasis. It is not known whether the increase in coagulation factors [406] 43 women with VWD Desmopressin No 65% [405] 90 women with various [404] 13 women with VWD Levonorgestrel associated with combined oral contraceptives con- [367] 41 women known to have et al. [329] 2 women with VWD Tranexamic acid No 2 [329] 7 women with VWD Oral contraceptives No 3 [313] 39 women known to Effectiveness of medical therapy for menorrhagia in women with VWD. tributes to the clinical response, but combined oral et al. et al. et al. et al. et al. contraceptives do reduce menstrual blood loss [322] et al. and increase haemoglobin concentrations in women Greer VWD, von Willebrand disease. Mohri [407] 3 women with VWD Tranexamic acid No 3 Kadir Rodeghiero Leissinger Greer Kingman Foster [339] 25 women known to have VWD Oral contraceptives No 88% Table 17. with anaemia [323–325]. Combined oral contracep- SourceKouides Population Treatment Controls Results Setting

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd VWD GUIDELINES 209 tives, used by millions of women for prolonged cysts [329,339–344]. Silwer [134], for example, periods of time, have been proven to be safe for long- reported that nine of 136 women (6.8%) who had term use [326] except in women with thrombophilia VWD experienced this problem. Ovulation is not [318]. Although no formal studies of the effects of normally accompanied by any clinically significant the contraceptive patch on haemostasis have been bleeding, but in a woman who has a congenital performed, the patch likely has effects similar to bleeding disorder such as VWD, the potential exists those of combined oral contraceptives [327]. for bleeding into the peritoneal cavity or bleeding For a woman who has VWD and would into the residual follicle, resulting in a haemorrhagic otherwise be a suitable candidate for an intrauter- ovarian cyst [343] or retroperitoneal haematoma ine device, the second choice of therapy should be [329]. Acute treatment of haemorrhagic ovarian the levonorgestrel-releasing intrauterine system. cysts with surgical therapy, tranexamic acid and The levonorgestrel-releasing intrauterine system is factor replacement has been reported [329,342,343]. a progestin-impregnated intrauterine device that is Oral contraceptives have been used to prevent believed to reduce menstrual blood loss by oppos- recurrences [340,341,343]. ing oestrogen-induced growth of the endometrium or lining of the uterus [328]. Pregnancy Women who do not respond to hormonal therapy and are being considered for treatment with desmo- Few options are available for the management of pressin or VWF concentrate should be referred to a menorrhagia or recurrent haemorrhagic ovarian haemophilia treatment centre or to a haematologist cysts in women who have VWD and desire preg- who has expertise in haemostasis. Treatments spe- nancy. Although data are limited to case reports, cific for VWD (such as desmopressin or VWF desmopressin, antifibrinolytics or VWF concentrate concentrate) or antifibrinolytic therapy, although may be tried [339]. they have not been proven to be effective for Ideally, planning for pregnancy begins before menorrhagia, may be tried. conception. Women who have VWD and are con- In addition to medical therapies, surgical therapies templating a pregnancy should be aware that they have been used to treat menorrhagia in women with may be at increased risk of bleeding complications VWD. Dilation and curettage (D&C), while occa- during pregnancy [345] and are definitely at sionally necessary to diagnose intrauterine pathology, increased risk of postpartum haemorrhage [139]. is not effective in controlling heavy menstrual bleed- Before conception or during pregnancy, women ing [329]. In two cases reported by Greer et al. [329] should be offered the opportunity to speak with a and two cases reported by Kadir et al. [330], D&C genetic counsellor regarding the inheritance of VWD resulted in further blood loss. Endometrial ablation, [346] and with a paediatric haematologist regarding however, reduced menstrual blood loss in seven of the evaluation of the infant after delivery. seven women who had VWD [331]. Three of these Women who have type 1, type 2 or type 3 VWD ) seven women ultimately required hysterectomy, com- and have FVIII levels <50 IU dL 1, VWF:RCo ) pared with the 12–34% of women without VWD <50 IU dL 1 or a history of severe bleeding should who usually require hysterectomy [332–336]. Wo- be referred for prenatal care and delivery to a centre men with VWD and who undergo hysterectomy may that, in addition to specialists in high-risk obstetrics, be at greater risk of perioperative bleeding complica- has a haemophilia treatment centre, a haematologist tions than other women, and bleeding may occur with expertise in haemostasis or both. Laboratory, despite prophylactic therapy [134,311]. Hysterec- pharmacy and blood bank support is essential. tomy carries the risk of bleeding complications, but Before any invasive procedure, such as chorionic women who require the operation should not be villus sampling, amniocentesis or cervical cerclage, deprived of its benefits. Because menorrhagia is often women with VWD should have laboratory assays for the primary bleeding symptom experienced by a FVIII and VWF:RCo to receive appropriate prophy- woman who has VWD, hysterectomy offers the laxis [346,347]. FVIII and VWF:RCo levels should possibility of the elimination of menorrhagia bleeding be obtained in the third trimester of pregnancy to symptoms and improved quality of life [336–338]. facilitate planning for the delivery [347]. Before delivery, all women with VWD should meet with an anaesthesiologist to plan for the possible need for the Haemorrhagic ovarian cysts administration of haemostatic agents or alternatives, Multiple case reports describe women who have if necessary, for regional anaesthesia at the time of VWD and have experienced haemorrhagic ovarian delivery [346]. A pregnant woman carrying a baby at

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 210 W. L. NICHOLS et al. risk for type 3 VWD or severe forms of types 1 or 2 achieved before delivery [329] and maintained for at VWD should be referred to a paediatric haematol- least 3–5 days afterward [9,212,329,345–347]. ogist for counselling regarding neonatal testing and There is no consensus on levels of VWF:RCo and potential perinatal bleeding complications in affected FVIII that are safe for regional anaesthesia [364], but ) infants [87,345,348]. if VWF:RCo and FVIII levels are 50 IU dL 1 or Data are limited on the use of desmopressin for higher and the coagulation screen is normal, regional VWD in pregnancy. Mannucci [349] reported using anaesthesia may be considered safe [345]. desmopressin for prophylaxis before procedures in Desmopressin may be used to raise factor levels in 31 pregnant women Ôwithout mishapÕ, but specific responders, but care must be taken in its administra- data were not provided. Desmopressin, in the lower tion at the time of childbirth. Women commonly doses used to treat diabetes insipidus, however, is receive 1–2 L or more of fluid at the time of a vaginal generally thought to be safe for mother and foetus. In delivery and 2–3 L or more at the time of caesarean a review of 53 women who were pregnant and used delivery. Fluids containing oxytocin, which also desmopressin, administered in doses of 7.5– causes fluid retention, combined with desmopressin ) 100 lgday 1 for diabetes insipidus, no adverse may result in fluid retention and life-threatening maternal or neonatal effects were attributable to hyponatraemia. Chediak and colleagues [363] the medication [269]. In an in vitro placenta model, reported complications of fluid retention in two desmopressin did not cross the placenta in detectable women who received desmopressin at the time of amounts [269]. childbirth. One woman who received three doses 18 h Tranexamic acid crosses the placenta [350] but has apart developed severe hyponatraemia (sodium level ) been used to treat bleeding during pregnancy in a of 108 mEq L 1) and experienced grand mal seizures. limited number of cases without adverse foetal Because NSAIDs, commonly prescribed for pain effects [351–356]. Data regarding aminocaproic acid after childbirth, may decrease platelet function and in pregnancy are limited, but aminocaproic acid was systemic haemostasis [315], alternative analgesics not found to be teratogenic in rabbits [357]. In cases should be considered. of its use during pregnancy, no adverse foetal effects have been reported [358]. Postpartum haemorrhage Postpartum haemorrhage is an anticipated problem among women with VWD. Miscarriage and bleeding during pregnancy In the By the end of gestation, an estimated 10–20% of a ) general population, miscarriage is common, and womanÕs blood volume, or at least 750 mL min 1, 12–13.5% of diagnosed pregnancies result in spon- flows through the uterus [365]. After delivery of the taneous abortion [359,360]. Although detailed data infant and placenta, the uterus must contract, and were not provided, in a study of 182 women who the uterine vasculature must constrict to prevent had severe VWD, Lak et al. [87] reported that exsanguination [366]. Failure of the uterus to con- miscarriage was no more frequent than in the general tract is the single most important cause of post- population. Other studies, however, have found a partum haemorrhage [366]. Nonetheless, women higher incidence of miscarriage among women with with VWD have a greater risk of postpartum VWD than in controls [139] or in the background haemorrhage than controls [134,139,367]. Multiple rate [339,345]. case series document an increased incidence of Bleeding complications during pregnancy other postpartum haemorrhage in women with VWD than miscarriage have been reported [329,339,361– (Table 18). 363]. Kadir et al. [345] found that 33% of women Perineal haematoma, a rare complication of vag- who had VWD bled during their first trimester. inal birth, occurs with some frequency in women with VWD. Greer et al. [329] reported one haema- Childbirth Table 18 summarizes nine case series toma in 13 vaginal deliveries, and Kadir and reporting pregnancy outcomes in women with VWD, colleagues [345] reported three haematomas in 49 including rates of miscarriage, peripartum prophy- vaginal deliveries. This is a relatively high frequency laxis, postpartum haemorrhage and perineal haema- compared with a rate of only 2.2 haematomas per toma. Prophylaxis included cryoprecipitate, fresh- 1000 vaginal births in a cohort of 26 187 spontane- frozen plasma, desmopressin and factor replacement. ous or operative vaginal deliveries [368]. No large prospective studies correlate VWF:RCo In women with VWD, vaginal bleeding is fre- and FVIII levels with the risk of bleeding at the time quently reported to occur more than 2–3 weeks of childbirth, but the opinion of experts is that postpartum. The duration of bleeding after delivery ) VWF:RCo and FVIII levels of 50 IU dL 1 should be in a normal patient is a median of 21–27 days [369–

This article is based on a U.S. government publication which is in the public domain. Haemophilia (2008), 14, 171–232 Journal compilation 2008 Blackwell Publishing Ltd hsatcei ae naUS oenetpbiainwihi ntepbi domain. public the in is which publication government U.S. a compilation on Journal based is article This Table 18. Pregnancies in women with VWD. Perineal Study Population Miscarriage Prophylaxis Postpartum haemorrhage haematoma Burlingame et al. [361] 5 pregnancies in 2 women None FVIII/VWF concentrates 1/5 (20%) None for 1/5 Lak et al. [87] 100 women with type 3 VWD Rate not Ôhigher than… FFP, cryo, FVIII/VWF 15/100 (15%) Not reported and had delivered at least 1 child the general Iranian concentrates 08BakelPbihn Ltd Publishing Blackwell 2008 populationÕ Caliezi et al. [362] 2 pregnancies in 1 woman with None FVIII/VWF concentrates 1/2 (50%) on day 15 None type 3 VWD for 2/2 from episiotomy Kadir et al. [345] 84 pregnancies in 31 women 18 of 72 pregnancies 10/54 with Ôno bleeding 10/54 (18%) 3/54 not terminated complicationsÕ primary*; 6/54 (11%) required transfusion; 11/54 (20%) secondary Foster [339] 69 pregnancies in 31 women 15 of 68 pregnancies 25/55 (46%) of those for In women who had Not reported with VWD unresponsive to DDAVP not terminated whom data were available; type 2A, 2B or 3 FVIII/VWF concentrates VWD, 6/18 (33%) (9); cryo (8); FFP (1) who were treated; 3/4 (75%) who were not treated Ramsahoye et al. [376] 24 pregnancies in 13 women None reported (1 5 caesarean deliveries: cryo 3/24 (12.5%) None foetal demise for 2/5; FVIII/VWF primary*; 6/24 at 38 weeks) concentrate (Haemate-Pà) (25%) secondary ; for 2/5; DDAVP for 1/5; 2/6 secondary had 19 vaginal deliveries: cryo been treated for 3/19; FVIII/VWF concentrate (Haemate-Pà; NHS 8Y) for 2/19 Greer et al. [329] 14 deliveries in 7 women with VWD Not reported Cryo (9) 5/9 who were 1/14 treated (1 primary*, 3 secondary ,1 Haemophilia both); 2/5 who GUIDELINES VWD were not treated (2 primary*) Chediak et al. [363] 10 pregnancies in 6 women with VWD 3/10 pregnancies Cryo for 5/7 deliveries; 4/5 ÔmassiveÕ 1 had Ôlumbar

(2008), DDAVP for 2/7 deliveries haematomasÕ Conti et al. [390] 5 deliveries in 5 women with VWD None None 2/5 ÔlateÕ None Cryo, cryoprecipitate; DDAVP, desmopressin; FFP, fresh-frozen plasma; FVIII/VWF, factor VIII/von Willebrand factor concentrate; NHS 8Y, National Health Service (UK) FVIII/VWF 14

171–232 , concentrate (8Y); VWD, von Willebrand disease. *Primary, postpartum haemorrhage within the ﬁrst 24 h after delivery.

Secondary, postpartum haemorrhage after 24 h after delivery. 211 àHaemate-P is the European equivalent of Humate-P. 212 W. L. NICHOLS et al.

371]. However, the VWF levels that are elevated C. Persons with activity levels of VWF:RCo higher ) during pregnancy return to baseline within than 10 IU dL 1 and factor VIII (FVIII) higher than ) 7–21 days [372,373], predisposing women with 20 IU dL 1 should undergo a trial of desmopressin VWD to delayed postpartum haemorrhage. In the while in a nonbleeding state. Persons with levels absence of a bleeding disorder, delayed or secondary below these thresholds are less likely to demonstrate postpartum haemorrhage is rare and occurs after clinical or laboratory responses to desmopressin, but <1% of deliveries [374,375]. In contrast, 20–25% of a desmopressin trial should still be considered in women with VWD had delayed postpartum haem- these individuals. orrhage, making delayed postpartum haemorrhage Grade B, level IIa [101,218,220,221,224] 15–20 times more common among these women See Evidence Table 6 [10] for additional informa- than in normal subjects [345,376]. tion and detail. Among the published series of cases of women who were pregnant and had VWD (Table 18), Management Recommendations V multiple cases of postpartum haemorrhage occurred despite prophylaxis. The mean ± SD time of pre- V. General Management sentation of postpartum haemorrhage in women with VWD was estimated to be 15.7 ± 5.2 days A. Treatment of persons who have von Willebrand after delivery [377]. The implication is that women disease (VWD) is aimed at cessation of bleeding or with VWD may require frequent evaluation — prophylaxis for surgical procedures. and possibly prophylaxis — for 2 weeks or more Grade C, level IV [1,7,9] postpartum. Weekly contact with these women is recommended during the postpartum period B. Continued bleeding, despite adequately replaced [347]. von Willebrand factor ristocetin cofactor (VWF:RCo) and factor VIII (FVIII) activity levels, requires evaluation of the person for other bleeding Management recommendations aetiologies, including anatomic. The recommendations are graded according to crite- Grade C, level IV ria described in Table 1. Management Recommen- C. Long-term prophylaxis is currently under inves- dations IV–X summarize the PanelÕs patient tigation in an international cooperative study, and management recommendations. Evidence Tables the long-term risks and benefits should be consid- 6–13 are provided in the full online document [10] ered carefully. for recommendations given a grade of B and having Grade C, level IV [208,209] two or more references. D. Individuals who are more than 2 years old, have VWD, and have not already been vaccinated should Management Recommendations IV be immunized against hepatitis A and B. Grade C, level IV [295] IV. Testing Before Treatment E. Persons with VWD should have the opportunity A. Before treatment, all persons suspected of having von Willebrand disease (VWD) should have to talk to a knowledgeable genetic counselor. Grade C, level IV [346] a laboratory-confirmed diagnosis of type and severity of VWD. This recommendation does not pre- F. At diagnosis, persons with VWD should be clude treatment that may be indicated for urgent or counseled to avoid aspirin, other nonsteroidal anti- emergency situations, despite the absence of confir- inflammatory drugs (NSAIDs), and other platelet- matory laboratory data. inhibiting drugs. Grade C, level IV [87,133–136,148,394,395] Grade C, level IV [296–298] B. Persons who do not have a definite diagnosis of G. Restriction of fluids to maintenance levels VWD but who have von Willebrand factor ristocetin should be considered in persons receiving desmo- cofactor activity (VWF:RCo) levels of 30– )1 pressin (especially for young children and in surgical 50 IU dL and have a bleeding phenotype may settings) to avoid the occurrence of hyponatraemia merit treatment or prophylaxis of bleeding in certain and seizures. clinical situations. Grade C, level IV [258–260] Grade B, level III [191]

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G. Topical agents, such as fibrin sealant or bovine Management Recommendations VI thrombin, may be useful adjuncts for oral surgery in persons with VWD. Careful attention to haemostasis VI. Treatment of Minor Bleeding and Prophylaxis of an extraction socket and to suturing of sockets is for Minor Surgery also important in oral surgery in persons with VWD. A. Epistaxis and oropharyngeal, soft tissue, or Grade C, level IV [237,293] minor bleeding should be treated with intravenous or nasal desmopressin, if appropriate, based on trial Management Recommendations VII testing. Grade B, level IIa [220,223,227,229,238] VII. Treatment of Major Bleeding and Prophylaxis See Evidence Table 7 [10] for additional informa- for Major Surgery tion and detail. A. All treatment plans should be based on objective lab- B. If elevation of von Willebrand factor (VWF) is oratory determination of response of von Willebrand necessary and response to desmopressin is inade- factor ristocetin cofactor (VWF:RCo) and factor VIII quate, VWF concentrate should be used, with dosing (FVIII) activity levels to desmopressin or to von primarily based on von Willebrand factor ristocetin Willebrand factor (VWF) concentrate infusion. cofactor activity (VWF:RCo) units and secondarily Grade B, level IIb [133,221,239,242–244,246– on factor VIII (FVIII) units. 253,288,403] Grade C, level IV [239,250] See Evidence Tables 11 and 12 [10] for additional C. For prophylaxis for minor surgery, initial treat- information and detail. ment should be expected to achieve VWF:RCo and ) B. Whenever possible, all major surgical proce- FVIII activity levels of at least 30 IU dL 1 and ) dures and bleeding events should be treated in preferably higher than 50 IU dL 1. hospitals with around-the-clock laboratory capa- Grade B, level III [220,223,237,239] bility and with clinical monitoring by a team that See Evidence Table 8 [10] for additional informa- includes a haematologist and a surgeon skilled in tion and detail. the management of bleeding disorders. D. For minor surgery, VWF:RCo and FVIII activity Grade C, level IV ) levels of at least 30 IU dL 1 and preferably higher ) C. For severe bleeding (e.g. intracranial, retroperi- than 50 IU dL 1 should be maintained for 1–5 days. toneal) or for prophylaxis during major surgery, Grade B, level III [239,245,246,253] initial target VWF:RCo and FVIII activity levels See Evidence Table 9 [10] for additional informa- )1 should be at least 100 IU dL . Subsequent dosing tion and detail. should maintain VWF:RCo and FVIII levels above a ) E. For persons with VWD, management of minor trough of 50 IU dL 1 for at least 7–10 days. bleeding (e.g. epistaxis, simple dental extraction or Grade B, level III [239,246,248–253,288,403] menorrhagia) with desmopressin and proper fluid See Evidence Table 12 [10] for additional infor- restriction can be performed without laboratory mation and detail. monitoring unless desmopressin is used more than D. To decrease risk of perioperative thrombosis, three times within 72 h. ) VWF:RCo levels should not exceed 200 IU dL 1, Grade C, level IV [257,316] ) and FVIII activity should not exceed 250 IU dL 1. F. For persons with mild to moderate von Wille- Grade C, level IV [277–279] brand disease (VWD), antifibrinolytics combined E. For major surgical procedures in selected patients with desmopressin are generally effective for oral with type 3 von Willebrand disease or acquired von surgery. VWF concentrate should be available for Willebrand syndrome who are at risk for poor VWF persons who cannot receive desmopressin or who recovery because of inhibitors, a preoperative trial bleed excessively despite this combined therapy. infusion of VWF concentrate with pharmacokinetic Grade B, level IIb [220,225,229,237–240] laboratory monitoring should be considered. See Evidence Table 10 [10] for additional infor- Grade C, level IV mation and detail.

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1. Should be referred to a centre that has high- Management Recommendations VIII risk obstetrics capabilities and expertise in haemostasis for prenatal care, delivery, termination VIII. Management of Menorrhagia and Haemor- of pregnancy, or management of miscarriage. rhagic Ovarian Cysts in Women With VWD Grade C, level IV A. Women who have menorrhagia or abnormal 2. Should receive prophylaxis with desmopressin vaginal bleeding should have a full gynaecologic or von Willebrand factor (VWF) concentrate evaluation before therapy. before invasive procedures. Grade C, level IV [312] Grade C, level IV [346,347] B. In an adolescent or adult woman who does not 3. Should achieve VWF:RCo and FVIII levels of desire pregnancy but may desire future childbearing, )1 the first choice of therapy for menorrhagia should be at least 50 IU dL before delivery and maintain combined oral contraceptives. those levels for at least 3–5 days afterward. Grade B, level III [339] Grade C, level IV [9,212,339,345,347] C. If VWF:RCo and FVIII levels can be monitored C. In an adolescent or adult woman who does )1 not desire pregnancy but may desire future child- and maintained above 50 IU dL during labor and bearing, the first choice of therapy to prevent delivery, and no other coagulation defects are pres- haemorrhagic ovarian cysts should be combined ent, then regional anaesthesia may be considered. oral contraceptives. Grade C, level IV [345] Grade C, level IV [340,341,343] D. Because coagulation factors return to prepre- D. If a woman would otherwise be a suitable gnancy levels within 14–21 days after delivery, candidate for an intrauterine device, the second healthcare providers should be in close contact with choice of therapy for menorrhagia should be the women during the postpartum period. levonorgestrel intrauterine system. Grade C, level IV [347] Grade B, level IIb [404] E. For a woman who desires pregnancy, desmo- Management Recommendations X pressin, antifibrinolytics, or VWF concentrate may be tried to control menorrhagia. X. Acquired von Willebrand Syndrome Grade C, level IV [339] A. Individuals who have acquired von Willebrand syndrome (AVWS) and who require surgery should F. Dilation and curettage is not usually effective to be considered for a pharmacokinetic trial of therapy manage excessive uterine bleeding in women with with desmopressin and/or von Willebrand factor VWD. (VWF) concentrate, with monitoring of von Wille- Grade C, level IV [329,330] brand factor ristocetin cofactor (VWF:RCo) and factor VIII (FVIII), to evaluate for possible acceler- Management Recommendations IX ated clearance of VWF. Grade C, level IV [114,152] IX. Management of Pregnancy and Childbirth in Women With VWD B. For persons who have AVWS and who bleed excessively despite therapy with desmopressin and A. Women planning for pregnancy should have, VWF concentrate, treatment with high-dose intra- before conception, an evaluation with a haematol- venous immunoglobulin (IGIV) should be consid- ogist and high-risk obstetrician, both of whom are ered, especially in IgG isotype monoclonal skilled in the management of von Willebrand disease gammopathy of uncertain significance (MGUS). (VWD). (See discussion of this use, not approved by the US Grade C, level IV [346] Food and Drug Administration, in the section B. Women with type 1, type 2, or type 3 VWD, Treatment of AVWS.) with factor VIII (FVIII) or von Willebrand factor Grade B, level IIa [114,299–302] ristocetin cofactor (VWF:RCo) activity levels See Evidence Table 13 [10] for additional infor- ) <50 IU dL 1 or a history of severe bleeding: mation and detail.

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ments, also is not known. Because type 1 VWD is the Opportunities and needs in VWD research, most common form of VWD, answers to these training and practice questions may have important consequences for Many recommendations in this guideline are based medical practice. on relatively limited evidence, thus underscoring the need for further research. Some of these opportuni- Heterogeneity of type 2 VWD The concentration of ties are discussed below. haemostatically effective large VWF multimers can be selectively decreased by accelerated proteolysis or by various defects in multimer assembly [51]. These Pathophysiology and classification of VWD variants now are grouped together as type 2A VWD, Determinants of VWF level and bleeding risk The risk but further subdivision of this category would be of bleeding in persons with VWD depends on the justifiable if specific mechanisms of disease were level of functional VWF and on many other factors associated with different clinical symptoms or that are poorly understood. The plasma level of VWF responses to therapy. can be influenced by mutations within or near the Most persons with type 2M VWD have been VWF gene. In addition, VWF levels depend on ABO identified by finding a profound defect in ristocetin- blood type [45], possibly on the Secretor locus [111], induced binding to platelets associated with a normal and on hormonal status and stress, as discussed in VWF multimer pattern [57,69,74]. Defects in bind- The VWF Protein and its Functions In Vivo. Rela- ing to collagen or other connective tissue elements tively few of the genetic and non-genetic determi- could cause a similar bleeding phenotype, but the nants of VWF level have been characterized, and VWF:RCo assay is insensitive to such defects [75]. how they interact is not known. In addition, little Collagen-binding abnormalities can be detected by quantitative information is available on the risk of the VWF:CB assays, but those assays are not used specific bleeding symptoms as a function of the level widely in the United States. The prevalence and of VWF in plasma. This information would be medical importance of collagen-binding defects in particularly useful for the management of patients type 2M VWD deserve further study. ) who have VWF levels in the range of 30–50 IU dL 1, for whom the risk of medically significant bleeding is Diagnosis and evaluation not well defined. VWF level in plasma alone does not account for Assessment of bleeding signs and symptoms The initial the observed variation in bleeding symptoms, and evaluation of patients for a medically important recent studies are starting to uncover some of the bleeding disorder can be difficult because mild underlying reasons. For example, persons who have bleeding is common in the healthy population. both low VWF and defects in platelet aggregation Specific symptoms have been assessed for clinical have more severe bleeding [378]. Increased bleeding relevance in retrospective studies, and some appear has also been associated with specific DNA markers to discriminate between healthy controls and persons for platelet membrane proteins [379]. It is likely that with diagnosed bleeding disorders (Table 9 and multiple haemostatic risk factors interact with VWF Fig. 3). However, the utility of these questions must level in plasma to determine the likelihood of be established prospectively for less highly selected bleeding or thrombosis. Understanding these inter- persons. actions and incorporating them into clinical practice will require additional basic, clinical, and epidemi- Quality and availability of laboratory testing Reliable ological research. testing for VWF:Ag and FVIII is widely available, but VWF:RCo, RIPA and VWF multimer analysis are Heterogeneity of type 1 VWD Partial quantitative much more variable in their performance character- deficiency of VWF can be caused by several mech- istics and can be difficult to obtain. Also, tests of anisms, as discussed in the section Classification of VWF:FVIIIB are offered by few laboratories. More VWD Subtypes. Some persons have dominant VWF robust methods for assessing VWF function and mutations that either decrease the secretion of VWF multimer structure must be developed for routine use multimers or accelerate their clearance from the in the diagnosis of VWD. In addition, the sensitivity circulation. The prevalence of increased clearance as and specificity of test ratios such as VWF:RCo/ a cause of type 1 VWD is not known. Whether these VWF:Ag should be established for identifying the different disease mechanisms correlate with distinct qualitative defects that characterize type 2A and type clinical features, including response to specific treat- 2M VWD. Criteria should be established for VWF

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 216 W. L. NICHOLS et al. multimer analysis to distinguish a signiﬁcant de- important clinical issues should be addressed by crease in large multimers (in types 2A and 2B VWD) studies of desmopressin in speciﬁc types of VWD. In from a substantially normal multimer distribution (in addition, the availability of desmopressin for s.c. types 1, 2M and 2N VWD). administration may improve management of VWD.

VWF gene sequencing Mutations that cause many Factor concentrates The available plasma-derived types of VWD can be identified by sequencing the products that contain VWF also contain FVIII as VWF gene in DNA samples from patients [24]. The part of the FVIII–VWF complex, and only two such locations of mutations appear to correlate well with products are currently licensed in the United States some disease phenotypes, suggesting that DNA for treatment of VWD. When administered to sequencing could be a useful diagnostic method in patients with VWD, the infused FVIII may add to VWD. With appropriate study and experience, DNA the endogenous FVIII production and cause mark- sequencing may become economical and feasible for edly elevated FVIII levels that are much greater than routine use. In addition, the widespread application the VWF levels achieved with treatment; these have of VWF gene sequencing would provide invaluable been associated with thrombosis [212]. High FVIII information about the prevalence of VWF mutations levels can be avoided by adjusting the dose of as a function of VWF level, the strength of the product administered, but VWF levels then may be relationship between VWF genotype and VWD phe- relatively low. Whether FVIII or VWF levels or both, notype, the penetrance of specific mutations, and the should be used to monitor treatment with FVIII– biochemical mechanisms that cause VWD. This VWF concentrates is unknown. Use of a pure VWF knowledge would also be an outstanding resource product in place of FVIII–VWF concentrates would for the identification and characterization of other avoid the disproportionate increase in FVIII. A pure factors that modify bleeding symptoms in VWD. VWF concentrate has been used in Europe [385] but is not currently available in the United States. Studies are needed to establish appropriate treatment and Management of VWD monitoring regimens for these products. In addition, Many of the standard treatments for VWD have prelicensure studies of recombinant VWF are needed limited experimental support. For example, the to establish its safety, efficacy and role in the intensity and duration of therapy necessary to treatment of VWD. The licensing of other products control bleeding have not been established for many containing both VWF and FVIII would also enhance clinical situations and often have been extrapolated therapeutic options. from anecdotal experience in haemophilia. The indications for prophylaxis of bleeding are not well Platelets Approximately 15% of the total VWF in defined. These issues should be addressed by appro- blood is found within platelets, and platelet VWF priate clinical studies. appears to contribute to haemostasis. Although VWD patients who have abnormal or low platelet Desmopressin Many persons with VWD respond to VWF have been described, there has been only desmopressin with a clinically useful rise in VWF and limited exploration of the feasibility and utility of FVIII, but the likelihood of a good outcome depends such testing, in part because of limitations of on the type of VWD and the underlying biochemical practical methods. Clinically, platelet transfusions mechanism of disease. In type 1 VWD, persons who have been reported to stop bleeding in some patients have accelerated clearance of plasma VWF may have with VWD who were not helped by transfusion of a transient response to desmopressin [43,225]. FVIII-VWF concentrates [289,290]. The efficacy and Whether desmopressin should be used at all in appropriate use of platelet transfusions in persons persons with type 2B VWD is controversial with VWD or AVWS need to be established. [226,234,254,255,380–383]. In type 2N VWD, the baseline FVIII level may be a good predictor of the Antifibrinolytics Tranexamic acid and aminocaproic magnitude and duration of the FVIII response to acid have been used alone or as adjunctive therapy to desmopressin [79,224,228,384]. The drug is thought treat bleeding in VWD. The safety, efficacy, and to be safe for use in pregnancy, but the published optimal dosing of these agents in VWD should be experience in this setting is limited [268,269]. Hypo- established by suitable clinical studies. In addition, natraemia and thrombotic events have occurred after the availability of orally administered tranexamic desmopressin, but risk factors for these events and acid would broaden the therapeutic options for their incidence have not been established. These antifibrinolytic therapy.

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in haemostasis [391]. Training opportunities need to Gene therapy of VWD be developed and expanded for haemostasis special- Severe type 3 VWD potentially can be treated with ists. Recent clinical training opportunities include a gene therapy. The gene for VWF is larger than could new NHLBI initiative for training in non-malignant easily be introduced into many vectors, but gutless haematology [392] and a recent clinical fellowship adenoviral vectors could easily accommodate a gene initiative from the National Hemophilia Foundation the size of VWF (8.5 kb). The prevalence of type 3 [393]. Recognition of haemostasis as a bona fide VWD and its clinical symptoms, however, does not clinical and laboratory subspecialty in the United place it in a high-priority category for gene therapy States could enhance entry into the field. trials. Point mutation repair initially was an exciting approach for VWD [386,387], but follow-up studies Acknowledgements have not achieved the same rate of success in vitro [388,389]. The authors thank the following persons for important contributions to this project and publications. At the National Heart, Lung, and Blood Issues specific to women Institute (Bethesda, Maryland), Sue Rogus RN, MS, VWF is particularly important for haemostasis dur- provided overall project coordination and super- ing menses and at childbirth. Consequently, women vision and Rebecca Link PhD, provided liaison and are affected disproportionately by having VWD, scientific expertise to the NHLBI Expert Panel on especially during their child-bearing years. von Willebrand Disease. Contractor staff from the American Institutes for Research (Silver Spring, Menorrhagia The incidence of menorrhagia appears Maryland) contributing to this project include Ann to vary inversely with VWF level, independent of Horton MS and Margot Raphael (editorial man- whether women meet criteria for having VWD [47]. agement support), Carol Creech, MILS; Elizabeth Because menorrhagia is so common, even a small Scalia, MILS; Heather Banks, MA, MAT; and Patti reduction in its severity could have important impli- Louthian (literature research and other editorial cations for womenÕs health. As discussed in the support). section Menorrhagia, several treatments have been Editing, proofreading and reference verification for used for menorrhagia associated with VWD, but this manuscript were provided by the Section of their efficacy has not been demonstrated convinc- Scientific Publications, Mayo Clinic and funded by ingly. Therefore, clinical studies would be useful to NHLBI. establish the effect of VWF level on menorrhagia and to evaluate specific treatments for women who have Disclosures Authors disclosing potential conflicts of VWD or low plasma levels of VWF. interest are Dr. Andra James (speaking and consulting fees, and research support from CSL Behring), Labour and delivery Several small case series indi- Dr. Marilyn Manco-Johnson (speaking and consult- cate that women who have VWD and VWF levels ing fees, and research support from CSL Behring), ) <50 IU dL 1 at delivery have an increased incidence Dr. Robert Montgomery (consultant for Baxter, CSL of immediate and delayed postpartum haemorrhage. Behring, GTI-Diagnostics, and Astra Zeneca; CSL These complications appear to be prevented by Behring fellowship for research support), Dr. Wil- replacement therapy with FVIII–VWF concentrate liam Nichols (CSL Behring Humate-P surgical trial before delivery and by either concentrate or des- study, supervision of ÔÔcentral laboratoryÕÕ activities at mopressin in the postpartum period [87,345,390]. the Mayo Special Coagulation Laboratory, via How the risk of bleeding correlates with VWF level contract through Mayo Clinical Trials Services), or FVIII level is not known, and the required Dr. Thomas Ortel (speaking fee from CSL Behring), intensity and duration of therapy have not been and Dr. J. Evan Sadler (consultant and Clinical established. Advisory Board member for Baxter). Drs. Margaret Rick and Mark Weinstein reported no potential conflicts of interest and contributed to this manu- Training of specialists in haemostasis script in their private capacities, and no official In the United States, despite scientific progress in endorsement or support by the National Institutes of basic and clinical research in bleeding and throm- Health or the Food and Drug Administration is botic disorders, including VWD, there is a shortage intended or should be inferred. All other authors of skilled clinicians and laboratorians with expertise reported no potential conflicts of interest.

This article is based on a U.S. government publication which is in the public domain. Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 171–232 218 W. L. NICHOLS et al.

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GUIDELINES

Management of severe perioperative bleeding Guidelines from the European Society of Anaesthesiology

Sibylle A. Kozek-Langenecker, Arash Afshari, Pierre Albaladejo, Cesar Aldecoa Alvarez Santullano, Edoardo De Robertis, Daniela C. Filipescu, Dietmar Fries, Klaus Go¨ rlinger, Thorsten Haas, Georgina Imberger, Matthias Jacob, Marcus Lance´, Juan Llau, Sue Mallett, Jens Meier, Niels Rahe-Meyer, Charles Marc Samama, Andrew Smith, Cristina Solomon, Philippe Van der Linden, Anne Juul Wikkelsø, Patrick Wouters and Piet Wyffels

The aims of severe perioperative bleeding management are systematic reviews with meta-analyses, randomised con- three-fold. First, preoperative identification by anamesis trolled trials, cohort studies, case-control studies and and laboratory testing of those patients for whom the peri- cross-sectional surveys were selected. At the suggestion operative bleeding risk may be increased. Second, imple- of the ESA Guideline Committee, the Scottish Intercollegiate mentation of strategies for correcting preoperative anaemia Guidelines Network (SIGN) grading system was initially used and stabilisation of the macro- and microcirculations in order to assess the level of evidence and to grade recommen- to optimise the patient’s tolerance to bleeding. Third, dations. During the process of guideline development, the targeted procoagulant interventions to reduce the amount official position of the ESA changed to favour the Grading of of bleeding, morbidity, mortality and costs. The purpose of Recommendations Assessment, Development and Evalu- these guidelines is to provide an overview of current know- ation (GRADE) system. This report includes general recom- ledge on the subject with an assessment of the quality of the mendations as well as specific recommendations in various evidence in order to allow anaesthetists throughout Europe fields of surgical interventions. The final draft guideline was to integrate this knowledge into daily patient care wherever posted on the ESA website for four weeks and the link was possible. The Guidelines Committee of the European sent to all ESA members. Comments were collated and the Society of Anaesthesiology (ESA) formed a task force with guidelines amended as appropriate. When the final draft was members of scientific subcommittees and individual expert complete, the Guidelines Committee and ESA Board ratified members of the ESA. Electronic databases were searched the guidelines. without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant Published online 25 April 2013

This article is accompanied by the following Invited Commentary: Spahn DR, Rossaint R. All we ever wanted to know about perioperative bleeding. Eur J Anaesthesiol 2013; 30:267–269.

From the Department of Anaesthesia and Intensive Care, Evangelical Hospital Vienna, Austria (SAKL), Department of Anaesthesia, Mother and Children’s section, Juliane Marie Center, Rigshospitalet, University of Copenhagen, Denmark and Department of Pediatric and Neonatal Intensive Care Service, Geneva University Hospital, Switzerland (AA), Department of Anaesthesia and Critical Care Medicine, Grenoble University Hospital, Grenoble, France (PA), Department of Anaesthesiology and Resuscitation, University Hospital Rio Hortega, Valladolid, Spain (CAAS), Department of Neurosciences, Odontostomatologic and Reproductive Sciences, University of Napoli Federico II, Naples, Italy (EDR), Department of Cardiac Anaesthesia and Intensive Care, Emergency Institute of Cardiovascular Disease, Bucharest, Romania (DCF), Department of General and Surgical Intensive Care Medicine, Medical University Innsbruck, Austria (DF), Department of Anaesthesiology and Intensive Care Medicine, University Hospital Essen, Universita¨t Duisburg-Essen, Germany (KG), Department of Anaesthesia, University Children’s Hospital Zurich, Switzerland (TH), Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (GI), Department of Anaesthesiology, University Hospital Munich, Germany (MJ), Department of Anaesthesia and Pain Therapy, Department of Intensive Care, Maastricht University Medical Centre, Netherlands (ML), Department of Anaesthesia and Critical Care Medicine, Hospital Clinico Universitario of Valencia, University of Valencia, Spain (JL), Department of Anaesthesia, Royal Free London NHS Foundation Trust, UK (SM), Department of Anaesthesiology and Intensive Care Medicine, University Hospital, Eberhard Karls University Tu¨bingen, Germany (JM), Department of Anaesthesiology and Critical Care Medicine, Franziskus Hospital Bielefeld, Germany (NRM), Department of Anaesthesia and Intensive Care Medicine, Hotel-Dieu and Cochin University Hospitals, Paris, France (CMS), Department of Anaesthesia, Royal Lancaster Inﬁrmary, Lancaster, UK (AS), Department of Anaesthesiology, Perioperative Medicine and General Intensive Care, Salzburg University Hospital SALK, Salzburg, Austria (CS), Department of Anaesthesiology, CHU Brugmann-HUDERF, Brussels, Belgium (PVDL), Department of Anaesthesiology and Intensive Care Medicine, Herlev Hospital, University of Copenhagen, Denmark (AJW), Department of Anaesthesiology, Ghent University Hospital, Belgium (PaW, PiW) Correspondence to Sibylle A. Kozek-Langenecker (chairperson of the guideline task force), Department of Anaesthesia and Intensive Care, Evangelical Hospital Vienna, Hans-Sachs-Gasse 10-12, 1180-Vienna, Austria E-mail: [email protected]

0265-0215 ß 2013 Copyright European Society of Anaesthesiology DOI:10.1097/EJA.0b013e32835f4d5b Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 271

Contents

1 Abbreviations ...... 271 2 Summary: Recommendations, suggestions and statements ...... 274 Transfusion of labile blood products...... 275 Visceral and transplant surgery ...... 278 Acute upper gastrointestinal bleeding ...... 279 Paediatric surgery ...... 279 Antiplatelet agents...... 279 Vitamin K antagonists ...... 280 Comorbidities involving haemostatic derangement ...... 281 3 Introduction ...... 283 4 Methods ...... 283 4.1 Selection of task force ...... 283 4.2 The search for evidence ...... 283 4.3 Review of the guideline...... 284 5 Coagulation monitoring ...... 284 5.1 Perioperative coagulation testing ...... 284 5.2 Evaluation of platelet function ...... 289 6 Anaemia management ...... 291 6.1 Preoperative correction of anaemia ...... 291 6.2 Intra- and postoperative optimisation of macro- and microcirculation ...... 295 6.3 Transfusion of labile blood products...... 297 7 Coagulation management...... 303 7.1 Indications, contraindications, complications and doses ...... 303 7.2 Correction of confounding factors ...... 305 7.3 Cost implications ...... 306 8 Multimodal approach (algorithms) in speciﬁc clinical ﬁelds ...... 308 8.1 Cardiovascular surgery ...... 308 8.2 Gynaecology and obstetrics ...... 315 8.3 Orthopaedic surgery and neurosurgery ...... 319 8.4 Visceral and transplant surgery ...... 325 8.5 Paediatric surgery ...... 331 9 Anticoagulation and antiplatelet therapy ...... 333 9.1 Introduction ...... 333 9.2 Antiplatelet agents...... 333 9.3 Anticoagulant agents ...... 335 10 Perioperative bleeding management in patients with comorbidities with haemostatic derangements and congenital bleeding disorders ...... 340 10.1 Patients with comorbidities involving haemostatic derangement ...... 340 10.2 Patients with congenital bleeding disorders...... 341 11 Final remarks ...... 349 12 References...... 351

1 ABBREVIATIONS A5, A10 Amplitude at 5/10 min following clotting time AAGBI Association of Anaesthetists of Great Britain and Ireland ACS Acute coronary syndrome ADP Adenosine diphosphate ALI Acute lung injury APA Anti-platelet agents APCC Activated prothrombin complex concentrate APTEM Thromboelastometry assay incorporating aprotinin and recombinant tissue factor as an activation enhancer aPTT Activated partial thromboplastin time

AT Antithrombin ATP Adenosine triphosphate AVB Acute variceal bleeding BART Blood conservation using antifibrinolytics in a randomised trial BAT Bleeding assessment tool CABG Coronary artery bypass graft CADP Collagen and ADP (PFA-100 assay) CCI Corrected count increment CEPI Collagen and epinephrine (PFA-100 assay) CFT Clot formation time (also called k time) CI Confidence interval CKD Chronic kidney disease CLD Chronic liver disease CMV Cytomegalovirus COX Cyclo-oxygenase CPA Cone and plate(let) analyser (Impact-R) CPB Cardiopulmonary bypass CT Clotting time CVP Central venous pressure DIC Disseminated intravascular coagulation DPG Diphosphoglycerol EACA e-aminocaproic acid EMA European Medicines Agency EXTEM Extrinsic thromboelastometry assay incorporating recombinant tissue factor as activation enhancer FF Functional fibrinogen (assay) FFP Fresh frozen plasma FIBTEM Fibrinogen thromboelastometry assay, incorporating recombinant tissue factor as activation enhancer and cytochalasin D as platelet inhibitor FNHTR Febrile non-haemolytic transfusion reactions FVIII Factor VIII FXa Factor Xa FXIII Factor XIII G Clot rigidity GP Glycoprotein Hb Haemoglobin HBV Hepatitis B virus HCV Hepatitis C virus HELLP Haemolysis, elevated liver enzymes and low platelets HEPTEM Thrombelastometry assay incorporating heparinase and ellagic acid as an activation enhancer HES Hydroxyethyl starch HIV Human immunodeficiency virus HTLV Human T-cell lymphotropic virus HTRs Haemolytic transfusion reactions HV Hyperoxic ventilation ICH Intracerebral haemorrhage ICS Intraoperative cell salvage ICT Intracardiac thrombi ICU Intensive care unit INR International normalised ratio INTEM Intrinsic thromboelastometry assay incorporating ellagic acid as activation enhancer LI30 Lysis index (% of clot strength remaining 30 min after CT) LMWH Low molecular weight heparin LTA Light transmittance aggregometry LY30 Lysis index (% of clot strength remaining 30 min after MA) MA Maximum amplitude MBD Mild bleeding disorders MCB Mucocutaneous bleeding Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 273

MCE Maximum clot elasticity MCF Maximum clot firmness MEA Multiple electrode aggregometry (Multiplate) ML Maximum lysis NATEM Native thromboelastometry assay (no activation enhancement or additional modifications) NICE National Institute of Health and Clinical Excellence NOA New oral anticoagulant agent NSAID Non-selective, non-steroidal anti-inflammatory drug OLT Orthotopic liver transplantation PAI Plasminogen activator inhibitor paO2 Partial pressure of oxygen PCC Prothrombin complex concentrate PCI Percutaneous coronary intervention PEP Pulmonary embolism prevention (trial) PFA-100 Platelet function analyser PPV Pulse pressure variation PT Prothrombin time r Reaction time RBC Red blood cell RBD Rare bleeding disorder RCT Randomised controlled trial rFVIIa Recombinant activated factor VII ROTEM Thromboelastometry SBT Skin bleeding time ScvO2 Central venous oxygen saturation SD Solvent and detergent SHOT Serious hazards of transfusion SIGN Scottish Intercollegiate Guidelines Network SLT Standard laboratory test SPRINT Systolic blood pressure intervention trial SSRI Selective serotonin reuptake inhibitors SVV Stroke volume variation TACO Transfusion-associated circulatory overload TAE Transcatheter arterial embolisation TA-GVHD Transfusion-associated graft-versus-host disease TEG Thromboelastometry TF Tissue factor THA Total hip arthroplasty TRALI Transfusion-related acute lung injury TRAP Thrombin receptor activator peptide TRICC Transfusion requirements in critical care (trial) TRIM Transfusion-related immunomodulation UFH Unfractionated heparin UGIB Upper gastrointestinal bleeding vCJD Variant Creutzfeldt-Jacob disease VKA Vitamin K antagonist VTE Venous thromboembolism VWD Von Willebrand disease VWF Von Willebrand factor

2 SUMMARY: RECOMMENDATIONS, We suggest that preoperative platelet function testing SUGGESTIONS AND STATEMENTS be used to identify decreased platelet function Grade of recommendation shown in bold type (see caused by medical conditions and antiplatelet medi- Table 1) cation. 2C

Evaluation of coagulation status Preoperative correction of anaemia We recommend the use of a structured patient interview We recommend that patients at risk of bleeding or questionnaire before surgery or invasive procedures, are assessed for anaemia 4–8 weeks before surgery. which considers clinical and family bleeding history and 1C detailed information on the patient’s medication. 1C If anaemia is present, we recommend identifying the We recommend the use of standardised questionnaires cause (iron deficiency, renal deficiency or inflammation). on bleeding and drug history as preferable to the routine 1C use of conventional coagulation screening tests such as aPTT, PT and platelet count in elective surgery. 1C We recommend treating iron deficiency with iron supplementation (oral or intravenous). 1B We recommend the application of transfusion algorithms incorporating predefined intervention triggers to guide If iron deficiency has been ruled out, we suggest treating haemostatic intervention during intraoperative bleeding. anaemic patients with erythropoietin-stimulating agents. 1B 2A We recommend the application of transfusion algorithms If autologous blood donation is performed, we suggest incorporating predefined intervention triggers based on treatment with erythropoietin-stimulating agents in order point-of-care (POC) coagulation monitoring assays to to avoid preoperative anaemia and increased overall guide haemostatic intervention during cardiovascular transfusion rates. 2B surgery. 1C Optimising macrocirculation Evaluation of platelet function We recommend aggressive and timely stabilisation of We suggest preoperative platelet function testing only in cardiac preload throughout the surgical procedure, as this addition to a positive bleeding anamnesis. 2C appears beneficial to the patient. 1B

Table 1 Grades of recommendation – GRADE system

Clarity of risk/beneﬁt Quality of supporting evidence Implications

1A Strong recommendation. High Benefits clearly outweigh risk Consistent evidence from well performed randomised, Strong recommendation, can quality evidence. and burdens, or vice versa. controlled trials or overwhelming evidence of some apply to most patients in other form. Further research is unlikely to change our most circumstances confidence in the estimate of benefit and risk. without reservation. 1B Strong recommendation. Benefits clearly outweigh risk Evidence from randomised, controlled trials with Strong recommendation, likely Moderate quality evidence. and burdens, or vice versa. important limitations (inconsistent results, to apply to most patients methodological flaws, indirect or imprecise), or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate. 1C Strong recommendation. Low Benefits appear to outweigh Evidence from observational studies, unsystematic Relatively strong quality evidence. risk and burdens, or vice clinical experience, or from randomised, controlled recommendation; might versa. trials with serious flaws. Any estimate of effect is change when higher quality uncertain. evidence becomes available 2A Weak recommendation. High Benefits closely balanced with Consistent evidence from well performed, randomised, Weak recommendation, best quality evidence. risks and burdens. controlled trials or overwhelming evidence of some action may differ depending other form. Further research is unlikely to change our on circumstances or confidence in the estimate of benefit and risk. patients or societal values. 2B Weak recommendation. Benefits closely balanced with Evidence from randomised, controlled trials with Weak recommendation, Moderate quality evidence. risks and burdens, some important limitations (inconsistent results, alternative approaches uncertainty in the estimates methodological flaws, indirect or imprecise), or very likely to be better for some of benefits, risks and strong evidence of some other form. Further research patients under some burdens. (if performed) is likely to have an impact on our circumstances confidence in the estimate of benefit and risk and may change the estimate 2C Weak recommendation. Low Uncertainty in the estimates of Evidence from observational studies, unsystematic Very weak recommendation; quality evidence. benefits, risks and burdens; clinical experience, or from randomised, controlled other alternatives may be benefits may be closely trials with serious flaws. Any estimate of effect is equally reasonable balanced with risks and uncertain. burdens.

We recommend the avoidance of hypervolaemia with We recommend that multiparous women be excluded crystalloids or colloids to a level exceeding the interstitial from donating blood for the preparation of FFP and for space in steady state, and beyond an optimal cardiac the suspension of platelets in order to reduce the inci- preload. 1B dence of transfusion-related acute lung injury. 1C We recommend against the use of central venous pres- We recommend that all RBC, platelet and granulocyte sure and pulmonary artery occlusion pressure as the only donations from first-or second-degree relatives be variables to guide fluid therapy and optimise preload irradiated even if the recipient is immunocompetent, during severe bleeding; dynamic assessment of fluid and all RBC, platelet and that granulocyte products be responsiveness and non-invasive measurement of cardiac irradiated before transfusing to at-risk patients. 1C output should be considered instead. 1B We recommend the transfusion of leukocyte-reduced We suggest the replacement of extracellular fluid losses RBC components for cardiac surgery patients. 1A with isotonic crystalloids in a timely and protocol-based manner. 2C Cell salvage Compared with crystalloids, haemodynamic stabilisation We recommend the routine use of red cell salvage which with iso-oncotic colloids, such as human albumin and is helpful for blood conservation in cardiac operations hydroxyethyl starch, causes less tissue oedema. C using CPB. 1A We suggest the use of balanced solutions for crystalloids We recommend against the routine use of intraoperative and as a basic solute for iso-oncotic preparations. 2C platelet-rich plasmapheresis for blood conservation during cardiac operations using CPB. 1A Transfusion triggers We recommend the use of red cell salvage in major We recommend a target haemoglobin concentration of orthopaedic surgery because it is useful in reducing 1 7–9gdl during active bleeding. 1C exposure to allogeneic red blood cell transfusion. 1A Oxygen fraction We recommend that intraoperative cell salvage is not We recommend that inspiratory oxygen fraction should contraindicated in bowel surgery, provided that initial be high enough to prevent arterial hypoxaemia in bleed- evacuation of soiled abdominal contents and additional ing patients, while avoiding extensive hyperoxia cell washing are performed, and that broad-spectrum antibiotics are used. 1C (PaO2 > 26.7 kPa [200 mmHg]). 1C

Monitoring tissue perfusion Storage lesions We recommend repeated measurements of a combi- We recommend that RBCs up to 42 days old should be nation of haematocrit/haemoglobin, serum lactate, and transfused according to the first-in first-out method in, the base deficit in order to monitor tissue perfusion, tissue blood services to minimise wastage of erythrocytes. 1C oxygenation and the dynamics of blood loss during acute bleeding. These parameters can be extended by Coagulation management measurement of cardiac output, dynamic parameters of We recommend treatment with fibrinogen concentrate if volume status (e.g. stroke volume variation, pulse pres- significant bleeding is accompanied by at least suspected sure variation) and central venous oxygen saturation. 1C low fibrinogen concentrations or function. 1C We recommend that a plasma fibrinogen concentration Transfusion of labile blood products <1.5–2.0 g l 1 or ROTEM/TEG signs of functional We recommend that all countries implement national fibrinogen deficit should be triggers for fibrinogen sub- haemovigilance quality systems. 1C stitution. 1C We recommend a restrictive transfusion strategy which is We suggest an initial fibrinogen concentrate dose of beneficial in reducing exposure to allogeneic blood pro- 25–50 mg kg 1. 2C ducts. 1A We suggest that the indication for cryoprecipitate is lack We recommend photochemical pathogen inactivation of available fibrinogen concentrate for the treatment of with amotosalen and UVA light for platelets. 1C bleeding and hypofibrinogenaemia. 2C We recommend that labile blood components used for In cases of ongoing or diffuse bleeding and low clot transfusion are leukodepleted. 1B strength despite adequate fibrinogen concentrations, it We recommend that blood services implement standard is likely that FXIII activity is critically reduced. In cases operating procedures for patient identification and that of significant FXIII deficiency (i.e. <60% activity), we staff be trained in early recognition of, and prompt suggest that FXIII concentrate (30 IU kg1) can be admi- response to, transfusion reactions. 1C nistered. 2C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 276 Kozek-Langenecker et al.

We recommend that patients on oral anticoagulant Cost implications therapy should be given prothrombin complex concen- Bleeding and transfusion of allogeneic blood products trate (PCC) and vitamin K before any other coagulation independently increase morbidity, mortality, length of management steps for severe perioperative bleeding. 1B stay in ICU and hospital, and costs. B We suggest that PCC (20–30 IU kg 1) can also be admi- Lysine analogues (tranexamic acid and e-aminocaproic nistered to patients not on oral anticoagulant therapy in acid; EACA) reduce perioperative blood loss and trans- the presence of an elevated bleeding tendency and fusion requirements; this can be highly cost-effective in prolonged clotting time. Prolonged INR/PT alone is several settings of major surgery and trauma. A not an indication for PCC, especially in critically ill patients. 2C We recommend restricting the use of rFVIIa to its licensed indication because, outside these indications, We suggest that off-label administration of recombinant the effectiveness of rFVIIa to reduce transfusion require- activated factor VII (rFVIIa) can be considered for bleed- ments and mortality remains unproven and the risk of ing which cannot be stopped by conventional, surgical or arterial thromboembolic events as well as costs are high. interventional radiological means and/or when compre- 1A hensive coagulation therapy fails. 2C Cell salvage can be cost-effective.A Antifibrinolytics and tranexamic acid The cost-effectiveness of a formula-driven transfusion We recommend the consideration of tranexamic acid protocol has not been investigated. (20–25 mg kg 1). 1A Implementation of transfusion and coagulation manage- We suggest the use of DDAVP under specific conditions ment algorithms (based on ROTEM/TEG) can reduce (acquired von Willebrand syndrome). There is no con- transfusion-associated costs in trauma, cardiac surgery vincing evidence that DDAVP minimises perioperative and liver transplantation. B bleeding or perioperative allogeneic blood transfusion in patients without a congenital bleeding disorder. 2B Goal-directed therapy with coagulation factor concentrates (fibrinogen and/or PCC) may reduce transfusion- Correction of confounding factors associated costs in trauma, cardiac surgery and liver We recommend maintaining perioperative normothermia transplantation. B because it reduces blood loss and transfusion require- Thromboembolic events are associated with increased ments. 1B in-hospital and post-hospital costs. B We suggest that rFVIIa may be used in treatment of Targeted therapy with fibrinogen and/or PCC guided patients with hypothermic coagulopathy. 2C by ROTEM/TEG is not associated with an increased While pH correction alone cannot immediately correct incidence of thromboembolic events. C acidosis-induced coagulopathy, we recommend that pH correction should be pursued during treatment of acidotic Algorithms in specific clinical fields coagulopathy. 1C Cardiovascular surgery We recommend that rFVIIa should only be considered Withdrawal of aspirin therapy increases the risk of throm- alongside pH correction. 1C bosis; continuation of aspirin therapy increases the risk of bleeding. A We suggest that calcium should be administered during massive transfusion if Ca2þ concentration is low, in order Withdrawal of clopidogrel therapy increases the risk of 1 thrombosis; continuation of clopidogrel therapy increases to preserve normocalcaemia (0.9 mmol l ). 2B the risk of bleeding. A Emergency radiological/surgical interventions to We recommend that a prophylactic dose of low mol- reduce blood loss ecular weight heparin should be administered subcu- We suggest that endovascular embolisation is a safe taneously 8–12 h before elective CABG surgery. This alternative to open surgical intervention after failed intervention does not increase the risk of perioperative endoscopic treatment for upper gastrointestinal bleeding. bleeding. 1B 2C We recommend that tranexamic acid or EACA should be We suggest super-selective embolisation as primary considered before CABG surgery. 1A therapy for treatment of angiogram positive lower gastro- We suggest considering prophylactic preoperative infusion intestinal bleeding. 2C of 2 g fibrinogen concentrate in patients with fibrinogen We suggest embolisation as first-line therapy for arterial concentration <3.8 g/L, because it may reduce bleeding complications in pancreatitis. 2C following elective CABG surgery. 2C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 277

Prothrombin complex concentrate is effective for Tranexamic acid reduces perioperative bleeding in rapid reversal of oral anticoagulation before cardiac gynaecological cancer surgery. C surgery.A We suggest against the use of tranexamic acid in We recommend that intraoperative tranexamic acid or benign gynaecological operations such as myomectomy. EACA administration should be considered to reduce 2B perioperative bleeding in high-, medium- and low-risk cardiovascular surgery. 1A Obstetric bleeding We recommend that tranexamic acid should be applied We recommend that peripartum haemorrhage should be topically to the chest cavity to reduce postoperative blood managed by a multidisciplinary team. An escalating loss following CABG surgery. 1C management protocol including uterotonic drugs, surgical and/or endovascular interventions, and procoagulant We recommend that fibrinogen concentrate infusion drugs should be available. 1C guided by point-of-care viscoelastic coagulation monitoring should be used to reduce perioperative blood loss in Risk awareness and early recognition of severe haemor- complex cardiovascular surgery. 1B rhage are essential. C We suggest that recombinant FVIIa may be considered We suggest that patients with known placenta accreta are for patients with intractable bleeding during cardiovas- treated by multidisciplinary care teams. 2C cular surgery once conventional haemostatic options have Cell salvage is well tolerated in obstetric settings, pro- been exhausted. 2B vided that precautions are taken against rhesus isoimmu- We suggest that antiplatelet therapy with aspirin or nisation. C clopidogrel may be administered in the early postopera- We suggest that using perioperative cell salvage during tive period without increasing the risk of postoperative caesarean section may decrease postoperative homolo- bleeding. 2C gous transfusion and reduce hospital stay. 2B We suggest that rFVIIa may be considered for patients We recommend that moderate (<9.5 g dl 1) to severe with intractable bleeding after cardiovascular surgery (<8.5 g dl 1) postpartum anaemia be treated with intra- once conventional haemostatic options have been venous iron rather than oral therapy. 1B exhausted. 2B Intravenous iron supplementation improves fatigue at 4, We recommend the use of standardised haemo- 8 and 12 weeks postpartum. B static algorithms with predefined intervention triggers. 1A Insufficient evidence exists to support the transfusion- sparing effect of intravenous iron supplementation. Gynaecological (non-pregnant) bleeding We suggest that treatment with erythropoietin may cor- We suggest against normovolaemic haemodilution rect anaemia more rapidly than treatment with folic acid because it does not reduce allogeneic transfusion. 2A and iron. 2C Cell salvage may reduce allogeneic transfusion in gynae- We suggest assessing fibrinogen concentration in parturi- cological (including oncological) surgery. C ents with bleeding, as concentrations <2gl 1 may We suggest using preoperative intravenous iron to reduce identify those at risk of severe PPH. 2C allogeneic transfusion requirements in gynaecological Platelet count <100 109 l 1 at the onset of labour, cancer patients receiving chemotherapy.2B particularly combined with plasma fibrinogen concen- We suggest using intravenous iron to correct preoperative tration <2.9 g l1, may indicate an increased risk of anaemia in women with menorrhagia. 2B PPH. C Preoperative fibrinogen and D-dimer evaluation in aPTT and PT are of little predictive value for PPH. C gynaecological cancer patients provide little useful infor- Thromboelastometry can identify obstetric coagulopathy mation. C and hyperfibrinolysis and guide haemostatic therapy.C Postoperative FFP transfusion is associated with an In life-threatening PPH, we suggest a transfusion proto- increased risk of venous thromboembolism in malignant col with a fixed product ratio or individualised procoa- gynaecological surgery. C gulant intervention and factor substitution. 2C rFVIIa increases thromboembolic risk and has not been Considering physiologically elevated fibrinogen con- shown to reduce mortality. B centrations in pregnancy, we suggest that a higher Tranexamic acid reduces the frequency of late bleeding trigger value for treating hypofibrinogenaemia may be after cone biopsy of the cervix. B required. C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 278 Kozek-Langenecker et al.

We recommend the administration of tranexamic acid in The intensity of oral anticoagulation with warfarin obstetric bleeding to reduce blood loss, bleeding duration measured by INR, shows a close correlation to the and the number of units transfused. 1B incidence and severity of bleeding complications, in particular with ICH. C We suggest that tranexamic acid be considered before caesarean section.2C We suggest administering tranexamic acid in total hip arthroplasty, total knee arthroplasty, and major spine In antepartum bleeding, we suggest administration of surgery. 2A tranexamic acid.2B Tranexamic acid may promote a hypercoagulable state We recommend that rFVIIa should only be considered as for some patients (with pre-existing thromboembolic last line therapy because of its thromboembolic risk. 1B events, hip fracture surgery, cancer surgery, age over We suggest that fibrinogen concentration and number of 60 years, women). Therefore, we suggest an individual platelets should be optimised before administration of risk-benefit analysis instead of its routine use in these rFVIIa. 2C clinical settings. 2A We suggest the use of rFVIIa in patients with neutralising Orthopaedic surgery and neurosurgery antibodies to FVIII undergoing major orthopaedic In elective orthopaedic surgery, we recommend the surgery. 2C implementation of a blood transfusion protocol (algorithm), together with staff education. 1B Prophylactic use of rFVIIa does not reduce perioperative blood loss or transfusion in non-haemophiliac and non- Allogeneic blood transfusion is associated with an coagulopathic patients undergoing major orthopaedic increased incidence of nosocomial infections. B surgery or neurosurgery, and it may increase the inci- Infusion of colloids in patients with severe bleeding can dence of thromboembolic events. We, therefore, recom- aggravate dilutional coagulopathy by additional effects on mend against the prophylactic use of rFVIIa in these fibrin polymerisation and platelet aggregation. C clinical settings. 1B We recommend that, for orthopaedic surgery, monother- We recommend restricting off-label use of rFVIIa to apy with aspirin does not need to be discontinued. 1B patients with severe bleeding who are unresponsive to other haemostatic interventions. 1C We recommend discontinuing dual antiplatelet therapy before urgent intracranial neurosurgery. A risk-benefit In patients with INR > 1.5, with life-threatening analysis is required for the continuation of aspirin mono- bleeding or ICH, we recommend that four-factor therapy during neurosurgery.1B PCCs (20–40 IU kg 1), supplemented with vitamin K (10 mg by slow intravenous infusion), should be We recommend against performing orthopaedic surgery used for rapid reversal of vitamin K-antagonists during the first three months after bare metal stent (VKA). 1C implantation or during the first twelve months after drug eluting stent implantation. 1C In patients with neutralising antibodies to FVIII undergoing major orthopaedic surgery, we suggest using acti- Preoperative medication with ADP-receptor antagonists vated PCCs (e.g. FEIBA, FVIII inhibitor bypassing or with new oral anticoagulants is associated with an agents). 2C increased risk of major bleeding and intracerebral haemorrhage (ICH), especially if used in combination. B New oral anticoagulants, such as rivaroxaban and dabigatran, may increase surgical bleeding and ICH growth. Reduced platelet activity is associated with early haema- We suggest that PCC, FEIBA or rFVIIa may be used as toma growth, more intraventricular haemorrhage and non-specific antagonists in life threatening bleeding or worse three-month outcome following ICH. C ICH. 2C Low platelet count, low plasma fibrinogen concentration and FXIII deficiency are predictive of bleeding compli- Visceral and transplant surgery cations in ICH, intracranial surgery and major spine Despite PT, aPTT and INR indicating coagulopathy in surgery, particularly when they occur in combination. C chronic liver disease (CLD), global coagulation tests (thrombin generation and TEG/ROTEM) suggest that Preoperative measurement of plasma fibrinogen concen- haemostasis is balanced in stable CLD. C tration provides more information on bleeding volume and transfusion requirements than standard screening Mild to moderate prolongation of the preoperative tests. C PT and INR do not predict bleeding in patients with CLD.C We suggest the use of viscoelastic tests (ROTEM/TEG) for monitoring perioperative haemostasis in major ortho- We recommend against the use of FFP for pre-procedural paedic surgery and neurosurgery. 2C correction of mild to moderately elevated INR. 1C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 279

We suggest a platelet count of 50 000 ml1 as a threshold in uraemia and no prediction of bleeding in this for platelet transfusion before liver biopsy. 2C setting.C PFA-100 is not predictive of bleeding risk in cirrhosis. C We suggest that conjugated oestrogen therapy should be used in uraemia. 2C Bleeding time is influenced by many variables and is not useful to stratify bleeding risk. C We suggest that desmopressin should be considered for reducing bleeding during surgery and for managing acute We recommend that, in acute liver failure, moderately bleeding in uraemic patients. 2C elevated INR should not be corrected before invasive procedures, with the exception of intracranial pressure There is no evidence to support use of rFVIIa in monitor insertion. 1C this setting. Fluid restriction, phlebotomy, vasopressors and transfu- Paediatric surgery sion protocols may be associated with low transfusion We suggest the use of perioperative coagulation analysis rates during orthotopic liver transplantation (OLT).C using viscoelastic point-of-care monitoring (ROTEM/ We recommend the use of perioperative coagulation TEG) for timely detection of coagulation defects includ- monitoring using ROTEM/TEG for targeted manage- ing dilutional coagulopathy and hyperfibrinolysis. 2C ment of coagulopathy. 1C No clear recommendation can be made regarding the Antifibrinolytic therapy reduces blood loss and transfu- choice of perioperative fluid replacement in children. C sion requirements in liver transplantation. B We suggest that a critical haemoglobin threshold of We recommend antifibrinolytic drugs for treatment of 8gdl 1 for RBC transfusion may be safe in severe pae- fibrinolysis (evident from microvascular oozing or TEG/ diatric perioperative bleeding. 2C ROTEM clot lysis measurement) and not for routine We suggest that transfusion of platelet concentrates may prophylaxis. Marginal grafts (e.g. donation after cardiac be considered if platelet count is <50 000–100 000 ml 1. death) increase the risk of fibrinolysis post-reperfusion. 1C 2C We recommend against rFVIIa for prophylaxis; rFVIIa No clear recommendation can be made regarding the should be used only as rescue therapy for uncontrolled indication and dosing of FFP transfusion in bleeding bleeding. 1A children, but severe side-effects have been reported.C Point of care platelet function tests may help to stratify We suggest that fibrinogen concentrate (30–50 mg kg 1) risk and rationalise platelet transfusion in patients taking or cryoprecipitate (5 ml kg 1) may be used to increase antiplatelet drugs. C plasma fibrinogen concentrations above trigger values of A low central venous pressure and restrictive fluid admin- 1.5–2.0 g l 1 or FIBTEM MCF > 7 mm in bleeding istration reduce bleeding during liver resection. B children. 2C We suggest that antifibrinolytic drugs should be con- We suggest that FFP may be used if no other fibrinogen sidered in cirrhotic patients undergoing liver resection. 2C source is available.2C Data for PCC in children are limited and no dose recom- Acute upper gastrointestinal bleeding mendation can be made.C We recommend that acute variceal bleeding should be No recommendation on the use of FXIII concentrate in managed by a multidisciplinary team. A specific multi- bleeding children can be made. modal protocol for upper gastrointestinal haemorrhage should be available. 1C We recommend against the use of rFVIIa in children. 1C We recommend that early treatment involves immediate We suggest against the routine use of desmospressin in use of vasopressors (somatostatin or terlipressin) to the absence of haemophilia A or mild von Willebrand reduce bleeding and early interventional endoscopy. disease. 2C Antibiotics must be started on admission. 1A We suggest that perioperative antifibrinolytic therapy Tranexamic acid reduces mortality but not rebleeding.B should be used to reduce blood loss and transfusion requirements in cardiac and non-cardiac paediatric rFVIIa should be used only as rescue therapy; we recom- surgery.2A mend against its routine use. 1C Antiplatelet agents Coagulopathy and renal disease We recommend that aspirin therapy should continue Point-of-care tests of platelet function and bleeding perioperatively in most surgical settings, especially car- time provide no reliable platelet function assessment diac surgery. 1C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 280 Kozek-Langenecker et al.

Where aspirin withdrawal is considered, we recommend a We suggest that severe bleeding related to subcutaneous time interval of 5 days. 1C low molecular weight heparin (LMWH) should be treated with intravenous protamine at a dose of 1 mg For intra- or postoperative bleeding clearly related to per 100 anti-FXa units of LMWH administered. 2C aspirin, we suggest that platelet transfusion be considered (dose: 0.7 1011 [i.e. two standard concentrates] per 7 kg We suggest that severe bleeding associated with subcu- body weight in adults). 2C taneous LMWH and unresponsive to initial administration of protamine could be treated with a second Clopidogrel increases perioperative bleeding. In cases of dose of protamine (0.5 mg per 100 anti-FXa units of increased bleeding risk, we recommend that it should be LMWH administered). 2C withdrawn for no more than 5 days.1C

Prasugrel increases perioperative bleeding. In cases of Fondaparinux increased bleeding risk, we recommend that it should be We suggest that the administration of rFVIIa could be withdrawn for no more than 7 days.1C considered to treat severe bleeding associated with sub- We recommend that antiplatelet agent therapy should cutaneous administration of fondaparinux (off-label treat- resume as soon as possible postoperatively to prevent ment). 2C platelet activation.1C Vitamin K antagonists We suggest that the first postoperative dose of clopidogrel We recommend that vitamin K antagonists (VKAs) or prasugrel should be given no later than 24 h after skin should not be interrupted for skin surgery, dental and closure. We also suggest that this first dose should not be a other oral procedures, gastric and colonic endoscopies loading dose. 2C (even if biopsy is scheduled, but not polypectomy), nor We recommend postponement of elective surgery follow- for most ophthalmic surgery (mainly anterior chamber, ing coronary stenting (at least 6 to 12 weeks for bare metal e.g. cataract), although vitreoretinal surgery is sometimes stent and one year for drug-eluting stents). 1C performed in VKA treated patients. 1C We recommend that a multidisciplinary team meeting We recommend that for low-risk patients (e.g. atrial should decide on the perioperative use of antiplatelet fibrillation patients with CHADS2 score 2, patients agents in urgent and semi-urgent surgery. 1C treated for > 3 months for a non-recurrent VTE) undergoing procedures requiring INR <1.5, VKA should be We suggest that urgent or semi-urgent surgery should be stopped 5 days before surgery. No bridging therapy is performed under aspirin/clopidogrel or aspirin/prasugrel needed. Measure INR on the day before surgery and give combination therapy if possible, or at least under aspirin 5 mg oral vitamin K if INR exceeds 1.5. 1C alone. 2C We recommend bridging therapy for high-risk patients We suggest that platelet transfusion should be con- (e.g. atrial fibrillation patients with a CHADS2 score > 2, sidered (dose: 0.7 1011 [i.e. two standard concentrates] patients with recurrent VTE treated for <3 months, per 7 kg body weight in adults) in cases of intra- or patients with a mechanical valve). Day 5: last VKA dose; postoperative bleeding clearly related to clopidogrel or Day 4: no heparin; Days 3 and 2: therapeutic subcu- prasugrel.2C taneous LMWH twice daily or subcutaneous UFH twice According to pharmacological characteristics, we suggest or thrice daily; Day 1: hospitalisation and INR measure- that the management of ticagrelor may be comparable to ment; Day 0: surgery.1C clopidogrel (i.e. withdrawal interval of 5 days). 2C We recommend that for groups 1 and 2 above, VKAs Platelet transfusion may be ineffective for treating bleed- should be restarted during the evening after the pro- ing clearly related to ticagrelor when given 12 h before. cedure. Subcutaneous LMWH should be given post- 2C operatively until the target INR is observed in two measurements.1C Heparin We recommend that for group 3 above, heparin (UFH or We recommend that severe bleeding associated with LMWH) should be resumed 6–48 h after the procedure. intravenous unfractionated heparin (UFH) should be VKA can restart when surgical haemostasis is achieved. treated with intravenous protamine at a dose of 1 mg 1C per 100 IU UFH given in the preceding 2–3 h. 1A We recommend that, in VKA treated patients undergoing We suggest that severe bleeding associated with subcu- an emergency procedure or developing a bleeding com- taneous UFH unresponsive to intravenous protamine at a plication, PCC (25 IU FIX kg 1) should be given. 1B dose of 1 mg per 100 IU UFH could be treated by continuous administration of intravenous protamine, with We recommend to assess creatinine clearance in patients dose guided by aPTT.2C receiving NOAs and being scheduled for surgery. 1B Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 281

New oral anticoagulants Patients with congenital bleeding disorders We suggest that new oral anticoagulant agents (NOAs) Von Willebrand disease should not be interrupted for skin surgery, dental and We suggest that if VWD is suspected preoperatively, the other oral procedures, gastric and colonic endoscopies patient be referred to a haematologist for assessment and (even if biopsy is scheduled, but not polypectomy), nor planning of the intervention. 2C for most ophthalmic surgery, (mainly anterior chamber, We recommend the use of bleeding assessment tools for e.g. cataract), although vitreoretinal surgery is sometimes predicting the perioperative risk of bleeding. 1C performed in NOA treated patients.2C We recommend that patients with VWD be managed We recommend that for low-risk patients (e.g. atrial perioperatively in collaboration with a haematologist. fibrillation patients with CHADS2 score 2, patients 1C treated for >3 months for a non-recurrent VTE) undergoing procedures requiring normal coagulation (normal We recommend desmopressin as a first-line treatment for diluted thrombin time or normal specific anti-FXa level), minor bleeding/surgery in patients with VWD, after a trial NOAs can be stopped 5 days before surgery. No bridging testing. The regimen is specified by published guide- is needed. 1C lines. 1C In patients treated with rivaroxaban, apixaban, edoxaban We recommend replacement of VWF with plasma- and in patients treated with dabigatran in which creati- derived products for major bleeding/surgery. Treatment nine clearance is higher than 50 ml min1, we suggest regimens are specified by published guidelines. 1C bridging therapy for high-risk patients (e.g. atrial fibrilla- We suggest that antifibrinolytic drugs be used as haemo- tion patients with a CHADS2 score >2, patients with static adjuncts. Treatment regimens are specified by recurrent VTE treated for <3 months). Day 5: last NOA published guidelines. 2C dose; Day 4: no heparin; Day 3: therapeutic dose of LMWH or UFH; Day 2: subcutaneous LMWH or We suggest that platelet transfusion may be used only in UFH; Day 1: last injection of subcutaneous LMWH case of failure of other treatments. 2C (in the morning, i.e. 24 h before the procedure) or subcutaneous UFH twice daily (i.e. last dose 12 h before the procedure), hospitalisation and measurement of Platelet defects diluted thrombin time or specific anti-FXa; Day 0: We suggest referring the patient to a haematologist for surgery. 2C assessment and planning of the intervention if inherited platelet defects are suspected preoperatively. 2C In patients treated with dabigatran with a creatinine clearance between 30 and 50 ml min1, we suggest We recommend the use of a bleeding assessment tool for to stop NOAs 5 days before surgery with no bridging. predicting the perioperative risk of bleeding. 1C 2C We recommend that patients with severe inherited We suggest that for groups 2 and 3, heparin (UFH or platelet disorders should be managed perioperatively LMWH) should be restarted 6–72 h after the pro- in collaboration with a haematologist. 1C cedure, taking the bleeding risk into account. NOAs We suggest preoperative haemostatic correction in may be resumed when surgical bleeding risk is under patients with inherited platelet disorders. 2C control. 2C We suggest desmopressin be used to prevent/control perioperative bleeding in patients with inherited platelet Comorbidities involving haemostatic derangement defects. 2C We suggest that patients with haemostatic derangements associated with systemic, metabolic and endocrine dis- We suggest antifibrinolytic drugs be used as haemostatic eases should be managed perioperatively in collaboration adjuncts in procedures involving patients with inherited with a haematologist.2C platelet defects. 2C We suggest that selective serotonin reuptake inhibitor We recommend that rFVIIa treatment should be con- (SSRI) treatment should not be routinely discontinued sidered in patients with Glanzmann thrombasthenia perioperatively. 2B undergoing surgery. 1C We suggest individualised perioperative discontinuation We recommend against routine platelet transfusion in of antiepileptic agents, such as valproic acid, which may patients with inherited platelet disorders. 1C increase bleeding. 2C There is insufficient evidence to recommend a threshold We do not recommend discontinuation of Gingko biloba for perioperative prophylactic platelet transfusion in extracts.1B thrombocytopenic patients. C

Haemophilia A and B Rare bleeding disorders We recommend that haemophilia patients should be We recommend that patients with rare bleeding disorders referred preoperatively to a haematologist for assess- should be referred preoperatively to a haematologist for ment/intervention. 1C assessment/intervention. 1C

We recommend that surgery in haemophilia patients We recommend that surgery in patients with rare should be performed in specialised centres with expertise bleeding disorders should be carried out in consultation in coagulation disorders. 1C with a haematologist with experience in factor defici- We recommend adequate perioperative replacement encies. 1C therapy to ensure safe surgery in haemophilia patients. 1C There is insufficient data to recommend routine peri- We suggest that perioperative replacement therapy (tar- operative supplementation of deficient factors in patients get factor level and duration) in haemophilia patients with rare bleeding disorders. C follows published guidelines. 2C We suggest that rFVIIa be used in perioperative bleeding We recommend either recombinant products or plasma- due to inherited FVII deficiency. 2C derived concentrates for perioperative replacement therapy in haemophilia patients 1C If rFVIIa is given to control perioperative bleeding in We suggest that coagulation factors be given periopera- inherited FVII deficiency, we suggest lower doses than in tively by continuous infusion. 2C haemophilia patients. 2C We suggest either rFVIIa or activated PCCs for haemo- There is insufficient data to recommend rFVIIa in peri- philia patients with inhibitors. 2C operative bleeding for patients with other rare bleeding We suggest antifibrinolytic drugs as perioperative adjunct disorders. C therapy in haemophilia patients. 2C There is insufficient data to recommend peri-procedural We suggest individualised perioperative thromboprophy- desmopressin or antifibrinolytic drugs in patients with laxis in haemophilia patients. 2C mild rare bleeding disorders. C

3 INTRODUCTION discontinuation of potentially harmful practices and Healthcare professionals face an increasingly difficult assessment of novel strategies.22–27 task in keeping up to date with the evidence on perioperative transfusion strategies, as the number of studies 4 METHODS published in this area has increased dramatically during 4.1 Selection of task force the last 20 years. Within the last 10 years alone, more In June 2010, the ESA Guideline Committee, chaired by than 100 different medical journals have published Andrew Smith, nominated the chairperson of the Sub- relevant systematic reviews.1 This not only reflects committee on Transfusion and Haemostasis, Sibylle the complexities of transfusion medicine but also the Kozek-Langenecker, to coordinate the core group of development of alternatives to transfusion and the the task force, consisting of the Subcommittee chairper- move towards evidence-based perioperative practice. sons Patrick Wouters (circulation), Cesar Santullano Thus, it is imperative to update evidence-based (intensive care medicine) and Eduardo de Robertis transfusion guidelines for healthcare professionals and (resuscitation and emergency medicine), and Subcom- researchers. mittee members Arash Afshari (evidence based practice) Particularly urgent is the need to assess the mounting and Klaus Go¨rlinger (transfusion and haemostasis). The evidence in support of restrictive transfusion strategies as ESA Guideline Committee defined the broad scope of being not only safe but also potentially beneficial in terms the guideline project, which prompted the core group to of mortality, morbidity, postoperative outcomes and long- invite 15 anaesthetist experts into the task force as term survival in both cardiac and non-cardiac surgery affiliate co-authors. Georgina Imberger (Copenhagen patients.2–9 This evidence is challenged by the wide- Trial Unit and Cochrane Anaesthesia Review Group) spread practice of perioperative allogeneic blood transfu- was invited into the task force for the evidence search. sion, especially in cardiac surgery, where 40–90% of patients receive blood transfusions, using approximately 4.2 The search for evidence 10–15% of the national supply of blood.10–14 There is To develop the scope of the guidelines, the task force also an urgent need to consider potential resource util- defined a series of key clinical questions about the isation issues associated with aggressive use of blood management of severe perioperative bleeding, a process products, as their preparation and storage are expen- completed in October 2010. These questions formed the sive.15,16 basis for reviewing the evidence and developing the recommendations. Growing evidence indicates that measures to support and monitor coagulation, such as antifibrinolytic drugs, point- We used three approaches to search for relevant pub- of-care technologies (e.g. thrombelastography, thromboe- lished evidence. First, we conducted a broad search on lastometry) and fluid therapy, are important for quality MEDLINE and Embase using exploded terms for improvement and may offer alternative effective ‘anaesthesia’ and ‘surgery’, combined with ‘bleeding’ approaches for limiting blood transfusion and decreasing or ‘blood loss’ in the title. This search was conducted perioperative bleeding.17–20 However, as many of the in December 2010 and included all publications from the current indications for, and alternatives to, transfusion are previous 10 years. The exact search strategy is detailed in not based on high quality evidence, there is a need for the Appendix (Supplemental Digital Content, http:// well designed and performed clinical trials, and high links.lww.com/EJA/A31). A total of 9376 citations were quality systematic reviews.21 Many of the existing data retrieved and reviewed for possible inclusion. are from retrospective studies (with their inherent short- Second, we conducted more specific MEDLINE and comings) and more randomised clinical trials are urgently Embase searches when necessary in some areas. Search needed. terms were developed with the help of the task force This guideline by the European Society of Anaesthe- members responsible for the given section. The exact siology (ESA) aims to provide an up-to-date review searches are detailed in the Appendix (Supplemental and synthesis of the evidence, with recommendations Digital Content, http://links.lww.com/EJA/A31). The which may guide practitioners towards safe and cost- searches were conducted between January and May effective strategies for minimising severe non-traumatic 2011, and included all publications from the previous perioperative bleeding and maximising blood conserva- 10 years. A total of 20 664 citations were retrieved and tion. Additionally, this guideline will identify knowledge reviewed for possible inclusion. The search was repeated gaps and new clinical questions which will guide the for the last sections to be included (6.3, 5.1) between May design of future clinical trials. Acknowledging the 2011 and May 2012. Third, we conducted a broad search variationintransfusionpractices across countries, for systematic reviews of anaesthesiological interven- hospitals, specialties and surgical procedures, concerted tions. The exact search strategy is detailed in the efforts will be needed for rapid implementation of Appendix (Supplemental Digital Content, http:// this guideline, promotion of safe and appropriate links.lww.com/EJA/A31). We searched MEDLINE and transfusion, avoidance of unnecessary transfusion, Embase, with no time restrictions. A total of 11 869 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 284 Kozek-Langenecker et al.

citations were retrieved and reviewed for possible Guidelines Committee and Board of the ESA before inclusion. submission for publication in the European Journal of Anaesthesiology. Because of the increasing evidence in From these three approaches, a total of 2686 publications this field, an update of the guidelines is planned every were selected for possible inclusion. We included sys- two years. tematic reviews, randomised controlled trials, cohort studies, case control studies and cross-sectional surveys. 5 COAGULATION MONITORING We did not include existing guidelines, narrative reviews, 5.1 Perioperative coagulation testing editorials, case series or case reports. We did not use 5.1.1 Introduction language restrictions. Traditionally, perioperative coagulation monitoring has Task force members reviewed the selected articles relied on clinical judgement and standard laboratory tests relevant to their sections. Our goal was to include all (SLTs). However, many SLTs were designed to test for relevant and robust evidence in these guidelines. There- coagulation factor deficiencies, not for predicting risk of fore, we included evidence that was sourced separately bleeding or guiding haemostatic management. Moreover, from the approaches described above and considered utility of SLTs in emergency situations is limited by slow references cited in published trials, sometimes leading turnaround times due to sample transport and plasma to the inclusion of trials published more than 10 years ago. preparation requirements.29–32 In contrast, viscoelastic Other evidence was sourced from the personal clinical point-of-care monitoring enables rapid intraoperative and academic experience of the task force members. diagnosis of the cause of bleeding. This section examines assays used to diagnose coagulation status periopera- The expertise of the task force guided the selection of tively. trials for inclusion, thereby involving a subjective assessment of a study’s relevance. Once selected, we reviewed 5.1.2 Standard laboratory tests for coagulation trials for their quality and applicability. According to the monitoring suggestion of the ESA Guideline Committee, we used SLTs can be performed using automated analysis, with the Scottish Intercollegiate Guidelines Network (SIGN) instrumentation, reagents and detection methods varying grading system28 to assess the level of evidence of a study between institutions. However, the principles underlying and to grade our recommendations based on the body of individual SLTs are consistent across platforms. supporting evidence. During the process of guideline development, the official position of the ESA changed, 5.1.2.1 Activated partial thromboplastin time matching many other scientific organisations in favouring Activated partial thromboplastin time (aPTT) measures the Grading of Recommendations Assessment, Develop- overall integrity of the intrinsic and common coagulation ment and Evaluation (GRADE) system. Therefore, all of pathways. Recalcified, citrated plasma is incubated at our recommendations and suggestions are assigned a 378C with partial thromboplastin and an activator.33,34 number (relating to the strength of the recommendation) Clotting time (time to fibrin strand formation) is and a letter (relating to the quality of the supporting recorded. aPTT is affected by levels of fibrinogen and evidence) according to the GRADE system (Table 1). coagulation factors II, V, VIII, IX, XI, and XII, and is Statements are accompanied only by a letter. According influenced by temperature, pH, heparin and oral antic- to the broad scope of the guideline project, the initial oagulants.35 aPTT indicates multiple coagulation factor manuscript was approximately 98 000 words in length. In deficiencies more clearly than it does single factor order to increase readability and future implementation, deficiencies. by May 2012 the contents of all sections had been condensed by approximately 46% and a list of recom- 5.1.2.2 Prothrombin time mendations was prepared (Section 2. Summary). Prothrombin time (PT) measures integrity of the extrinsic and common pathways; it is affected by levels of 4.3 Review of the guideline fibrinogen and coagulation factors II, V, VII and X.35 These guidelines have undergone the following review Recalcified, citrated plasma and tissue thromboplastin process. The final draft was reviewed by members of the are incubated at 378C. Clotting time is recorded as for relevant Subcommittees of the ESA’s Scientific Commit- aPTT. PT measurements can be standardised by con- tee who were not involved in the initial preparation of the version to an international normalised ratio (INR) to guideline, as well as by external reviewers. The draft was allow monitoring of anticoagulant therapy with cou- posted on the ESA website from 13 July 2012 to 19 marins. August 2012 and all ESA members, individual and national, were contacted by electronic mail to invite them 5.1.2.3 Fibrinogen concentration to comment. Comments were collated by the chair of the Fibrinogen is essential for effective coagulation and is the guideline task force and the guideline was amended as first factor to be depleted during massive bleeding and appropriate. The final manuscript was approved by the haemodilution.36 Its concentration is often determined Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 285

indirectly using the Clauss method.37 Diluted, citrated Coagulation initiation. Recorded as reaction (r) time or plasma is activated with thrombin, and clotting time is clotting time (CT), both parameters represent the time to recorded as for PT and aPTT. Fibrinogen concentration reach an amplitude of 2 mm (i.e. initiation of clot for- is inversely proportional to clotting time, and is calculated mation, partially dependent on thrombin generation).42 using calibration standards. Clauss assays are sensitive to Clot formation. Time for amplitude to increase from 2 to heparin, fibrinogen degradation products35 and colloids 20 mm, expressed as k time or clot formation time (CFT). such as hydroxyethyl starch.38–40 Fibrinogen levels can The alpha (a) angle (tangent of the slope between 2 and also be determined using a PT-based assay, although this 20 mm) provides another measure of clot formation rate. may be too variable for clinical use.41 Alternatively, immunological detection is possible using antifibrinogen Clot strength. Maximum amplitude (MA) or maximum antibodies, providing a measure of fibrinogen quantity clot firmness (MCF), both measured in mm, represent but not functionality. the combined effects of platelet aggregation and fibrin polymerisation. Clot rigidity (G) and maximum clot 5.1.2.4 Platelet count elasticity (MCE) may also be used to assess clot strength. In the perioperative setting, platelet count (concen- G and MCE have a curvilinear relationship with MA and tration) is commonly measured. This, however, does MCF, respectively, making them conceptually and 43,44 not assess the functional activity of platelets. statistically important. Amplitude at early time- points (A5, A10, etc.) may be used to predict maximum 5.1.2.5 Assaying specific coagulation factors clot firmness. Tests for individual coagulation factors, including factors Clot stability. This is measured by reduction of clot II, V, VII, VIII, IX, X and XIII, can be used to confirm strength after MA or MCF has been reached, and typically specific deficiencies (e.g. congenital). Other biomarkers expressed as lysis index (LY30 or LI30; % of clot strength of coagulation and fibrinolysis can also be measured, such remaining 30 min after MA or CT, respectively). Maxi- as D-dimers for exclusion of pulmonary embolism and mum lysis (ML; greatest % decrease in amplitude [from deep vein thrombosis. MCF] observed during the assay period) is also used. Low lysis index or high ML can indicate hyperfibrinolysis. 5.1.3 Point-of-care coagulation monitoring Point-of-care (POC) coagulation monitoring uses whole blood and is performed in the emergency room, operating 5.1.3.2 Commonly used blood modification agents for POC coagulation assays theatre, or the central laboratory. Turnaround times for POC tests are shorter than for SLTs. As with SLTs, POC POC coagulation monitoring can be performed using coagulation monitoring can be performed using various recalcified, citrated blood alone (NATEM assay; clotting analytical platforms and reagents, so this section will focus initiated intrinsically by the surface of the cup and pin). on assay principles. For global coagulation analysis, the More usually, activators are added to accelerate coagu- principal POC tests use thrombelastography (TEG; lation, and modifying agents can suggest the cause of Haemoscope Inc., Niles, IL) or thromboelastometry observed coagulopathy. The following are the most com- (ROTEM; Tem International GmbH, Munich, Germany), monly used assays. which each operate on similar principles. Unless stated Intrinsic activation (e.g. kaoTEG or INTEM assay). otherwise, the term ‘POC coagulation monitoring’ within Addition of a contact activator (e.g. kaolin or ellagic acid) this section refers to TEG/ROTEM assays. stimulates intrinsic activation, providing an assay analogous to aPTT. 5.1.3.1 Parameters recorded using point-of-care coagulation monitoring Extrinsic activation (e.g. rapidTEG or EXTEM assay). Addition of (recombinant) tissue factor (TF) activates Blood samples for POC coagulation analysis are placed in coagulation via the extrinsic pathway, providing an assay a reaction chamber and a pin is immersed. Oscillation is analogous to PT. introduced and viscoelasticity of the sample is measured via movement of the pin. As the blood clots, fibrin Heparin anticoagulation (e.g. hepTEG or HEPTEM polymerisation progressively changes the viscoelasticity. assay). Addition of heparinase to an intrinsically activated Overall, POC coagulation assays are more representative assay degrades heparin in the blood, enabling identifi- of in vivo coagulation than conventional laboratory tests. cation of coagulopathy caused by heparin. Unlike SLTs, POC coagulation monitoring extends Fibrin clot quality (e.g. functional fibrinogen [FF] or beyond initial fibrin polymerisation. The clot formation FIBTEM assay). This involves addition of a platelet and degradation profile can be assessed for up to 60 min, inhibitor (e.g. abciximab or cytochalasin D) to an extrin- with coagulation dynamics represented graphically. sically activated assay. This test measures strength of the Numerical values indicate the speed and quality of clot fibrin-based clot. Low FF/FIBTEM clot strength usually formation. indicates fibrinogen deficiency. Adequate FF/FIBTEM Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 286 Kozek-Langenecker et al.

clot strength in the presence of decreased overall clot Recommendation strength in bleeding patients may indicate platelet We recommend the use of standardised questionnaires deficiency. on bleeding and drug history as preferable to the routine use of conventional coagulation screening tests such as Hyperfibrinolysis (e.g. APTEM assay). This involves aPTT, PT and platelet count in elective surgery. 1C addition of the antifibrinolytic agent aprotinin to an extrinsic activation assay. Improved coagulation with A standardised questionnaire on bleeding and drug aprotinin indicates hyperfibrinolysis. history is superior to the routine use of conventional coagulation screening tests such as aPTT, PT and plate- POC devices with multiple channels allow several assays let count in elective surgery.52 In patients with a positive (e.g. extrinsic, intrinsic, fibrinogen and hyperfibrinolysis) bleeding history, a physician experienced in haemosta- to be performed simultaneously. seology or haematology should be consulted. If indicated, additional tests to assess haemostatic disorders are advi- 5.1.4 Which approaches can be used for preoperative sable, in particular with regard to primary haemostasis, for evaluation of coagulation status? example, von Willebrand diagnostics, platelet function Preoperative coagulation monitoring may influence sub- tests (PFA-100) or whole blood impedance aggregometry sequent decisions concerning the management of perio- (Multiplate).69,70 This concept enables goal-directed perative bleeding. Bleeding risk may be elevated by therapy of hereditary and acquired disorders of primary congenital coagulation disorders such as von Willebrand haemostasis.52,70–72 However, the value of PFA-100 in disease (VWD) or by routine medication for underlying detecting preoperative disorders of primary haemostasis conditions. Coagulation tests may suggest increased is still under discussion.73,74 Although, an increasing bleeding risk, but they cannot predict intraoperative or number of patients are treated with dual antiplatelet postoperative bleeding caused by exogenous factors. therapy guided by PFA-100, the primary ADP-cartridge Thoracic or abdominal procedures lasting >2 h and with is not able to detect the effect of ADP-receptor blood loss >500 ml carry particular risks, and may require 74–77 45 antagonists, such as thienopyridines, reliably. In laboratory analysis for bleeding risk stratification. 1 addition, the new Innovance PFA P2Y cartridge is yet to be evaluated for this purpose.78,79 5.1.4.1 Standardised bleeding history and clinical evaluation Recommendation 5.1.4.2 Preoperative use of standard laboratory tests We recommend the use of a structured patient interview Application of preoperative SLTs is well covered by or questionnaire before surgery or invasive procedures, existing guidelines.34,46,80 However, current ESA guide- which considers clinical and family bleeding history and lines do not recommend their use.81 SLTs were originally detailed information on the patient’s medication. 1C designed to indicate coagulation factor deficiencies, not to assess clinical risk of haemorrhage.82,83 Normal ranges Structured patient interviews are a primary tool for pre- for PT and aPTT are based on the general population and operative assessment of bleeding risk. Clinical and family may not apply to surgical patients with massive bleed- history and current drug therapy are considered. Recent ing.82 Accordingly, aPTT and PT fail to identify occult guidelines from the UK, Austria and Italy recommend bleeding disorders among paediatric patients at high risk structured questionnaires.34,45–47 Investigations have of bleeding.84 shown that such questionnaires identify patients at risk of bleeding.48–57 In a study by Eberl et al.,49 a positive Low preoperative fibrinogen concentrations potentially predictive value of 9.2% was reported for the use of indicate increased risk of intraoperative bleeding during standardised bleeding history. In addition, three groups cardiac surgery.85,86 In the obstetric setting, fibrinogen have strongly recommended a questionnaire instead of measurement is reported as the parameter best correlated SLTs.48,51,57 Data suggest that these questionnaires also with postpartum bleeding volume and haemostatic have the potential to quantify the risk of bleeding for impairment.87 Preoperative measurement of fibrin mono- inherited coagulopathies.58 mer or fibrin degradation product may also allow risk stratification for intraoperative blood loss.88,89 Physical examination should be performed as a second step, focusing on signs of bleeding and diseases which SLTs are typically performed using plasma, with plate- may cause haemostatic failure (e.g. liver disease, inher- lets and other blood cells removed, and thus do not reflect ited coagulation abnormalities).59 Physical examination the true physiological clotting process.90 Nor can SLTs can detect bleeding disorders not identified by conven- provide rapid assessment of fibrinolysis, platelet dysfunctional tests (e.g. scurvy presenting with soft tissue bleed- tion, or haemostatic response to injury or surgery. A ing).33 Gender, body mass index and comorbidities systematic review found that abnormal SLT results do including arterial hypertension, diabetes mellitus and not predict intra- or postoperative bleeding.91 False renal dysfunction are independent risk factors for bleed- positive and false negative results are likely,92 necessitating and transfusion.60–68 ing further tests and incurring additional costs. Italian Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 287

guidelines recommend routine preoperative PT, tendency are present, or if the planned operation requires aPTT and platelet count assessment.46 However, special consideration, comprehensive assessment is indi- in patients without a previous history of bleeding or cated. Otherwise, the only crucial blood analysis is ABO bleeding disorders, SLTs are not generally recom- blood grouping.110 mended.33,34,47,59,80,82,93–95 Selective laboratory testing is advised because it is more cost-effective and more 5.1.5 Which coagulation monitoring tests can be evidence based.92,95 Preoperative assessment of aPTT, used to guide intraoperative haemostatic therapy? PT, INR, fibrinogen and platelet count is warranted in Correct diagnosis of the cause of bleeding is essential for patients with bleeding disorders, a history of bleeding or a effective haemostatic intervention. In emergency situ- clear clinical indication (e.g. HELLP syndrome [haemo- ations and high-risk surgical procedures, this diagnosis lysis, elevated liver enzymes and low platelets], liver must be made as quickly as possible. Intervention can be 34,46 disease, leukaemia or haemophilia). There is cur- guided by clinical judgement, SLTs or POC monitoring. rently little evidence to support additional, routine appli- We discuss the evidence for each below. cation of point-of-care INR testing in the preoperative setting to predict bleeding tendency, despite the fact that 5.1.5.1 Intraoperative use of standard laboratory tests many recent devices provide results which are compar- Several guidelines have explored intraoperative use of able with laboratory testing. SLTs.46,110–112 There is little evidence to support their utility in this setting. Measurement of fibrinogen (Clauss 5.1.4.3 Preoperative use of POC coagulation monitoring method), D-dimer and antithrombin (AT) may, in con- Preoperative POC measurement of coagulation does not junction with clinical assessment and SLTs, facilitate 96–100 predict bleeding during or after surgery. POC diagnosis or exclusion of disseminated intravascular monitoring assays are instead designed for rapid diagnosis coagulation (DIC).112 This approach, however, is incom- of bleeding causes, which is of most value intraopera- patible with emergency situations because SLTs have tively. Indiscriminate preoperative coagulation monitor- typical turnaround times of 30–60 min.35,113 Accordingly, ing using POC assays is unlikely to be cost-effective, but the applicability of SLTs in trauma has never been it may be warranted in combination with SLTs in proven.113 In cardiovascular surgery, hypofibrinogenae- patients with bleeding disorders such as VWD, factor mia has been identified as a major factor contributing to XII deficiency, and haemophilia A with dysfibrino- haemorrhage after CPB;114 however, for laboratory 101 genaemia. measurement of fibrinogen to be useful, analysis would need to begin before the patient is removed from CPB, 5.1.4.4 What is the role of genetic predictors? which is prevented by sensitivity of the Clauss assay to In neurosurgery patients, tumour necrosis factor-alpha heparin. In liver transplantation, attempts to establish polymorphism is associated with increased bleeding transfusion triggers for haemostasis management, based risk.102,103 Low levels of plasminogen activator inhibi- either on SLTs or POC monitoring assays, have been tor-1 (PAI-1) correlate with increased bleeding risk in inconclusive.115 transurethral resection of the prostate;104 PAI-1 poly- There is insufficient data to recommend routine intra- morphism may also influence bleeding risk in cardiac operative coagulation monitoring using SLTs.95 Conver- surgery.105 Polymorphism of GPIIIa can exacerbate sely, recent Italian guidelines recommend prolonged PT bleeding in cardiac surgery following aspirin pretreat- and aPTT (>1.5 times normal) as a trigger for adminis- ment.106 Angiotensin converting enzyme II genotype tration of fresh frozen plasma (FFP);112 the same guide- may be associated with reduced blood loss in geriatric lines also suggest ‘blind’ FFP administration if the tests patients undergoing hip arthroplasty.107 In addition, poly- cannot be performed within a reasonable time. A recent morphisms have been identified in seven distinct factors review of haemostatic test results during postpartum which may contribute to the wide variation in bleeding haemorrhage found that FFP was routinely over tendency.108 E-selectin polymorphism has also been administered with respect to guidelines for PT- and identified as a risk factor for increased bleeding during aPTT-guided transfusion.87 Moreover, fibrinogen con- cardiopulmonary bypass (CPB).109 centrations declined in many patients despite excessive Currently, no recommendation can be made on the value FFP transfusion, suggesting that alternative interven- of genetic testing for evaluating bleeding risk. tions may have been more suitable.

5.1.4.5 What is the best approach for preoperative 5.1.5.2 Intraoperative use of point-of-care coagulation evaluation of coagulation status? monitoring Assessment of bleeding history, including physical exam- A recent Cochrane review showed a lack of evidence that ination, remains the best tool for identifying patients with POC monitoring improves mortality compared with increased risk of perioperative bleeding complications. If ‘usual care’.17 This is unsurprising given that POC bleeding history is positive, clinical signs of bleeding monitoring assays only establish the presence and cause Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 288 Kozek-Langenecker et al.

of haemostatic impairment; it is the subsequent inter- including 100 patients.119 In this latter study, the use of ventions that influence patient outcome. Bleeding may an algorithm based on POC testing was associated with be reduced by improving consistency of therapeutic improved outcomes including significantly reduced decisions, using different transfusion triggers or using mortality. Routine use of such algorithms could reduce alternative interventions. For example, POC monitoring transfusion requirements, improve outcomes and lower is used to guide administration of coagulation factor costs. concentrates, which has been shown to decrease allo- Prospective studies have also demonstrated the utility of geneic blood product transfusion requirements and was MCF from fibrin clot quality assessment (TF þ cyto- associated with improved outcomes.116–120 The tech- chalasin D) to guide administration of fibrinogen con- niques (e.g. thrombelastography) and devices (e.g. centrate in cardiovascular surgery patients (target MCF: TEG) are routinely given prominence over the individual 22 mm).116,117 These studies suggest that individualised assays. Some studies have used a single assay (e.g. kaolin fibrinogen concentrate dosing, based on target MCF activation)121,122 but simultaneous performance of values, may decrease blood loss and transfusion require- several assays may be critical for accurate diagnosis of ments following CPB. bleeding causes. Selection of appropriate assays for POC diagnosis should be considered carefully.123 Similar individualised dosing of cryoprecipitate, based on A10 values from fibrin clot quality assays (TF þ cyto- Intraoperative point-of-care monitoring in trauma. POC chalasin D), has been reported following elective CPB.131 coagulation monitoring has been used in case studies and Prediction of cryoprecipitate requirements using this patient cohorts to diagnose and treat bleeding in trauma approach has high sensitivity and specificity. patients.118,124–126 CT and MCF from extrinsic activation (TF) and fibrin clot quality (TF þ cytochalasin D) Intraoperative point-of-care monitoring in liver surgery. assays,118,124,125 as well as CT, CFT and MCF from Individualised (‘theragnostic’) dosing of cryoprecipitate intrinsic activation (ellagic acid) assays,126 have been using thrombelastography has been described in a 132 used successfully to monitor haemostasis and guide treat- liver transplant patient with afibrinogenaemia. More ment with fibrinogen concentrate and prothrombin com- recently, a transfusion algorithm based on POC intrinsic plex concentrate (PCC). Such treatment has been shown (kaolin) activation test results was compared with an SLT to reduce exposure to allogeneic blood products com- based protocol in orthotopic liver transplantation (OLT) 133 pared with non-standardised strategies which do not patients. Mortality was unaffected and the authors utilise POC coagulation monitoring.118 The evidence reported reduced exposure to FFP using the POC guided suggests that POC assays measuring extrinsic activation algorithm. Overall, the results indicate that POC intrinsic and fibrin clot quality may be useful to guide adminis- activation assays can be used to guide transfusion during tration of fibrinogen concentrate and PCC in trauma. OLT surgery. Prospective, randomised trials are now required. A retrospective study investigated routine POC Additional case studies describe POC coagulation monitoring of fibrinolysis in OLT, using extrinsic þ monitoring in trauma patients. Nylund et al.127 reported (TF) activation and hyperfibrinolysis (TF aprotinin) rFVIIa administration in a paediatric trauma patient in tests to determine whether tranexamic acid should be 134 response to poor k and a-angle values obtained by administered. This targeted approach to antifibrino- intrinsic (kaolin) activation assay. Walker et al.128 lytic therapy may improve patient responses and reduce reported the assessment of MCF in extrinsic (TF) and exposure to FFP. þ fibrin clot quality (TF cytochalasin D) assays before Intraoperative point-of-care monitoring in obstetrics. epidural insertion after massive transfusion. POC assays with intrinsic (ellagic acid) and extrinsic (TF) activation, as well as fibrin clot quality (TF þ Intraoperative point-of-care monitoring in cardiovas- cytochalasin D), have been compared in pregnant women cular surgery. The value of POC monitoring to guide and non-pregnant controls.135 Clotting time and clot haemostatic therapy following CPB has been demon- formation time were reduced and clot strength was strated in several randomised, controlled trials.119,121,129 increased in the pregnant group, demonstrating hyper- In one of them, four parallel assays (intrinsic [ellagic coagulability. Studies are needed to ascertain the poten- acid], intrinsic þ heparinase, extrinsic [TF] þ aprotinin, tial use of POC monitoring for treating postpartum and extrinsic þ cytochalasin D) were used to guide bleeding, and to determine an appropriate range of haemostatic intervention in patients undergoing aortic reference values for these patients. surgery with circulatory arrest.129 Furthermore, first-line therapy with fibrinogen concentrate and PCC based on Additional POC techniques have been described, for POC testing was associated with decreased transfusion example, POC assessment of PT and INR, which appears requirements and a decreased incidence of thromboem- to be rapid and accurate.136 However, the usefulness of bolic events in a cohort study including 3865 patients120 PT/INR may be limited outside the setting of vitamin K as well as in a prospective randomised controlled trial antagonist anticoagulation. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 289

5.1.6 Postoperative evaluation of coagulation significantly reduced patient exposure to allogeneic status blood products in seven out of eight studies.144 Potential complications following surgery include thromboembolic events and, conversely, recurrent or excessive Long turnaround times may preclude the use of some bleeding. Postoperative coagulation monitoring in the tests in emergency situations. Even in the absence of intensive care unit (ICU) can provide information regard- definitive evidence, implementation of POC assays appears rational if the alternative is haemostatic manage- ing appropriate haemostatic interventions or further pro- 119,120 cedures which may be required. ment guided by clinical judgement alone. A prospective study recently demonstrated superior turn- Kashuk et al.137 assessed the use of POC extrinsic (TF) around times, and quality of assessment, with POC activation tests to identify critically ill patients at risk of monitoring compared with PT and aPTT.31 Transfusion thromboembolic events. Hypercoagulability, defined as algorithms incorporating POC coagulation monitoring are G >12 400 dyn cm 2, was confirmed in 86/152 patients. effective in reducing blood loss, reducing exposure to Clot strength (MA from POC assays) has been used to allogeneic blood products and improving the safety and measure the effects of clopidogrel after coronary artery cost-effectiveness of haemostatic therapy in cardiac bypass surgery.138 In splenectomised thalassaemic surgery.121,129,144 patients, whole blood intrinsic (ellagic acid) and extrinsic (TF) activation assays consistently indicated hypercoa- Perioperative coagulation monitoring is beneficial only if gulability, while thrombin generation tests performed the results contribute to clinically effective decisions. using platelet-poor plasma did not.139 Other evidence Patients with similar conditions may receive different treatments if protocols and triggers for coagulation man- from POC assays, aPTT, platelet counts and fibrinogen 145 measurement has confirmed a tendency towards hyper- agement are not in place. In a study of transfusion coagulability following splenectomy.140 Current evi- triggers used for bleeding management in OLT patients, dence suggests that POC measurements of the speed substantial variability was observed in transfused quantities of FFP, platelets and cryoprecipitate when of clot initiation, formation and strength/elasticity/rigid- 115 ity, can identify patients at risk of thromboembolic different monitoring assays were used. The authors events. concluded that further studies would be required to determine optimal monitoring procedures for guiding There is minimal evidence to support using either SLTs haemostatic intervention. or POC coagulation monitoring to guide haemostatic intervention in the postoperative period. Trials compar- 5.2 Evaluation of platelet function ing POC guided transfusion with conventional coagu- Identification of platelet function is important for lation management have included analysis of samples informing perioperative haemostatic management. drawn up to 24 h after CPB, but have not reached specific There are several methods for assessing platelet func- conclusions on the importance of postoperative monitor- tion, each with its own limitations. The number of 121,129 ing. existing devices and their clinical validation is constantly evolving as is their utility in various settings. In this 5.1.7 Are patient outcomes improved by algorithms section, we will briefly address some of the existing that incorporate coagulation monitoring for commercial tests with sufficient clinical validation. How- perioperative haemostatic management? ever, separation of these devices into different subsets of Recommendations sections does not exclude their application in other We recommend the application of transfusion algorithms clinical settings. incorporating predefined intervention triggers to guide haemostatic intervention during intraoperative bleeding. Recommendations We suggest preoperative platelet function testing only in 1B addition to a positive bleeding anamnesis. 2C We recommend the application of transfusion algorithms We suggest that preoperative platelet function test- incorporating predefined intervention triggers based on ingbeusedtoidentifydecreased platelet function POC coagulation monitoring assays to guide haemo- caused by medical conditions and antiplatelet medi- static intervention during cardiovascular surgery. 1C cation. 2C Haemostatic intervention in bleeding patients is generally determined empirically. Consequently, transfusion 5.2.1 Which platelet function tests can be used practices differ substantially among institutions.141–143 preoperatively for identifying disturbances of primary To reduce this variability, guidelines typically recom- haemostasis? mend administration of blood products according to pre- The Platelet Function Analyser (PFA-1001, Siemens, defined transfusion triggers which can be measured using Tarrytown, NY) test can be performed at the point-of- coagulation tests. In a review of trigger guided transfusion care to rapidly identify platelet defects before during cardiovascular surgery, use of an algorithm surgery.52,146 It has shown high sensitivity and specificity Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 290 Kozek-Langenecker et al.

for platelet function screening performed preoperatively TEG analysis is associated with reduced bleeding, in patients with a positive bleeding history.52 reduced transfusion requirements, reduced costs and improved outcomes in cardiac surgery.119,120,160 The PFA-100 test measures platelet response to agonists in citrated whole blood and can be used preoperatively at the point-of-care. However, the PFA-100 has demon- 5.2.2.3 Liver surgery strated a relatively low predictive value for bleeding Flow cytometry has been used to quantify platelet acti- risk.146 In cardiac surgery patients, preoperative PFA- vation during liver transplantation, from the preoperative 100 data have been shown to correlate with postoperative through to the postoperative period.161 Whole blood blood loss in some studies147 but not others.148 impedance platelet aggregometry has been used to correlate platelet activation with ischaemia/reperfusion The Cone and Plate(let) Analyser (CPA, Impact-R) test injury in paediatric liver transplantation.162 has been used successfully for screening of primary haemostasis abnormalities such as von Willebrand Patients with liver disease may display altered platelet disease.149–151 The test can detect disturbances in count163,164 and platelet function.165–167 In this setting, primary haemostasis by measuring deposition of platelets there is little evidence to indicate whether current diag- from whole blood on to an artificial surface. nostic tests are useful for the preoperative identification of patients with increased perioperative bleeding risk.168 5.2.2 Preoperative platelet function testing in Flow cytometry provides no evidence of systemic platelet different clinical settings activation during liver transplantation.161 5.2.2.1 Trauma In a study of trauma patients, platelet function measured 5.2.2.4 Obstetrics using the PFA-100 analyser showed a significant differ- 152 Among pregnant women with type 1 Gaucher disease, ence between survivors and non-survivors. To be abnormal CPA results have been associated with useful in an emergency, a platelet function test needs increased risk of peripartum haemorrhage.169 Further- to be applicable at the point-of-care and be capable of more, a study using a modified LTA assay found that generating results quickly. A recent study used multiple patients with unexplained recurrent miscarriage have electrode aggregometry (MEA, Multiplate) to assess significantly increased platelet aggregation in response platelet function of trauma patients on admission to 153 to arachidonic acid, providing a rationale for using aspirin the emergency room. ADPtest and TRAPtest values in this setting.170 below the normal range were associated with increased mortality.153 5.2.3 Which platelet function tests can be used preoperatively for identifying the effects of 5.2.2.2 Cardiac surgery antiplatelet therapy? The MEA ADPtest has provided results comparable with Before surgery the medical history should be taken and light transmittance aggregometry (LTA; considered as the patient’s exposure to antiplatelet medication should the ‘gold standard’ in platelet function testing) in coron- be determined.47,171 In patients with a positive bleeding ary artery bypass graft (CABG) patients not taking anti- anamnesis, full blood count, including examination of platelet therapies.154 Platelet dysfunction is a major cause platelet count and size,172 and PFA-100 collagen-epi- of bleeding following cardiac surgery.155,156 Platelet acti- nephrine and collagen-ADP52 are first level tests in vation (dysfunction) has been shown using Hemo- 1 preoperative evaluation. Antiplatelet therapy is associ- STATUS (Medtronic, Minneapolis, MN) testing ated with increased risk of perioperative bleeding but during CPB.157 there is no consensus on the optimal timing of pre- MEA measurements taken preoperatively correlate operative discontinuation. Reduced platelet function closely with subsequent platelet transfusion require- caused by antiplatelet medication can be quantified ments, more so than Impact-R tests.158 When selecting by evaluating the response to platelet agonists pre- a platelet test for use during cardiac surgery, awareness of operatively. antiplatelet therapy is crucial because this may exacer- Depending on the test reagent used, MEA is sensitive to bate surgical bleeding.47 As well as correlating with aspirin, thienopyridines and glycoprotein (GP) IIb/IIIa platelet transfusion requirements,158 the MEA ADPtest inhibitors (e.g. abciximab), and has been used success- (performed 0.5–1 days before surgery) can predict post- fully for differential diagnosis.173–175 MEA provides operative bleeding in patients taking thienopyridines and differential diagnostic information by using platelet ago- undergoing CPB.159 nists as test reagents (e.g. collagen, arachidonic acid, Three recently published studies (one retrospective and ADP, thrombin receptor activator peptide [TRAP], von two prospective randomised clinical trials) have shown Willebrand factor [VWF]).173–175 However, clinical trials that perioperative platelet function testing using MEA or are needed to assess the value of MEA in perioperative TEG Platelet Mapping in combination with ROTEM or monitoring of aspirin and clopidogrel. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 291

PlateletWorks (Helena Laboratories, Beaumont, TX) is 5.2.4.3 Point-of-care testing immediately after surgery an electronic impedance based cell counting method, and on arrival at the intensive care unit allowing point-of-care measurement of platelet count Following discontinuation of CPB, patients with severe and aggregation. PlateletWorks has the potential for aortic stenosis183 or drug- or CPB-induced platelet monitoring clopidogrel reversal176 and is sensitive to dysfunction119 may benefit from desmopressin. These the effects of aspirin and GPIIb/IIIa inhibitors (e.g. patients can be identified using HemoSTATUS, a point- abciximab).177,178 of-care test which measures platelet function independently of platelet count.185 Upon arrival at the ICU, VerifyNow is a point-of-care turbidimetric test which patients at risk of requiring platelet transfusion have detects agonist-induced platelet aggregation in whole been identified using MEA.186 blood samples. It can monitor the effects of aspirin, thienopyridines and GPIIb/IIIa inhibitors. The Verify- 5.2.4.4 Which platelet function tests can be used Now P2Y12 assay performed before heparinisation (prior to coronary stenting) has successfully identified patients postoperatively for monitoring haemostasis? on clopidogrel and at risk of atherothrombotic compli- MEA has been used successfully to detect changes in 154,187 cations but did not identify those at risk of bleeding.179 platelet function after cardiac surgery. Platelet function testing (e.g. PFA-100) can be used to detect The PFA-100 test can be used to monitor the effects of changes in platelet reactivity after surgery and to monitor desmopressin or antiplatelet therapy with aspirin but not the effectiveness of antiplatelet medication. However, 180 with thienopyridines. evidence for the postoperative use of platelet function tests is limited. 5.2.4 Which platelet function tests can be used intraoperatively for monitoring the effects of 5.2.4.5 Are patient outcomes improved by algorithms surgery? which incorporate platelet function testing for Platelet function decreases intraoperatively, irrespective intraoperative haemostatic monitoring? of surgery type. Static tests which capture only a single Both laboratory and point-of-care platelet function tests time point do not reflect the dynamic nature of coagulo- are included in some algorithms for managing periopera- pathic bleeding. For example, LTA is not suitable for tive bleeding188,189 but there is currently insufficient intraoperative platelet function testing because of the evidence to answer this question definitively. long turnaround time. Point-of-care tests which can be performed rapidly are required, e.g. the HemoSTATUS 6 ANAEMIA MANAGEMENT platelet function test, MEA and PlateletWorks (clinical 6.1 Preoperative correction of anaemia data are lacking for PlateletWorks). In general, a platelet 6.1.1 Introduction 1 count of 100 000 ml is needed for quantitative Perioperative anaemia increases the risk of numerous analysis. complications such as cardiac events, pneumonia and postoperative delirium.190,191 Associations between 5.2.4.1 Blood loss and synthetic colloid or crystalloid anaemia and higher rates of both morbidity and mortality replacement are well established for patients undergoing cardiac Platelet count decreases intraoperatively through major surgery.192,193 A recent, large cohort study demonstrated blood loss and dilution from volume resuscitation. Syn- that these associations also apply to non-cardiac surgery; thetic colloids or crystalloids may affect platelet func- the odds ratio for mortality among patients with anaemia tion,181 although it has also been reported that these versus those without was 1.42.194 Preoperative anaemia agents have no effect.182 Further studies are required has been shown to be predictive for perioperative trans- to ascertain the effects of synthetic colloids and the most fusion of allogeneic blood products such as red blood appropriate point-of-care tests to evaluate these effects. cells, which itself carries a significant risk of adverse events and mortality.192,195,196 There is some tolerance to postoperative anaemia among patients without cardio- 5.2.4.2 Monitoring therapeutic interventions vascular disease, but for each 1 g dl1 decrease in post- Both PFA-100 and MEA have been used successfully to operative haemoglobin concentration below 7 g dl 1, assess improvement in platelet function intraoperatively mortality has been shown to increase by a factor of following administration of desmopressin.71,93,183 Platelet 1.5.191 Estimates of the prevalence of anaemia in surgical transfusion therapy can be guided and monitored using patients range widely, from 5% to 76%.197 High rates point-of-care testing, for example with the PFA-100 have been reported in cancer patients (e.g. breast cancer, collagen and epinephrine (CEPI), and collagen and colon cancer), while lower rates have been observed in ADP (CADP) assays.184 Following platelet transfusion, orthopaedic patients.197,198 PFA-100 results provided a better indication of transfusion outcome than the previous ‘gold standard’, the Allogeneic blood transfusion has long been used for corrected count increment (CCI).184 correcting perioperative anaemia. However, there is a Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 292 Kozek-Langenecker et al.

general move to minimise this approach due to short- 6.1.3 Preoperative treatment comings associated with allogeneic blood products, such Recommendation as limited blood supply and safety concerns.190 Among We recommend treating iron deficiency with iron supple- patients undergoing transurethral resection of the pros- mentation (oral or intravenous). 1B tate, a low preoperative haemoglobin concentration has been reported as the only reversible factor with the Most (though not all) studies report that preoperative oral potential to reduce transfusion.199 Preoperative autolo- iron supplementation is effective in raising haemoglobin gous blood donation has been suggested as one means of concentration and decreasing perioperative transfusion. treating perioperative anaemia while avoiding transfusion Two controlled studies have investigated the effects of at of allogeneic blood products. However, the process of least 2 weeks of preoperative oral iron supplementation. donation increases the risk of preoperative anaemia and it The first was a retrospective comparison of colorectal surgery patients with anaemia who either received or did is contraindicated in patients with pre-existing anae- 203 mia.198,200 Alternative means of managing perioperative not receive iron supplementation. The second was anaemia include iron supplementation and adminis- a randomised, placebo-controlled trial of oral ferrous tration of erythropoietin-stimulating agents, as well as sulphate, also performed in the colorectal surgery setting, with patients recruited whether or not they had anae- cell salvage and restriction of postoperative blood with- 204 drawal.190 mia. In both of these studies, iron supplementation produced a significant increase in haemoglobin concen- 6.1.2 Preoperative assessment tration, as well as significantly decreased blood transfusion rates during surgery. Recommendation We recommend that patients at risk of bleeding are The efficacy of oral iron has also been demonstrated in assessed for anaemia 4–8 weeks before surgery. 1C patients with anaemia. In a study by Cuenca et al.,205 oral This recommendation is essentially empirical. There are iron supplementation was taken for 30–45 days preopera- no trials proving whether assessment of patients has an tively by knee replacement surgery patients. Reduced impact on their outcomes, or proving the optimum time transfusion of allogeneic blood products was observed, before surgery when patients should be assessed. How- compared with a retrospective control group not receiving ever, as interventions have been shown to be effective iron. This was the case for patients with anaemia (haemo- 1 among patients with anaemia, it is valuable to assess globin [Hb] <13.0 g dl ) as well as those with higher patients before elective surgery to allow the possibility haemoglobin concentrations. In another study, a signifi- 1 of treating anaemia before the procedure, and the period cant 1.1 g dl increase in haemoglobin concentration was of 4–8 weeks provides enough time for treatment to observed in response to 4 weeks preoperative treatment take effect. with oral iron supplementation among hip or knee replacement patients with anaemia (Hb <12.0 g dl1 before Recommendation iron supplementation).206 Furthermore, Quinn et al.207 If anaemia is present, we recommend identifying the showed in a prospective observational study that oral iron cause (e.g. iron deficiency, renal deficiency or inflam- sulphate (200 mg, three times daily for a median of mation). 1C 39 days) increased haemoglobin concentration by 1 This is another empirical recommendation. There are 1.73 g dl (P < 0.001) among colorectal cancer surgery numerous possible causes of anaemia, and accurate diag- patients presenting with preoperative anaemia. nosis enables appropriate treatment to be administered In contrast to the results described above, one prospec- before surgery. There are no clinical trials comparing tive, observational study reported that oral iron supple- outcomes among patients with or without accurate diag- mentation is not effective for increasing haemoglobin nosis of their anaemia. concentration.208 Eighty seven patients with haemo- Accurate diagnosis requires a work-up after determi- globin concentrations between 10.0 and 15.0 g dl 1 nation of a low haemoglobin concentration.191,201,202 received iron sulphate (300 mg three times daily) for at Serum ferritin concentration below 30 mgl1 signifies least 3 weeks before hip or knee arthroplasty, and a nutritional iron deficiency for which iron therapy is 0.14 g dl 1 decrease in haemoglobin concentration administered, although referral to a gastroenterologist (P ¼ 0.015) was observed. may be considered to rule out malignancy.191 A serum Although oral iron supplementation may be suitable for a ferritin concentration of 30–100 mgl 1 signifies possible high proportion of patients, there are some in whom iron deficiency, while a concentration above 100 mgl 1 intravenous iron should be considered, e.g. for patients indicates that anaemia is related to causes such as chronic unable to tolerate oral iron (usually due to gastrointestinal disease (renal or otherwise) or inflammation. In this case, side effects).190 further tests are needed (e.g. assessment of renal function and vitamin B12/folic acid concentrations) to ascertain the Among women with complicated pregnancy or compli- diagnosis.191,201,202 cated childbirth, intravenous iron sucrose has been shown Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 293

to increase haemoglobin concentration by 2.1 g dl 1 Recommendation within 7 days of administration.209 A comparator group If iron deficiency has been ruled out, we suggest treating of patients received oral iron supplementation, and these anaemic patients with erythropoietin-stimulating agents. women showed no increase in haemoglobin concen- 2A tration (possibly because of the short time period). In another study of intravenous iron sucrose, administered Erythropoietin reduces transfusion of allogeneic blood preoperatively to patients scheduled for orthopaedic products, although not in patients with near normal surgery, a significant increase in haemoglobin con- haemoglobin concentrations and not in patients under- centration was observed.210 Munoz et al.211 reported going colorectal cancer surgery. In a meta-analysis of in a prospective, observational study that intravenous cardiac surgery and orthopaedic surgery studies, reduced perioperative transfusion of allogeneic blood products iron sucrose (mean dose 1000 mg), administered over 217 3–5 weeks to patients with preoperative anaemia, was observed among patients receiving erythropoietin. increased haemoglobin concentration by 2.0 g dl1 The odds ratio for the proportion of patients transfused (P < 0.001), resolving anaemia in 58% of patients. with allogeneic blood with erythropoietin was 0.36 (P ¼ 0.0001) in orthopaedic surgery and 0.25 (not signifi- In contrast to these results, a randomised controlled trial cant) in cardiac surgery. The dose of erythropoietin had performed in 60 patients undergoing colorectal cancer no statistically significant effect on the odds ratio. resection reported that intravenous iron administered 14 Another meta-analysis examined the effect of erythro- days before surgery had no impact on haemoglobin poietin on allogeneic blood transfusion among patients 212 concentration, in comparison with placebo. undergoing cardiac surgery.218 For patients not under- Intravenous iron may provide a greater increase in going autologous blood transfusion, the relative risk of haemoglobin concentration than oral iron. In a random- allogeneic blood transfusion with erythropoietin was 0.53 ised, prospective study, women with anaemia caused by (P < 0.01), and for those undergoing autologous blood menorrhagia (Hb < 9.0 g dl1) were treated with intrave- transfusion, the relative risk was 0.28 (P < 0.001). In nous iron sucrose (total calculated iron deficit divided contrast to these meta-analyses, a Cochrane review of into two ampoules, three times per week) or oral iron pre- and perioperative erythropoietin among colorectal protein succinylate daily.213 Treatment was administered cancer surgery patients reported no significant effect on the proportion of patients receiving allogeneic blood during the 3 weeks before elective surgery, and a signifi- 219 cantly greater increase in haemoglobin concentration was transfusion. A meta-analysis of studies of erythropoie- observed in the intravenous group (3.0 vs. 0.8 g dl1, tin-stimulating agents in a broader population of cancer P < 0.0001). patients showed that these agents can reduce the need for red blood cell transfusions with no impairment of One study has shown that preoperative intravenous iron survival.220 However, in this context, erythropoietin- can reduce transfusion among patients undergoing surgery stimulating agents are recommended only according to 214 for trochanteric hip fracture. The transfusion rate was the label (i.e. start treatment only if haemoglobin con- 39.1% among patients receiving intravenous iron, com- centration is <11.0 g dl1, and discontinue treatment pared with 56.7% in a retrospective control group. In when the haemoglobin concentration increases to contrast, a randomised controlled trial performed in 12.0–13.0 g dl1), because when used off-label (i.e. to patients undergoing colorectal cancer resection showed achieve higher concentrations of haemoglobin), they that transfusion rates were no different between patients are associated with reduced survival among cancer 212 receiving preoperative intravenous iron or placebo. patients.220 Intravenous iron appears to be well tolerated. Older Individual randomised controlled trials have reported preparations of iron for intravenous administration were 190 significant reductions in allogeneic blood product associated with a risk of anaphylactic reactions. How- transfusions among patients undergoing orthopaedic ever, a number of studies performed in recent years have surgery,221–225 cardiac surgery226 and surgery for color- reported a lack of adverse events associated with intra- 227–229 209,210,214,215 ectal cancer or other gastrointestinal tract malig- venous iron, while others have reported 230 213 nancies. However, the effect of erythropoietin on favourable tolerability. Today’s intravenous iron prep- transfusion rates has been shown to be non-significant arations may therefore be considered as being much safer in hip replacement patients with near normal preopera- than those available in previous decades, although the tive haemoglobin concentrations,231 radical prostatect- possibility of adverse events such as hypotension, arthral- 232 190 omy patients with near normal haematocrit and gia, abdominal discomfort and back pain remains. colorectal cancer patients with anaemia.233 Other safety concerns with intravenous iron include infection and cancer progression,190 but prospective Based on the available data, erythropoietin-stimulating data confirm lack of association with bacteraemia216 agents have been recommended for orthopaedic surgery and there are no data to confirm increased risk of cancer patients with anaemia, in whom nutritional deficiencies progression. are absent or have been corrected.191 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 294 Kozek-Langenecker et al.

Two large, randomised controlled trials have shown the alpha versus standard care involving 680 spinal surgery potential for erythropoietin to increase haemoglobin con- patients, DVT, diagnosed either by Doppler imaging or centration. The first, involving 695 orthopaedic surgery by adverse event reporting, occurred in a higher pro- patients with preoperative haemoglobin concentrations portion of patients in the epoietin alpha group.242 Such between 10.0 and 13.0 g dl1, showed that preoperative data prompted the Food and Drug Administration (FDA) epoietin alpha produced higher haemoglobin concen- to require a warning to be added to the package inserts for trations from the day of surgery until discharge from erythropoietin and darbepoietin alpha, stating that DVT hospital (P < 0.001).224 In the second study, involving prophylaxis should be considered. 204 colorectal cancer surgery patients, those receiving preoperative epoietin alpha 300 IU kg 1 per day showed Recommendation significantly higher haemoglobin concentrations than If autologous blood donation is performed, we suggest controls on the day before and the day after surgery.227 treatment with erythropoietin-stimulating agents in order Significant increases in haemoglobin concentrations have to avoid preoperative anaemia and increased overall been reported in several other randomised controlled transfusion rates. 2B trials of preoperative erythropoietin performed in A meta-analysis has shown that autologous blood patients undergoing orthopaedic surgery,234 gynaecolo- donation reduces transfusion of allogeneic blood pro- gical cancer surgery235 and hysterectomy.236,237 ducts, but that it increases overall transfusion rates. Other Treatmentwithepoietinalpha(40,000IUonpreopera- studies suggest that autologous blood donation does not tive days 21, 14, 7 and 1) was shown in a prospective, necessarily reduce allogeneic blood transfusion. In a large observational study to increase haemoglobin concen- retrospective study involving 541 spinal surgery patients, trations in orthopaedic surgery patients by 2.0 g dl1 those undertaking autologous blood donation had 1/25 of and1.8gdl1 in patients aged 65 years and <65 years, the chance of requiring allogeneic blood products com- 244 respectively.238 In a second study of orthopaedic pared with control patients who did not donate. How- surgery patients performed by the same group, a ever, the overall transfusion rate was higher in the similar increase in haemoglobin concentration was autologous donation group. These results reflect those observed in response to similar preoperative treatment of a Cochrane meta-analysis which concluded that, with epoietin alpha.239 Another prospective, non- although autologous blood transfusion reduces allogeneic randomised study of preoperative recombinant human blood transfusion, overall transfusion (including autolo- 245 erythropoietin reported dose-dependent increases in gous blood) is increased. A randomised controlled trial haemoglobin concentrations among gynaecological performed in 32 cardiac surgery patients reported that surgery patients both before surgery and on dis- autologous blood donation was associated with decreased charge.240 In an earlier study, epoietin alpha at a dose allogeneic blood transfusion (0.59 vs. 5.01 U per 246 of 600 IU kg1 weekly provided a larger increase from patient). However, this result may have been influ- baseline in haemoglobin concentration compared with a enced by the fact that blood donation patients also daily dose of 300 IU kg1.241 received 3 weeks of treatment with recombinant human erythropoietin. There may be a risk of thrombotic complications with erythropoietin-stimulating agents, and prophylaxis for Evidence from other studies suggests that autologous deep vein thrombosis (DVT) should be considered. Early blood donation may not reduce patients’ exposure to studies did not show an increased risk of DVT among allogeneic blood products. In a prospective study con- patients receiving erythropoietin.190,242 A meta-analysis ducted in patients undergoing hip replacement surgery, published in 1998 reported a lack of ‘convincing evi- there was no significant difference in exposure to allogeneic blood products between autologous donors and dence’ that erythropoietin causes thrombotic compli- 247 248 cations,217 although an increased occurrence of such non-donors. In a retrospective study by Jawan et al., events was noted in some studies with limited patient performed to compare liver resection patients donating numbers. More recent studies of erythropoietin (or epoie- their own blood preoperatively with those not doing so, tin alpha), designed primarily to assess efficacy, have none of the patients required perioperative transfusion of suggested a lack of significant safety concerns.224,240,243 blood products. Consequently, all predonated blood was In addition, a Cochrane review of erythropoietin in discarded. In another retrospective study, performed colorectal cancer surgery reported no significant differ- in knee/hip arthroplasty patients, autologous blood ence in thrombotic events between patients receiving donation was associated with increased perioperative erythropoietin and controls.219 transfusion and the authors suggested that autologous donation may create a ‘self-defeating cycle of blood However, data from an open-label study involving 681 donation followed by blood transfusion’.249 Autologous spinal surgery patients showed a clear increase in the blood transfusion may be considered for patients with incidence of DVT among recipients of erythropoietin.190 multiple antibodies (for whom donor blood may be Similarly, in a randomised, open-label study of epoietin difficult to obtain). Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 295

Autologous blood donation increases preoperative In a retrospective study, intraoperative cell salvage (ICS) anaemia. In a retrospective study of patients scheduled was used together with autologous blood donation in hip for knee replacement surgery, haemoglobin concen- surgery patients, and homologous blood transfusion was trations before autologous blood donation were compared avoided in all 154 patients.254 Donation volumes were with those immediately before surgery.200 The percen- 800 ml for patients undergoing total hip arthroplasty and tage of patients with a haemoglobin concentration in the 1200 ml for patients undergoing rotational acetabular range of 10–13 g dl1 (at high risk for perioperative osteotomy. transfusion) increased from 26.2% to 55.7%. In the liver 248 resection study by Jawan et al., significantly lower 6.2 Intra- and postoperative optimisation of perioperative haemoglobin concentrations were observed macro- and microcirculation in autologous blood donation patients than in non-donors. 6.2.1 Introduction Another comparative retrospective study reported that Massive bleeding affects delivery of blood to organs and patients undertaking autologous blood donation had tissues (due to hypovolaemia), as well as the oxygen- significantly lower haemoglobin concentrations before carrying capacity of blood (due to anaemia). Because surgery than patients not making autologous donations; normal haemoglobin concentrations provide a large the authors concluded that ‘autologous blood donation oxygen carrying capacity, priority goes to intravascular 244 induced preoperative anaemia’. volume replacement with plasma substitutes devoid of Randomised controlled trials indicate that erythropoietin red blood cells (RBCs). Transfusion of RBCs is required may be used to increase the proportion of patients able to only when the haemoglobin concentration decreases to make autologous blood donations (assuming a minimum levels at which overall nutrient demands cannot be met. haematocrit threshold for making a donation)228 and to This section focuses on rational fluid substitution tech- reduce the extent to which autologous blood donation niques and anaemia management in patients suffering lowers haemoglobin concentration.250 severe haemorrhage.

One randomised controlled trial assessed prophylactic 6.2.2 Evidence-based medicine and perioperative administration of autologous fresh frozen plasma (FFP) fluid therapy after CPB in patients undergoing coronary artery bypass 251 Creating reliable and generally acceptable outcome surgery. This intervention failed to produce significant based evidence on perioperative fluid management is reductions in transfusion or blood loss compared with currently not feasible due to a lack of controlled studies, administration of hydroxyethyl starch. the limited representation of clinical scenarios and the Autologous platelet-rich plasma may be superior to auto- absence of a consistent terminology. Several studies have logous whole blood in decreasing transfusion of allogeneic evaluated the impact of perioperative fluid therapy on 255–268 blood products. Farouk et al.252 performed a randomised patient outcomes. However, few qualify to serve as trial comparing administration of platelet-rich plasma with a basis for recommendations. The better studies have 256,263–265,268 acute normovolaemic haemodilution in patients under- been performed in abdominal surgery, going open heart surgery. Platelet-rich plasma produced a where perioperative fluid needs may differ considerably 269 significant decrease in transfusion of blood products com- from other surgical procedures. Patients at high-risk pared with acute normovolaemic haemodilution. are often excluded, even if they represent the typical collective.270 The impact of perioperative fluid management on outcome cannot be isolated from other inter- 6.1.3.1 Other possible treatment approaches ventions271 and only two prospective trials included Combined use of intravenous iron, erythropoietin, vita- details of therapeutic strategy beyond fluid therapy.261,262 min B12, folic acid, and restrictive transfusion may reduce Perioperative fluid management must be embedded in a transfusion requirements. Limited evidence suggests larger perioperative therapeutic concept in order to that patients with anaemia might benefit from combi- impact on patient outcome. nation therapy. In a prospective study, patients undergoing total knee replacement received intravenous iron 6.2.3 Optimising macrocirculation sucrose and, if haemoglobin concentration remained 6.2.3.1 Preload optimisation <13.0 g dl 1, additional erythropoietin. These measures, Recommendation together with restrictive transfusion, ‘seem to reduce We recommend aggressive and timely stabilisation of allogeneic blood transfusion’, although there was no cardiac preload throughout the surgical procedure, as control group.215 Retrospective assessment of a similar this appears beneficial to the patient. 1B approach to managing anaemia in hip fracture patients showed a reduction in transfusion compared with oral iron Hypovolaemia decreases cardiac output and tissue or intravenous iron only.253 Haemoglobin concentrations oxygen supply. Both the extent and duration of 48 h after surgery were higher in the oral iron group, but tissue hypoperfusion determine the severity of cellular this difference was not apparent 7 days after surgery. damage and should be kept to a minimum with timely Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 296 Kozek-Langenecker et al.

volume substitution. Two recent meta-analyses con- 6.2.4 Considerations for microcirculation cluded that a goal-directed approach to maintaining 6.2.4.1 Compartmental fluid dynamics tissue perfusion reduces mortality, postoperative organ Basic physiological principles during steady state assume failure and surgical complications in high-risk surgical the presence of a cell membrane, quantitatively imperme- patients.272,273 able to electrolytes, proteins and colloids, and a vascular barrier which retains proteins and colloids, but is freely Recommendation permeable to electrolytes and other small solutes. Water We recommend the avoidance of hypervolaemia with flows passively across all compartments and distributes crystalloids or colloids to a level exceeding the interstitial according to the amount of osmotically and oncotically space in steady state, and beyond an optimal cardiac active substances. This leads to the following primary preload. 1B distribution pattern: free water evenly across all the com- The relationship between risk and total volume trans- partments (intravascular volume effect negligible); iso- fused appears to follow a U-shaped curve (infusing too tonic crystalloids within the extracellular fluid space much can be as deleterious as infusing too little).274 Fluid (intravascular volume effect around 20%); and iso-oncotic excess can have a negative impact on cardiac, pulmonary colloids and proteins within the intravascular space (intra- and bowel function, wound healing and water and sodium vascular volume effect around 100%).276,277,287–289 Thus, regulation.275 Surgery causes inflammation276 and the the infusion of crystalloids has been associated with sub- corresponding release of mediators causes local tissue stantial interstitial oedema (unpublished observations). oedema.277 Artificial hypervolaemia predisposes patients to interstitial oedema, which appears to be associated 6.2.4.2 Crystalloids versus colloids with perioperative mortality.278 Recommendation We suggest the replacement of extracellular fluid losses Recommendation with isotonic crystalloids in a timely and protocol based We recommend against the use of central venous pres- manner. 2C sure and pulmonary artery occlusion pressure as the only variables to guide fluid therapy and optimise preload Compared with crystalloids, haemodynamic stabilisation during severe bleeding; dynamic assessment of fluid with iso-oncotic colloids, such as human albumin and responsiveness and non-invasive measurement of car- hydroxyethyl starch, causes less tissue oedema. C diac output should be considered instead. 1B Losses from the extracellular space occur continuously via To determine the amount of fluid required, high fidelity perspiration and urinary output. During fasting, these monitoring is necessary. The monitored variable should losses are not replaced and substitution is required. predict whether or not a fluid bolus will increase Healthy adults perspire around 0.5 ml kg 1 h 1, and the cardiac output. corresponding value during major abdominal surgery is 1mlkg1 h1.290 This loss, together with urinary output, Central venous pressure (CVP) remains the most should be replaced. There is no evidence that additional widely used clinical marker of volume status, despite administration of crystalloid preserves organ function. numerous studies showing no association between CVP and circulating blood volume.279 Several studies have In healthy patients, stabilisation of cardiac preload with demonstrated that dynamic parameters such as stroke iso-oncotic colloids such as human albumin and hydro- volume variation (SVV) or pulse pressure variation xyethyl starch causes less tissue oedema than do crystal- (PPV) provide better prediction of fluid responsiveness loids. It is unclear whether this translates into any clinical in mechanically ventilated patients with a normal heart outcome benefit. The safety profile of artificial colloids rhythm. Fluid challenges and the leg-raising test is unconfirmed. represent simple and valid alternatives;280 no data The most important colloid solutions are human albumin, prove the superiority of substitution regimens guided hydroxyethyl starch, gelatin and dextran. The volume by SVV or PPV. effect of gelatin preparations appears inferior to that of The most extensively studied and successfully used starch or albumin preparations.291–293 However, a recent method to maximise cardiac preload is the oesophageal review concluded that such effects are temporary and do Doppler device.259,281–286 not translate into different clinical outcomes.292 While side effects of colloids remain a concern, a recent sys- 6.2.3.2 Delayed and low-volume resuscitation tematic review failed to show any significant safety techniques differences between the available colloids.294 The general implementation of a delayed or low-volume resuscitation protocol for the severely bleeding patient 6.2.4.3 Chlorine balanced solution cannot be recommended at this time. However, such a Recommendation protocol may be applied for specific lesions, provided that We suggest the use of balanced solutions for crystalloids surgical control of bleeding is imminent. and as a basic solute for iso-oncotic preparations. 2C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 297

In balanced crystalloids, metabolic anions (mainly acetate 6.2.4.6 Monitoring tissue perfusion or lactate) are used instead of chloride to establish elec- Recommendation troneutrality and isotonicity in vitro. Although no out- We recommend repeated measurements of a combi- come benefit has been shown, there is little reason to nation of haematocrit/haemoglobin, serum lactate, and question the rationale for using balanced solutions.295 base deficit in order to monitor tissue perfusion, tissue oxygenation and the dynamics of blood loss during acute 6.2.4.4 Transfusion triggers bleeding. These parameters can be extended by Recommendation measurement of cardiac output, dynamic parameters of We recommend a target haemoglobin concentration of volume status (e.g. stroke volume variation, pulse pres- 7–9gdl 1 during active bleeding. 1C sure variation) and central venous oxygen saturation. 1C It has been demonstrated that acute anaemia There is no easily applicable tool for monitoring blood (Hb < 5gdl1) can be tolerated in healthy individuals, volume in a clinical setting. Consequently, surrogate because compensatory mechanisms (predominantly an parameters (e.g. haematocrit/haemoglobin, central increase of cardiac output) can ensure sufficient tissue venous pressure, pulmonary capillary wedge pressure, oxygenation.296 stroke volume variation, pulse pressure variation, serum lactate concentration, base deficit) are used. Some of During bleeding, patients may be less able to tolerate these parameters have been demonstrated to be inap- anaemia because the compensatory mechanisms may be propriate, such as central venous pressure and pulmonary impaired. However, it is not known whether the lowest capillary wedge pressure, while others require specific tolerable haemoglobin concentration is determined monitoring tools which are not widely available, includ- by volume status. Recent data from patients under- ing stroke volume variation and pulse pressure variation going surgery and under intensive care indicate that a with special monitors. restrictive transfusion regimen (Hb 7–8 g dl 1)isas effective and as safe as a liberal transfusion regimen Due to low sensitivity and specificity, haematocrit and (Hb 9–11 g dl1).9,297–300 Considering the lack of haemoglobin concentration should not be used as exclu- benefits from higher haemoglobin concentrations, and sive measures to monitor the extent of acute blood the potential side effects of transfusing allogeneic blood, loss.304,305 However, since haemoglobin concentration haemoglobin concentrations above 9 g dl1 cannot be is one important determinant of systemic oxygen deliv- supported.4 ery, it should be monitored regularly. It has been speculated that haemoglobin concentration Serum lactate concentration and base deficit reflect might influence coagulation. At high haemoglobin con- global tissue perfusion and oxygenation in haemorrhagic centrations, erythrocytes congregate in the inner lumen shock. Although both can be influenced by many differ- of blood vessels, resulting in localisation of thrombocytes ent factors, their concentrations can be used to determine at the vessel wall, and this may improve clot formation. severity of haemorrhagic shock, guide substitution and Furthermore, erythrocytes stimulate thrombin gener- transfusion protocols306,307 and potentially predict survi- ation, thereby providing material for clot formation.301 val.308 However, it has not yet been shown whether the However, no randomised controlled trials have proved outcome of severe bleeding can be improved if volume that increasing haemoglobin concentration above 9 g dl1 resuscitation is guided by serum lactate concentration reduces bleeding or the number of blood transfusions. and base deficit.309 Central venous oxygen saturation (ScvO ) is used in 6.2.4.5 Oxygen fraction 2 sepsis to guide volume therapy and other measures to Recommendation optimise oxygen delivery.310 Although it has been We recommend that inspiratory oxygen fraction should demonstrated that ScvO reflects blood loss in the early be high enough to prevent arterial hypoxaemia in bleed- 2 stages of haemorrhagic shock,311 circulation is centralised ing patients, while avoiding extensive hyperoxia during severe haemorrhage, which raises ScvO2. There- (PaO2 > 26.7 kPa [200 mmHg]). 1C fore, ScvO2 values during severe haemorrhage must be The use of high inspiratory oxygen fractions during interpreted cautiously.312 artificial ventilation (hyperoxic ventilation, HV) is traditionally advised for emergencies on the basis that 6.3 Transfusion of labile blood products severe arterial hypoxaemia potentially endangers oxy- 6.3.1 Infectious risk of allogeneic blood components gen delivery. However, it has been demonstrated that Recommendation the side effects of HV (e.g. vasoconstriction) may We recommend that all countries implement national worsen patient outcomes.302,303 Overall, current evi- haemovigilance quality systems. 1C dence supports the use of HV to achieve physiological arterial oxygen partial pressures during haemorrhagic Although tremendous progress has been made regarding shock. the safety of blood components, there remains a residual Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 298 Kozek-Langenecker et al.

risk of transfusion-related infection.313 Most transfusion restrictive transfusion (Hb concentration maintained at services in Europe and the USA require that all donations 7–9gdl1) with liberal transfusion (Hb concentration are screened for hepatitis B and C viruses (HBV; HCV), maintained at 10–12 g dl1); 30-day mortality was higher human immunodeficiency virus (HIV) and syphilis.314–317 with liberal transfusion.321 A recent Cochrane review of Universal testing for other infectious agents such as West RBC transfusion triggers included 17 RCTs.8 A lower RBC Nile Virus, malaria, Chagaz disease and human T-cell transfusion trigger reduced postoperative infection by lymphotropic virus (HTLV) is not justified because of 24%, with no adverse effects on mortality, cardiac morbid- their restricted geographical distribution; instead, donor ity or length of hospital stay. Transfusion in acute coronary screening is employed. Potential donors are asked ques- syndrome has been associated with increased mortality,322 tions on travel history, drug abuse, sexual behaviour, etc; except in the elderly where it reduces fatality if the however, residual risks remain. There is also a risk that haematocrit is below 30%.323 laboratory testing of donated blood is not effective. There is usually a period during which the donation is infectious Recommendation but will screen negative because the infectious marker is We recommend photochemical pathogen inactivation not present at detectable levels. Shortening of this ‘win- with amotosalen and UVA light for platelets. 1C dow period’ is a major target of all screening programmes. Pathogen inactivation kits have recently been licensed In addition to known infectious agents, there is also the for plasma and platelets, but not for RBCs. Such tech- threat of new or emerging pathogens.313 Due to increased nology is probably most important for new and emerging travel and spread of mosquitoes, the most important infectious threats or in situations in which testing is only emerging threats are the mosquito borne Dengue, partially effective (e.g. bacterial contamination of platelet Chikungunya and Zika viruses.318 products). Bacterial contamination is another issue of transfusion Solvent and detergent (SD) was the first pathogen inacti- practice. Since the introduction of disposable collection vation technique, introduced for plasma in the early 324 systems, the incidence of bacterial contamination has 1990 s. The process is based on disruption of the viral decreased dramatically. However, platelets, which are envelope but is only effective against lipid-enveloped stored at room temperature and suspended in plasma, viruses and is not applicable for use with RBCs or platelets. still present a significant risk. The greatest risk of con- More recently, the combination of photosensitisers and tamination occurs during collection, because bacteria are white or ultraviolet light has been developed to act at the 319 present on the donor’s skin. Disinfection techniques nucleic acid level.325 The principle of this approach is have improved, and small sideways collectors used to that viral and bacterial pathogens (except prions) need collect the first 30 ml of donated blood reduce the con- genetic material to be viable, whereas therapeutic blood tamination risk. Additional measures include the use of components do not. The Intercept Blood System (Cerus closed systems and improvements in processing area Corporation, Concord, CA) for platelets and plasma uses hygiene. photoactive amotosalen to irreversibly block the replica- Most countries have developed a national haemovigi- tion of DNA and RNA. The Systolic Blood Pressure lance system to identify adverse outcomes of transfusion. Intervention Trial (SPRINT) examined the therapeutic Introduced in 1996, the UK Serious Hazards of Transfu- efficacy and safety of platelets treated with amotosalen 326 sion (SHOT) scheme involves compulsory reporting of all and ultraviolet light. This RCT showed that the use of transfusion-related incidents. The latest SHOT report pathogen-inactivated platelets is not associated with (2009) demonstrated a tremendous reduction in serious increased bleeding and confirmed a lack of either toxicity outcomes compared with the first report (1996).320 How- or neoantigen formation associated with this photoche- 326 ever, links between infection and transfusion are not mical process. always made. Another photoinactivation method applied to plasma is Recommendation methylene blue combined with visible light. Few RCTs We recommend a restrictive transfusion strategy which is have assessed this method, and there are concerns over beneficial in reducing exposure to allogeneic blood pro- reduced efficacy of methylene blue treated plasma in 327 ducts. 1A patients with thrombotic thrombocytopaenic purpura. One of the most effective ways to reduce transfusion Photoinactivation is less applicable to RBCs because of related infection is to introduce a restrictive transfusion their high optical density, which impairs penetration of protocol, i.e. transfuse only what is really necessary photoactive molecules. Nevertheless, research with ribo- (RBCs, plasma or platelets) and only when it is really flavin is ongoing. necessary. Recommendation The Transfusion Requirements in Critical Care (TRICC) We recommend that labile blood components used for multicentre randomised controlled trial compared transfusion are leukodepleted. 1B Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 299

The infectious risk of leukocyte-mediated viruses (cyto- staff be trained in early recognition of, and prompt megalovirus [CMV], HTLV, HIV) may be reduced by response to, transfusion reactions. 1C prestorage removal of leukocytes from blood components. For RBCs, this can be achieved by using dedi- Haemolytic transfusion reactions (HTRs) are typically cated filters, while for platelet products, leukocytes are caused by transfusion of RBCs carrying antigens to which removed during the collection process via apheresis. the recipient has significant alloantibodies. The vast Third-generation leukocyte depletion filters appear majority of cases are attributable to bedside clerical/ effective in preventing primary CMV infection in neo- procedural errors, either when taking samples for pre- transfusion screening or before the administration of the nates, adult cancer patients and bone marrow transplant 333 patients. Leukodepletion does not remove all leukocytes, blood component. but there is evidence that CMV seronegative and leukor- The pathogenesis of HTRs may be related to comp- educed blood components are equivalent, provided that lement activation after IgM antibodies have been fixed 6 328 5 10 white cells remain in the product transfused. (severe acute HTRs), or to IgG antibodies (e.g. anti-D, Universal leukodepletion of blood components was intro- anti-K) in patients who have been sensitised either by duced in the UK in 1998 on the basis that it reduces the pregnancy or by previous transfusion (less severe acute HTRs; approximately 1 in 25 000 transfused units of risk of variant Creutzfeldt-Jacob disease (vCJD) trans- 334 mission.329 RBCs). Onset of HTRs can be delayed by approximately 1 week following transfusion, by anamnestic or Another benefit of prestorage leukodepletion is preven- secondary immune responses in previously primed tion of febrile non-haemolytic transfusion reactions patients. (FNHTRs). These are the most frequent adverse reactions following transfusion of blood components, with The first signs of both acute and delayed HTRs are fever 335 an incidence of 1% with non-leukodepleted RBCs and and chills. Hypotension, tachycardia, nausea and 5–10% with platelets.330 The main cause of FNHTRs is vomiting, loin and chest pain, and renal failure may be antibodies in the recipient being directed against anti- associated with acute HTRs or, less commonly, with gens on the donor’s white cells and platelets.331 Leukor- delayed HTRs. Anaesthesia may mask the typical symp- eduction of transfused blood components to <5 106 toms of renal failure and red cell destruction may be leukocytes per unit has been shown to significantly noted by the presence of haemoglobinuria and excessive reduce the occurrence of FNHTRs.329,332 bleeding because of disseminated intravascular coagulation. Haemoglobinaemia, haemoglobinuria, jaundice and DIC may also occur with acute HTRs, in relation 6.3.2 Immunological complications of blood to intra- or extravascular haemolysis. transfusion The SHOT report is a haemovigilance data collection The most frequent cause of intravascular HTRs is ABO system involving all UK hospitals. Since it began, 6653 incompatibility attributable to procedural errors. Most transfusion-related adverse events have been recorded. deaths occur with transfusion of group A or group B to In the first SHOT report (1996–1997) there were 141 group O recipients. reports, 36 cases of major morbidity and 12 deaths, Occasionally HTRs may be associated with transfusion of representing a serious outcome percentage of 34% plasma or even platelets. Here, transfusion of group O (48/141). By 2009, the serious outcome percentage had plasma containing antibodies against A or B antigens on decreased to 6.7% (86/1279). Two hundred and eighty the recipient’s RBCs leads to haemolysis. two reports (22%) were attributable to incorrect blood component transfusion (e.g. wrong ABO and Rh Rarely, incompatibility between RBCs from one donor group).320 It is estimated that approximately 1 in and the plasma from another donor causes haemolysis in 30 000 transfused RBC units are ABO incompatible the recipient (interdonor incompatibility). and that around 1 in 500 000 deaths are due to ABO The American Association of Blood Banks guidelines incompatibility. This is ten-fold higher than the risk of recommend that if an HTR is suspected, transfusion acquiring HIV infection by transfusion in the UK.317 must be stopped immediately.330 This is because the Other immune mediated causes of transfusion-related severity of haemolysis is related to the volume of incom- morbidity and mortality identified by SHOT include patible blood transfused. Treatment should be guided by haemolytic transfusion reactions, FNHTRs, allergic the clinical manifestations. For mild symptoms, careful and anaphylactic reactions, transfusion-related acute lung observation may suffice, but severe reactions demand injury (TRALI) and transfusion-associated graft-versus- vigorous therapy. For example, exchange transfusion may host disease (TA-GVHD). be lifesaving in cases of ABO incompatibility and severe Recommendation haemolysis. Renal failure may be prevented by main- We recommend that blood services implement standard taining urine output with fluids and diuretics. Pressure operating procedures for patient identification and that support may be needed in the presence of hypotension Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 300 Kozek-Langenecker et al.

and shock, while DIC should be managed according to The 2009 SHOT report includes 21 cases of TRALI out local protocols. of the total of 1279 reported adverse incidents.320 How- ever, mild forms of TRALI may go unnoticed and severe Febrile non-haemolytic transfusion reactions (FNHTRs) cases may be attributed to factors such as circulatory are defined as an increase in body temperature of 18C overload; therefore, the true incidence is probably under- occurring in association with the transfusion of blood estimated. components and not explained by other aspects of the patient’s medical condition. Chills, rigor and discomfort In the UK and Belgium, donations from multiparous may be present and usually respond well to antipyretic women are excluded for the preparation of FFP and agents. Because fever is present in other transfusion platelets. This strategy appears to be beneficial in redu- reactions, such as acute HTR, TRALI and bacterial cing the incidence of TRALI.338–340 contamination, diagnosis of FNHTR is made by exclu- In France, HLA antibody screening of previously preg- sion. If in doubt, a direct antiglobulin test should be nant female donors has been found acceptable in case performed and concentrations of free haemoglobin of shortage. should be assessed. Allergic and anaphylactic reactions develop as a type 1 Recommendation hypersensitivity response to plasma proteins present in We recommend that all RBC, platelet and granulocyte transfused blood components, meaning that an immedi- donations from first-or second-degree relatives be irra- ate allergic reaction follows any subsequent contact with diated even if the recipient is immunocompetent, and all the antigen to which the recipient has been previously RBC, platelet and that granulocyte products be irradiated sensitised. Crosslinking of antigen with surface IgE before transfusing to at-risk patients. 1C stimulates degranulation of the mast cells.336 These cells Transfusion-associated graft-versus-host disease (TA- are usually distributed in the skin and in the mucosa of GVHD) is a potential complication if the transfused gastrointestinal and respiratory tracts, hence the symp- blood component contains viable T-lymphocytes and toms of itching, flare reactions, bronchoconstriction, there is disparity in HLA-antigens between donor and nausea and vomiting, diarrhoea and abdominal cramps. recipient.341 The main risk factors are: congenital immu- Benign skin allergic responses to transfusion of plasma- nodeficiency disorders; Hodgkin’s disease; Erythroblasto- containing blood components, including RBCs and sis fetalis and premature birth (neonates); intrauterine platelets, manifest as local erythema, urticaria and prur- transfusion; stem cell transplants; donations from first- itus in 1–3% of cases. Anaphylactic transfusion reactions or second-degree relatives; HLA-matched cellular are much less frequent (1 in 20 000–400 000 units products; and recipient-donor pairs from genetically transfused). In the event of anaphylaxis, the infusion homogeneous populations. should be stopped immediately and adrenaline administered. Circulatory and respiratory support may be indi- The immune cells of immunocompetent recipients far cated. Diagnosis of an anaphylactic transfusion reaction outnumber donor T-lymphocytes, so the latter are usually must be made by demonstrating deficiency of IgA and eliminated by a host-versus-graft response. However, if presence of IgG anti-IgA in the recipient. Patients should functional T-lymphocytes are transfused from a donor who subsequently receive blood components from an IgA- is homozygous for one of the recipient’s haplotypes, the deficient donor population or autologous transfusion.337 recipient may fail to recognise them as foreign. The donor T-lymphocytes recognise the host as foreign, proliferate Recommendation and cause TA-GVHD. Because the onset of clinical symp- We recommend that multiparous women be excluded toms is delayed for 8–10 days after transfusion, careful from donating blood for the preparation of FFP and for the monitoring is warranted. Typical features of TA-GVHD suspension of platelets in order to reduce the incidence include fever, maculopapular skin rash affecting the palms, of TRALI. 1C diarrhoea and hepatitis. Infection leads to deterioration in Transfusion-related acute lung injury (TRALI) is poten- health, with death occurring within 1 month in over 90% of tially life-threatening and occurs within 6 h of transfusion cases.337 The quickest way to diagnose TA-GVHD is by of plasma containing blood products.338 Patients with skin biopsy; histological changes including basal cell layer TRALI commonly present with fever, chills, hypo- degeneration with vacuolisation, dermal epithelial layer tension, dyspnoea, non-productive cough and cyanosis. separation and bulla formation are evident. It is useful also Severe hypoxaemia is common, so many patients need to establish the persistence of donor T-lymphocytes in supplemental oxygen and mechanical ventilation. the recipient’s circulation or tissues, using DNA Because there is no pathognomonic feature or diagnostic analysis.342–344 However, their presence alone does not test available for TRALI, diagnosis is by exclusion. Most necessarily indicate TA-GVHD because donor lympho- cases improve within 2–3 days if adequate respiratory and cytes can persist after transfusion. Because concomitant circulatory support is provided. The fatality rate from medical conditions may conceal TA-GVHD symptoms, TRALI is 5–8%. the incidence is underestimated. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 301

There is no effective treatment of TA-GVHD. Prevention apheresis. For this technique, one (or more) com- is by removing donor lymphocytes or by destroying their ponent(s) are collected from the donor by centrifugation proliferative capacity. Leukodepletion to less than 106 and the unwanted components are returned to the white cells per unit does not eliminate the risk. However, donor’s circulation. The main advantage of apheresis is since the introduction of universal leukodepletion in the the collection of more than one dose of a selected UK, a significant decrease in TA-GVHD cases has been component per donation, reducing the number of donors observed and the 2009 SHOT report (UK) does not record to whom recipients are exposed. any cases.320 The mainstay of prevention remains gamma For preparation of FFP at the Belgian Military Hospital, irradiation of cellular blood components to prevent donor the plasma units are weighed and then subjected to inline leukocyte proliferation.345 However, because of the low leukodepletion by gravity filtration. Pathogen inacti- incidence of TA-GVHD in immunocompetent recipients vation is performed using the Intercept Blood System receiving blood components from unrelated donors, (amotosalen and ultraviolet light). Each unit (approxi- gamma irradiation is not warranted on a routine basis. mately 200 ml) is frozen at 758C, before storage at Recommendation 858C for up to 1 year. All FFP units undergo quality We recommend the transfusion of leukocyte reduced control, including determination of factor VIII (FVIII) RBC components for cardiac surgery patients. 1A and protein concentrations, as well as leukocyte, RBC and platelet counts. The concept of transfusion-related immunomodulation (TRIM) explains laboratory immune aberrations per- Leukodepletion of platelet components takes place ceived after blood transfusion. Initially, TRIM only during the last step of separation. After a 2 h collection encompassed the effects of allogeneic transfusion attribu- period, aliquots of plasma and suspension liquid are table to immunomodulation (e.g. cancer recurrence, post- added to produce two platelet units, each containing operative nosocomial infection, virus activation), but approximately 4 1011 platelets. Each platelet unit recently the potential effects of proinflammatory mech- undergoes pathogen inactivation by amotosalen and anisms (e.g. multiple organ failure, mortality) were ultraviolet light.325 Amotosalen is removed by filtration added.346 before storage at 20–228C (shelf life: 5–7 days). Quality control involves measuring volume and pH, as well as Increased cancer recurrence after blood transfusion has platelet, RBC and leukocyte counts. Other techniques been shown in in vitro studies, animal models and obser- used for platelet production are the ’buffy coat’ method vational studies.347 However, a randomised controlled favoured in Europe and the platelet-rich plasma (PRP) study did not find any difference in colorectal cancer technique used in North America.355 recurrence after 2 and 5 years.348 The true effect of TRIM on cancer recurrence remains to be demonstrated After their separation from whole blood, RBCs are in a sufficiently powered RCT. suspended in Nutricel additive solution (Bayer AG, Leverkusen, Germany). Nutricel provides a shelf life The influence of allogeneic blood transfusion on post- of 49 days, 7 days longer than the more commonly used operative nosocomial infections has been investigated in SAGM solution. Promptly after collection, the units are several meta-analyses.349–352 However, because of differ- leukodepleted by gravity filtration. Quality control, per- ences in surgical patients, definitions for postoperative formed on 1 in 20 units, includes determination of blood infection and type of transfused blood components, the group, haemoglobin concentration and haematocrit, leu- evidence is inconclusive. kocyte count, lactate dehydrogenase (LDH), 2,3-dipho- Higher mortality rates among transfused versus non-trans- sphoglycerate (2,3-DPG), adenosine triphosphate (ATP), fused patients can generally be explained by patient potassium and lactate concentrations, and pH. European selection, because anaemia is an independent risk factor. guidelines suggest RBC units produced by apheresis However, in cardiac surgery, increased postoperative should have a haematocrit of 50–70% when suspended infection attributable to TRIM has been demonstrated in SAGM solution and 55–70% when Nutricel is used. among patients receiving leukocyte containing RBCs compared with those receiving leukocyte reduced RBCs.353 In 6.3.4 Cell salvage the same RCT, inhospital mortality and length of hospital Recommendation stay were also increased in patients receiving leukocyte We recommend the routine use of red cell saving which containing RBCs. A subsequent RCT conducted by the is helpful for blood conservation in cardiac operations same authors confirmed the results of their first trial.354 using CPB. 1A In light of the potential adverse effects of transfusing 6.3.3 Preparation of labile blood components allogeneic blood components, the ever increasing cost Because very few indications remain for whole blood and the shrinking donor pool, strategies to reduce transfusion, it is now common for plasma, platelets, perioperative blood transfusion are being developed. RBCs, granulocytes and stem cells to be collected by Intraoperative cell salvage (ICS) has been proposed as a Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 302 Kozek-Langenecker et al.

key method for reducing perioperative blood transfu- beneficial is in major orthopaedic surgery, such as hip sion.356 replacement, spinal operations and repair of pelvic fractures.357,367,368 Other indications for ICS include In order to be cost-effective, an initial ‘stand-by’ setup abdominal aortic aneurysm repair,369 hepatectomy, using only a sterile reservoir, a double lumen suction radical prostatectomy, nephrectomy, cystectomy and catheter and a solution for anticoagulation is required. emergency medicine (e.g. major abdominal and/or Once sufficient wound blood has accumulated, the main thoracic trauma).370 washing device is installed. Several devices are available and all use the principle of centrifugation to separate RBCs Definite contraindications to ICS include the intraopera- from plasma and the wash solution. After priming the tive use of sterile water, hydrogen peroxide or alcohol, as system with 100–200 ml of heparin solution (30 IU ml1), these substances would induce severe RBC haemoly- 1), the flow is adjusted to an anticoagulant:blood ratio of sis.371 When shed blood is potentially contaminated with 1:5 to 1:7.357 Shed blood is aspirated, anticoagulated at the bacteria, amniotic fluid or malignant cells, the decision to suction catheter tip and stored in a sterile reservoir use ICS should be made on a case-by-case basis.356 equipped with a microaggregate filter. Anticoagulated In cancer surgery, there is concern about the risk of re- and filtered wound blood is pumped into the centrifuge infusing malignant cells, which could cause metastases. for RBC separation. The RBCs are then washed and Certainly, aspiration of blood from close to the tumour suspended in saline to obtain a haematocrit of 50–70%. site should be avoided. Leukodepletion may reduce the Leukocytes are removed with the buffy coat to varying risk, but residual cancer cells after filtration are unaccep- degrees.358–361 table because it has been demonstrated that one single ICS should be considered for all operations with signifi- tumour cell is capable of causing metastasis.372 Despite cant likely blood loss, i.e. >20% of the patient’s estimated these considerations, studies in urological cancer surgery blood volume.362 Cardiac surgery using CPB is a major have shown ICS not to affect biochemical recurrence or indication.363 In this setting, significantly reduced blood long term survival.373,374 In 2008, the UK National Insti- loss and transfusion requirements have been demon- tute of Health and Clinical Excellence (NICE) approved strated, with decreased complication rates and reduced the use of ICS in urological malignancy surgery.375 It is systemic inflammation related to removal of most but not well known that DNA proliferation of radiosensitive all cytokines from suctioned blood. Routine use of red tumour cells can be eradicated by gamma irradia- cell saving is recommended by the American Society of tion.376,377 Irradiation has also been shown not to impair Thoracic Surgeons and the Society of Cardiovascular RBC quality.376 Therefore, irradiation of intraoperatively Anesthesiologists for blood conservation in cardiac oper- salvaged wound blood could potentially increase the ations using CPB.364 However, ICS is contraindicated in acceptance of ICS in cancer surgery. patients with infection or malignancy and in situations in Recommendation which the blood is exposed to topical clotting agents (e.g. We recommend that intraoperative cell salvage is not fibrin glue or any other thrombin containing compound). contraindicated in bowel surgery, provided that initial Recommendation evacuation of soiled abdominal contents and additional We recommend against the routine use of intraoperative cell washing are performed, and that broad-spectrum platelet-rich plasmapheresis for blood conservation antibiotics are used. 1C during cardiac operations using CPB. 1A Contamination of the surgical field (e.g. bowel surgery, Platelet dysfunction is a major factor in CPB-induced penetrating abdominal trauma or infected wounds) has coagulopathic bleeding. It would therefore seem reason- typically been considered as a contraindication to ICS. able to remove platelet-rich plasma from circulating However, the literature indicates no difference in infec- whole blood before starting CPB, for infusion at the tion rate after laparotomy for abdominal trauma in end of surgery. However, a meta-analysis found that patients receiving allogeneic blood components or cell intraoperative platelet-rich plasmapheresis was not salvaged blood. There also seems to be no correlation beneficial.365 The process is labour intensive and tech- between microbial organisms grown from cell salvaged nical mistakes might be harmful.366 blood and those involved in postoperative pneumonia, bacteraemias or urinary tract infections. An RCT in patients undergoing laparotomy for abdominal injuries 6.3.4.1 Other surgical settings demonstrated that ICS significantly reduced allogeneic Recommendation blood usage without increasing postoperative infection or We recommend the use of red cell salvage in major mortality rate.378 Consequently, the Association of orthopaedic surgery because it is useful in reducing Anaesthetists of Great Britain and Ireland (AAGBI) exposure to allogeneic red blood cell transfusion. 1A guidelines state that, in the setting of bowel surgery, In off-pump cardiac surgery, red cell salvage is recom- red cell salvage is indicated, provided that initial evacua- mended. Another area in which ICS has proved to be tion of the soiled abdominal contents and additional cell Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 303

washing are performed, and that broad-spectrum anti- units which may be ineffective for some patients could biotics are used. nonetheless be beneﬁcial for others.

During the peripartum period, shed blood can be 7 COAGULATION MANAGEMENT contaminated with amniotic fluid and fetal blood, 7.1 Indications, contraindications, complications so reinfusion carries a theoretical risk of amniotic and doses fluid embolism. However, with no proven case of this, 7.1.1 Introduction NICE has approved the use of cell salvage in obste- Many treatment protocols for perioperative bleeding use trics.379 Leukodepletion filters are advocated because fixed ratios of allogeneic blood products. However, trans- their use reduces amniotic fluid contamination,380 but fusion of allogeneic blood products increases morbidity the resulting reduction in reinfusion speed must be and mortality, and fixed ratios might not improve out- considered. comes.141,396–408 We searched for evidence on the use of fibrinogen concentrate, cryoprecipitate, factor XIII 6.3.5 Storage lesions (FXIII) concentrate, recombinant activated factor VII Recommendation (rFVIIa), PCC, vitamin K, desmopressin (DDAVP), apro- We recommend that RBCs up to 42 days old should be tinin and tranexamic acid in severe perioperative bleed- transfused according to the first-in, first-out method in ing. the blood services to minimise wastage of erythrocytes. 1C 7.1.2 Fibrinogen concentrate The legal maximum period for storing RBCs is 42 days. Recommendation Biochemical and biomechanical modifications occurring We recommend treatment with fibrinogen concentrate if during prolonged storage are described as storage significant bleeding is accompanied by at least sus- 381 lesions. During storage of RBCs, lactic acid accumu- pected low fibrinogen concentrations or function. 1C lates in the blood bag and degrades 2,3-DPG.382 This increases the oxygen affinity of haemoglobin, meaning We recommend that a plasma fibrinogen concentration 1 that less oxygen is delivered to tissues. After storage of <1.5–2.0 g l or ROTEM/TEG signs of functional fibri- RBCs for 42 days, the majority of 2,3-DPG is degraded. nogen deficit should be triggers for fibrinogen substi- Although half of it recovers in vivo within 24 h after tution. 1C 383 transfusion, this might not be fast enough for critical We suggest an initial fibrinogen concentrate dose of patients needing immediate restoration of oxygen 25–50 mg kg 1. 2C delivery.384 In addition, ATP content is reduced in stored RBCs, resulting in morphological changes385 which cause In severe bleeding, fibrinogen reaches critical con- 36,409 changes in blood viscosity. Membrane remodelling may centrations early, and haemorrhagic tendency is lead to IgG binding and accelerated erythrocyte destruc- increased when fibrinogen concentration is <1.5– 1 36,85,114,182,409–414 tion.386 A recent review by Kim-Shapiro387 hypothesises 2.0 g l . that storage-associated RBC fragility causes the release of Studies have consistently shown that fibrinogen can free haemoglobin, which consumes nitric oxide, a key increase clot firmness,124,125,415–429 and data on the player in blood flow regulation and inflammation. efficacy of fibrinogen concentrate in acquired fibrinogen Several prospective and retrospective studies have deficiency are increasing. In three randomised trials and attempted to link prolonged storage duration of RBCs two prospective cohort studies, fibrinogen concentrate with adverse clinical outcome,388–391 but the results are optimised coagulation, reduced perioperative bleed- 116,117,430,431 inconclusive. A recent meta-analysis found a lack of ing and significantly reduced transfusion. support for the suspicion that transfusion of ‘old’ RBCs Furthermore, in cardiac surgery, first-line therapy with increases morbidity and mortality.392 fibrinogen concentrate and PCC based on POC testing has been associated with decreased transfusion require- 393 Alfano and Tarasev reported that erythrocyte mem- ments, decreased incidence of thromboembolic events brane fragility correlated well with transfusion efficacy and reduced mortality.119,120 and that mechanical fragility differed between RBCs of the same age. These findings suggest that the traditional 7.1.3 Cryoprecipitate blood service inventory management founded on the Recommendation first-in, first-out method could be replaced by an We suggest that the indication for cryoprecipitate is lack approach taking into account the quality of the RBCs. of available fibrinogen concentrate for the treatment of It would also become possible to prioritise the best bleeding and hypofibrinogenaemia. 2C performing RBC units for the sickest patients. Recently, Raval et al.394 demonstrated that mechanical fragility is In contrast to cryoprecipitate, freeze dried fibrinogen independent of age but correlates with storage solution concentrate offers standardised fibrinogen content, faster and donor gender. Vincent et al.395 suggest that RBC reconstitution and improved efficacy.432,433 In addition, Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. 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the risks of pathogen transmission and immune-mediated conventional, surgical or interventional radiological complications are reduced with fibrinogen concen- means and/or when comprehensive coagulation therapy trate.434,435 fails. 2C Recombinant FVIIa is licensed for the treatment of 7.1.4 Factor XIII patients with haemophilia and inhibitory antibodies, or Recommendation Glanzmann thrombasthenia.462 There is conflicting evi- In cases of ongoing or diffuse bleeding and low clot dence about the use of rFVIIa in surgical bleeding; strength despite adequate fibrinogen concentrations, it is reduced blood loss and transfusion requirements have likely that FXIII activity is critically reduced. In cases of been reported,463–466 while some randomised clinical significant FXIII deficiency (i.e. <60% activity), we trials have failed to show a benefit. A recent meta-analysis suggest that FXIII concentrate (30 IU kg 1) can be admi- of patients undergoing liver surgery did not find any nistered. 2C benefit from prophylactic rFVIIa.467 A Cochrane analysis Clinical studies have shown an increased bleeding concluded that prophylactic rFVIIa reduced blood loss tendency in surgical patients with FXIII activity and transfusion requirements in non-haemophilic <60%.410,413,436–442 However, more data are needed on patients, while mortality did not change. However, there the effect of FXIII concentrate on bleeding and trans- was also a trend towards increased thromboembolic com- fusion requirements.418,443–448 plications with rFVIIa.468,469 Recombinant FVIIa should be administered before 7.1.5 Prothrombin complex concentrate haemostasis is severely compromised.470 The optimum Recommendation dose is 90–120 mgkg 1, and this can be repeated. Hypo- We recommend that patients on oral anticoagulant fibrinogenaemia,471 thrombocytopaenia, hypothermia, therapy should be given PCC and vitamin K before acidosis and hyperfibrinolysis45,472 should all be treated any other coagulation management steps for severe before rFVIIa is used. perioperative bleeding. 1B 1 We suggest that PCC (20–30 IU kg ) can also be 7.1.7 Antifibrinolytics and tranexamic acid administered to patients not on oral anticoagulant therapy Recommendation in the presence of an elevated bleeding tendency and We recommend the consideration of tranexamic acid prolonged clotting time. Prolonged INR/PT alone is not (20–25 mg kg 1). 1A an indication for PCC, especially in critically ill patients. 2C The efficacy of antifibrinolytics has been well studied in patients undergoing elective surgical procedures.473–477 PCC is recommended for acute reversal of oral anti- A large meta-analysis found that tranexamic acid provides 449,450 coagulation. Some centres also administer PCC a similar reduction in perioperative transfusion to that in cases of massive bleeding and prolonged clotting seen with aprotinin, but with improved safety.478–480 125,398 times, although it must be acknowledged that for Tranexamic acid doses of up to 25 mg kg1 are usually perioperative bleeding, the data are very limited. Animal recommended; these can be repeated or followed by 451–456 trials have shown that PCC can reduce blood loss, continuous infusion (1–2 mg kg1 h1). and two retrospective analyses have shown benefit in patients with bleeding complications.457,458 Other animal An analysis of tranexamic acid use in 20 211 trauma 459 patients showed that it improves survival rates by studies have shown conflicting results. A mean dose of 481 30 IU kg1 increased normalised PT in patients with approximately 10%. reduced coagulation activity.460 7.1.8 Aprotinin Animal studies suggest that PCC administration might be Aprotinin is no longer available. Aprotinin was withdrawn associated with an increased risk of thromboembolic from the market because of safety concerns. complications or DIC.423,461 Vitamin K is required for the synthesis of factors II, VII, IX, and X, and proteins C, 7.1.9 Desmopressin (DDAVP) S and Z. These factors might be decreased in patients on Recommendation oral anticoagulant therapy, those with severe malnu- We suggest the use of DDAVP under specific conditions trition or severe liver disease, or in newborns. PCC should (acquired von Willebrand syndrome). There is no con- be administered in these cases of acute severe surgical vincing evidence that DDAVP minimises perioperative bleeding.119,120,449,450 bleeding or perioperative allogeneic blood transfusion in patients without a congenital bleeding disorder. 7.1.6 Recombinant activated factor VII 2B Recommendation A Cochrane analysis showed that desmopressin does not We suggest that off-label administration of rFVIIa can be significantly reduce the risk of exposure to allogeneic considered for bleeding which cannot be stopped by RBC transfusion. In patients undergoing liver resection, Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 305

desmopressin has no effect on transfusion require- A pH decrease from 7.4 to 7.0 can reduce FVII activity in ment482,483 vitro by >90% and FVII/TF activity by >60%.491 Other in vitro data show rFVIIa sensitivity to temperature as In cardiovascular surgery, desmopressin has been shown well as pH.492 Addition of rFVIIa in vitro improves clot to reduce postoperative blood loss in patients with severe reaction times and clot formation rates in mild–moderate, aortic valve stenosis undergoing aortic valve replace- but not severe, hypothermia.493 In adult surgical patients, ment.183 In contrast, desmopressin was not effective in rFVIIa may be less effective in acidotic coagulopathy.494 patients undergoing CABG who were previously treated Conversely, rFVIIa efficacy was reported in another study with aspirin.484,485 to be affected by volume expansion but not acidosis or hypothermia.495 7.2 Correction of confounding factors þ In thromboelastometric studies of healthy volunteers, 7.2.1 Correction of temperature, pH, Ca2 hypothermia-induced coagulopathy was exacerbated by 7.2.1.1 Introduction acidosis, whereas acidosis without hypothermia had no Hypothermia and acidosis each induce coagulopathy. A significant effects on coagulation. Thromboelastometry core temperature of 348C inhibits thrombin generation, performed at 378C may therefore overestimate the integ- fibrinogen synthesis and platelet function, and increases rity of coagulation for patients experiencing hypothermia fibrinolysis. Acidosis (pH 7.1) inhibits thrombin gener- and acidosis.496 ation and platelet function, while accelerating fibrinogen degradation. Reversal of acidosis does not correct acido- A study in pigs showed that acidosis-induced depletion of sis-induced coagulopathy. The positively charged Ca2þ plasma fibrinogen concentration and platelet count is not enhances fibrin polymerisation, coagulation factor activity reversed by neutralisation of pH with bicarbonate.497 and platelet activity. Recommendation Recommendation We suggest that calcium should be administered during þ We recommend maintaining perioperative normothermia massive transfusion if Ca2 concentration is low, in order because it reduces blood loss and transfusion require- to preserve normocalcaemia (0.9 mmol l 1). 2B ments. þ 1B In a cohort study, the nadir of Ca2 concentration was A meta-analysis found that even mild hypothermia (<18C more important than the lowest recorded fibrinogen below normal) increases blood loss by approximately 16% concentration, acidosis and platelet count in predicting and relative risk of transfusion by approximately 22% in hospital mortality. Major risk factors for severe hypocal- surgical patients.486 Intraoperative maintenance of nor- caemia included acidosis and amount of FFP trans- mothermia has been shown in plastic surgery to support fused.498 Whole blood clotting time is prolonged in normal coagulation.487 In hip arthroplasty, aggressive rats with severe ionised hypocalcaemia.499 intraoperative warming (tympanic membrane maintained þ FVIIa activity is calcium dependent. Thus, Ca2 may at 36.58C) reduces perioperative blood loss compared stimulate intrinsic FVIIa activity by a combination of with conventional warming (368C).488 However, in charge neutralisation and loop stabilisation.500 healthy, anaesthetised adults, reduction of body temperature to 328C induced only minor effects on coagu- 7.2.2 Emergency radiological/surgical interventions lation.489 Hypothermic effects may go undetected, to reduce blood loss because coagulation tests are typically performed at 378C. 7.2.2.1 Introduction A pig model has shown that hypothermia (328C) delays Angiotherapy can be diagnostically and therapeutically onset of thrombin generation (FVIIa/TF pathway) with- effective in patients with gastrointestinal bleeding. It out affecting late thrombin generation (propagation provides a surgical alternative for patients with high phase). In this study, acidosis (pH 7.1) slightly inhibited surgical risk. Candidate patients have typically failed early thrombin generation and significantly impaired late to respond to medical and/or endoscopic therapy. thrombin generation.490 Recommendations Recommendation We suggest that endovascular embolisation is a safe We suggest that rFVIIa may be used in treatment of alternative to open surgical intervention after failed patients with hypothermic coagulopathy. 2C endoscopic treatment for upper gastrointestinal bleeding. 2C While pH correction alone cannot immediately correct acidosis-induced coagulopathy, we recommend that pH We suggest superselective embolisation as primary correction should be pursued during treatment of acidotic therapy for treatment of angiogram positive lower gastro- coagulopathy. 1C intestinal bleeding. 2C We recommend that rFVIIa should only be considered We suggest embolisation as first-line therapy for arterial alongside pH correction. 1C complications in pancreatitis. 2C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. 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Transcatheter arterial embolisation (TAE) is well toler- these are supplied ‘free of charge’ by the government. ated and effective for upper gastrointestinal bleeding However, activity based costs are usually 3.2–4.8 times after failed endoscopic treatment.501,502 It has a lower higher than acquisition costs.522 Some hospitals use vir- mortality rate than surgery,503,504 and low incidences of tual internal transfer prices, which have to be ‘paid’ by technique-related complications and recurrent bleed- the transfusing department to the blood bank in order to ing.505,506 When a microcatheter cannot be advanced to compensate for activity based costs of the blood bank the bleeding site, TAE with N-butyl cyanoacrylate may (e.g. storage and crossmatching). Furthermore, transfu- be used to treat upper gastrointestinal bleeding, even in sion-associated adverse events such as acute lung injury coagulopathic patients.507 (ALI), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), TAE can also be used for lower gastrointestinal bleed- nosocomial infections and sepsis, as well as ischaemic ing,508 with a success rate of 76–97% and low frequencies events (myocardial infarction, stroke, acute renal failure, of acute ischaemia or recurrent bleeding.509–511 multiple organ failure) are associated with secondary TAE is less invasive than surgery and equally successful costs for hospitals, governments and health insurance in controlling arterial bleeding in pancreatitis.512 In companies. It has been shown that each additional day patients with head and neck cancer and massive tumour with mechanical ventilation at a US ICU increases the bleeding, TAE has a low incidence of adverse events and hospital cost by $3800–4000.523,524 In the UK, the is associated with longer survival than that in patients ‘return-to-theatre cost’ resulting from a bleeding compli- who are not candidates for the procedure.513 cation in cardiac surgery has been calculated as £2617.525 Furthermore, a study in cardiac surgery in Augsburg, 7.3 Cost implications Germany, demonstrated that excessive postoperative 7.3.1 Introduction haemorrhage, defined as drainage volume >200 ml in Hospital care providers have limited resources and funds any one of the first 6 h after surgery, was associated with allocated for transfusion divert funding from competing significant increases in adverse events (e.g. four-fold clinical and therapeutic strategies. The total cost of increase in the incidence of stroke; incidence of renal supplying patients with haemostatic therapies involves failure doubled), length of ICU stay (doubled), mortality a complex array of activities surrounding the supply (four-fold increase) and hospital costs (increased from s s 526 515 process, together with the cost of the consequences 8027 to 15 404). Murphy et al. reported that following administration. For example, unnecessary overall hospitalisation costs increased by >40% in trans- transfusions are likely to be associated with unnecessary fused compared with non-transfused patients in cardiac morbidity and additional indirect hospitalisation costs. In surgery in the UK. Therefore, clinical interventions this section, we assess the direct and indirect cost implica- which prevent or address severe perioperative bleeding, tions of haemostatic therapies. reduce transfusion requirements and reduce transfusion- associated adverse events are likely to be cost-effective. 7.3.2 Do bleeding, massive haemorrhage and transfusion of allogeneic blood products increase 7.3.3 Does prophylactic use of antifibrinolytic drugs costs? or recombinant factor VIIa reduce costs? Recommendation Recommendations Bleeding and transfusion of allogeneic blood products Lysine analogues (tranexamic acid and e-aminocaproic independently increase morbidity, mortality, length of stay acid; EACA) reduce perioperative blood loss and trans- in ICU and hospital, and costs. B fusion requirements; this can be highly cost-effective in several settings of major surgery and trauma. A Bleeding and transfusion of allogeneic blood products (e.g. packed RBCs, FFP, platelets) are indepen- We recommend restricting the use of rFVIIa to its dently associated with increased morbidity and mor- licensed indication because, outside these indications, tality.3,4,321,388,396,399,400,514–519 Thus, allogeneic blood the effectiveness of rFVIIa to reduce transfusion require- transfusion is associated with increased costs.515,520 ments and mortality remains unproven and the risk of These costs can be differentiated into primary or acqui- arterial thromboembolic events as well as costs are high. sition costs for allogeneic blood products (paid by the 1A hospital or the government), activity based costs of blood Literature regarding the use of aprotinin to reduce bleed- transfusion (including all process costs from the indica- ing and transfusion requirements has not been analysed tion to blood transfusion until monitoring of effects and because aprotinin was withdrawn from the market in adverse events) and secondary costs of transfusion-associ- 2007.475,527,528 ated adverse events.521 Acquisition costs for allogeneic blood products differ widely among countries in Europe Lysine analogues (tranexamic acid and EACA) have been and are difficult to determine in countries where hospitals shown to reduce the requirement for allogeneic blood do not have to pay for allogeneic blood products because transfusion in orthopaedic surgery,477,529–538 trauma,18,481 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. 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cardiac surgery,475,528,539–544 postpartum haemor- randomised trials.15,16,571–573 There are no data on the rhage,19,545,546 and liver resection and transplanta- impact of formula driven transfusion protocols on costs. tion.476,480,483,540,547,548 Head-to-head comparisons show a lower risk of death 7.3.6 Does implementation of point-of-care with lysine analogues compared with aprotinin. The diagnostics (thromboelastography, lysine analogues appear to be free of serious adverse thromboelastometry, platelet function tests such as whole-blood impedance aggregometry) and effects, but safety data are sparse.480 Tranexamic acid subsequent goal-directed therapy reduce costs? has been shown to be cost-effective, reducing transfusion Recommendation requirements without increasing the incidence of deep Implementation of transfusion and coagulation manage- vein thrombosis.535 Lysine analogues appear to be ment algorithms (based on ROTEM/TEG) can reduce particularly cost- and lifesaving in countries with limited transfusion-associated costs in trauma, cardiac surgery financial resources.549 Cost-effectiveness analysis based and liver transplantation. B on the CRASH-2 trial data indicated that early administration of tranexamic acid to bleeding trauma patients is O’Keeffe et al.574 and Cotton et al.575 demonstrated in two highly cost-effective in all income settings.550 retrospective studies in trauma patients that the implementation of a massive transfusion or exsanguination No prospective randomised trials dealing with the pro- protocol significantly reduced overall blood product phylactic administration of rFVIIa have shown any effect consumption and produced cost savings. Furthermore, on mortality.467,540,551–554 The costs for 400 mgkg 1 Go¨rlinger et al. showed in two retrospective studies in rFVIIa are very high compared to a reduction in transfu- visceral surgery, liver transplantation and cardiovascular sion requirement of 2.6 U RBCs. Prospective randomised surgery that the implementation of a thromboelastome- trials in patients with intracerebral haemorrhage showed a try-based transfusion and coagulation management significantly increased incidence of arterial thromboem- algorithm significantly reduced transfusion requirements bolic complications, including myocardial and cerebral and costs.120,576 These results were confirmed by a recent infarction (7 vs. 2% [P ¼ 0.12] and 10 vs. 1% [P ¼ 0.01], prospective randomised clinical trial in coagulopathic respectively).555–557 A distinct trend towards serious cardiac surgery patients.119 A significant reduction in thromboembolic adverse events, including stroke, was transfusion requirements, transfusion-associated adverse observed in prospective randomised studies in liver events and costs, as well as improved outcomes (includ- transplantation (placebo 10%; 60 mgkg 1 rFVIIa 19%; ing 6-month mortality), was demonstrated in the POC 120 mgkg 1 rFVIIa 12%; P > 0.05) and cardiac surgery compared to the control group. (placebo 7%; 40 mgkg 1 rFVIIa 14% [P ¼ 0.25]; 80 mgkg1 rFVIIa 12% [P ¼ 0.43]).558,559 Most recent In principle, point-of-care tests of haemostatic function guidelines recommend not to use rFVIIa in non- can facilitate the optimal management of excessive approved indications. Its emergency use should be bleeding and reduce transfusion by enabling tailored restricted to situations in which all other options failed haemostatic therapy and differentiation between micro- to control severe bleeding.540,560–563 vascular and surgical bleeding. The potential reductions in allogeneic blood product transfusion and re-explora- 7.3.4 Does cell salvage reduce costs? tion rates have important implications for overall patient Recommendation safety and healthcare costs. For example, re-exploration Cell salvage can be cost-effective. A for bleeding in patients undergoing coronary artery bypass surgery is associated with a 4.5-fold increase in Cell salvage has been shown to be cost-effective in 185,526,577 578 overall perioperative mortality. Spalding et al. minimising perioperative transfusion of allogeneic blood 120 (1422 cardiac surgery patients) and Go¨rlinger et al. products.363,564,565 (3865 cardiac surgery patients) demonstrated significant reductions in allogeneic blood product transfusion and 7.3.5 Do formula driven transfusion protocols (1:1:1 cumulative costs for allogeneic blood products and concept for RBC:FFP:platelet transfusion) reduce coagulation factor concentrates after implementation costs? of thromboelastometry-guided coagulation management Recommendation algorithms. Similar results, including significant reduc- The cost-effectiveness of a formula driven transfusion tions in transfusion and coagulation management costs, protocol has not been investigated. were reported by Go¨rlinger et al.,120,576 Weber et al.119 and Several retrospective and some prospective cohort Hanke et al.579 after implementation of thromboelasto- studies – mostly performed in military trauma metry-guided algorithms in visceral surgery, liver patients – suggest that early fresh frozen plasma transfu- transplantation, and aortic arch replacement in acute type sion with an FFP to PRBC ratio between 1:2 and 1:1 A aortic dissection in a German university hospital. reduces 30-day mortality.566–570 However, the evidence Further multicentre prospective randomised clinical for this is of low quality, with a lack of prospective trials evaluating ROTEM/TEG-guided goal-directed Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. 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therapy (‘theragnostic’ approach) versus fixed ratio con- thromboembolic events result in significantly increased cepts (1:1:1 approach) in trauma patients and other costs both inhospital and after discharge.603–605 Further- clinical settings are urgently needed. more, off-label use of rFVIIa, either prophylactically or therapeutically, has been shown to be associated with an increased risk of arterial thromboembolic events.554 7.3.7 Does goal-directed therapy with coagulation 120 factor concentrates (fibrinogen and/or prothrombin However, Go¨rlinger et al. demonstrated in a large complex concentrate) reduce costs? retrospective cohort study (3865 cardiac surgery patients) Recommendation that first-line therapy with fibrinogen concentrate and Goal-directed therapy with coagulation factor concen- PCC based on ROTEM analysis was associated not only trates (fibrinogen and/or PCC) may reduce transfusion- with decreased allogeneic blood transfusion but also with associated costs in trauma, cardiac surgery and liver a significantly reduced incidence of thrombotic/throm- ¼ transplantation. B boembolic events (1.77 vs. 3.19%; P 0.0115) and costs. These results were confirmed by a recent study in which Fibrinogen deficiency plays a major role in trauma- the incidence of thromboembolic events was 0% in the induced coagulopathy and other clinical settings POC versus 4% in the control group.119 This suggests that 414,425,436,562,580–582 associated with severe bleeding. secondary costs may be reduced by preventing throm- Administration of fibrinogen concentrate has been boembolic events due to a targeted haemostatic therapy demonstrated to be consistently effective in animal in bleeding patients. However, this effect has to be models and in patients with acquired fibrinogen confirmed by larger safety studies. Furthermore, a 420,422,426,581,583–585 deficiency. recently published cohort study on the safety and efficacy The efficacy, safety and cost-effectiveness of modern of PCC and fibrinogen concentrates in 266 patients four-factor PCCs for rapid reversal of oral anticoagulation undergoing liver transplantation did not show a signifi- has been proven in several cohort and prospective, cantly increased incidence of thromboembolic events in randomised studies.449,563,586–598 patients receiving coagulation factor concentrates compared to patients who did not need any haemostatic There is growing evidence that targeted therapy using intervention (7.1% vs. 4.5%; P ¼ 0.31).606 Details about coagulation factor concentrates guided by viscoelastic the risk of thromboembolic events associated with PCC measurements enables effective correction of severe in the setting of VKA reversal are presented in section 7.3 599–602 120 coagulopathy. Go¨rlinger et al. demonstrated in and section 8.3. a retrospective study (3865 cardiac surgery patients) that first-line therapy with coagulation factor concentrates 8 MULTIMODAL APPROACH (ALGORITHMS) (fibrinogen and PCC) based on point-of-care coagulation IN SPECIFIC CLINICAL FIELDS testing (ROTEM and Multiplate) decreased allogeneic 8.1 Cardiovascular surgery blood transfusion, thrombotic/thromboembolic events 8.1.1 Introduction and costs, and a more recent study confirmed these Complex cardiovascular surgery may be accompanied results.119 Similar results, including significant reduction by major blood loss, which can lead to loss and con- of transfusion and coagulation management related costs, sumption of coagulation factors and haemodilution. were reported by Go¨rlinger et al.576 in visceral surgery and Coagulopathy in cardiac surgery patients may be liver transplantation. Furthermore, in a study modelling exacerbated by concurrent antithrombotic therapy, the cost-effectiveness of PCC in emergency warfarin extracorporeal circulation, hypothermia and volume reversal in the United Kingdom, PCC appeared to be replacement using crystalloids/colloids.607–610 Failure more cost-effective than FFP.597 to restore haemostasis and restrict perioperative bleeding increases the risk of re-exploration, transfusion 7.3.8 Is the use of coagulation factor concentrates requirements, time spent in the ICU, morbidity and (fibrinogen and/or prothrombin complex mortality.611–613 In this section, we assess the best concentrate) associated with an increased incidence evidence on the use of different haemostatic therapies of thromboembolic events and costs? to control perioperative bleeding in cardiovascular Recommendation surgery. Thromboembolic events are associated with increased inhospital and post-hospital costs. B Targeted therapy with fibrinogen and/or PCC guided by 8.1.2 Which therapies influence perioperative bleeding when administered in the preoperative ROTEM/TEG is not associated with an increased inci- period? dence of thromboembolic events. C Recommendations Both bleeding and blood transfusion increase the inci- Withdrawal of aspirin therapy increases the risk of throm- dence of ischaemic and thromboembolic adverse events bosis; continuation of aspirin therapy increases the risk of and costs.514 Here, both bleeding complications and bleeding. A Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 309

Withdrawal of clopidogrel therapy increases the risk review (23 studies) reporting that clopidogrel exposure of thrombosis; continuation of clopidogrel therapy within 7 days before CABG could increase major bleed- increases the risk of bleeding. A ing, haemorrhagic complications and transfusion requirements.622 In elective CABG, a three-arm RCT (n ¼ 130) We recommend that a prophylactic dose of low molecular subsequently compared clopidogrel therapy continued weight heparin should be administered subcutaneously up to surgery with clopidogrel discontinuation at 3 or 8–12 h before elective CABG surgery. This intervention 5 days preoperatively.623 Continued clopidogrel therapy does not increase the risk of perioperative bleeding. 1B resulted in increased blood loss at 12 h and at drain We recommend that tranexamic acid or EACA should be removal, plus increased postoperative homologous blood considered before CABG surgery. 1A and FFP transfusion. Outcomes did not differ significantly between clopidogrel discontinuation at 3 vs. We suggest considering prophylactic preoperative infu- 5 days. sion of 2 g fibrinogen concentrate, because it may reduce bleeding following elective CABG surgery. 2C 8.1.2.2 Heparin Prothrombin complex concentrate is effective for rapid Heparins may be administered before CABG to reduce reversal of oral anticoagulation before cardiac surgery.A the risk of deep vein thrombosis, particularly following discontinuation of antiplatelet therapy. In a prospective 8.1.2.1 Antiplatelet therapies study (n ¼ 75) comparing preoperative aspirin, subcu- Aspirin. Aspirin is widely used to treat coronary artery taneous unfractionated heparin (UFH) and a no-treat- disease. Because aspirin impairs platelet aggregation, ment control, preoperative UFH therapy caused the discontinuation of aspirin therapy may be considered greatest reduction of postoperative chest-tube drainage before elective CABG surgery to minimise perioperative volume following CABG surgery.624 Recent guidelines bleeding risk. Management of patients receiving aspirin from the American College of Cardiology Foundation and has been discussed in several guidelines which recom- the American Heart Association625 recommend that the mend that aspirin is withdrawn between 2 and 10 days use of UFH can be continued until a few hours before before elective CABG surgery.364,614–616 CABG and that low molecular weight heparin (LMWH) can be administered 12 h before surgery, each without Urgent or emergency CABG is often performed on increased perioperative blood loss. Prospective compari- patients receiving aspirin up to the day of surgery. A son (n ¼ 64) of subcutaneous LMWH (enoxaparin), intra- recent meta-analysis of eight RCTs concluded that treat- venous heparin and no-treatment control has shown that ment with 325 mg per day of aspirin within 7 days of on- enoxaparin does not increase bleeding or transfusion pump CABG surgery increased postoperative mediast- requirements when given >8 h before coronary artery inal drainage volume (doses <325 mg did not increase bypass.626 Additionally, a randomised comparison bleeding).617 The authors concluded that a large RCT is (n ¼ 43) of UFH and enoxaparin showed that subcu- needed to assess the effects of preoperative aspirin in the taneous administration of each, up to 12 h before surgery, contemporary cardiovascular setting. These data corro- has similar effects on coagulation parameters, whole borated findings from another meta-analysis (ten studies; blood count, and RBC and FFP transfusion requirements five RCTs)618 and a single-blind RCT (n ¼ 200),619 each following elective CABG surgery.627 showing that aspirin intake <7 days before CABG increased postoperative chest-tube drainage volume 8.1.2.3 Warfarin and RBC and FFP transfusion requirements. Among No studies addressing the effects of preoperative warfarin the studies included in the meta-analysis by Alghamdi therapy on perioperative bleeding in cardiovascular et al. was a double-blind RCT demonstrating that the surgery were retrieved. Recommendations concerning increased blood loss associated with preoperative aspirin cessation of warfarin therapy before cardiac surgery have was most apparent for patients carrying the GPIIIa allele been presented elsewhere.614 PIA2.106 For these patients, additional haemostatic measures such as antifibrinolytic drugs, FFP or platelet 8.1.2.4 Antifibrinolytic therapy (tranexamic acid and transfusions may be considered.106 e-aminocaproic acid) Clopidogrel. Preoperative clopidogrel therapy may Numerous studies have reported the use of the antifi- increase postoperative bleeding after CABG. Exist- brinolytic drugs aprotinin, tranexamic acid and EACA to ing guidelines recommend discontinuing clopidogrel reduce blood loss in cardiovascular surgery. However, 5–7 days before elective surgery.614–616,620 A meta- aprotinin was withdrawn worldwide following a multi- analysis of 11 comparative studies (4002 patients) con- centre RCT (n ¼ 2331) which demonstrated an increased cluded that clopidogrel administration within 5–7 days risk of mortality associated with its use, compared with before urgent CABG surgery increases blood loss and tranexamic acid and EACA, in high-risk cardiac transfusion requirements for RBC, FFP and platelets.621 surgery.475 Recent Italian recommendations for preopera- These findings were supported by a later systematic tive management of perioperative transfusion report that Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 310 Kozek-Langenecker et al.

tranexamic acid is favoured over EACA in cardiovascular receiving FFP did not reach target INR values within surgery due to the increased potency of tranexamic acid 15 min and even multiple FFP dosing failed to achieve and the increased availability of supporting evidence.47 the target INR in 80% of cases, necessitating administration of PCC. No further studies were identified which Tranexamic acid is typically administered continuously evaluated preoperative transfusion with FFP, platelets during surgery, although use of a single preoperative or cryoprecipitate. bolus has been reported. A best evidence topic presented 12 studies reporting prophylactic use of tranexamic acid in cardiac surgery and concluded that tranexamic acid 8.1.2.7 Coagulation factor replacement therapy reduces blood loss, transfusion requirements and reopera- Antithrombin (AT) concentrate. It has been proposed tion due to bleeding.628 Among the doses reported that AT (previously AT III) may limit consumptive were single boluses in the ranges of 2–10 g and 20– coagulopathy by suppressing thrombin generation during 150 mg kg 1 before sternotomy. One double-blind cardiac surgery. This was investigated in a double-blind placebo-controlled randomised trial (n ¼ 80) also showed RCT (n ¼ 20) in which placebo or AT was infused before that 30 mg kg 1 tranexamic acid given immediately incision in elective CABG patients.634 No difference in before CPB reduced blood loss up to 16 h after elective postoperative blood loss at 6 or 12 h was evident between CABG in patients receiving aspirin up until surgery.539 the AT and placebo groups. Recommendations on the Consistent with these data, a double-blind placebo- use of AT concentrates suggest that further studies are controlled randomised trial (n ¼ 100) showed that 2 g needed in patients undergoing extracorporeal circula- tranexamic acid administered before incision reduced tion.635 4 h postoperative blood loss after off-pump CABG with 629 . A prospective randomised pilot cell salvage. This confirmed results from two previous Fibrinogen concentrate study (n ¼ 20) demonstrated that prophylactic fibrinogen placebo-controlled randomised trials assessing the 1 infusion is potentially useful for reducing bleeding after efficacy of 100 mg kg tranexamic acid administered elective CABG.430 Compared with untreated controls, before incision. One double-blind trial (n ¼ 312) reported patients receiving 2 g fibrinogen concentrate immedi- tranexamic acid to reduce perioperative blood loss and ately before surgery experienced reduced 12 h chest- transfusion rates during CABG with cardiopulmonary 630 tube drainage volume, with no apparent hyper- bypass (CPB); the other (n ¼ 22) demonstrated that coagulability. tranexamic acid reduced intra- and postoperative blood loss during elective surgery with CPB.631 Prothrombin complex concentrate (PCC). A four-factor PCC has been shown to be more effective than FFP for No prospective studies were identified which compared reversal of oral anticoagulation in semi-urgent cardiac a single preoperative bolus of tranexamic acid with surgery.633 Compared with FFP, administration of a tranexamic acid administration throughout surgery. How- half-dose of PCC (based on body weight and initial ever, a four-arm prospective randomised trial (n ¼ 150) INR, according to the manufacturer’s instructions) prior compared a preoperative bolus of EACA with two intra- to CPB resulted in faster correction of INR, with less operative EACA dosing regimens and a no-treatment 632 associated bleeding. control in elective CABG. Although EACA administration reduced postoperative chest-tube drainage Recombinant activated factor VII (rFVIIa). rFVIIa has volume when administered preoperatively, the effect been administered preoperatively ahead of successful was significantly enhanced by administering EACA intra- palliative open heart surgery in a cyanotic infant with operatively. FVII deficiency.636 A dose of 30 mgkg1 rFVIIa was administered 2 h before surgery and then another 8.1.2.5 Desmopressin (DDAVP) immediately before surgery, with further doses post- No evidence was identified describing preoperative use operatively. No further reports of preoperative rFVIIa of desmopressin in cardiovascular surgery. Existing therapy were identified. guidelines on perioperative blood transfusion and blood conservation in cardiac surgery suggest preoperative uti- 8.1.3 Which therapies can be used to control lity of desmopressin may be limited to a small number of bleeding intraoperatively? patients diagnosed as having defects in primary haemo- Recommendations stasis.364 We recommend that intraoperative tranexamic acid or EACA administration should be considered to reduce 8.1.2.6 Allogeneic blood products (fresh frozen plasma, perioperative bleeding in high-, medium- and low-risk platelets and cryoprecipitate) cardiovascular surgery. 1A A prospective randomised trial (n ¼ 40) was identified in which FFP was compared with prothrombin complex We recommend that tranexamic acid should be applied concentrate (PCC) for reversal of oral anticoagulation topically to the chest cavity to reduce postoperative blood prior to CPB in semi-urgent cardiac surgery.633 Patients loss following CABG surgery. 1C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 311

We recommend that fibrinogen concentrate infusion platelet function had not been reported below a prota- guided by point-of-care viscoelastic coagulation monitor- mine to heparin ratio of 2.6:1.643 This contrasts with ing should be used to reduce perioperative blood loss in reports suggesting that lower ratios (1.5:1 in vitro642 complex cardiovascular surgery. 1B and 1.3:1 in vivo644) can prolong coagulation and impair platelet function. Further studies are required to clarify We suggest that recombinant FVIIa may be considered the most appropriate ratios of protamine to heparin for for patients with intractable bleeding during cardiovas- use in cardiac surgery. cular surgery once conventional haemostatic options have been exhausted. 2B 8.1.3.3 Antifibrinolytic therapy (tranexamic acid and 8.1.3.1 Heparin e-aminocaproic acid) Heparin anticoagulation is used during cardiovascular Intraoperative antifibrinolytic therapy is covered in 364 surgery to limit coagulation factor activation, thus pre- guidelines for blood conservation and anticoagulation 614 venting overt thrombosis of the CPB circuit. Heparin management in cardiac surgery. Each recommends dosing may be partially influenced by the length of time using aprotinin, tranexamic acid or EACA to limit blood spent on CPB and patient responses to heparin may be loss and transfusion requirements. Safety and efficacy variable. Dosing and monitoring of heparin anticoa- outcomes for each drug have been compared in a meta- 528 gulation is addressed in guidelines on perioperative analysis of 138 RCTs in cardiac surgery. Aprotinin, blood conservation management in cardiac surgery364 tranexamic acid and EACA all reduced perioperative and also on antiplatelet and anticoagulation management blood loss and RBC transfusion compared with placebo. in cardiac surgery.614 We retrieved four prospective stu- High-dose aprotinin showed the greatest efficacy, dies (n ¼ 26, n ¼ 39, n ¼ 44 and n ¼ 53) investigating although aprotinin also increased the risk of renal dys- heparin monitoring using heparin concentration-based function. This finding was consolidated by the BART approaches, as opposed to a standard activated clotting (blood conservation using antifibrinolytics in a random- 637–640 ¼ 475 time-based approach, during cardiac surgery. Use ised trial) study (n 2331), which compared aprotinin, of heparin concentration-based systems was consistently tranexamic acid and EACA in high-risk cardiac surgery associated with reduced postoperative blood loss and (all administered as a preoperative bolus, followed by increased avoidance of transfusion. Although useful in continuous intraoperative infusion), and was terminated principle, heparin concentration-based monitoring is not early due to an elevated mortality rate associated with widely used in clinical practice. In addition, a number of aprotinin. Aprotinin was subsequently withdrawn from monitoring devices are available, so large randomised the market and further meta-analyses using RCT data trials comparing different systems may be warranted. have confirmed the increased mortality risk associated with aprotinin in cardiac patients.645,646 8.1.3.2 Protamine Since aprotinin was withdrawn, it has not been estab- Administration of protamine is commonly used to reverse lished whether tranexamic acid or EACA is the better the effects of heparin anticoagulation. Correct dosing of therapeutic option. Further analysis of the BART study protamine is important because insufficient protamine data found no differences in safety or clinical effective- results in residual heparin. Conversely, excess protamine ness of tranexamic acid and EACA, although lower costs also impairs coagulation,641 possibly due to antiplatelet were reported for EACA.647 Data supporting EACA activity.642 Protamine dosing in cardiac surgery is administration was identified from a double-blind, addressed in guidelines on the management of perio- placebo-controlled randomised trial (n ¼ 78) in which perative blood conservation364 and also on the manage- EACA was found to be as effective as aprotinin for ment of antiplatelet and anticoagulation therapy.614 The reducing blood loss during CABG surgery.648 Conversely, prospective studies that we identified which investigated a recent three-arm RCT (n ¼ 90) comparing antifibrino- heparin monitoring using heparin concentration-based lytic drugs in open heart surgery found that both aprotinin approaches all found that heparin concentration-based and tranexamic acid significantly reduced blood volumes measurements led to administration of smaller doses of in suction bottles and drainage tubes compared with protamine.637–640 If these results are confirmed in larger EACA;649 tranexamic acid also exhibited the least evi- studies, and if such approaches become part of normal dence of renal dysfunction. Although neither tranexamic practice, heparin concentration-based monitoring could acid nor EACA has been conclusively demonstrated as improve the accuracy of protamine dosing. Another being superior in the cardiovascular setting, we identified important issue concerning protamine administration in more high quality evidence published since 2007 which cardiac surgery is uncertainty over acceptable ratios of supports use of tranexamic acid than was identified for protamine to heparin. Typical ratios of protamine to EACA. This includes a double-blind, placebo-controlled heparin are around 1.3:1, although a best evidence topic randomised trial (n ¼ 222) showing that tranexamic on the risk of bleeding associated with high-dose prota- acid (preoperative bolus followed by infusion through- mine reported that increased bleeding and impaired out CPB) decreased chest-tube drainage volume and Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 312 Kozek-Langenecker et al.

transfusion requirements following elective CABG.650 Most of the evidence which we retrieved involved use of Also identified was a double-blind RCT (n ¼ 220) eval- CPB (on-pump surgery). Off-pump CABG surgery is uating tranexamic acid versus aprotinin infusion through- associated with less blood loss and transfusion than on- out primary CABG or valve replacement surgery,651 pump CABG. A systematic review of eight RCTs was which showed no overall difference in blood loss or performed to determine the utility of tranexamic acid in RBC transfusion between treatment groups. Similarly, off-pump CABG.657 Tranexamic acid reduced the risk of a three-arm RCT (n ¼ 298) comparing aprotinin, tranexa- allogeneic blood component transfusion, but larger trials mic acid and placebo in low- to medium-risk CPB were deemed necessary to draw conclusions about blood patients652 found that tranexamic acid significantly loss and adverse events. We also identified a meta- reduced blood loss and transfusion requirements com- analysis (17 trials) supporting the use of antifibrinolytic pared with placebo, without increasing the incidence of drugs in CABG patients receiving aspirin throughout the serious adverse events. Additionally, a meta-analysis of perioperative period.543 Tranexamic acid and EACA all 25 RCTs (n ¼ 5411) and four matched observational reduced chest-tube drainage volume and perioperative studies (n ¼ 5977)653 was retrieved, which concluded that transfusion requirements without increasing the rate of tranexamic acid has clear benefits in reducing blood loss, adverse events. reoperation for bleeding and transfusion with allogeneic blood components compared with placebo. 8.1.3.4 Allogeneic blood products (fresh frozen plasma, Tranexamic acid administration regimens vary widely.645 platelets and cryoprecipitate) Our evidence base typically reported an initial bolus after Patients undergoing cardiovascular surgery are regularly induction of anaesthesia, followed by continuous infusion transfused with FFP and/or platelet concentrate. Some during CPB. Tranexamic acid may also be added to the patients may also receive cryoprecipitate, although this has been withdrawn in many countries due to safety bypass circuit, or another bolus administered before chest 434 closure. One RCT was identified which directly assessed concerns. Intraoperative use of FFP, platelets and the benefits of tranexamic acid given intraoperatively; a cryoprecipitate is addressed in a guideline on periopera- double-blind trial examined 67 children with cyanotic tive blood transfusion and blood conservation in cardiac 654 surgery364 and also in recent Italian recommendations for congenital heart defects undergoing surgery with CPB. 112 All patients received 15 mg kg1 tranexamic acid before intraoperative management of perioperative bleeding. incision, then either placebo or an identical dose of We retrieved no studies examining the haemostatic tranexamic acid at the end of CPB. Blood loss and efficacy of platelet or cryoprecipitate transfusion on peri- transfusion requirements did not differ between the operative bleeding in cardiac patients, although three groups. Tranexamic acid may also be used topically. A systematic reviews were identified which questioned double-blind RCT (n ¼ 38) compared topical application the efficacy of FFP. One review assessed the effects of of tranexamic acid (1 g in 100 ml saline) or placebo to the prophylactic FFP transfusion at the end of CPB in six pericardial and mediastinal cavities before chest closure RCTs; four were conducted in patients undergoing 655 following CABG. Tranexamic acid reduced postopera- CABG surgery and two reported cardiac surgery with tive chest-tube drainage volume and platelet transfusion CPB.408 It was concluded that routine FFP transfusion requirements compared with placebo. following CPB did not reduce subsequent blood loss. Variation in EACA administration regimens has also been These findings are consistent with a recent systematic 645 review of RCTs since 2004 which evaluates the clinical reported. Two RCTs were identified which compared 658 EACA dosing regimens. In the first study, patients effectiveness of FFP. Twenty-one studies were (n ¼ 150) were randomised to receive no EACA, one included and a meta-analysis of the largest subgroup 150 mg kg1 preoperative bolus, one 150 mg kg1 preo- (cardiac surgery) showed no significant reduction in perative bolus plus 1 g h1 infusion for 6 h, or three sep- 24-h blood loss following FFP transfusion. In addition, arate 150 mg kg1 boluses before, during and after CPB.632 a review of seventy studies (including 21 set in cardiovascular surgery) concluded that FFP transfusion was not The greatest reduction in blood loss and transfusion 585 requirements was seen in the groups receiving EACA clinically effective and may even be detrimental. In intraoperatively. Neither intraoperative regimen proved each systematic review, the evidence was reported to be superior to the other. In a subsequent study, patients of low quality due to small patient numbers and/or (n ¼ 90) received either placebo, a 150 mg kg1 EACA poor methodology. bolus followed by a 15 mg kg1 h1 infusion of EACA commencing before incision, or a 150 mg kg1 bolus of 8.1.3.5 Desmopressin (DDAVP) EACA followed by a 15 mg kg1 h1 infusion of EACA Much of the evidence concerning intraoperative use of commencing after heparinisation.656 Both EACA regimens desmopressin has been considered in an existing guide- reduced chest-tube drainage volumes but the timing did line on perioperative transfusion and blood conservation not affect outcomes, suggesting that EACA administration in cardiac surgery.364 Potential use of desmopressin is is unnecessary before heparinisation. suggested to be limited to excessively bleeding patients Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 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with primary haemostasis disorders, such as CPB-induced identified describing intraoperative PCC administration platelet dysfunction and type 1 VWD. Consistent with in cardiac patients. Analysis of five patients undergoing this, we retrieved two RCTs reporting that adminis- CABG and two patients undergoing valve replacement tration of 0.3 mgkg1 desmopressin at the end of CPB suggested that PCC could be valuable for controlling did not reduce perioperative blood loss or transfusion bleeding in patients responding poorly to standard blood requirements in elective CABG (n ¼ 66)659 or complex products.457 An earlier chart review of cardiothoracic congenital heart surgery (n ¼ 60).660 Similar findings were surgical patients (n ¼ 60) indicated that PCC could safely reported following desmopressin treatment of 100 CABG reduce blood product consumption.664 Larger, prospec- patients receiving aspirin until the day before surgery.485 tive evaluations are required. Recombinant activated factor VII. Although indicated for 8.1.3.6 Coagulation factor replacement therapy patients with congenital coagulation factor deficiencies, Factor XIII concentrate. A three-arm, double-blind RCT use of rFVIIa has been frequently reported for unlicensed (n ¼ 75) was identified which investigated FXIII con- indications in patients with major bleeding.665 Guidelines centrate as haemostatic therapy in coronary surgery for the use of rFVIIa in massive bleeding562 and for with extracorporeal circulation.443 Following protamine perioperative blood conservation in cardiac surgery364 administration, patients received placebo or 1250 or recommend that rFVIIa may promote haemostasis during 2500 U of FXIII. No significant differences in postopera- severe intractable bleeding following CPB. However, due tive blood loss or transfusions were observed. Subgroup to concerns over potential thromboembolic risks, use of analysis indicated that FXIII therapy may be most effec- rFVIIa is recommended only if all conventional haemo- tive in patients displaying subnormal FXIII levels static options have been exhausted. Additionally, the following CPB. patient’s next of kin should be informed that rFVIIa is being used outside of the currently approved indica- Fibrinogen concentrate. Two systematic reviews have tions.562 suggested fibrinogen concentrate to be potentially useful for treating surgical bleeding.585,661 One review included We retrieved reports published subsequent to these guide- 21 trials investigating efficacy of fibrinogen concentrate; lines which support existing recommendations for rFVIIa three were prospective studies reporting intraoperative in cardiac surgery. Systematic reviews of rFVIIa in cardiac use in cardiovascular surgery.585 The second review surgery (one including 35 studies and one including 46 included four reports; two were prospective studies in studies),666,667 paediatric cardiac surgery (29 studies)668 cardiovascular surgery.661 Each review concluded that and vascular surgery (15 studies)669 concluded that rFVIIa fibrinogen concentrate therapy could improve clot firm- may reduce severe haemorrhage but that large prospective ness and decrease transfusion requirements, blood loss randomised trials are required to define efficacy, dose and and postoperative drainage volumes. The evidence was side-effects. Similarly, a systematic analysis of rFVIIa in acknowledged to be of insufficient quality, indicating a on-pump cardiac surgery (19 studies) recommended need for large RCTs. against routine prophylaxis and emphasised that although rFVIIa may be considered as rescue therapy, high quality Since then, data has become available from a randomised, data supporting this indication is lacking.670 double-blind, placebo-controlled trial (n ¼ 61)662 which supports intraoperative infusion of fibrinogen concentrate 8.1.3.7 Fibrin sealant (fibrin glue) during complex cardiovascular surgery. Patients with Fibrin sealant consists of fibrinogen, thrombin and other diffuse bleeding following CPB were treated with throm- additives and can be applied to wounds to create a fibrin- boelastometry-guided fibrinogen concentrate as first-line based clot and promote haemostasis. We retrieved a haemostatic therapy, which reduced the need for transfu- recent prospective RCT in which 82 senior patients sion with RBC, FFP and platelets.662 These data corro- received either fibrin sealant or bone wax injected into borated findings from two smaller prospective cohort the sternal marrow cavity after CABG surgery involving studies, one in repair of thoracoabdominal aortic aneur- CPB.671 The fibrin sealant group displayed reduced post- ysm (n ¼ 18),117 the other involving aortic valve operation operative chest-tube drainage volume, less RBC transfu- with ascending aorta replacement (n ¼ 15).116 Similarly, sion requirements and a shorter hospital stay. No thrombelastography guided fibrinogen concentrate differences in adverse outcomes were reported. Blinding therapy following CPB has been reported to reduce was not reported so further trials may be required to postoperative chest tube drainage volume and FFP trans- confirm these findings. fusion in cyanotic children undergoing cardiac surgery.663 Prothrombin complex concentrate. Recommendations on 8.1.4 Which therapies influence bleeding in the the use of PCC suggest that it may help to control postoperative period? intractable bleeding in major surgery,635 although there Recommendations is little evidence so far to support this indication in We suggest that antiplatelet therapy with aspirin cardiovascular surgery. Two retrospective reports were or clopidogrel may be administered in the early Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 314 Kozek-Langenecker et al.

postoperative period without increasing the risk of post- 8.1.4.4 Desmopressin (DDAVP) operative bleeding. 2C No high quality evidence was identified supporting the efficacy of postoperative administration of desmopressin We suggest that rFVIIa may be considered for patients in cardiovascular surgery. with intractable bleeding after cardiovascular surgery once conventional haemostatic options have been exhausted. 2B 8.1.4.5 Coagulation factor replacement therapy Recombinant activated factor VII. As described for 8.1.4.1 Antiplatelet therapies (aspirin and clopidogrel) intraoperative therapy, use of rFVIIa to control intractable bleeding constitutes an unlicensed indication. Due Guidelines on the use of aspirin and other antiplatelet agents during CABG surgery616 and on antiplatelet and to the potential thromboembolic risks, rFVIIa should 614 therefore be considered only if conventional haemostatic anticoagulation management in cardiac surgery make several recommendations on the postoperative admin- approaches have failed. In this situation, guidelines for the use of rFVIIa in massive bleeding562 and for perio- istration of antiplatelet therapies. We retrieved no 364 further high quality evidence evaluating the effects of perative blood conservation in cardiac surgery suggest that rFVIIa may be used for refractory bleeding following postoperative antiplatelet therapy on postoperative bleeding. However, a prospective, multicentre, observa- CPB. The patient’s next of kin should be informed that rFVIIa is being used off-label.562 tional trial was identified in which patients (n ¼ 5065) undergoing CABG received aspirin therapy in the early A best evidence topic was identified addressing the postoperative period.672 Aspirin was associated with question: is rFVIIa useful for intractable bleeding after numerous clinical benefits and was reported to have cardiac surgery?676 Of 129 reports identified, 13 were no association with increased postoperative bleeding. presented as the best evidence. The study concluded Another prospective observational trial investigated that a dose of 60–90 mgkg1 rFVIIa could be used for patients (n ¼ 117) undergoing elective CABG (on- and patients with intractable bleeding post-cardiac surgery, off-pump) who were administered aspirin or aspirin plus with a repeated dose after 2–4 h. A double-blind RCT clopidogrel in the early postoperative period, according (n ¼ 172) was also identified in which rFVIIa was used to to a predefined protocol.673 Chest-tube drainage, trans- treat patients experiencing intractable bleeding after fusion frequency, transfusion quantity and risk of cardiac surgery.559 Patients received placebo, 40 mgkg1 reoperation for bleeding were all comparable between 1 rFVIIa or 80 mgkg1 rFVIIa, on average 2.8 h after the groups, indicating that early postoperative clopido- admission to the postoperative care unit. Treatment with grel does not increase bleeding risks compared with rFVIIa significantly reduced the incidence of reoperation aspirin alone. for bleeding and subsequent transfusion requirements, although both rFVIIa groups exhibited a non-significant 8.1.4.2 Antifibrinolytic therapy (tranexamic acid and trend towards increased serious adverse events. This e-aminocaproic acid) suggests the need for large RCTs to assess safety of A randomised, double-blind, placebo-controlled study rFVIIa in this setting. was identified which investigated the effects of continued tranexamic acid dosing in the postoperative period 8.1.5 What is the evidence for the use of haemostatic 674 following elective cardiac surgery involving CPB. All management algorithms in cardiovascular surgery? patients (n ¼ 510) received 1 g tranexamic acid before Recommendations 1 incision, a continuous infusion of 400 mg h until the We recommend the use of standardised haemostatic completion of operation, and 500 mg in the CPB prime. algorithms with predefined intervention triggers. 1A Thereafter, patients received an infusion for 12 h with placebo, 1 mg kg1 h1 tranexamic acid or 2 mg kg1 h1 Several studies have demonstrated that standardised tranexamic acid. Postoperative administration of tranexa- transfusion algorithms for administration of haemostatic mic acid had no effect on blood loss or transfusion require- therapy can result in reduced perioperative blood loss and ments. transfusion requirements. A recent review evaluated eight studies (five prospective) using preset therapeutic transfusion triggers, measured using laboratory-based 8.1.4.3 Allogeneic blood products (fresh frozen plasma, haemostasis tests and/or point-of-care coagulation platelets and cryoprecipitate) monitoring devices, to guide haemostatic intervention No high quality evidence was identified supporting the during cardiovascular surgery. In seven of the eight efficacy of FFP, platelets or cryoprecipitate adminis- studies, the use of an algorithm significantly reduced tered postoperatively following cardiovascular surgery. patient exposure to allogeneic blood products.144 Administration of allogeneic blood components has been addressed recently by Italian recommendations We retrieved additional prospective studies which eval- for postoperative management of perioperative trans- uated the effectiveness of standardised treatment algor- fusion.675 ithms in cardiovascular surgery. One RCT compared Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 315

cardiac surgery patients (n ¼ 69) in whom perioperative endometriosis).682 No evidence was identified comparing transfusion management was conducted in accordance gynaecological RBC transfusion triggers with those in with either a strict TEG-guided protocol (using kaolin- other settings. activated TEG and PlateletMapping assays), or Autologous transfusion683–692 and intraoperative haemo- physician-directed administration with reference to dilution693–695 exemplify strategies to minimise allo- aPTT, INR, fibrinogen concentration and platelet geneic transfusion.696 However, autotransfusion is count.677 TEG-based management reduced total blood associated with high costs, together with risks of labora- product usage by almost 60% compared with the laboratory and clerical errors.696–698 In addition, transfusion of tory test-based approach, although this was not statisti- colloids can result in haemodilution, which may compro- cally significant. A larger RCT confirmed the potential mise coagulation413,431 and therefore may not reduce value of TEG in guiding haemostatic management.121 In allogeneic transfusions 699,700. this study, patients (n ¼ 224) undergoing elective CABG with CPB again received transfusions based on either kaolin-activated TEG or clinicians’ judgement combined Should cell salvage be used in gynaecological surgery? with laboratory test results. Patients in the TEG group Recommendation received significantly lower amounts of FFP, platelets Cell salvage may reduce allogeneic transfusion in gynae- and tranexamic acid, while the total number of units cological (including oncological) surgery. C transfused was also lower compared with patients man- Increasing evidence supports the use of filters to clear aged using laboratory tests and clinical judgement. shed blood of cancer cells, avoiding reinfusion and Another RCT was identified which supports the use dissemination.701 Retrospective studies suggest that of viscoelastic point-of-care tests to guide coagulation cell salvage reduces allogeneic transfusion require- management.129 Patients (n ¼ 56) requiring aortic surgery ments.702–706 with hypothermic circulatory arrest were administered haemostatic interventions according to a ROTEM- guided transfusion algorithm (INTEM, HEPTEM, Should intravenous iron or erythropoietin be used to correct FIBTEM and APTEM tests) or based on ‘standard perioperative anaemia? practice’ (transfusion guided by clinical judgement and Recommendations laboratory test results). Postoperative blood loss and rate We suggest using preoperative intravenous iron to of reoperation for bleeding were comparable between reduce allogeneic transfusion requirements in gynaeco- groups, although ROTEM-guided therapy substantially logical cancer patients receiving chemotherapy.2B reduced allogeneic transfusion requirements, particularly We suggest using intravenous iron to correct preopera- for FFP. Furthermore, recent studies have demonstrated tive anaemia in women with menorrhagia. 2B that first-line therapy with coagulation factor concentrates (fibrinogen and PCC) based on point-of-care coagu- Intravenous iron increases haemoglobin concentration lation testing (ROTEM and Multiplate) decreases and reduces RBC transfusion in anaemic gynaecological allogeneic blood transfusion, thrombotic/thromboem- cancer patients receiving chemotherapy,707,708 without bolic events and costs.119,120 compromising quality of life.708 Intravenous iron corrects preoperative anaemia in patients with menorrhagia.213 8.2 Gynaecology and obstetrics Preoperative erythropoietin increases haemoglobin con- 8.2.1 Gynaecological (non-pregnant) bleeding centration, particularly if co-administered with 235,250,707,709,710 8.2.1.1 Treatment of perioperative anaemia iron, but concerns exist regarding safety 678 Gynaecological operations such as cancer surgery and in cancer patients. hysterectomy may be complicated by anaemia and 678 perioperative blood loss. Among gynaecological oper- 8.2.1.2 Coagulation monitoring and treatment ations, excision of a malignant ovarian tumour is the most 679 Gynaecological cancer patients are prone to increased common cause of severe bleeding, and transfusion and blood viscosity and fibrinogen concentrations,711–713 and reoperation due to bleeding are prevalent in hyster- 680,681 perioperative transfusion >2 l increases the risk of post- ectomy. operative venous thromboembolism.713 Perioperative haemostatic monitoring and intervention is critical. Minimising gynaecological RBC transfusion Recommendation We suggest against normovolaemic haemodilution Use of standard laboratory tests and point-of-care devices for gynaecological coagulation monitoring because it does not reduce allogeneic transfusion. 2A Recommendation Gynaecological oncologists report a mean pre- Preoperative fibrinogen and D-dimer evaluation in chemotherapy transfusion threshold of 7.9 g dl1 haemo- gynaecological cancer patients provide little useful infor- globin (higher for ovarian debulking; lower for mation. C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 316 Kozek-Langenecker et al.

Elevated preoperative plasma fibrinogen concentrations Related topics of PPH such as diagnosis of PPH, treat- and positive D-dimer tests provide little clinically useful ment of atony and retained placental tissue, arterial information.714 PT, aPTT and INR may be elevated for embolisation, etc. is beyond the scope of this guideline. several days postoperatively.715 We recommend other evidence-based clinical guidelines such as the WHO guidelines for the management of What are the indications for fresh frozen plasma, platelets postpartum haemorrhage and retained placenta.729 and fibrinogen replacement therapy? Recommendation Obstetric triggers for red blood cell transfusion Postoperative FFP transfusion is associated with an Recommendations increased risk of venous thromboembolism in malignant We recommend that peripartum haemorrhage should be gynaecological surgery. C managed by a multidisciplinary team. An escalating man- FFP transfusion after surgical exploration for resection of agement protocol including uterotonic drugs, surgical adnexal/peritoneal cancer appears to increase risk of and/or endovascular interventions, and procoagulant venous thromboembolism without affecting survival,715 drugs should be available. 1C although the study was prone to confounding-by indica- Risk awareness and early recognition of severe haemor- tion bias. No relevant studies were identified for fibrino- rhage are essential. C gen concentrate or cryoprecipitate in gynaecological surgery. We suggest that patients with known placenta accreta are treated by multidisciplinary care teams. 2C What are the indications for recombinant activated factor Postpartum haemorrhage (PPH) should be treated VIIa? promptly. Delayed recognition of and response to acute Recommendation bleeding is a leading cause of maternal mortality and ‘near rFVIIa increases thromboembolic risk and has not been misses’.730 Suboptimal haematocrit during the acute phase shown to reduce mortality. B of PPH is associated with end organ dysfunction.731 In rFVIIa has been successfully administered for periopera- postpartum haemorrhagic shock, myocardial ischaemia is tive bleeding in malignant and non-malignant gynaeco- typically associated with impaired contractility at systolic logical surgery.716 However, rFVIIa increases the risk of blood pressure <88 mmHg, diastolic blood pressure venous thromboembolism, without improving <50 mmHg and heart rate >115 beats per min.732,733 mortality.717 No studies examining the use of PCC or No clinical studies of transfusion triggers in life-threaten- FXIII were identified. ing obstetric haemorrhage were retrieved; however, general adherence to a haemoglobin threshold of 8.1 g dl1 What are the indications for antifibrinolytics (tranexamic 734 acid)? has been reported. Recommendations There is currently debate over RBC transfusion triggers Tranexamic acid reduces the frequency of late bleeding for postoperative anaemia.735 Up to 68% of postpartum after cone biopsy of the cervix. B transfusions may not adhere to guideline recommen- 734,736–738 Tranexamic acid reduces perioperative bleeding in dations, and RBC units are often transfused 735 gynaecological cancer surgery. C in duplicate without an obvious rationale. Transfusion of 1–2 U of RBCs during postpartum recovery may not We suggest against the use of tranexamic acid in benign impact on length of hospital stay.739 gynaecological operations such as myomectomy. 2B Anaemia peaks at around 48 h after delivery but may Tranexamic acid reduces menstrual bleeding in menor- initially go undetected.736 Haemoglobin concentration 718 rhagia without increased thrombotic risk. Tranexamic and health related quality of life physical fatigue scores acid also protects against late bleeding after cone biopsy correlate in the first week postpartum.740 of the cervix719 and reduces blood loss in gynaecological cancer surgery720, but not during myomectomy.721 Early diagnosis and treatment of coagulopathic amniotic fluid embolism is associated with increased survival.741 8.2.2 Obstetric bleeding Treatment by a multidisciplinary team may reduce early 8.2.2.1 Treatment of postpartum anaemia maternal morbidity in women with placenta accreta, 742 Anaemia develops in up to 29% of third trimester preg- compared with standard obstetric care. nancies,722 while postpartum bleeding is the major risk factor for severe postpartum anaemia.723 Transfusion in Should cell salvage be used in obstetrics? this setting may complicate delivery.414,724–728 Here, we Recommendations assess whether treating obstetric haemorrhage requires Cell salvage is well tolerated in obstetric settings, pro- correction of anaemia, and the therapeutic options avail- vided that precautions are taken against rhesus isoim- able. munisation. C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 317

We suggest that using perioperative cell salvage during following treatment of anaemic (Hb < 10 g dl1) parturi- caesarean section may decrease postoperative homo- ents with erythropoietin and oral or intravenous iron,767 logous transfusion and reduce hospital stay. 2B although this evidence is from a small patient population. Erythropoietin and iron may be used to treat patients Perioperative cell salvage has been used in obstetric with severe anaemia (Hb < 8gdl 1) and pronounced surgery but is not widely established due to staff training clinical symptoms or rejection of donor blood.757 and technology issues.743 Concerns exist regarding potential amniotic fluid embolism and rhesus isoimmunisa- tion.744 Filters reduce contamination with amniotic 8.2.2.2 Postpartum haemorrhage: coagulation fluid,745–748 although fetal RBC may remain after leuko- monitoring and management cyte filtration;747 therefore, Kleihauer testing and Anti-D Acquired obstetric coagulopathy affects approximately 749 21% of deliveries, with complications including PPH treatment may be recommended. Severe hypertension 725 is rare following infusion of salvaged blood.750 requiring transfusion, increased risk of placental abruption,768 placenta praevia and accreta,769 amniotic Cell salvage may be useful for caesarean section, especi- fluid embolism,741,770 retained dead fetus771 and post- ally for Jehovah’s Witnesses and when complicated by haemorrhagic shock.772,773 Obstetric conditions also placenta praevia, placenta accreta or reoperation due to account for 1–5% of clinical cases of DIC.774 In this 744,750–755 bleeding . Jehovah’s Witnesses who are pre- section, we evaluate the evidence for coagulation pared to accept perioperative cell salvage often require monitoring in severe obstetric bleeding. that the system be set up to allow for continuous con- nectivity, including during transport to the postoperative Fibrinogen measurement ward. A comparison with standard treatment has shown Recommendations cell salvage to reduce postoperative homologous transfu- 756 We suggest assessing fibrinogen concentration in par- sion and hospitalisation. turients with bleeding, as concentrations <2gl1 may identify those at risk of severe PPH. 2C Intravenous iron or erythropoetin in the treatment of Plasma fibrinogen concentrations increase during preg- postpartum anaemia nancy to a normal third-trimester range of 4.5–5.8 g l1. Recommendations 775 Fibrinogen concentrations decrease with increasing We recommend that moderate (<9.5 g dl1) to severe 1 blood loss and may serve as a marker of haemostatic (<8.5 g dl ) postpartum anaemia be treated with intra- impairment.87,776,777 Plasma fibrinogen concentration venous iron rather than oral therapy. 1B below 2 g l1 is associated with the development of severe 1 Intravenous iron supplementation improves fatigue at 4, 8 PPH, comprising a decrease in haemoglobin by 4gdl , and 12 weeks postpartum. B transfusion of 4 U RBCs, requirement for haemostatic intervention (angiographic embolisation, surgical arterial Insufficient evidence exists to support the transfusion- ligation or hysterectomy) and death.414 Evaluation of sparing effect of intravenous iron supplementation. fibrinogen concentration at the onset of labour is of less 778 We suggest that treatment with erythropoietin may cor- predictive value. rect anaemia more rapidly than treatment with folic acid and iron. 2C Platelet count Recommendation Alternatives to RBC transfusion for maintaining haemo- Platelet count <100 x 109 l 1 at the onset of labour, globin concentrations are required. Patients with mod- 1 1 particularly combined with plasma fibrinogen concen- erate (Hb < 9.5 g dl ) to severe (Hb < 8.5 g dl ) tration <2.9 g l 1, may indicate an increased risk of anaemia may benefit from intravenous iron PPH. C therapy,757–763 which elicits more rapid recovery from shorter treatment compared with oral therapy.758–763 Platelet count <100 109 l1 at the onset of labour is Intravenous iron may also improve fatigue score, but associated with increased risk of PPH and is exacerbated not overall quality life assessment, up to 12 weeks post- by plasma fibrinogen concentration <2.9 g l1.778 Platelet partum.763 No evidence was identified comparing differ- count during the ninth month of pregnancy does not ent intravenous iron therapies, and the safety of iron correlate with platelet count at the onset of labour.778 carboxymaltose requires further investigation.764 In A single platelet count does not predict development of addition, the transfusion-sparing potential of intravenous severe PPH. However, severe PPH typically involves a iron remains unclear.209 time-dependent decrease in platelet count, whereas non- Co-administration of erythropoietin and iron has been severe PPH usually involves a stabilisation of platelet advocated for treating postpartum anaemia.765,766 Treat- count during the first 24 h of bleeding.414 Low platelet ment should begin within 96 h and appears to be safe.767 count is associated with increased RBC and FFP transfu- Increased haemoglobin concentration has been reported sion.87 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 318 Kozek-Langenecker et al.

Activated partial thromboplastin time and prothrombin time by FFP and platelet transfusions in 20% and 16% of Recommendation cases, respectively. 736 Transfusion of FFP, platelets and aPTT and PT are of little predictive value for PPH. C cryoprecipitate may be a marker for bleeding severity and 731 414 volume of RBCs required. An algorithm for managing aPTT and PT are poor predictors of severe PPH. 785 aPTT, but not PT, shows a small but significant corre- obstetric haemorrhage suggests transfusion with FFP lation with estimated blood loss in PPH, while increased if INR is >1.5, with platelets if the platelet count is <25 000 ml1, and with cryoprecipitate if fibrinogen PT and aPTT are associated with greater RBC and FFP 1 transfusion requirements.87 concentration is <100 mg dl . For uncontrolled, life- threatening haemorrhage, a multitransfusion protocol is recommended: 6 U RBCs, 4 U FFP and 1 U platelets.785 Thrombelastography or thromboelastometry Others advocate ROTEM-based assessment770 or Recommendation damage control resuscitation (RBC:FFP:platelet ratio Thromboelastometry can identify obstetric coagulopathy of 1:1:1) for management of placenta accreta requiring and hyperfibrinolysis and guide haemostatic therapy.C multiple transfusions.786 FIBTEM, a bedside thromboelastometric fibrin clot Rapid haemostatic surgery avoiding hypothermia and quality test, provides results in 5–15 min and can indicate using intravenous saline may enhance survival in a a reduced contribution of fibrinogen to clot strength.779 low-resource setting, based on data showing that 88% FIBTEM maximum clot firmness is significantly of Jehovah’s Witnesses survived haemorrhagic shock decreased during PPH. following uterine rupture.787 Thromboelastometric measurements can identify the hypercoagulability seen in normal pregnancy775 and also 780,781 What are the indications for fibrinogen substitution with in caesarean section, pre-eclampsia and HELLP fibrinogen concentrate or cryoprecipitate? 782 syndrome. They can potentially allow rapid recog- Recommendation nition of hyperfibrinolysis and guide therapy with Considering physiologically elevated fibrinogen concen- tranexamic acid, fibrinogen concentrate, PCC, FFP 770 trations in pregnancy, we suggest that a higher trigger and platelets. value for treating hypofibrinogenaemia may be required. C

Hyperfibrinolysis Fibrinogen concentrations are typically elevated 1 775 Overall fibrinolytic capacity decreases during preg- (approximately 5 g l ) in pregnancy , so the potential nancy,783,784 although there is little evidence of hyper- for FFP (which has an average fibrinogen concentration 1 581 fibrinolysis in severe PPH versus non-severe PPH.414 of 2.5 g l ) to supplement fibrinogen concentration is Hyperfibrinolysis is associated with obstetric coagulo- limited. Fibrinogen concentrate represents an alternative pathic complications including shock, DIC and amniotic therapy, and empirical use in bleeding patients (8–33% fluid embolism.770 obstetric) has indicated potential reductions in blood loss and transfusion requirements.426,583,584 Trigger levels for fibrinogen substitution vary between 1 and 2 g l1,witha 8.2.2.3 Haemostatic treatment of obstetric 426,583,584,726,788 haemorrhage mean administered dose of 2–4 g. Studies During normal pregnancy, maternal haematological investigating cryoprecipitate in obstetric patients were adaptation includes anaemia, neutrophilia, mild throm- not identified. bocytopaenia, increased levels of procoagulant factors No serious adverse events were reported with fibrinogen 722 and diminished fibrinolysis. Here, we assess the concentrate in the obstetric setting, although one study specific perioperative transfusion requirements of obste- associated haemostatic treatment (including fibrinogen tric patients due to pregnancy related haematological substitution) with an increased risk of venous thrombo- changes. sis.726

What are the indications for transfusion with fresh frozen What are the indications for the use of antiﬁbrinolytic plasma and platelets? therapies (tranexamic acid) in obstetrics? Recommendation Recommendations In life-threatening PPH, we suggest a transfusion proto- We recommend the administration of tranexamic acid in col with a ﬁxed product ratio or individualised procoagu- obstetric bleeding to reduce blood loss, bleeding lant intervention and factor substitution. 2C duration and the number of units transfused. 1B A single centre US study reported that 0.87% of US We suggest that tranexamic acid be considered before deliveries involve transfusion with haemostatic blood caesarean section.2C products.727 Approximately 1.25 in 1000 deliveries are complicated by major obstetric haemorrhage (require- In antepartum bleeding, we suggest administration of ment of >5 U RBCs).731 RBC transfusion is accompanied tranexamic acid.2B Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 319

To balance the procoagulant effects which occur natu- of rFVIIa may not decrease transfusion requirements, rally during delivery, fibrinolysis is also increased.783 although this may reflect its frequent use in complex However, abnormal fibrinolysis is associated with com- coagulopathic bleeding.828 Plasma fibrinogen concen- plications including placental abruption with antepartum tration and platelet count should be optimised before bleeding,722,789 intrauterine death771 and amniotic fluid administration of rFVIIa.829 embolism.722,741,790 Administration of rFVIIa was potentially linked to three Antifibrinolytic therapy, used prophylactically for vaginal thromboembolic events in a study including 110 other- or caesarean delivery, or when postpartum bleeding wise healthy obstetric patients,466 and its use in PPH evolves,791 may prevent such complications. Several has been associated with lower limb ischaemia and pul- studies suggest that tranexamic acid administered monary embolism, albeit with favourable clinical out- 10–20 min before caesarean section may reduce peri- comes.830 Although rFVIIa potentially carries a operative blood loss.546,791–794 Tranexamic acid may thromboembolic risk, no difference in mortality has been reduce antepartum bleeding in placental abruption and identified in other patient categories.717 placenta praevia, and appears safe during pregnancy and postpartum.791 8.3 Orthopaedic surgery and neurosurgery 8.3.1 Bleeding risk of different orthopaedic and In a recent study, tranexamic acid reduced blood loss and neurosurgical procedures 42-day transfusion requirements in PPH.19 No severe side-effects (e.g. thromboembolic complications) were Recommendation In elective orthopaedic surgery, we recommend the observed, although the study was not powered to assess implementation of a blood transfusion protocol (algor- safety. Mild transient adverse manifestations such as ithm), together with staff education. nausea, vomiting, dizziness and ‘seeing stars’ occurred 1B more frequently in the tranexamic acid group than in the There is a lack of standardised definitions for the report- control group, possibly due to the relatively high dose ing of bleeding events.536,831 Therefore, the incidence used in this trial (4 g). of bleeding and severe bleeding differs remarkably between studies. Orthopaedic surgery is often associated What are the indications for other coagulation factor with clinically relevant bleeding and the need for allo- concentrates (prothrombin complex concentrate and factor geneic blood transfusion.480,534,832–839 The implementa- XIII)? tion of a blood transfusion protocol (algorithm) together In a case of amniotic fluid embolism following vaginal with staff education, based on early preoperative detec- delivery, stable clotting was achieved by thromboelasto- tion and treatment of anaemia, perioperative blood metry-guided coagulation therapy comprising tranexamic salvage and retransfusion, and a restrictive transfusion acid, fibrinogen concentrate, platelets and PCC, as well as trigger, has been shown to reduce allogeneic blood trans- RBC and FFP in a 1:1 ratio.770 No further reports were fusion and the need for preoperative autologous blood retrieved describing PCC or FXIII therapy in obstetric donation. 191,243,565,832–836,838–849 patients with non-inherited coagulation deficiency. Severe bleeding with the need for allogeneic blood transfusion is relatively uncommon in neurosurgery What are the indications for the use of recombinant factor (affecting 6.7% of patients undergoing neurosurgery in VIIa? 2010 at University Hospital Essen, Germany; unpub- Recommendations lished observations). However, haematoma growth has We recommend that rFVIIa should only be considered a major impact on neurological outcomes and mortality in as last-line therapy because of its thromboembolic risk. patients with intracerebral haemorrhage (ICH).850,851 1B Therefore, ICH has to be treated early. We suggest that fibrinogen concentration and number of Recommendation platelets should be optimised before administration of Allogeneic blood transfusion is associated with an rFVIIa. 2C increased incidence of nosocomial infections. B rFVIIa can be considered as second-line haemostatic Allogeneic blood transfusion is associated with an therapy alongside intrauterine tamponade, uterine com- increased incidence of nosocomial infections such as pression sutures, pelvic vessel ligation and interventional wound infection and pneumonia,4,399,852–856 increased radiology.795 Case reports796–821 and retrospective length of hospital stay, and increased hospital studies795,822–824 support off-label use of rFVIIa for costs.837,852,856,857 severe obstetric coagulopathic bleeding. Subjective evaluation has shown rFVIIa administration to arrest Recommendation bleeding in 75–97% of cases.466,824–827 rFVIIa may also Infusion of colloids in patients with severe bleeding can prevent postpartum hysterectomy,827 although other aggravate dilutional coagulopathy by additional effects on studies do not support this finding.810,828 Administration fibrin polymerisation and platelet aggregation. C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 320 Kozek-Langenecker et al.

Coagulopathy in patients undergoing orthopaedic surgery reduce the rate of death from vascular causes, myocardial is usually caused by pre-existing coagulation disorders, infarction or stroke, without increasing major bleeding.887 medication with oral anticoagulants or antiplatelet drugs, In another study, there was no significant difference or dilutional coagulopathy due to severe blood loss and between ticagrelor and clopidogrel in the risk of stroke; volume resuscitation with crystalloids and colloids. however, intracranial bleeding was more common with Colloids, and especially high molecular weight hydro- ticagrelor.888 xyethyl starch (HES) solutions, have dose-dependent In summary, monotherapy with aspirin or clopidogrel effects on fibrin polymerisation and platelet aggregation, seems not to be associated with a significantly increased aggravating coagulopathy.30,411,858–864 risk of ICH or haematoma growth, but dual antiplatelet therapy, therapy with prasugrel, or a combination with 8.3.2 Bleeding risk due to pre-existing coagulation other risk factors such as fibrinolytic therapy or VWD disorders and medications increase the risk of ICH and subsequent haematoma Recommendations 882,883,889 growth. Therefore, dual antiplatelet therapy We recommend that, for orthopaedic surgery, monother- should be discontinued before urgent intracranial neuro- apy with aspirin does not need to be discontinued. 1B surgery.876,890 There is need for a risk-benefit analysis of We recommend discontinuing dual antiplatelet therapy the continuation of aspirin monotherapy during neuro- before urgent intracranial neurosurgery. A risk-benefit surgery. analysis is required for the continuation of aspirin mono- Recommendation therapy during neurosurgery. 1B We recommend against performing orthopaedic surgery COX-2 selective NSAIDs do not increase perioperative during the first three months after bare metal stent blood loss in patients undergoing total knee arthro- implantation or during the first twelve months after plasty.835,865–867 Therefore, it is not necessary to discon- drug-eluting stent implantation. 1C tinue these drugs before surgery. In contrast, ibuprofen, Following bare metal stent implantation or drug-eluting diclofenac and indomethacin significantly increase peri- stent implantation, elective orthopaedic surgery should operative blood loss in total hip arthroplasty.835,866–868 not be performed during the first three months or twelve Therefore, discontinuation of non-selective NSAIDs months respectively, because surgery results in a pro- is advised. haemostatic condition and increases the risk of stent Pretreatment with daily low-dose aspirin was associated thrombosis. with a small increase in postoperative transfusion but no major bleeding in patients undergoing proximal femoral 8.3.3 Screening tests to predict bleeding in fracture surgery.869–872 Neither aspirin nor clopidogrel orthopaedics and neurosurgery monotherapy needs to be discontinued before urgent Recommendation orthopaedic surgery, and surgery should not be delayed Preoperative medication with ADP receptor antagonists in patients receiving such treatment.872–879 or with new oral anticoagulants is associated with an increased risk of major bleeding and ICH, especially if Recent studies examining the effect of prior antiplatelet used in combination. B therapy on outcome in patients with spontaneous ICH have shown conflicting results.880 A large, prospective Preoperative administration of ADP receptor antagonists trial demonstrated that antiplatelet medication at ICH such as clopidogrel, prasugrel and ticagrelor, or new onset was not associated with increased haemorrhage oral anticoagulants such as dabigatran, rivaroxaban and volumes, haemorrhage growth, or clinical outcome at apixaban is associated with an increased risk of major 90 days.881 However, the combination of aspirin and bleeding and ICH, especially if used in combina- clopidogrel compared to clopidogrel alone after recent tion.882,886,888,891–894 Of note, these drugs cannot be ischaemic stroke or transient ischaemic attack has been monitored with conventional coagulation screening tests associated with an increased risk of bleeding events.882 such as aPTT, PT and platelet count.895–899 Antiplatelet therapy, and especially dual antiplatelet Recommendation therapy, has also been associated with an increased risk Reduced platelet activity is associated with early haema- of ICH after fibrinolytic therapy in patients with ischae- toma growth, more intraventricular haemorrhage and mic stroke.883 A third study suggested that antiplatelet worse 3-month outcome following ICH. C medication may potentially increase ICH volume.884 A meta-analysis and systematic literature review reported Conflicting evidence exists as to whether the direct that antiplatelet therapy at the time of ICH increased thrombin inhibitor dabigatran enlarges haematoma mortality but had no effect on functional outcome.885 volume in experimental ICH.900,901 However, a recent Prasugrel is associated with an increased risk of major/ case report has reported the development of an epidural fatal bleeding, compared to clopidogrel.886 Compared to haematoma and severe intraoperative haemorrhage in a clopidogrel, ticagrelor has been shown to significantly spine trauma patient on dabigatran.902 Furthermore, Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 321

neuraxial blockade is contraindicated in patients on prospective observational study in patients undergoing dabigatran, even 34 h after withdrawal of the drug.903 intracranial surgery, a postoperative platelet count below 150 000 ml1 was associated with a 2.5-fold increase in Conflicting data also exist regarding whether or not prior relative risk of postoperative haematoma requiring revi- antiplatelet therapy has an impact on haemorrhage sion surgery, and in combination with FXIII activity growth or outcome after ICH and traumatic brain <60%, the relative risk for haematoma increased to injury.880,881,884,901,904,905 A recently published meta- 9.7.410 In the same study, preoperative FXIII activity analysis including a 25 cohort multivariate analysis <80% was associated with a 3.9-fold increase in relative showed that antiplatelet therapy at the time of ICH, risk of postoperative haematoma requiring revision compared to no antiplatelet therapy, was independently surgery, which increased to 6.4-fold for postoperative associated with increased mortality but not with poor 410 885 FXIII activity <60%. The third risk factor was fibrino- functional outcome. Furthermore, cerebral micro- gen concentration of <3.0 g l 1 preoperatively or bleeds are a potential risk factor for ICH in patients <1.5 g l 1 postoperatively, with a 2.9- and 2.5-fold treated with antiplatelet drugs or warfarin.906–908 increased relative risk of postoperative haematoma The efficacy of platelet transfusion in patients on anti- respectively. The highest relative risk of postoperative platelet therapy suffering from ICH or traumatic brain haematoma (12.2-fold) was achieved with the combi- injury is also currently under discussion.880,909–911 Con- nation of a postoperative FXIII activity <60% and flicting data exist concerning the impact of antiplatelet fibrinogen concentration <1.5 g l1. A postoperative pro- drugs on ICH growth on one hand, and the efficacy of longation of PT (<60% activity compared to normal; platelet transfusion to stop bleeding on the other, and can relative risk, 6.2) or aPTT (>35 s; relative risk, 4.8) in part be explained by the variable response to anti- had less impact on the relative risk for postoperative platelet drugs. Several authors reported a close corre- haematoma, even in combination with low FXIII activity lation between platelet function testing using ADP as (<60%).410 an activator in whole blood impedance aggregometry FXIII activity cannot be measured by conventional (Multiplate) or whole blood turbidimetric aggregometry coagulation screening tests. Of note, in a study determin- (VerifyNow) and bleeding complications, transfusion ing the effect of colloid infusion (HES 200/0.5 or modi- requirements for platelet concentrates and outcome after fied gelatin 4%) on haemostasis in patients undergoing ICH.912–916 In addition, reduced platelet activity has knee replacement surgery, the activity of FXIII been associated with early haematoma growth, more decreased from 89.0 to 58.5%.860 Acute diffuse post- intraventricular haemorrhage and worse 3-month out- operative bleeding due to acquired FXIII deficiency come after ICH.917,918 Therefore, point-of-care testing has also been reported after free flap operations in plastic of platelet function may be helpful to detect platelet surgery.930 Furthermore, there are several case reports dysfunction in patients with ICH or prior to neuraxial dealing with spontaneous subdural haematomas or recur- surgery or blockade, and to guide corresponding rent spontaneous ICH in children and young adults therapy.914,919–922 Also, thrombin time and ecarin clotting related to FXIII deficiency.931–933 Prophylactic therapy time may be helpful to identify emergency patients with a FXIII concentrate in young patients with con- treated with oral direct thrombin inhibitors such as dabi- genital FXIII deficiency was associated with a marked gatran.896,898,923 decrease of bleeding episodes.934–936 Furthermore, some FXIII polymorphisms are associated with an increased Recommendation risk of aneurysmal subarachnoid haemorrhage.937,938 In Low platelet count, low plasma fibrinogen concen- summary, FXIII seems to play an important role in tration and FXIII deficiency are predictive of bleeding postoperative bleeding complications in neurosurgery. complications in ICH, intracranial surgery and major spine surgery, particularly when they occur in combi- Recommendation nation. C Preoperative measurement of plasma fibrinogen concen- In a multivariate analysis of predictors of haematoma tration provides more information on bleeding volume enlargement in spontaneous ICH, a low concentration and transfusion requirements than standard screening of fibrinogen (2.41 0.08 g l 1 vs. 2.86 0.04 g l 1 in tests. C patients with and without haematoma growth, respect- Preoperative plasma fibrinogen concentration has been ively) was the only haematological parameter shown to be shown to be strongly associated with increased periopera- an independent predictor of haematoma growth, with an tive bleeding and transfusion requirements (>2 U RBC) odds ratio of 0.74 for one standard deviation change 939 in scoliosis surgery. In this prospective observational (0.09 g l 1; P ¼ 0.042).924 study, total blood loss correlated significantly with pre- Most guidelines recommend a transfusion threshold of operative fibrinogen concentration but with neither 100 000 ml1 platelets in patients undergoing neuro- platelet count, aPTT nor PT. Patients with blood loss surgery, based on expert opinion.925–929 However, in a in the upper quartile had significantly lower preoperative Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 322 Kozek-Langenecker et al.

plasma fibrinogen concentrations (2.6 0.6 vs. 3.1 2.3 times for each increase of INR by 1.945,949 Further- 0.6 g l1; P ¼ 0.002). Patients undergoing extensive more, patients with INR >3.0 had a significantly greater transfusion (>2 U RBC) had significantly lower preopera- haematoma volume and a higher mortality.952 In sum- tive fibrinogen plasma concentrations (2.5 0.7 vs. mary, the intensity of oral anticoagulation with warfarin, 3.1 0.6 g l1; P ¼ 0.002), while preoperative platelet measured by INR, shows a close correlation to the count, aPTT, and PT did not differ. These results incidence and severity of bleeding complications, in indicate that preoperative fibrinogen concentration is a particular to ICH. limiting factor for postoperative haemostasis during and after scoliosis surgery. Preoperative measurement of fibri- 8.3.4 Antifibrinolytics nogen concentration provides more information on blood Recommendations loss and transfusion requirement than standard screening We suggest administering tranexamic acid in total hip tests.939 arthroplasty, total knee arthroplasty, and major spine surgery. 2A Recommendation Tranexamic acid may promote a hypercoagulable state for We suggest the use of viscoelastic tests (ROTEM/TEG) some patients (with pre-existing thromboembolic events, for monitoring perioperative haemostasis in major ortho- hip fracture surgery, cancer surgery, age over 60 years, paedic surgery and neurosurgery. 2C women). Therefore, we suggest an individual risk-benefit Hypocoagulability in thrombelastography (prolonged r analysis instead of its routine use in these clinical set- and k time, reduced a-angle and maximum amplitude) tings. 2A has been shown to be associated with an increased Antifibrinolytic medication has been shown to reduce incidence of bleeding complications in paediatric neuro- perioperative blood loss, allogeneic blood transfusions surgical patients, whereas standard coagulation tests and associated costs in major orthopaedic surgery such (platelet count, PT, aPTT, and plasma fibrinogen) were as total hip or knee arthroplasty.477,953–955 Although not.940 However, pre-, intra- and postoperative fibrinogen concerns exist about increased thrombotic events with concentrations were >3gl 1 in both groups in this study. the use of these agents, large meta-analyses suggest In several studies, thromboelastometry (FIBTEM test) that tranexamic acid can be employed safely and effica- has been shown to successfully diagnose fibrinogen ciously to decrease perioperative blood loss and trans- deficiency, as well as fibrin polymerisation disorders, such fusion requirements without increased risk of as those induced by colloid infusion or dysfibrinogenae- thromboembolic complications in major orthopaedic mia.30,40,123,411,427,862,864,941–943 surgery.480,534,645,953,954,956–958 Recommendation However, further studies are needed to clarify the neuro- The intensity of oral anticoagulation with warfarin, logical risk, appropriate indications and dosing of tra- measured by INR, shows a close correlation to the nexamic acid.653 In addition, the use of antifibrinolytics in incidence and severity of bleeding complications, in patients with cancer cannot be recommended, because particular with ICH. C no beneficial effect has been shown and the risk of thromboembolic complications may be increased.959,960 The incidence of ICH in patients on oral anticoagulation Tranexamic acid may also promote hypercoagulability with warfarin has been reported at 0.1%–3.7% per following pre-existing thromboembolic events and hip patient-year, and the incidence of major bleeding at fracture surgery, in patients over 60 years, and in 1.2–13.1% per patient-year. Independent risk factors women.961 for major bleeding and ICH have been identified as the indication for oral anticoagulation (e.g. atrial fibrilla- Data showing favourable efficacy and safety are best for tion or cerebral ischaemia), the patient’s age (65, 66–85 tranexamic acid,480,954,962 whereas in comparison, the or >85 years) and the intensity (INR) and duration of data for EACA are sparse.477,529,531,963–967 In several anticoagulation.944–950 Patients anticoagulated with war- RCTs, hip/knee replacement patients received tranexa- farin because of cerebral ischaemia had 19 times the risk mic acid as a single preoperative intravenous bolus dose of ICH compared to patients with atrial fibrillation.945 of 10–15 mg kg1.535,538,968–972 In some RCTs, a second The incidence of ICH was twice as high for patients dose was given 3 h later or at the time of tourniquet >65 years of age, and around two times higher again in deflation,531,973–975 while in others a continuous patients >85 years of age.945,947 An INR of 1.6–2.0 was infusion of 1 mg kg1 h1 was started after the initial associated with insufficient anticoagulation,946,948 bolus.530,976–979 Oral administration of tranexamic acid whereas an INR of 2.0–3.0 is considered as effective (1 g preoperatively and then every 6 h for 18 h postopera- and safe.946,949 However, the incidence of ICH increased tively) has also been shown to be effective in patients significantly with INR values >3.0;946–949,951 here, the with total knee replacement.980 In hip fracture surgery, incidence of ICH increased by a factor of 1.37 for each tranexamic acid (15 mg kg1 as a single or double bolus increase of INR by 0.5, and the risk for death increased dose at surgical incision and 3 h later) reduces allogeneic Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 323

blood transfusion but may promote hypercoagulabil- shown that a small dose of rFVIIa (20 mgkg1) reduced ity.532,961,981 Thus, further safety evaluation is required PT and aPTT but did not significantly reduce blood before recommending routine use of tranexamic acid in loss.989,990 Moreover, the drug failed to produce a signifi- this setting. In several RCTs performed in children and cant reduction in blood loss or transfusion volume in adults undergoing scoliosis/spine surgery, a loading dose an RCT in 49 spinal surgery patients.991 One patient of 10–30 mg kg1 tranexamic acid followed by a continu- with advanced cerebrovascular disease who received ous infusion of 1 mg kg1 h1 has been shown to be 30 mgkg1 rFVIIa died six days after surgery due to an effective and well tolerated.904,982,983 EACA has been ischaemic stroke. In addition, there was also no significant administered to scoliosis surgery patients (loading dose reduction in perioperative blood loss or transfusion of 100 mg kg1 followed by 10 mg kg1 h1 until the end of blood components in a randomised, placebo-controlled surgery).966 trial including 48 patients undergoing major pelvic-acetabular surgery.992 Therefore, there is little evidence to In neurosurgery, 1 g tranexamic acid immediately after suggest that prophylactic rFVIIa reduces perioperative the diagnosis of aneurysmal subarachnoid haemorrhage, blood loss or transfusion requirements in major ortho- followed by 1 g every 6 h until the aneurysm was paedic surgery. occluded, reduced mortality from early rebleeding by 80%.984 However, data on the efficacy and safety of In studies of non-haemophiliac, coagulopathic neuro- antifibrinolytics in intracranial surgery are sparse and surgical patients, 40–120 mgkg1 rFVIIa rapidly nor- relate mainly to aprotinin, which was withdrawn in malised PT (baseline INR > 2) and aPTT within 2007.985 20 min;993–995 this allows a shorter transit time to intervention/craniotomy.996,997 Although rFVIIa can reduce the change in ICH volume, no significant effect on 8.3.5 Recombinant activated factor VIIa mortality, modified Rankin Scale score or extended Recommendations Glasgow Outcome Scale score has been demon- We suggest the use of rFVIIa in patients with neutralising strated.555,557,998–1000 However, a significant increase in antibodies to FVIII undergoing major orthopaedic thromboembolic adverse events has been observed with surgery. 2C rFVIIa (e.g. myocardial infarction, stroke), especially in Prophylactic use of rFVIIa does not reduce perioperative elderly patients and those with pre-existing vascular blood loss or transfusion in non-haemophiliac and non- diseases.554–557,717,981,998,999,1001–1003 Furthermore, there coagulopathic patients undergoing major orthopaedic is no reliable evidence that haemostatic drugs are surgery or neurosurgery, and it may increase the inci- effective in reducing mortality or disability in patients dence of thromboembolic events. Therefore, we recom- with traumatic brain injury.981,1004–1007 Therefore, the mend against the prophylactic use of rFVIIa in these use of rFVIIa in paediatric patients with brain tumours clinical settings. 1B should be restricted to patients with life-threatening bleeding who are unresponsive to conventional treat- We recommend restricting off-label use of rFVIIa to ment.1008,1009 patients with severe bleeding who are unresponsive to other haemostatic interventions. 1C 8.3.6 Prothrombin complex concentrate and new oral Continuous infusion of rFVIIa (initial preoperative bolus anticoagulants of 90 mgkg 1 followed by a continuous infusion of Recommendations 50 mgkg1 h1 for a median of 20 days) was effective In patients with INR > 1.5, with life-threatening bleeding and well tolerated in a prospective study of patients with or ICH, we recommend that four-factor PCCs (20– neutralising antibodies to FVIII undergoing elective 40 IU kg1), supplemented with vitamin K (10 mg by major orthopaedic surgery. Postoperative bleeding was slow intravenous infusion), should be used for rapid controlled by an additional single bolus of 60 mgkg 1 reversal of VKAs. 1C rFVIIa.986 A recently published consensus protocol for In patients with neutralising antibodies to FVIII under- the use of rFVIIa in elective orthopaedic surgery in going major orthopaedic surgery, we suggest using acti- haemophiliac patients with inhibitors recommended vated PCCs (e.g. FEIBA, FVIII inhibitor bypassing an initial bolus dose of rFVIIa in the range of 120– agents). 2C 180 mgkg 1 to cover surgery and concomitant use of antifibrinolytic agents and fibrin sealants.987 Conversely, New oral anticoagulants, such as rivaroxaban and dabi- there is a lack of evidence to suggest that rFVIIa might be gatran, may increase surgical bleeding and ICH growth. effective and well tolerated in severe intractable bleeding We suggest that PCC, FEIBA or rFVIIa may be used as during spinal surgery. non-specific antagonists in life-threatening bleeding or ICH. 2C rFVIIa reduced intraoperative transfusion requirement for RBCs in 26 adolescent patients with scoliosis, who For life-threatening bleeding or ICH among oral anti- received rFVIIa perioperatively.988 Other studies have coagulation patients receiving VKAs, for INR > 1.5, Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 324 Kozek-Langenecker et al.

guidelines recommend PCCs or rFVIIa for immediate of thromboembolic events.449,587,588,590,591,596,633,1023,1024, reversal of INR, with co-administration of vitamin K 1040,1042,1053,1054 In a recent meta-analysis, only 12 patients (10 mg by slow intravenous infusion).45,562,592,598, (1.4%) treated with PCCs for VKA reversal had a throm- 1010–1015 Despite consistency between recommen- boembolic event, of which two were fatal.1055 The inci- dations, adherence to them is poor in several countries dence of thromboembolic events was 1.8% in patients where FFP is used instead of PCC.593,595,1016–1020 treated with 4-factor PCCs and 0.7% in patients treated These data indicate a requirement for education in this with 3-factor PCCs, and these data are consistent with field,1019 potentially including information on the three other reviews and pharmacovigilance data.1022,1056 The different types of PCC available with different com- occurrence of thromboembolic events is not surprising positions and different indications.594,595,1021,1022 Four- because VKAs are prescribed to patients with a high risk factor PCCs are most effective for rapid reversal of of thrombotic events.596,1022,1054,1055,1057 Excessive VKA-induced anticoagulation because they replace all substitution with PCCs should be avoided, and accurate four vitamin K-dependent coagulation factors (II, VII, monitoring of coagulation status may allow thrombotic IX, and X), and some of them also contain inhibitors risk to be reduced.1022,1058,1059 Four patients (1.9%) such as protein C, S, and Z.941,1021 Three-factor PCCs treated with a solvent/detergent-treated and nano- are used to treat haemophilia B (in the US) and are used filtrated four-factor PCC have shown seroconversion for warfarin reversal where four-factor PCCs are not for parvovirus B19.588,590,1055 No other cases of viral available (e.g. in Australia).592,1010,1011,1018,1023–1027 transmission or infectious complications after adminis- Three-factor PCCs contain little FVII and are less tration of PCCs have been published during the last effective in correcting INR.592,1028–1030 Activated 15 years.1043,1055–1057 1 PCCs such as FEIBA (Baxter Healthcare Corp, In contrast to rFVIIa (100 mgkg 1), 4-factor PCCs USA; FVIII inhibitor bypassing agent) are indicated (20–40 mgkg 1) not only correct PT, INR and lag time in patients with haemophilia and antibodies (inhibitors) in endogenous thrombin potential, but they also normal- against FVIII or FIX.1031–1033 At a median initial dose ise thrombin generation and activity of coagulation fac- of 100 U kg 1, FEIBA has been shown to be effective, tors II, VII, IX and X, while additionally shortening well tolerated (low incidence of thromboembolic bleeding time and reducing blood loss.454,1060–1062 A events) and cost-effective in patients with FVIII/FIX higher dose of PCC (50 mgkg 1) may induce hyper- inhibitors undergoing major orthopaedic and other coagulable thrombin generation, potentially increasing surgery.1031,1032,1034–1038 However, activated PCCs are the risk of thromboembolic events.1059,1061 This under- not used for rapid reversal of VKA-induced anti- lines the need to avoid excessive substitution with PCCs, coagulation. and may be particularly important in bleeding patients Compared with FFP, which takes 14–50 h to correct with coagulation factor deficiency due to liver dys- INR, four-factor PCCs provide quicker and more con- function.120,420,457,458,1063–1068 Based on point-of-care trolled correction of INR (a target INR of 1.2–1.4 can be thromboelastometric results, four-factor PCCs have achieved within 3–30 min) and improved bleeding been used in combination with fibrinogen concentrate control.402,449,586–588,590,591,594,595,906,1014,1015,1017,1021,1030, in several cohort studies in trauma, neurosurgery, 1039–1045 Recommended doses for emergency VKA cardiac surgery, visceral surgery and liver transplan- reversal in the presence of ICH are 20–40 IU kg1 tation.118,120,125,398,576,1058 These studies show significant PCC (0.8–1.6 ml kg1; fixed or calculated from body reductions in transfusion requirements, transfusion- weight, baseline and target INR), 15–120 mgkg1 rFVIIa associated adverse events, and thromboembolic events or 15–30 ml kg1 FFP.403,591,1012,1014 Transfusion-associ- with PCC; however, prospective RCTs are needed ated circulatory overload and subsequent acute lung for confirmation. injury complications, which occur in 1–8% of hip/knee The recent approval of new oral anticoagulants, such as arthroplasty patients receiving FFP, can be avoided by rivaroxaban and dabigatran, is changing the therapeutic using PCC.141,400,401,906,1045–1049 The incidence and landscape.1057,1069–1072 These drugs may hamper extent of haematoma growth are significantly lower in haemostatic management because they cannot be mon- patients receiving PCCs compared with FFP and itored by simple conventional laboratory assays, their vitamin K,850 which is attributable to more rapid reversal pharmacokinetics vary significantly between patients of INR. Haematoma growth is associated with poor (in particular dependent on age and renal function), they neurological outcome, and aggressive management of may increase surgical bleeding and ICH growth, and they VKA-associated ICH with rapid INR correction appears have no validated antagonists.893,1073–1080 In some animal to translate into improved outcomes following ICH;1050 models, rFVIIa, FEIBA and PCC partially improved however, this is yet to be proved by well-designed laboratory parameters in animals treated with fondapar- RCTs.1051,1052 inux, rivaroxaban or dabigatran, but it is unclear whether For rapid reversal of VKAs, studies have shown that PCCs these drugs would be effective in treating bleeding have a favourable safety profile, with a low incidence patients.898,900,1081–1084 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 325

8.4 Visceral and transplant surgery OLT can be performed without FFP transfusion;1096 this 8.4.1 Should coagulopathy associated with chronic may be advantageous in avoiding volume overload.1097 liver disease be corrected before invasive PT and INR do not reflect bleeding risk in CLD, as the procedures? 1098 Haemostatic changes coinciding with liver disease were concurrent anticoagulant reduction is not assessed. traditionally thought to confer bleeding diathesis. Recent Thrombin generation is similar in healthy and cirrhotic individuals, and there is no definite association between data challenge this theory, leading to a concept of 1099 ‘re-balanced haemostasis’ in patients with chronic liver INR and bleeding risk among liver disease patients. disease (CLD).1085,1086 In addition, INR values may vary between laboratories, so defining cut-off values is problematic.1100

8.4.1.1 What is the evidence that haemostasis is 8.4.1.3 Should FFP be used to correct prolonged INR ‘re-balanced’ in CLD? before invasive procedures? Recommendation Recommendation Despite PT, aPTT and INR indicating coagulopathy in We recommend against the use of FFP for preprocedural CLD, global coagulation tests (thrombin generation and correction of mild-to-moderately elevated INR. 1C TEG/ROTEM) suggest that haemostasis is balanced in stable CLD. C Implementation of practice guidelines is recommended to prevent inappropriate transfusion.1101 Evidence In CLD, procoagulant concentrations are typically suggests that FFP should not be administered to non- decreased (except FVIII, which is elevated). However, bleeding patients when INR is 2. Although PT and most endogenous anticoagulants (antithrombin, proteins 1087 INR are often used to guide FFP transfusion, no corre- C and S) are also depleted, maintaining haemostatic lation has been established between degree of coagulo- balance. Thrombin generation in stable liver disease is pathy and transfusion outcome,16 nor has optimal FFP similar, or elevated, compared with healthy individ- dosing been determined. uals.1087,1088 No randomised studies with clinical endpoints have CLD patients often exhibit thrombocytopaenia and investigated the effectiveness of FFP transfusion in platelet adhesion/aggregation abnormalities. These CLD. Current evidence suggests no benefit in correcting changes may be counterbalanced by increased VWF mild-to-moderate INR elevations before invasive pro- levels and reduced VWF-cleaving activity of ADAMTS cedures in CLD patients. 13.1089 Platelet hyperactivity has been reported in chole- 1090,1091 static liver disease. 8.4.1.4 What level of thrombocytopaenia should be Elevated fibrinolysis and clot instability are balanced by tolerated in CLD? increased plasminogen activator inhibitor (PAI-1) levels. Recommendation 1 PAI-1 levels are high in acute liver failure and cholestatic We suggest a platelet count of 50 000 ml as a liver disease; clinically significant fibrinolysis is rare in threshold for platelet transfusion before liver biopsy. 2C 1092,1093 both conditions. The evidence supporting platelet count cutoff values is ‘Re-balanced’ haemostasis in CLD is reflected in the limited. Moreover, platelet count does not represent 1099 increasing number of CLD patients undergoing major platelet function. Current consensus, with supporting 1102 abdominal surgery without requiring transfusion.1094 evidence, suggests that a preoperative platelet count 1 However, as venous thromboembolic events are common >50 000 ml may be acceptable. Severe thrombocyto- 1 in cirrhotic patients, they cannot be considered ‘auto- paenia (50 000 platelets ml ) occurs in 1% of 1103 anticoagulated’.1095 patients. Due to an assumed increased bleeding risk, this value is a common trigger for prophylactic preoperative platelet transfusion. 8.4.1.2 What is the evidence that INR reflects bleeding risk in patients with chronic liver disease? A platelet count 50 000 ml1 may trigger platelet trans- Recommendation fusion in cirrhotic patients during active bleeding929 and Mild to moderate prolongation of the preoperative is recommended as a threshold for platelet transfusion PT and INR do not predict bleeding in patients with before liver biopsy, despite limited supporting evi- CLD.C dence.1099 PT, aPTT and INR are widely used to assess CLD Thrombocytopaenia (<150 000 platelets ml1) occurs in patients preoperatively, although evidence that these 75% of liver disease patients,1104 limiting thrombin parameters predict bleeding risk is poor.91 Massicotte generation and potentially increasing bleeding risk.1102 et al.1094 reported that INR does not predict OLT trans- Among liver disease patients undergoing invasive pro- fusion requirements and that preoperative INR correc- cedures, bleeding occurred in 31% of cases with severe tion is unnecessary. Observational studies suggest that thrombocytopaenia, and none of those with moderate Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 326 Kozek-Langenecker et al.

thrombocytopaenia.1104 However, among patients with Coagulopathy is almost always treated in ALF patients severe thrombocytopaenia, the prevalence of significant before invasive procedures;1114 however, such practice is coagulopathy did not differ between those who bled and not supported by data and there are no evidence-based those who did not. guidelines recommending an appropriate target INR. Historical consensus suggests a target INR <1.5,1115 1112 8.4.1.5 Platelet function in cirrhosis although available data challenge this. Transfusion- Recommendations free OLT has been described in patients with ALF, with PFA-100 is not predictive of bleeding risk in cirrhosis. C INR up to 8, and INR does not predict intraoperative blood loss. Bleeding time is influenced by many variables and is not useful to stratify bleeding risk. C PT and INR can be corrected using rFVIIa, which has been used before intracranial pressure monitor insertion. Primary haemostasis may function effectively in cirrhosis, However, the evidence for rFVIIa efficacy in reducing and low platelet count alone might not increase bleeding bleeding complications is limited.1116,1117 Optimal dosing 1089 risk. Primary haemostasis in cirrhosis has been remains uncertain, as does the thrombogenic potential of 1105 assessed using bleeding time, where bleeding time rFVIIa.1118 Before invasive procedures, fibrinogen con- increased progressively from Child-Pugh class A to class centrations <1gl1 should be corrected with cryopreci- C. However, the validity of prolonged bleeding time as a pitate or fibrinogen concentrate. Platelet count risk factor for bleeding in cirrhosis remains uncer- 50 000 ml1 is acceptable1115,1119 and there are no clear 1106,1107 tain. Assessment of bleeding risk using the plate- guidelines concerning clotting factors. With the excep- 1108 let count has been recommended instead. tion of intracranial pressure monitor insertion, INR Chronic inflammation coupled with increased vWF con- should not be corrected preoperatively. centrations may enhance platelet activity in cirrhosis, INR correction with FFP introduces volume overload potentially explaining normal bleeding time measure- and haemodilution. Correction of coagulation factor con- ments in patients with low platelet counts. Alternatively, centrations above 30% requires up to 30 ml kg1 FFP.403 altered vasoreactivity and/or arterial dysfunction, both well Plasma exchange plasmapheresis with FFP may correct documented in cirrhosis, may explain prolonged bleeding INR and improve haemostasis.1120 PCC with vitamin K time. PFA-100 closure time is prolonged in cirrhosis, can rapidly correct markedly elevated PT/INR before 1109 although the prognostic value of this is unknown. urgent invasive procedures.1065 Further, prospective Anaemia may potentially increase bleeding tendency by RCTs are required in this area. impairing platelet function; its impact warrants further investigation.1110 8.4.3 Orthotopic liver transplantation Median transfusion during orthotopic liver transplantation (OLT) has decreased from 20 to 2 U since the 8.4.2 Acute liver failure and invasive procedures 1980 s. The procedure is now often performed without Recommendation transfusion, although massive transfusion is still required We recommend that, in acute liver failure, moderately occasionally. Coagulopathic bleeding may be related to elevated INR should not be corrected before invasive dilutional coagulopathy or hyperfibrinolysis. procedures, with the exception of intracranial pressure monitor insertion. 1C The aetiology of liver failure is an independent parameter for predicting massive blood loss.1121 Fewer Acute liver failure (ALF) is defined by encephalopathy bleeding complications are observed in cholestatic liver and coagulopathy (INR > 1.5) within 26 weeks of onset of disease compared with viral or toxic liver disease.1092 acute liver disease. Severity of coagulopathy is a useful Preoperative PT/INR does not predict the need for prognostic marker for monitoring hepatic function. A transfusion,1122 whereas preoperative haemoglobin con- review of >1000 patients with ALF reported a mean centration does.1123 INR of 3.8.1111 Patients are therefore assumed to have a bleeding diathesis, although clinically significant bleed- Practice varies between centres with regard to transfu- ing is rare (around 5%) and TEG results are typically sion thresholds and coagulation monitoring.1124,1125 The normal.1093,1112 Haemostatic alterations in ALF differ number of RBC units transfused intraoperatively shares from those in CLD. Thrombocytopaenia is less common an inverse relationship with patient survival,1126 and in ALF, pro- and anticoagulant depletion is more severe guidelines are intended to limit unnecessary transfu- and fibrinolysis is inhibited due to high PAI-1 concen- sion.1127 trations.1113 TEG clot strength is most influenced by platelet count, followed by fibrinogen concentration, 8.4.3.1 Methods to reduce blood loss in liver then procoagulant factor levels.1112 Prophylactic FFP transplantation transfusion to correct INR is not justified in ALF and Both RBC and platelet transfusion independently predict compromises INR as an indicator of liver function. poor outcome in OLT.517 Approaches to minimising Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 327

transfusion include normothermia, because hypothermia 8.4.4 Coagulation monitoring reduces platelet function and impairs coagulation Differences between centres in coagulation monitoring enzyme activity. Even mild hypothermia (<35.58C) contribute to variations in OLT transfusion practice.115 increases blood loss by 16% and the relative risk of Laboratory-based coagulation tests are unsuitable transfusion by 22%.486 because of slow turnaround times and inability to diagnose hyperfibrinolysis.1135 8.4.3.2 Intraoperative fluid management Recommendation 8.4.4.1 Global coagulation tests: thrombelastography Fluid restriction, phlebotomy, vasopressors and transfu- (TEG)/thromboelastometry (ROTEM) sion protocols may be associated with low transfusion Recommendation rates during OLT.C We recommend the use of perioperative coagulation monitoring using ROTEM/TEG for targeted management In cirrhotic patients, volume loading only marginally of coagulopathy. 1C increases cardiac output while portal hyperaemia and bleeding are increased. Low transfusion rates (<80%) TEG monitoring can reduce transfusion requirements during OLT have been reported using fluid restriction, by 30%.1136,1137. However, high quality data supporting phlebotomy, vasopressors and transfusion proto- the effectiveness of such practice is lacking.1138 In a cols.1128,1129 However, aggressive volume restriction Cochrane review of TEG/ROTEM haemostatic may increase renal dysfunction, limiting its use in some monitoring,17 only one RCT related to liver transplan- patients.1130 tation133 and this was not blinded. Other evidence suggests TEG/ROTEM monitoring may help reduce When using colloids, third-generation starch solutions are bleeding and transfusion of FFP and platelets in recommended because they have less effect on coagu- liver transplantation.1139 As RBC and platelet translation and reduce blood loss and transfusion compared fusions are associated with increased mortality, TEG/ with second-generation starches.863 Patients with end- ROTEM could help to improve patient outcomes; stage liver disease may exhibit delayed clot formation and however, larger trials are required to investigate reduced clot firmness following even moderate fluid this.519,1127 dilution.1131 TEG/ROTEM can facilitate targeted management of Thrombin generation in OLT patients is usually normal specific coagulopathies, potentially reducing transfusion or supranormal,1086 supporting restrictive FFP transfu- requirements.134,1137 Diagnostic capability is maximised sion during OLT. If massive bleeding is not evident, FFP using different activators and modifiers (described else- transfusion may increase bleeding due to portal hyper- where in this guideline – see section 4.2.3.2). TEG/ aemia.1097 ROTEM can identify hyperfibrinolysis, indicating antifibrinolytic therapy.1140 In addition, the FIBTEM test 8.4.3.3 Intraoperative cell salvage can guide administration of fibrinogen concentrate or Intraoperative cell salvage (ICS) has been used to cryoprecipitate,1058 in turn reducing platelet and RBC reduce autologous transfusion requirements and pro- transfusions.1141 vide cost savings for over two decades.1132 As OLT A heparin effect is commonly evident during reperfusion, often involves minimal RBC transfusion, a full ICS due to heparin administered to the donor and endogen- setup is not always justifiable. Thus, it is recommended ous vascular endothelial heparinoids.1140 Reversal with that a ‘stand by’ setup is available. Washed erythrocytes protamine is rarely indicated because the effects of the lack clotting factors and platelets, so transfusion heparin are temporary and do not usually increase bleed- therapy must be tailored accordingly. Heparin anti- ing risk.1142 coagulation of salvaged blood appears safe because washed cells contain minimal heparin. Alternatively, citrate may be used. 8.4.5 Pharmacological therapy 8.4.5.1 Antifibrinolytic drugs UK guidelines1133 state that ICS may be considered for Recommendation hepatocellular tumour surgery if there is a significant risk Antifibrinolytic therapy reduces blood loss and transfu- of major bleeding. Risk of malignant cell reinfusion sion requirements in liver transplantation. B should be balanced against risk of allogeneic transfusion-related complications. Leukodepletion filters We recommend antifibrinolytic drugs for treatment reduce reinfusion risks1134 but also reduce reinfusion of fibrinolysis (evident from microvascular oozing or speed. OLT studies have not shown any risk of bacterial TEG/ROTEM clot lysis measurement) and not for contamination. During ICS, blood should be collected routine prophylaxis. Marginal grafts (e.g. donation after only after ascitic fluid has been removed and should cease cardiac death) increase the risk of fibrinolysis following once biliary anastomosis begins. reperfusion. 1C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 328 Kozek-Langenecker et al.

Lack of tissue plasminogen activator (tPA) clearance no reduction in transfusion. Off-label ‘rescue’ therapy increases fibrinolysis during OLT.1143 Dramatically elev- with rFVIIa may help to control haemorrhage. However, ated levels of tPA follow reperfusion, causing explosive systematic reviews show no reduction in mortality and primary hyperfibrinolysis1144 and, potentially, diffuse increased risk of arterial thromboembolism.554,717 bleeding. Hyperfibrinolysis typically subsides within an hour but may persist with poorly functional or marginal 8.4.6 Pulmonary emboli and intracardiac thrombi in 1145 grafts. This scenario rarely occurs in ALF due to orthotopic liver transplantation elevated PAI-1. Antifibrinolytic drugs have been used Perioperative intracardiac and pulmonary emboli are rare prophylactically and therapeutically for TEG-deter- but potentially lethal complications of OLT. A systematic 1137,1146 mined fibrinolysis. review reported an incidence of 1% and mortality of 1153 A Cochrane review demonstrated that antifibrinolytic 68%. The aetiology is uncertain but unlikely to be therapy helps to reduce blood loss and perioperative causally related to venovenous bypass or antifibrinolytics. allogeneic blood transfusion.480 Tranexamic acid and One study described a 1.9% incidence of intracardiac 1154 EACA were generally as effective as aprotinin. Aprotinin thrombi (ICT), mostly in association with reperfusion. was not associated with increased risk of vascular occlu- Portal hypertension and intraoperative haemodialysis were sion and death,1147 but an increased risk of renal failure independent risk factors. Routine intraoperative transoe- could not be excluded.480 An observational study invol- sophageal monitoring is recommended to identify ICT. ving OLT patients found a significant risk of transient ICT has been linked with hypercoagulability according to renal dysfunction with aprotinin, but no increase in renal TEG, even when conventional tests suggest hypocoagul- 1155 failure or mortality.1148 ability. In addition, the value of thromboelastometry was demonstrated in a fatal cardiopulmonary embolism A meta-analysis of antifibrinolytic drugs concluded that following aprotinin therapy.1156 both aprotinin and tranexamic acid reduce RBC transfusion in OLT.476 Aprotinin, but not tranexamic acid, also Postoperative LMWH prophylaxis for thromboembolic reduces intraoperative FFP transfusion. There was no complications is not administered universally. However, evidence of antifibrinolytic therapy increasing risks of accumulating evidence supports LMWH prophylaxis and 1157 hepatic artery thrombosis, venous thromboembolism or extended postoperative coagulation monitoring. mortality. Similarly, a review of over 1400 OLT patients found no difference in arterial or venous thromboembo- 8.4.7 Antiplatelet therapy and platelet function lism between patients receiving aprotinin and no treat- testing ment.1149 However, this does not preclude risks in Recommendation specific patient subgroups or with specific doses. EACA POC platelet function tests may help to stratify risk and is widely used in the USA despite the existence of only rationalise platelet transfusion in patients taking anti- one RCT, and this study demonstrated no benefit versus platelet drugs. C placebo.547 A small number of OLT patients receive antiplatelet As massive bleeding has become less frequent during therapy for prevention of coronary/cerebral vascular dis- OLT, there have been moves from routine to selective ease or for coronary stent insertion. An observational antifibrinolytic prophylaxis (high-risk patients), and onto study involving coronary stented patients undergoing treatment only. Predicting hyperfibrinolysis is proble- cardiac surgery reported that although the risks of major matic because bleeding is greatly influenced by the donor bleeding decreased, the risk of major adverse cardiac and liver, which is not reflected in preoperative assess- cerebrovascular events increased if antiplatelet therapy ment.1150 Treatment using tranexamic acid/EACA is was interrupted for more than 5 days preoperatively.1158 recommended if microvascular oozing or fibrinolysis is In emergency surgery or OLT, prior therapeutic inter- evident. Timing and degree of fibrinolysis is important; ruption is not feasible. non-severe fibrinolysis occurring after reperfusion may The degree of platelet inhibition is variable; ‘hypo- resolve spontaneously.1066 Lowest effective doses are responders’ may be at increased risk of ischaemic events, uncertain; tranexamic acid is currently given in 1–2 g while ‘hyper-responders’ may have increased risk of increments. bleeding.1159 Bleeding risk may be stratified using point-of-care platelet function analysers: minimal risk Recombinant activated factor VII is associated with platelet inhibition <30%, but >60% Recommendation inhibition with 2- to 6-fold increased risk.1160 Cardiac We recommend against rFVIIa for prophylaxis; rFVIIa surgery patients with high platelet inhibition appear to should be used only as rescue therapy for uncontrolled have increased bleeding risk and increased transfusion bleeding. 1A requirements. Patients in the lower tertile of platelet Two RCTs have investigated prophylactic rFVIIa in aggregation (measured using multiple electrode aggre- OLT:1151,1152 both demonstrated correction of INR but gometry) receive more platelet concentrate than upper Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 329

tertile patients.159,186 Similarly, the m-TEG platelet 8.4.9.1 Acute variceal bleeding mapping assay (Haemonetics, Braintree, MA) has shown Recommendations that >70% inhibition increases bleeding risk.1161 Platelet We recommend that acute variceal bleeding should be mapping has been used to guide antiplatelet therapy in a managed by a multidisciplinary team. A specific multi- Budd-Chiari patient with an occluded transjugular intra- modal protocol for upper gastrointestinal haemorrhage hepatic portosystemic shunt.1162 Tranexamic acid may should be available. 1C partially reverse the effect of antiplatelet therapy.72 We recommend that early treatment involves immediate Platelet function tests may potentially predict platelet use of vasopressors (somatostatin or terlipressin) to transfusion requirements although no ‘gold standard’ test reduce bleeding and early interventional endoscopy. or cut-off value has yet been established. Studies are Antibiotics must be started on admission. 1A ongoing.1163 Variceal bleeding is a major complication of portal hypertension and a leading cause of death in cirrhosis. Although 8.4.8 Liver resection management and prognosis have improved,1170 early Blood loss during liver resection is a major determinant of mortality following acute variceal bleeding (AVB) perioperative outcome. Selective vascular occlusion tech- remains high (15–24%). niques help to control blood loss, with complete vascular occlusion employed in excessive bleeding. Intermittent AVB outcomes can be improved by experienced multi- clamping or ischaemic preconditioning may reduce disciplinary management and immediate interventional 1170 ischaemic liver injury.1164 endoscopy. Early risk assessment (Rockall scoring system or Blatchford score) is important. Combined 8.4.8.1 Haemodynamic interventions to reduce blood pharmacological and endoscopic intervention is recom- loss mended for initial treatment of acute bleeding. Vaso- Recommendation active drugs (preferably somatostatin or terlipressin) may A low central venous pressure and restrictive fluid admin- improve control of haemorrhage and should be given istration reduce bleeding. B immediately if variceal bleeding is suspected, with maintenance for 2–5 days.1171 Fluid restriction and maintenance of low central venous pressure (CVP) during hepatic resection reduce blood Following stabilisation with fluid and blood support, loss.1165 However, low CVP may increase complications emergency diagnostic endoscopy and endoscopic variceal including air embolism and renal failure.1166 It is uncer- treatment should be performed by a skilled endoscopist. tain whether fluid restriction during hepatic resection Antibiotic prophylaxis forms an integral component of increases the risk of renal dysfunction, although this risk AVB treatment, commencing at admission and main- 1172 is generally considered minimal. tained for 7 days. For acute refractory bleeding, rescue therapy should begin immediately. Balloon tamponade may be necessary and shunt therapies are often 8.4.8.2 Pharmacological interventions to reduce blood loss effective if initial treatment fails. Recommendation We suggest that antifibrinolytic drugs should be con- 8.4.9.2 Fluid Resuscitation and pharmacological sidered in cirrhotic patients undergoing liver resection. 2C interventions Recommendations A Cochrane review reported reduced allogeneic transfu- Tranexamic acid reduces mortality but not rebleeding.B sion in patients receiving aprotinin or tranexamic acid.1165 Desmopressin, rFVIIa and AT did not decrease trans- rFVIIa should be used only as rescue therapy; we recom- fusion. However, because all of the studies had a high risk mend against its routine use. 1C of bias (likely type I and type II errors), no general Blood volume resuscitation should be undertaken as soon recommendations can be made without further large as possible with the aim of maintaining systolic blood trials. A separate systematic review showed no difference pressure at around 100 mmHg. Optimal volume replace- 467 between rFVIIa and placebo. ment remains controversial. No high-quality RCTs have compared crystalloids with colloids in patients with 8.4.9 Acute upper gastrointestinal bleeding UGIB; however, in critical care, a meta-analysis and a In decompensated CLD, bleeding is often triggered by large RCT suggest no differences between them.1173,1174 haemodynamic alterations arising from portal hyperten- Conservative volume replacement and transfusion is sion, endothelial dysfunction, renal failure, bacterial recommended. Because colloids remain intravascular infection, endogenous heparinoids1167,1168 and DIC. for longer and reduce the total administration volume, Acute upper gastrointestinal bleeding (UGIB) is a com- they may be preferable. Vasoactive drugs have been mon medical emergency, with a mortality in excess of shown to counteract portal pressure increases induced 7%.1169 by volume expansion. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 330 Kozek-Langenecker et al.

Blood transfusion should generally aim to maintain haemo- We suggest that desmopressin should be considered for globin at 7–8 g dl1. Abnormal PT/INR and platelet count reducing bleeding during surgery and for managing acute correlate poorly with bleeding and TEG may provide more bleeding in uraemic patients. 2C useful information.1175,1176 In active bleeding, FFP should There is no evidence to support use of rFVIIa in this be given to maintain INR < 2 and platelets given to setting. maintain platelet count >60 000 ml 1.1102 The value of antifibrinolytic drugs in treating UGIB is unclear. Meta- Bleeding complications are common in acute and chronic analyses suggest that tranexamic acid does not lower rates renal failure.1189 Modern dialysis techniques, combined of rebleeding or surgery, but that it reduces mortality with correction of anaemia using erythropoietin, have (relative risk 0.61);1177,1178 large RCTs are needed to reduced spontaneous haemorrhage, although bleeding confirm these findings. diathesis remains a problem in uraemic patients undergoing invasive/surgical procedures. Several measures are PT can be corrected using rFVIIa in CLD patients with available to reduce bleeding risk in advanced CKD UBIG. Benefits over standard therapy are not evident,1179 patients: although a possible indication exists in uncontrolled bleeding.1180 European guidelines on rFVIIa recommend 1. Renal replacement therapy (peritoneal dialysis or against its use in elective liver surgery or bleeding epi- haemodialysis) improves platelet function by remov- sodes in patients with Child-Pugh A cirrhosis. Efficacy in ing uraemic toxins.1185 Child-Pugh B and C is uncertain and thromboembolic 2. Correction of anaemia in CKD with erythropoietin events remain a concern.1181 helps to prevent uraemic bleeding. Increased erythrocyte numbers improve platelet function,1190 and 8.4.10 Coagulopathy and renal disease decreased haemoglobin concentration may intensify Patients with chronic kidney disease (CKD) have 1191 platelet dysfunction. haemostatic derangement with variable clinical manifes- 3. Desmopressin can treat platelet dysfunction in tations.1182 As CKD advances, procoagulant abnormal- uraemic patients. Desmopressin induces VWF ities (impaired tPA release, increased PAI-1, elevated release, improving platelet adhesion/aggregation. fibrinogen and increased TF/FVIII) persist.1183 Patients Desmopressin shortens bleeding time within 1 h, with also develop platelet dysfunction, comprising impaired 1192 effects lasting 4–8 h, and a single dose of GPIIb/IIIa receptor function, altered release of ADP and 1 0.3 mgkg , intravenously or subcutaneously, is effec- serotonin from platelet granules, and faulty arachidonic 1 tive. Doses of 3 mgkg can also be administered acid and prostacyclin metabolism.1184 Uraemic toxins nasally. Desmopressin is effective as both prophylaxis may stimulate nitric oxide release, exacerbating platelet 1193,1194 and treatment of perioperative bleeding. dysfunction. Correction of anaemia in CKD patients may 4. Cryoprecipitate has been used to treat uraemic improve platelet function.1185 bleeding. It is effective 1 h after infusion, with maximum effect after 4–12 h. Up to 50% of uraemic 8.4.10.1 Assessment of platelet function in chronic patients fail to respond to cryoprecipitate. Cryopre- kidney disease cipitate carries a risk of pathogen transmission and is Recommendation rarely used in CKD.1182 Point-of-care tests of platelet function and bleeding time 5. Conjugated oestrogens may reduce bleeding in provide no reliable platelet function assessment in urae- uraemic patients,1195 particularly those with gas- mia and no prediction of bleeding in this setting .C trointestinal or intracranial bleeding or under- CKD patients typically have normal/slightly reduced going major surgery. An oral dose of 25 mg platelet counts. Skin bleeding time (SBT) has been used normalises SBT for 3–10 days.1196 Low dose to assess platelet function, but this has poor reproduci- transdermal oestrogen (oestradiol 50–100 mgper bility. The PFA-100 has better sensitivity and specificity day) reduces gastrointestinal bleeding and improves than SBT.1186 However, correlation has not been shown bleeding time.1197 between PFA-100 closure times and bleeding compli- 6. Tranexamic acid shortens bleeding time in uraemic cations after percutaneous renal biopsy.1187 A review of patients. However, it may accumulate in patients with point-of-care platelet function tests found inconsistent renal insufficiency and there is no evidence of results, so the authors could not recommend any single superiority over other therapies. Therefore, tranexa- test for bleeding risk assessment.1188 mic acid should be considered only in the acute setting when other treatments have proved unsatis- 8.4.10.2 Correction of bleeding diathesis and treatment factory.1185 of bleeding in patients with renal failure 7. Anecdotal reports suggest that rFVIIa may control Recommendations bleeding in uraemic patients.1198 However, there are We suggest that conjugated oestrogen therapy should be no data supporting its safety, efficacy or dosing in used in uraemia. 2C this setting. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 331

8.5 Paediatric surgery 8.5.4 Red blood cell transfusion 8.5.1 Introduction Recommendation Severe perioperative bleeding in paediatric patients We suggest that a critical haemoglobin threshold of has typically been treated as it is in adults. Despite 8gdl 1 for RBC transfusion may be safe in severe developmental changes in the coagulation system, paediatric perioperative bleeding. 2C haemostatic capacity is excellent in newborns and Haemoglobin concentrations vary with age and gender, children.1199–1201 Nonetheless, recognition of these and RBC transfusion should be tailored accordingly. The developmental changes may improve the management required transfusion volume can be calculated as: body of acquired paediatric coagulopathy. weight (kg) x desired increment in haemoglobin concentration (g dl1)x5.1218 In massive bleeding, haemoglobin concentrations should be maintained at 8gdl1,1219 8.5.2 Coagulation monitoring while in stable, critically ill children, 7 g dl1 may Recommendation suffice.1220 We suggest the use of perioperative coagulation analysis using viscoelastic point-of-care monitoring 8.5.5 Platelet transfusion (ROTEM/TEG) for timely detection of coagulation defects including dilutional coagulopathy and hyper- Recommendation We suggest that transfusion of platelet concentrates may fibrinolysis. 2C be considered if platelet count is <50 000–100 000 ml 1. Diagnosing paediatric perioperative coagulopathy 2C requires rapid, robust coagulation monitoring, alongside 1202–1205 In children and adults, transfusion thresholds for platelets age specific reference ranges. ROTEM and vary according to the type of surgery and platelet func- TEG can complement standard coagulation tests, especi- 35,114,1136,1206,1207 tionality. Current data suggest maintaining platelet count ally in the perioperative setting. In a at 50 000–100 000 ml1.1221 Transfusion of one unit of meta-analysis, TEG- or ROTEM-guided transfusion platelet concentrate per 10 kg body weight, or 5 ml kg1 was shown not to affect overall mortality in patients with of apheresis platelet concentrate, should raise platelet severe bleeding, but it was associated with significantly 1 17 count by 20 000–50 000 ml . reduced bleeding. Data supporting the effectiveness of ROTEM/TEG-guided paediatric coagulation therapy are limited.427,940,1208–1210 8.5.6 Fresh frozen plasma Recommendation No clear recommendation can be made regarding the indication and dosing of FFP transfusion in bleeding 8.5.3 Fluid resuscitation children, but severe risks have been reported.C Recommendation No clear recommendation can be made regarding Transfusion of FFP for treatment of severe bleeding is the choice of perioperative fluid replacement in recommended by several guidelines but is not supported children. C by high quality evidence. Despite age-dependent variations in coagulation No randomised, controlled trials have demonstrated that factor levels, the pathophysiology underlying paedia- FFP controls paediatric perioperative bleeding. Prophy- tric perioperative bleeding is comparable to adults. lactic FFP in preterm babies appears not to reduce Dilutional coagulopathy is encountered in adults and mortality or disability associated with haemorrhagic/ children alike.427,943,1211–1213 However, a negative ischaemic brain injury.1222 Intraoperative FFP transfu- impact of colloids on haemostasis should be sion during paediatric craniofacial surgery may not reduce considered and closely monitored. Cardiopulmonary RBC transfusion or blood loss compared with albu- bypass may cause additional haemostatic disturbances, min,1223,1224 although other results do suggest improved including platelet dysfunction and excessive fibri- postoperative coagulation.1225 UK guidelines recom- nolysis.1213 mend avoiding FFP for simple volume replacement1226 and one UK study questioned the overall clinical benefits Fluid resuscitation can cause dilutional coagulopa- of FFP.405 thy.1214–1216 Pronounced coagulation disturbance following HES infusion1214,1216 and minor disturbances Guidelines typically recommend 10–15 ml kg1 FFP for following gelatin solution or albumin1214 have been adults and children with acquired bleeding and pro- reported. A meta-analysis suggests that colloids are no longed aPTT or PT (>1.5 times normal).45,57,1219,1226,1227 more effective than crystalloids for reducing mortality in However, this may be insufficient to achieve haemo- critically ill adults.1217 Together, no clear recommen- stasis,402,403,1228 and the potential for volume overload dation can be made regarding choice of fluid for paedia- may preclude increased dosing. Side-effects of FFP tric perioperative resuscitation. include TRALI340,1229 an increased mortality in children Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 332 Kozek-Langenecker et al.

with ALI, 1230 transfusion-associated cardiac overload,1231 Acquired FXIII deficiency appears prevalent in surgical sepsis in severely burned paediatric patients,1232 transfu- and acute care settings.437 A randomised trial in adults,448 sion-related immunomodulation346 and multiple organ together with other investigations,410,439,443 suggest failure.396 maintaining FXIII levels above 50–60% of normal during perioperative bleeding. FXIII may be supplemented 8.5.7 Coagulation factor concentrates using FXIII concentrate (20 IU kg1)1235 or FFP trans- Coagulation factor concentrate therapy for congenital fusion. No data exist on paediatric FXIII supplementa- disorders1221,1233 has established the potential for pae- tion. diatric coagulation factor concentrate therapy in acquired perioperative coagulopathies. However, there is a lack of 8.5.7.4 Recombinant activated factor VII randomised, controlled trial data in children. Recommendation We recommend against the use of rFVIIa in children. 1C 8.5.7.1 Fibrinogen concentrate Recommendations rFVIIa has been described as useful for controlling severe We suggest that fibrinogen concentrate (30–50 mg kg1) bleeding in cardiac1236–1238 and neurosurgical procedures or cryoprecipitate (5 ml kg1) may be used to increase in children,1008,1239 although a prospective, randomised plasma fibrinogen concentrations above trigger values trial in paediatric cardiac surgery showed no difference in of 1.5–2.0 g l1 or FIBTEM MCF >7 mm in bleeding blood loss with rFVIIa versus placebo.1240 Failure of children. 2C rFVIIa to reduce RBC transfusion requirements has been reported in adult trauma patients.1241 rFVIIa may be We suggest that FFP may be used if no other fibrinogen efficacious only if fibrinogen concentration and platelet source is available.2C count are sufficient.1242 Undirected rFVIIa adminis- Fibrinogen is the first clotting factor to reach critically low tration may potentially increase thromboembolic compli- concentrations during life-threatening haemorrhage in cations.554,667,717,1243,1244 adults and children. European guidelines45,562 recommend higher thresholds (1.5–2 g l1) than international guide- 8.5.7.5 Desmopressin lines.1227 Fibrinogen substitution can be performed using Recommendation cryoprecipitate (5 ml kg 1), but this is not available in all We suggest against the routine use of desmospressin in countries due to safety concerns. FFP may not provide an the absence of mild haemophilia A or von Willebrand adequate increase in plasma fibrinogen concentra- disease. 2C tions.1211. In contrast, fibrinogen concentrate (30 mg kg 1) has been used effectively to treat fibrinogen deficiency Desmopressin has been shown to provide modest (ROTEM FIBTEM maximum clot firmness 7 mm) reductions in postoperative blood loss and transfusion during paediatric craniofacial surgery.427 This is supported requirements, without influencing mortality.1245 Maxi- by evidence from prospective adult studies demonstrating mum effects are observed at a dose of 0.3 mgkg1.1246 the effectiveness of fibrinogen concentrate in aortic However, paediatric studies in cardiac surgery1247,1248 surgery,116 radical cystectomy431 and major orthopaedic and other surgical settings1249–1251 have shown no surgery.411 reduction in allogeneic blood transfusion after desmopressin administration. Fibrinogen concentrate has a favourable safety profile.424,1234 8.5.7.6 Antifibrinolytics 8.5.7.2 Prothrombin complex concentrate Recommendation Recommendation We suggest that perioperative antifibrinolytic therapy Data for PCC in children are limited and no dose recom- should be used to reduce blood loss and transfusion mendation can be made.C requirements in cardiac and non-cardiac paediatric surgery.2A PCC can help to correct dilutional coagulopathy by increasing thrombin generation.457,460,664 In adults, In paediatric patients undergoing cardiac and scoliosis 20–30 IU kg1 PCC should be sufficient to increase surgery with high bleeding risk, tranexamic acid mark- thrombin potential, but there is no evidence on the edly reduced perioperative blood loss and RBC trans- safety, effectiveness or optimal dosing of PCC for fusion.534,1252 Similar effects have been reported for paediatric perioperative bleeding. tranexamic acid in paediatric craniosynostosis surgery.537 Optimal dosage remains uncertain, with wide variations 8.5.7.3 Coagulation factor XIII in reported loading doses (10–100 mg kg1) and infusion Recommendation rates (1–10 mg kg 1 h 1). In paediatric cardiac surgery, No recommendation on the use of FXIII concentrate in repeated doses are suggested to be more efficacious than bleeding children can be made. a single bolus.1253 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 333

9 ANTICOAGULATION AND ANTIPLATELET The first postoperative aspirin should be a loading dose, THERAPY given no later than 24 h after skin closure. 9.1 Introduction Antithrombotic therapies have a range of indications and Platelet aggregation is restored approximately 4 days in this section we describe how they are used in anaes- after aspirin discontinuation. Point-of-care testing has thesia and intensive care. demonstrated significant recovery of platelet aggregation within 48 h after aspirin cessation, with baseline values re-established within 5 days.1255 Experimental studies 9.2 Antiplatelet agents have reported enhanced platelet aggregation after inter- Perioperative interruption and maintenance of antiplate- ruption of aspirin.1256,1257 Platelet thrombi produced after let agents (APAs) are associated with increased cardio- aspirin withdrawal appear more resistant to physiological vascular or haemorrhagic complications, respectively. fibrinolysis. Aspirin or anticoagulant withdrawal has been Guidelines for perioperative APA therapy are based on linked to myocardial infarction or stroke. small observational studies, case reports and expert opinion, so recommendations are weak. In patients with In a cohort of acute coronary syndrome (ACS) patients, coronary stents, the main risk factor for stent thrombosis Collet et al.1258 reported ACS to be associated with aspirin is interruption of APA. If these patients require surgery, interruption in 5.4% of patients. Ischaemic events were the optimum delay between stent implantation and typically observed 12 days after aspirin withdrawal. Other surgery is unclear, as is the need for (or optimal duration reports associate aspirin interruption with thrombotic of) interruption of APA therapy. events in patients with a history of coronary heart disease, stroke1259 and peripheral artery disease.1260 9.2.1 Aspirin Surgical bleeding risk associated with APA therapy has Aspirin and other NSAIDs inhibit platelets by inactivat- been poorly evaluated. In patients undergoing total hip ing platelet cyclooxygenase-1 (COX-1). Although the replacement, preoperative aspirin was associated with effect is irreversible, NSAIDs are weak antiplatelet drugs only a minor increase in bleeding compared with placebo because they affect only one of the many platelet acti- (Pulmonary Embolism Prevention [PEP] trial).1261 vation pathways. Randomised trials have shown that aspirin is effective at doses of 50–100 mg per day. There Systematic reviews have analysed aspirin-associated is no convincing evidence that doses >325 mg per day are bleeding risks in non-cardiac surgery. Burger et al.1262 more effective in reducing the risk of serious vascular pooled data from 49 590 patients (14 981 on aspirin). events, and higher doses may increase the risk of adverse Aspirin increased the rate of bleeding complications events (e.g. thrombotic or gastrointestinal).1254 1.5-fold but did not increase their severity (except in intracranial surgery and possibly transurethral prostatect- Peak plasma aspirin concentrations occur 30–40 min after omy). Giannarini et al.1263 showed that continued low- ingestion (or 3–4 h for enteric coated aspirin). Platelet dose aspirin (100 mg per day) in men undergoing trans- function is inhibited within 1 h. The half-life of aspirin is rectal prostate biopsy did not increase the incidence of 15–20 min, although platelet inhibition lasts for the life- mild bleeding, although the durations of self-limiting span of affected platelets.1254 haematuria and rectal bleeding were prolonged. Aspirin is indicated and effective for secondary preven- In patients referred for transurethral prostatectomy, open tion of vascular events. Long-term aspirin therapy prostatectomy and transurethral resection of bladder reduces the risk of myocardial infarction, stroke or vas- tumour, postoperative bleeding did not differ signifi- cular death among high-risk patients (e.g. those with cantly between patients in whom aspirin was initiated chronic stable angina, prior myocardial infarction, early (24 h) or late (3 weeks) after surgery.1264 Several unstable angina, transient ischaemic attack or minor other articles report similar findings. In general, aspirin stroke). In such patients, a major vascular event is should not be withdrawn perioperatively unless the risk avoided in 3–5% of individuals over 30 months. of bleeding exceeds the thrombotic risk from withholding Recommendations the drug. Aspirin is administered preoperatively for most We recommend that aspirin therapy should continue vascular procedures. The Eighth ACCP Guidelines perioperatively in most surgical settings, especially car- strongly recommend aspirin for carotid endarterectomy; diac surgery. 1C aspirin, 75–325 mg per day should be given preoperatively and continued indefinitely (grade of recommen- Where aspirin withdrawal is considered, we recommend dation: 1A).1265 Two studies have since been published. a time interval of 5 days. 1C 1266 Oscarsson et al. conducted a randomised, double- Treatment discontinuation increases thrombotic risk; this blind, placebo-controlled trial to compare the effect of risk should always be discussed. Following aspirin low-dose aspirin with that of placebo on myocardial withdrawal, aspirin treatment should resume as soon as damage, cardiovascular and bleeding complications possible postoperatively to prevent platelet activation. in high-risk patients undergoing non-cardiac surgery. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 334 Kozek-Langenecker et al.

Aspirin (75 mg) or placebo was given 7 days before for the duration of withdrawal (no more than 7 days for surgery and continued until the third postoperative prasugrel). day. One hundred and nine of the patients received aspirin and 111 received placebo. Treatment with aspirin Recommendations resulted in a 7.2% absolute risk reduction (95% CI, 1.3– Clopidogrel increases perioperative bleeding. In cases of 13%) for postoperative major adverse cardiovascular increased bleeding risk, we recommend that it should be events (MACE). The relative risk reduction was 80% withdrawn for no more than 5 days.1C (95% CI, 9.2–95%). No significant differences in bleed- Prasugrel increases perioperative bleeding. In cases of ing complications were seen between the two groups. increased bleeding risk, we recommend that it should be The STRATAGEM study was a randomised, multicen- withdrawn for no more than 7 days.1C tre, blinded study in which 145 patients in the aspirin group were treated for 10 days preoperatively, and 146 We recommend that antiplatelet agent therapy should patients were in the placebo group.1267 No significant resume as soon as possible postoperatively to prevent difference was observed in either the primary outcome platelet activation.1C score, or at day 30, in the number of major complications We suggest that the first postoperative dose of clopido- between groups. In addition, no difference in major grel or prasugrel should be given no later than 24 h after bleeding was observed. In summary, these studies skin closure. We also suggest that this first dose should showed that there was no risk in continuing aspirin not be a loading dose. 2C perioperatively. Several publications have described perioperative hae- Recommendation morrhagic complications associated with clopidogrel, and For intra- or postoperative bleeding clearly related to the risk may increase when clopidogrel is combined with aspirin, we suggest that platelet transfusion be con- aspirin. However, such risks may be acceptable if with- sidered (dose: 0.7 x 1011 [i.e. two standard concentrates] drawal is also associated with a high risk of thrombotic per 7 kg body weight in adults). 2C complications. Severe bleeding in patients on aspirin may require A study of clopidogrel in healthy volunteers showed high immediate platelet transfusion.1075 interindividual variability in platelet inhibition during treatment and recovery of platelet function after discontinuation. This may be explained in part by genetic 9.2.2 Thienopyridines: clopidogrel and prasugrel polymorphism of CYP450 involved in the metabolism The thienopyridine derivatives ticlopidine and clopido- of clopidogrel. A low level of inhibition of platelet aggre- grel inhibit ADP-induced platelet activation by binding gation may be associated with an increased incidence of covalently to the P2Y12 receptor. These agents are more cardiac events, but no evidence was identified establish- potent than aspirin, although platelet activation remains ing a relationship between clopidogrel platelet inhibition possible with high concentrations of agonists acting and bleeding. through phospholipase C. In a porcine study, clopidogrel prolonged ear-immersion Clopidogrel is absorbed rapidly and metabolised exten- bleeding time more than did aspirin.1268 However, no sively. The main systemic metabolite is the carboxylic clinical comparison of aspirin and clopidogrel has been acid derivative SR 26334. The plasma elimination half- performed in surgical patients. life of SR 26334 is approximately 8 h.1254 Recommendation Prasugrel is a new thienopyridine agent and a highly We recommend postponement of elective surgery potent APA. It requires conversion to an active metab- following coronary stenting (at least 6 to 12 weeks olite before binding to the platelet P2Y12 receptor, and for bare metal stent and one year for drug-eluting its antiplatelet activity is more rapid, consistent and stents). 1C pronounced than that of clopidogrel.1254 It is rapidly absorbed and the hepatic CYP system converts it into Kaluza et al.1269 reported that surgery performed within the active form. The active metabolite concentration 4 weeks after insertion of a bare metal stent (BMS) is peaks 30 min after administration and has an elimination associated with 20% mortality, caused either by ischae- half-life of approximately 3.7 h. Differences in metabolic mic events following APA interruption or haemorrhagic processing result in higher concentrations of active events while APA therapy was maintained. Other studies metabolite and therefore improved inhibition of platelet confirm that the first month following BMS placement is aggregation with prasugrel compared with clopido- a high-risk period for non-cardiac surgery. Nuttall grel.1254 No data are available regarding perioperative et al.1270 reported a postoperative cardiac event rate of use of prasugrel. Its antiplatelet effect lasts for the 10.5% for surgery within 1 month after stent insertion, platelet’s lifespan (7 days). Recommendations for versus 3.8% between 1 and 3 months, and 2.8% after clopidogrel should be applicable to prasugrel, except 90 days. A global consensus statement recommends Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 335

avoidance of non-emergency non-cardiac surgery during surgery. Preoperative risk factors were anaemia, severe the first 4–6 weeks following BMS placement. renal failure, urgent surgery, high-risk surgery and interruption of antiplatelet treatment for more than 5 days Recommendations preoperatively. We recommend that a multidisciplinary team meeting should decide on the perioperative use of antiplatelet The Triton TIMI 38 study showed increased haemor- agents in urgent and semi-urgent surgery. 1C rhagic complications in CABG patients treated with dual antiplatelet therapy including prasugrel, compared with We suggest that urgent or semi-urgent surgery should be patients treated with clopidogrel.886 performed under aspirin/clopidogrel or aspirin/prasugrel combination therapy if possible, or at least under aspirin Recommendation alone. 2C We suggest that platelet transfusion should be considered (dose: 0.7 x 1011 [i.e. two standard concentrates] per 7 kg Clopidogrel is approved for reduction of atherosclerotic body weight in adults) in cases of intra- or postoperative events following recent stroke, recent myocardial infarc- bleeding clearly related to clopidogrel or prasugrel.2C tion or established peripheral arterial disease. The clinical benefit of clopidogrel and aspirin, versus aspirin No studies of platelet transfusion for reversal of clopido- alone, has been confirmed in patients experiencing per- grel or prasugrel treatment were retrieved. cutaneous coronary intervention (PCI) or acute myocardial infarction. The benefit of dual antiplatelet 9.2.3 Ticagrelor therapy versus aspirin alone in patients with ACS is In contrast to the thienopyridines, ticagrelor acts directly around one-third of the benefit of aspirin versus no on the P2Y12 receptor rather than requiring cytochrome antiplatelet therapy. In the future, prasugrel may be P450 biotransformation. Metabolites of ticagrelor are also used similarly to clopidogrel, but currently, prasugrel is active.1277 Like prasugrel, ticagrelor provides faster ‘co-administered with acetylsalicylic acid for the preven- (<2 h), greater (approximately 70%) and more consistent tion of atherothrombotic events in patients with ACS P2Y12 inhibition than does clopidogrel (30–40%). Tica- undergoing primary or delayed PCI’. A large phase III grelor has a rapid onset of action, reversible binding and study (TRITON) compared prasugrel with clopidogrel in relatively short duration of action (48–72 h), necessitating 13 608 patients with ACS scheduled to undergo PCI. twice-daily oral administration. The half-life of the active Prasugrel reduced rates of ischaemic events including compound is 12 h. Following cessation, inhibition of stent thrombosis, but increased the risk of major/fatal platelet aggregation declines to <10% within 4.5 days.1277 bleeding.886 Recommendations Drug-eluting stents (DESs) have been associated with According to pharmacological characteristics, we suggest 1271 stent thromboses at a rate of 1% per year. Mortality for that the management of ticagrelor may be comparable to this complication is 40–50% and the major risk factor for clopidogrel (i.e. withdrawal interval of 5 days). 2C stent thrombosis may be APA withdrawal.1272 Eisenberg et al.1273 identified 161 cases of late or very late stent Platelet transfusion may be ineffective for treating bleed- thrombosis; 19 cases occurred in patients receiving dual ing clearly related to ticagrelor when given 12 h before. antiplatelet therapy at the time of the event. The median 2C time to event was 7 days if both APAs were stopped The PLATO trial conducted in 18 000 ACS patients simultaneously, 7 days if a thienopyridine was withdrawn showed reduced mortality from vascular causes, myo- first with no ill effect and aspirin subsequently stopped, cardial infarction and stroke with ticagrelor compared and 122 days if the thienopyridine was removed but with clopidogrel.887 Ticagrelor increased the rate of acetylsalicylic acid was maintained. Maintaining APAs bleeding unrelated to surgical procedures but did not throughout the procedure appears to be the safest increase the overall rate of major bleeding. approach. Among DES patients undergoing non-cardiac surgery, the period of risk for major cardiac events seems No studies on efficacy of platelet transfusion in patients to be 1 year.1274 The incidence of perioperative stent treated with ticagrelor were retrieved. When ticagrelor thrombosis remains controversial. Godet et al.1275 has been administered within the preceding 12 h, reported two stent thromboses in 96 DES patients under- its presence in plasma may render platelet transfusion going non-cardiac surgery, while Schouten et al.1276 ineffective. observed three late stent thromboses in 99 DES patients undergoing invasive procedures. The risk of stent throm- 9.3 Anticoagulant agents bosis seems to increase over 50-fold during the perio- 9.3.1 Heparin perative period, compared with the annual cumulative Heparin is used in clinical practice as unfractionated risk (0.5–1.5%). Finally, Albaladejo et al.1158 observed heparin (UFH) and low-molecular weight heparins major postoperative cardiovascular complications in (LMWHs) and it is necessary to distinguish between 10.9% of coronary stent patients undergoing non-cardiac the two when making recommendations. Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 336 Kozek-Langenecker et al.

9.3.1.1 Unfractionated heparin LMWHs include bemiparin, certoparin, dalteparin, UFH is a heterogeneous mixture of branched glycosami- enoxaparin, nadroparin, reviparin and tinzaparin. noglycans; its mean molecular weight is approximately These products differ in molecular weight, pharmacoki- 15 000 Da (range 3000–30 000 Da).1278 UFH binds anti- netics, anti-FIIa/anti-FXa activity and approved indica- thrombin, forming a complex which inactivates thrombin tions, but recommendations apply equally to all and coagulation factors Xa, IXa, XIa and XIIa.1278 LMWHs.1280 UFH may be administered intravenously or subcu- LMWHs bind to and activate antithrombin. Unlike taneously. With intravenous administration, the half-life UFH, not all LMWH molecules can inhibit thrombin is >1 h (70–100 min). With subcutaneous administration, (only those with 18 saccharides).1281 The anticoagulant the onset of anticoagulation is delayed by approximately action of LMWH is therefore based mainly on FX 1 h and peak plasma concentrations are reached at 3 h. inhibition. Unlike UFH, LMWHs have low platelet Clearance occurs via binding to endothelial cells and interaction. macrophages, followed by renal metabolism. The process LMWHs have almost 100% bioavailability after subcu- is non-linear and dose-dependent with a half-life after the taneous administration. Peak plasma concentration is intravenous administration of a therapeutic dose ranging reached approximately 3–4 h after administration and from 70–100 min.1278 the elimination half-life is around 4–6 h (assuming nor- Indications for UFH include perioperative thrombopro- mal renal function).1281 phylaxis (US more than Europe), deep vein thrombosis Monitoring the anticoagulant effects of LMWH is usually (DVT) or pulmonary embolism, anticoagulation in CPB unnecessary and can be achieved by measuring plasma (extracorporeal pump) or haemodialysis, coronary path- anti-FXa activity (only necessary in some special cases ology (unstable angina, myocardial infarction) and dis- such as severe renal insufficiency, morbid obese patients seminated intravascular coagulation. or pregnancy). Recommendations We recommend that severe bleeding associated with Recommendations We suggest that severe bleeding related to subcu- intravenous UFH should be treated with intravenous taneous LMWH should be treated with intravenous pro- protamine at a dose of 1 mg per 100 IU UFH given in tamine at a dose of 1 mg per 100 anti-FXa units of LMWH the preceding 2–3 h. 1A administered. 2C We suggest that severe bleeding associated with sub- We suggest that severe bleeding associated with subcutaneous UFH unresponsive to intravenous protamine cutaneous LMWH and unresponsive to initial adminis- at a dose of 1 mg per 100 IU UFH could be treated by tration of protamine could be treated with a second dose continuous administration of intravenous protamine, with of protamine (0.5 mg per 100 anti-FXa units of LMWH dose guided by aPTT.2C administered). 2C Rapid, effective reversal of UFH can be achieved using Protamine administration does not completely reverse intravenous protamine (1 mg protamine neutralises LMWH anticoagulation; although it neutralises anti-FIIa 100 IU of UFH). When UFH has been infused continu- activity, it has limited effects on anti-FXa activity. This is ously, the dose of protamine should be calculated from because protamine binds poorly to small LMWH frag- the UFH dose administered during the preceding 2–3 h. ments with 8–14 saccharides.1282 The clinical signifi- Protamine can cause hypotension and bradycardia, but cance of this is unclear and there are few data slow administration (over 1–3 min) reduces the risks. describing protamine in LMWH-related human haemor- Protamine is less effective with subcutaneously adminis- rhage. In clinical practice, protamine (1 mg per 100 anti- tered UFH, necessitating continuous and prolonged infu- FXa units of LMWH administered; conversion of enox- sion of protamine. aparin: 40 mg ¼ 4000 international anti-FXa units) is Activated partial thromboplastin time (aPTT) and/or the suggested if haemorrhage occurs within 8 h of LMWH plasma concentration of anti-FXa are typically used to administration. A second dose of protamine (0.5 mg per monitor the effect of usual therapeutic doses of UFH;1279 100 anti-FXa units administered) may be administered if for higher doses (e.g. in cardiac surgery), activated clot- bleeding continues. ting time is the preferred measurement. 9.3.2 Fondaparinux 9.3.1.2 Low molecular weight heparins Fondaparinux is a synthetic analogue of the pentasac- LMWHs are obtained from UFH by chemical or enzy- charide sequence found in UFH or LMWH, with selec- matic depolymerisation. They are widely employed in tive action against FXa.1283 It binds to antithrombin and clinical practice due to their favourable risk/benefit pro- enhances antithrombin inhibition of FXa. Thrombocy- file, once-daily dosing and reduced requirement for topaenia is unlikely to occur in patients receiving fonda- monitoring. parinux.1284 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 337

Fondaparinux is indicated for preventing venous throm- Day 4: no heparin; Days 3 and 2: therapeutic subcu- boembolism (VTE), for initial treatment of VTE and for taneous LMWH twice daily or subcutaneous UFH twice myocardial infarction. or thrice daily; Day 1: hospitalisation and INR measurement; Day 0: surgery.1C The anti-FXa activity of fondaparinux is higher than that of LMWH. Administered subcutaneously, fondaparinux We recommend that for groups 1 and 2 above, VKAs has an elimination half-life of 17 h in patients without should be restarted during the evening after the procedure. renal impairment (21 h in elderly patients),1285 allowing Subcutaneous LMWH should be given postoperatively once-daily administration. Peak plasma concentration until the target INR is observed in two measurements.1C occurs 1.7 h after subcutaneous administration. We recommend that for group 3 above, heparin (UFH or Routine coagulation monitoring is not recommended but, LMWH) should be resumed 6–48 h after the procedure. as with LMWH, it may occasionally be useful to deter- VKA can restart when surgical haemostasis is achieved. mine anti-FXa activity (e.g. patients with renal insuffi- 1C ciency). We recommend that in VKA-treated patients undergoing Recommendation an emergency procedure or developing a bleeding com- We suggest that the administration of rFVIIa could be plication, PCC (25 IU FIX kg 1) should be given. 1B considered to treat severe bleeding associated with VKA treatment is monitored by measuring INR.592,1024 subcutaneous administration of fondaparinux (off-label Before surgical intervention, INR should be brought treatment). 2C below 1.5. VKA treatment may be interrupted before No drug acts as an antidote to fondaparinux. rFVIIa has elective surgery and resumed after surgery (with the first been proposed to control severe bleeding, but no evi- meal). Postoperative heparin is given if the INR is <2. dence exists to support this.1286 For urgent surgery, PCC (25 IU FIX kg1) should be given, and additional administration of 5 mg vitamin K1 (intravenous, subcutaneous or oral) is recommended. 9.3.3 Vitamin K antagonists (VKAs) VKAs are used in patients with mechanical heart valves, 9.3.4 Oral inhibitor of activated thrombin atrial fibrillation or venous thromboembolic disease. Dabigatran etexilate (Pradaxa, Boehringer Ingelheim, Long-acting VKAs are used more commonly than Ingelheim am Rhein, Germany) is the only available oral acenocoumarol (Table 2). antithrombin drug, and is licensed throughout Europe for Recommendations use in orthopaedic surgery. The bioavailability of dabi- We recommend that vitamin K antagonists (VKAs) gatran etexilate is 6–8%, its Tmax is 2 h and its terminal should not be interrupted for skin surgery, dental and half-life is 14–17 h. Dabigitran is renally eliminated and other oral procedures, gastric and colonic endoscopies exhibits no interaction with food.1284 (even if biopsy is scheduled, but not polypectomy), nor Two pivotal orthopaedic surgical studies have shown the for most ophthalmic surgery (mainly anterior chamber, efficacy of once-daily oral dabigatran (150 mg or 220 mg) e.g. cataract), although vitreoretinal surgery is sometimes to be as effective as subcutaneous enoxaparin.1287,1288 performed in VKA-treated patients. 1C Both drugs had similar safety profiles, with no signs of We recommend that for low-risk patients (e.g. atrial hepatotoxicity. A third study, comparing identical doses fibrillation patients with CHADS2 score 2 and patients of dabigatran and enoxaparin (30 mg twice daily), failed to treated for >3 months for a non-recurrent VTE) under- demonstrate equivalence, because more distal throm- going procedures requiring INR < 1.5, VKA should be boses were observed with dabigatran.1289 However, rates stopped 5 days before surgery. No bridging is needed. of proximal thrombosis, major bleeding and symptomatic Measure INR on the day before surgery and give 5 mg events did not differ between dabigatran and enoxaparin. oral vitamin K if INR exceeds 1.5. 1C The efficacy of dabigatran has been demonstrated in We recommend bridging therapy for high-risk patients atrial fibrillation patients; in a large study with a 2-year (e.g. atrial fibrillation patients with a CHADS2 score >2, follow-up, the frequency of primary outcomes (stroke or patients with recurrent VTE treated for <3 months, systemic embolism) was 1.53% per year with 110 mg patients with a mechanical valve). Day 5: last VKA dose; dabigatran twice-daily and 1.11% per year with 150 mg

Table 2 Vitamin K antagonists

VKA Molecule Half-life Steady state Initial dose Duration

Short half-life Acenocoumarol (Sintrom1) 10 h 2–3 days 4 mg 48–96 h 1 Long half-life Fluindione (Previscan ) 30–40 h 3–4 days 20 mg 48–72 h 1 Warfarin (Coumadin ) 35–80 h 3–6 days 5 mg 96–120 h Phenprocoumone (Marcoumar1) 3–4 days 6 days 6 mg 120–150 h

dabigatran twice-daily compared with 1.69% per year for although bleeding at the surgical site was not classified warfarin.1290 Relative risk with 110/150 mg dabigatran was as major bleeding. By integrating the surgical site, it was 0.91 and 0.66, respectively (P < 0.001 for non-inferiority found that haemorrhage occurred more frequently with and superiority). Rates of major bleeding were 2.71% per rivaroxaban than with enoxaparin.1296 year, 3.11% per year and 3.36% per year with 110 mg A study of high-risk patients with atrial fibrillation dabigatran, 150 mg dabigatran and warfarin, respectively. (ROCKET-AF trial) used a composite endpoint of all- Elsewhere, recurrent VTE was observed in 2.4% of cause stroke and non-central nervous system systemic patients receiving dabigatran (150 mg twice-daily), com- embolism.894 Rivaroxaban 20 mg once-daily, showed pared with 2.1% of patients receiving warfarin.1291 comparable benefits to warfarin (2.12% vs. 2.42%; Similar rates of major bleeding episodes were observed P < 0.001 for non-inferiority). Rates of major bleeding (1.6% vs. 1.9%). Overall, fixed-dose dabigatran was as were comparable between rivaroxaban and warfarin effective as warfarin, had a similar safety profile and did (3.60% vs. 3.45%; P ¼ 0.576). Compared with warfarin, not require laboratory monitoring. patients receiving rivaroxaban suffered fewer intracranial haemorrhages (0.49% vs. 0.74%; P ¼ 0.019), fewer critical The lack of biological monitoring with dabigatran could organ bleeds (0.82% vs. 1.18%; P ¼ 0.007) and fewer be considered as progress but may also bring insecurity to bleeding-related deaths (0.24% vs. 0.48%; P ¼ 0.003). physicians. A thrombin inhibitor assay (Hemoclot; Aniara, West Chester, OH) is now available to monitor Oral rivaroxaban alone (15 mg twice-daily for 3 weeks, dabigatran therapy.1292 then 20 mg once-daily) has been compared with subcutaneous enoxaparin followed by oral VKA (warfarin or No antidote is available for dabigatran etexilate. Dialysis acenocoumarol) for 3, 6 or 12 months for the treatment of has been shown to be effective to remove dabigatran. DVT (EINSTEIN DVT study).1297 Rivaroxaban dis- Treatments proposed for bleeding include PCC and played non-inferiority in the primary efficacy outcome rFVIIa, but neither has been tested clinically. Van Ryn (36 events [2.1%] vs. 51 events [3.0%] with enoxaparin/ et al.1292 investigated dabigatran neutralisation using a VKA; P < 0.001). The principal safety outcome occurred selective antibody; clinical data are awaited. In emergen- in 8.1% of patients in each group. cies, it may be advisable to wait for two half-lives (34 h) for dabigatran concentrations to reach acceptable con- Safety will remain a concern until high quality data are centrations. However, given widely varying interindivi- available. A specific anti-FXa activity test will become dual elimination rates, this is merely a fallback solution. available for monitoring rivaroxaban therapy.897 At the present time, the European Medicines Agency approval 9.3.5 Oral direct factor Xa inhibitors limitations should be adhered to. Several activated factor X (FXa) inhibitors are now mar- No antidote to rivaroxaban is available. Proposed therapy keted or in advanced stages of development. for major bleeding includes PCC and rFVIIa. No patient data exists which support this proposal, although PCC 9.3.5.1 Rivaroxaban effectiveness has been demonstrated in healthy volun- Rivaroxaban (Xarelto; Bayer Schering Pharma, Berlin- teers.1081 FXa analogues, which could potentially reverse Wedding, Germany) is an orally active oxazolidone anti-FXa agents, are currently being developed. In derivative and the first available oral anti-FXa agent. It emergencies, it may be necessary to wait for two half- is a potent anticoagulant with a wide therapeutic window. lives (14–26 h) to allow rivaroxaban to fall to acceptable Rivaroxaban has a bioavailability of 80% and a T of max concentrations. However, this is merely a fallback solution, 2–4h.1293 Rivaroxaban inhibits FXa (K 0.4 nM) and i given interindividual variability in rivaroxaban elimination binds to both free and clot-bound FXa. Two-thirds of rates. rivaroxaban is renally eliminated; its half-life is 9–13 h. The incidence of thromboembolic events was 49% lower 9.3.5.2 Apixaban (9.6% vs. 18.9%) in knee arthroplasty patients who Apixaban (Eliquis; Bristol-Myers Squibb, New York, NY) received rivaroxaban (10 mg once-daily) compared with is an oral, reversible, direct FXa inhibitor related to 40 mg enoxaparin (RECORD3 study).1294 An increased rivaroxaban. Its bioavailability is 51–85%, K is 0.08 nM bleeding incidence was not observed with rivaroxaban. In i and half-life is 10–15 h.1293 Elimination of apixaban is the RECORD1 study (35 days of prophylaxis after hip both hepatic/biliary (75%) and renal (25%). surgery), the primary efficacy outcome occurred in 1.1% of patients who received rivaroxaban compared with 3.7% In phase III studies, apixaban (2.5 mg twice-daily) was in the enoxaparin group (P < 0.001).1295 Major VTE administered following rheumatological surgery. In total occurred in 0.2% of patients receiving rivaroxaban and knee arthroplasty (ADVANCE-1 study),1298 the rate of the 2.0% of patients receiving enoxaparin (P < 0.001). Major primary efficacy outcome was 9.0% with apixaban and bleeding affected 0.3% of patients receiving rivaroxaban 8.8% with enoxaparin (30 mg twice-daily). Bleeding inci- compared with 0.1% receiving enoxaparin (P ¼ 0.18), dence was 2.9% with apixaban and 4.3% with enoxaparin Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 339

(P ¼ 0.03). However, apixaban did not meet the non- interindividual variability in the elimination rate of apix- inferiority criteria because the overall rate of primary aban, this is merely a fallback solution. events was lower than anticipated. 9.3.5.3 Edoxaban The ADVANCE-2 study, also in knee replacement surgery, compared apixaban with 40 mg enoxaparin, Edoxaban (Daiichi Sankyo Co., Ltd., Tokyo, Japan) is administered once-daily.1299 The primary efficacy out- the third oral anti-FXa agent to be marketed. After oral come occurred in 15.1% of patients receiving apixaban administration, peak plasma concentrations of edoxaban and 24.4% receiving enoxaparin (P < 0.001). Major VTE are achieved within 1–2 h. Terminal elimination half-life for doses of 30–150 mg is typically 8–10 h, with 36–45% occurred in 1.1% of patients treated with apixaban and 1293 2.2% of patients treated with enoxaparin (relative risk eliminated renally. 0.50; P ¼ 0.019). Clinically relevant bleeding occurred in Oral edoxaban (15–90 mg once-daily) was compared with 3.5% of patients receiving apixaban and 4.8% of patients subcutaneous dalteparin (5000 IU once-daily) follow- given enoxaparin (P ¼ 0.09). In hip replacement patients ing hip replacement surgery. Both drugs were given for (ADVANCE-3 study), the relative risk reduction with 7–10 days.1302 Frequencies of VTE were 28.2%, 21.2%, apixaban was 64% (1.4% vs. 3.9%, P < 0.0001).1300 Apix- 5.2%, and 10.6% for 15, 30, 60 and 90 mg edoxaban once- aban was also statistically superior to a 40 mg dose of daily, respectively (statistically significant dose response, enoxaparin for preventing major VTE (0.45% vs. 1.14%; P < 0.001), and 43.8% in patients receiving dalteparin P ¼ 0.0054). Bleeding event rates were similar for both (P < 0.005). Bleeding incidence was low and comparable treatment groups. between groups. A large development programme for apixaban is now No antidote to edoxaban is available. FXa analogues, almost completed. In patients with atrial fibrillation, which could potentially reverse the effects of anti Xa the AVERROES study892 was stopped prematurely agents, are being developed. In emergencies, it may be because apixaban reduced the risk of stroke or systemic necessary to wait for two half-lives (10–22 h) to allow embolism by 57% compared with aspirin, with no sig- edoxaban to reach acceptable concentrations. However, nificant increase in major haemorrhage risk. The given wide variability in interindividual elimination rates, ARISTOTLE study1301 compared apixaban and warfarin this is merely a fallback solution. in 18 201 patients with atrial fibrillation. The rate of the primary outcome (ischaemic or haemorrhagic stroke, or 9.3.6 Management of patients scheduled for a systemic embolism) was 1.27% per year in the apixaban procedure and treated with new oral anticoagulant group, compared with 1.60% per year in the warfarin agents (emergency procedures excluded) group (hazard ratio with apixaban, 0.79; 95% CI, 0.66– Physicians from outside the field may be unaware of 0.95; P ¼ 0.01 for superiority). The rate of major bleeding the pharmacological characteristics of many new oral was 2.13% per year in the apixaban group, compared with anticoagulant agents (NOAs). A multidisciplinary, inter- 3.09% per year in the warfarin group (hazard ratio, 0.69; national group of physicians (Groupe d’Inte´reˆten 95% CI, 0.60–0.80; P < 0.001), and the rates of death from He´mostase Pe´riope´ratoire) has issued proposals for mana- any cause were 3.52% and 3.94%, respectively (hazard ging patients treated with NOAs.1078 As for VKA therapy, ratio, 0.89; 95% CI, 0.80–0.99; P ¼ 0.047). three patient groups are considered. For biological monitoring, assessment of anti-FXa may be Recommendations useful (Table 3). We recommend to assess creatinine clearance in patients receiving NOAs and being scheduled for surgery. No antidote to apixaban is available. FXa analogues, 1B which could potentially reverse anti-FXa agents, are We suggest that NOAs should not be interrupted for skin currently under development. In emergencies, it may surgery, dental and other oral procedures, gastric and be necessary to wait for two half-lives (20–30 h), to allow colonic endoscopies (even if biopsy is scheduled, but not apixaban to reach acceptable concentrations. Given wide polypectomy), nor for most ophthalmic surgery, (mainly

Table 3 Comparison of new oral antithrombotic agents

Rivaroxaban Apixaban Edoxaban Dabigatran Etexilate

Target Factor Xa Factor Xa Factor Xa Thrombin Brand name Xarelto Eliquis Lixiana Pradaxa Route of administration Oral Oral Oral Oral Bioavailability 80% 51–85% 60% 6–8% Tmax 2–4h 3h 1–3h 2h Half-life 9–13h 9–14h 5–11h 14–17h Frequency of administration Once-daily Twice-daily Once-daily Once- or twice-daily Renal excretion 66% (half inactive) 25% 36–45% 80% Antidote No No No No

anterior chamber, e.g. cataract), although vitreoretinal thyroid disease, all responded favourably to desmopres- surgery is sometimes performed in NOA-treated patients. sin.1305 2C We recommend that for low-risk patients (e.g. atrial 10.1.2 Patients on chronic medication associated fibrillation patients with CHADS2 score 2, patients with haemostatic derangements treated for >3 months for a non-recurrent VTE) under- Medications other than antiplatelet and anticoagulant going procedures requiring normal coagulation (normal agents (discussed elsewhere in these guidelines – see diluted thrombin time or normal specific anti-FXa level), section 9) may potentially affect haemostasis, including NOAs can be stopped 5 days before surgery. No bridging selective serotonin reuptake inhibitors (SSRIs), valproic therapy is needed. 1C acid and Ginkgo biloba. In patients treated with rivaroxaban, apixaban, edoxaban Recommendation and in patients treated with dabigatran in which creati- We suggest that SSRI treatment should not be routinely nine clearance is higher than 50 ml min 1, we suggest discontinued perioperatively. 2B bridging therapy for high-risk patients (e.g. atrial fibrilla- SSRIs have been associated with an increased bleeding tion patients with a CHADS2 score >2, patients with tendency, due to serotonin depletion from platelets.1306 recurrent VTE treated for <3 months). Day 5: last NOA Bleeding frequency appears proportionate to the degree dose; Day 4: no heparin; Day 3: therapeutic dose of of serotonin reuptake inhibition. LMWH or UFH; Day 2: subcutaneous LMWH or UFH; Day 1: last injection of subcutaneous LMWH (in the In patients undergoing orthopaedic surgery, intraoperative morning, i.e. 24 h before the procedure) or subcutaneous blood loss increased by 75% among patients using SSRIs, UFH twice daily (i.e. last dose 12 h before the pro- and the risk of blood transfusion almost quadrupled cedure), hospitalisation and measurement of diluted (adjusted odds ratio, 3.71). Patients taking non-serotoner- thrombin time or specific anti-FXa; Day 0: surgery. 2C gic antidepressants had no increased risk (odds ratio, 0.74).1307 However, comedications (NSAIDs, methotrex- In patients treated with dabigatran with a creatinine clear- ate or iron supplements) also increased transfusion risk. ance between 30 and 50 ml min 1, we suggest to stop NOAs 5 days before surgery with no bridging therapy. 2C A study of patients undergoing elective primary total hip arthroplasty reported increased (95 ml or 17%) intraopera- We suggest that for groups 2 and 3, heparin (UFH or tive blood loss among SSRI users compared with users of LMWH) should be restarted 6–72 h after the procedure, non-serotoninergic antidepressants.1308 However, transfu- taking the bleeding risk into account. NOAs may be sion requirements were not increased. Similarly, preopera- resumed when surgical bleeding risk is under control. 2C tive SSRI therapy has been shown not to increase 10 PERIOPERATIVE BLEEDING allogeneic RBC transfusion during CABG surgery. MANAGEMENT IN PATIENTS WITH Adjusted relative risks for transfusion among users of COMORBIDITIES WITH HAEMOSTATIC SSRIs, non-selective serotonin reuptake inhibitor anti- DERANGEMENTS AND CONGENITAL depressants and other antidepressants were 1.1, 0.9, and BLEEDING DISORDERS 1.0, respectively, compared with patients not using antidepressants.1309 A retrospective Australian study per- 10.1 Patients with comorbidities involving formed on 4136 patients who underwent CABG surgery haemostatic derangement also showed that neither SSRI use, nor SSRI and conco- 10.1.1 Systemic, metabolic and endocrine diseases mitant antiplatelet medication, increased the risk of any Recommendation bleeding events.1310 However, in a large cohort study, it We suggest that patients with haemostatic derange- has been shown that patients taking an SSRI together with ments associated with systemic, metabolic and endo- aspirin or dual antiplatelet therapy following acute myo- crine diseases should be managed perioperatively in cardial infarction were at increased risk of bleeding.1311 collaboration with a haematologist.2C Therefore, discontinuation of SSRIs before surgery is not Systemic, metabolic and endocrine diseases (e.g. amyloi- recommended.1312 When used alongside other antiplatelet dosis, hypothyroidism) are associated with haemostatic agents, perioperative use of SSRIs should be indivi- derangements. Optimal management strategies for these dualised. coagulopathies remain unclear. Recommendation Acquired FX deficiency causes the most frequent bleed- We suggest individualised perioperative discontinuation 1303 ing manifestations in amyloidosis and is treated of antiepileptic agents, such as valproic acid, which may similarly to inherited FX deficiency. increase bleeding. 2C Bleeding diathesis in overt hypothyroidism is mainly due The antiepileptic drug valproic acid decreases levels of to acquired type 1 VWD.1304 In a study of patients with FVII, FVIII, FXIII, platelets, VWF, fibrinogen, protein C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 341

and antithrombin.1313,1314 However, clinically relevant also limited predictive value for identifying patients detriment to haemostasis is uncommon.1315,1316 with common MBDs but high negative predictive values.1326,1327 Recommendation We do not recommend discontinuation of Gingko biloba However, questionnaires can be used to assess bleeding extracts.1B severity of VWD. A mucocutaneous bleeding score (spontaneous, mucocutaneous symptoms) was at least The effects on blood coagulation have been questioned as effective as laboratory testing (circulating levels of due to some case reports of spontaneous bleeding VWF and FVIII:C) for predicting bleeding after tooth after taking Ginkgo preparations. A meta-analysis of extraction, and superior to laboratory testing following 18 randomised controlled trials did not indicate a higher surgery.1328 In children with VWD, the median bleeding bleeding risk associated with standardised Ginkgo biloba score has been reported as 7, compared with 0 in con- extracts provided as daily oral therapy.1317 trols.1329 The most frequent clinically signiﬁcant bleed- Ginkgo biloba combined with aspirin also has no impact ing symptoms were surgical bleeding, bleeding after on coagulation indices.1318,1319 tooth extraction and menorrhagia.

10.2 Patients with congenital bleeding 10.2.1.2 Perioperative management disorders Recommendations 10.2.1 Von Willebrand disease We recommend that patients with VWD be managed VWD is the most common hereditary bleeding disorder perioperatively in collaboration with a haematologist. 1C with an estimated prevalence of 0.6–1.3%.1320 The dis- Reviews and guidelines covering the management of ease is caused by deficiency or dysfunction of VWF and is 1320,1321,1330,1331 classified into three major categories, which are specifi- VWD have been published. All agree that cally treated: partial quantitative deficiency (type 1); patients should be managed in specialised centres. How- qualitative deficiency (type 2, with four variants: 2A; ever, recommendations for the diagnosis and treatment of 2B; 2 M; and 2N); and total deficiency (type 3).1320,1321 VWD are based on observational studies and case series, Acquired von Willebrand syndrome comprises defects in and are therefore of low grade. VWF concentration, structure or function arising from There are three strategies to prevent or control bleeding 1322 medical disorders or treatments. in VWD: release stored endogenous VWF by stimulating Bleeding in VWD is due to impaired platelet adhesion endothelial cells with desmopressin; replace VWF using and/or reduced levels of FVIII1320 and is usually mild.1321 plasma-derived concentrates; or promote haemostasis with antifibrinolytic drugs or platelet transfusion. 10.2.1.1 Preoperative evaluation The National Heart, Lung, and Blood Institute guide- Recommendations lines recommend the following:1320 We suggest that if VWD is suspected preoperatively, the patient should be referred to a haematologist for assess- 1. Treat minor bleedings with desmopressin after a trial ment and planning of the intervention.2C performed before clinical use. 2. Use VWF concentrate if the response to desmopressin We recommend the use of bleeding assessment tools for is inadequate. predicting the perioperative risk of bleeding.1C 3. Administer desmopressin and VWF concentrate based Diagnosis of VWD is complex, and no universal approach on VWF:RCo and FVIII activity concentrations. applies. Initial tests for diagnosing VWD include VWF 4. For severe bleeding or prophylaxis for major surgery, ristocetin cofactor activity (VWF:RCo), VWF antigen VWF:RCo and FVIII levels should be 100– (VWF:Ag) and FVIII coagulant activity (FVIII:C).1320 200 IU dl 1 and 100–250 IU dl 1, respectively. Laboratory testing should be guided by history and 5. Subsequent dosing should maintain VWF:RCo and physical examination.1323 FVIII levels above 50 IU dl 1 for 7–10 days. 6. For prophylaxis for minor surgery, VWF:RCo and Structured questionnaires and bleeding scores are useful 1 1324 FVIII levels should be >30 IU dl (preferably for the diagnosis. A quantitative bleeding assessment >50 IU dl 1) with maintenance for 1–5 days. tool (BAT) has been evaluated for diagnosing mild 7. For oral surgery in mild–moderate VWD, combined bleeding disorders (MBDs).1325 The positive predictive desmopressin and antifibrinolytic drugs should be values in patients referred for haemostatic or familial given. evaluation were 71.0% and 77.5%, respectively. Bleeding 8. Restrict fluids to maintenance levels in young children scores 3 had a high negative predictive value which and surgical patients receiving desmopressin. increased to 99.6% when aPTT measurement was added. Therefore, exclusion of MBDs may be feasible based on Italian guidelines are similar, except for the lower target BAT and aPTT. In children, the bleeding scores have and peak concentrations of FVIII recommended for Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 342 Kozek-Langenecker et al.

prophylaxis before major surgery and to be avoided for 20–40 U kg1 every 8–24 h for maintenance.1320 For preventing the risk of thrombosis, respectively.1330 minor surgery, the doses are slightly lower, given less frequently and for a shorter duration. Treatment of Other European centres recommend that guidelines VWD-related bleeding with VWF concentrates should should be stratified for the severity of bleeding, the type take account of individual product content and pharma- of surgery and also for the bleeding score in either VWD cokinetic data for the relevant disease severity.1351 type 1, 2 or 3.1332 Perioperative monitoring of FVIII:C and VWF:RCo may Recommendation help determine appropriate dosing.1320 Depending on We recommend desmopressin as a first-line treatment for VWD type and the concentrate used, PFA-100 might minor bleeding/surgery in patients with VWD, after a trial be useful for monitoring the response to FVIII/VWF testing. Treatment regimens are specified by published substitution.1352 guidelines. 1C Adverse reactions to VWF concentrates include allergic Despite a lack of RCTs investigating desmopressin and anaphylactic reactions.1343 in VWD, desmopressin has been shown to increase plasma VWF and FVIII concentrations from two-fold VWF concentrates contain FVIII, and therefore carry a 1353 to more than five-fold over baseline concentrations, with potential thromboembolic risk; antithrombotic pro- 1341 good and excellent results in most surgical adult phylaxis should be considered. 1333–1336 1337–1339 patients as well as children. Recommendation The standard desmopressin dose is 0.3 mgkg1 given We suggest that antifibrinolytic drugs should be used as intravenously, repeated every 12–24 h.1320 Response haemostatic adjuncts. Treatment regimens are specified rates are reduced in children <2 years old.1337 by published guidelines. 2C Desmopressin is usually effective in type 1 VWD; how- Antifibrinolytic therapy may facilitate effective clotting. ever, not all patients respond to this agent.1320 In a type 1 Evidence supporting local application of antifibrinolytics VWD cohort (n ¼ 77), 83% of patients displayed a com- is limited, but this treatment has a pharmacodynamic 1354 plete response to desmopressin; 13% exhibited a partial rationale. Adjuvant local therapy with tranexamic acid response and 4% had no response.1333 Similarly, a 17% added to desmopressin prevented bleeding compli- risk of bleeding complications after adenotonsillar pro- cations during oral surgery in 84% of VWD patients 1334 cedures was reported in children receiving prophylactic and reduced the need for factor concentrates. 1340 desmopressin. These studies reinforce the import- For adults, a dose of 4–5 g EACA (oral or intravenous) is ance of a preoperative test infusion of desmopressin. recommended, followed by 1 g h1 until bleeding is 1321 Desmopressin is variably effective in types 2A, 2N and controlled, or for 5–7 days postoperatively. Tranexa- 1 2 M VWD, ineffective in type 3 VWD1330 and contro- mic acid is given intravenously at a dose of at 10 mg kg 1320,1321,1330 versial in type 2B VWD.1321 every 8–12 h. Tachyphylaxis and hyponatraemia are frequent adverse Recommendation effects of desmopressin.1321,1332 Arterial thrombosis has We suggest that platelet transfusion should be used only also been reported anecdotally.1341 Hyponatraemia and in case of failure of other treatments.2C 1338 seizures have been reported in paediatric cases. When haemorrhage persists despite increased VWF/FVIII levels, administration of platelet concentrate can be help- Recommendation 1355 ful. Platelet concentrates are effective, particularly in We recommend replacement of VWF with plasma- patients with type 3 VWD, probably because of their role in derived products for major bleeding/surgery. Treatment transporting VWF to sites of vascular injury.1321 regimens are specified by published guidelines. 1C VWF can be supplied by cryoprecipitate or human 10.2.2 Platelet defects plasma-derived concentrates. Cryoprecipitate is not Many classification schemes have been proposed for inher- virus-inactivated and its use is strongly discouraged, ited platelet disorders.1356,1357 They are uncommon con- except in life-threatening situations when concentrates ditions which can alter circulating platelet numbers, are not available.1320 function or both. Prominent inherited platelet defects Plasma-derived VWF concentrates may prevent exces- include Glanzmann thrombasthenia (deficiency or func- sive bleeding in over 90% of VWD patients.1321 The tional defect of receptor GPIIb/IIIa) and Bernard-Soulier efficacy has been confirmed in surgical paediatric1342,1343 syndrome (dysfunction or absence of receptor GPIb/IX/V). and adult patients with VWD.1336,1343–1350 Both conditions may cause severe bleeding.1356,1358,1359 For bleeding treatment/prevention in major surgery, Bleeding with other platelet abnormalities is usually a loading dose of 40–60 U kg 1 is recommended, with mild/moderate, so they are described as MBDs;1359 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 343

VWD is included in this category. Typically, they mani- Most MBDs respond to desmopressin and/or antiﬁbrino- fest as mucocutaneous bleeding, or bleeding following lytic drugs, regardless of aetiology.1359 However, trauma or invasive surgical or dental procedures. platelet function disorders require specialist management.1356,1358

10.2.2.1 Preoperative evaluation The benefits of prophylactic correction of congenital Recommendations platelet dysfunction were shown in a prospective study We suggest referring the patient to a haematologist for including 72 patients with impaired primary haemo- 93 assessment and planning of the intervention if inherited stasis. Patients with inherited primary haemostatic platelet defects are suspected preoperatively. 2C impairment (platelet dysfunction including VWD) were preoperatively treated with desmopressin. Most non- We recommend the use of bleeding assessment tools for responders, defined by persistently abnormal PFA-100 predicting the perioperative risk of bleeding. 1C platelet function tests, additionally received tranexamic Diagnosis of platelet defects is challenging. Bleeding acid or aprotinin; those with VWD were treated with history is a prerequisite for diagnosing bleeding disorders VWF concentrate, conjugated oestrogens and platelet and should inform the selection of laboratory investi- transfusion. In almost all cases, prophylactic treatment gations.1360 However, MBDs may be undetectable from successfully corrected PFA-100 parameters. The fre- the bleeding history.1359 Bleeding scores and quantitative quency of blood transfusion was lower (9.4% vs. 12.2%: 1361 ¼ BATs have been proposed for diagnosing MBDs. P 0.202) in preoperatively treated patients with Prospective studies found that structured bleeding ques- impaired haemostasis than in patients without impaired tionnaires have a high negative predictive value but a haemostasis. In a retrospective group, the frequency of low/moderate positive predictive value both in adults1325 blood transfusion was significantly higher (89.3% vs. and in children referred for diagnosis.1327 Measurement 11.3%: P < 0.001) in patients without preoperative cor- of aPTT in addition to a bleeding score significantly rection of impaired haemostasis than in patients without increased the diagnostic efficiency for exclusion of impaired haemostasis. Thus, preoperative correction of patients with suspected MBD in a low-prevalence set- impaired primary haemostasis appears possible in most ting.1325 patients, and reduces homologous blood transfusions. In children, it was shown that questionnaire scores differ Recommendation among diagnostic groups, giving the potential for strati- We suggest that desmopressin should be used to fication of bleeding severity and therefore prediction of prevent/control perioperative bleeding in patients with bleeding risk during surgical or dental procedures.1362 inherited platelet defects. 2C However, no relationship is apparent between bleeding The more common, less severe platelet disorders severity and VWF/platelet function variables and the typically respond well to desmopressin, either pro- diagnostic efficacy of laboratory testing for hereditary phylactically before elective procedures or following 1357,1365 mucocutaneous bleeding was 40.4%.1363 Therefore, trauma. Desmopressin shortens bleeding time platelet function defects constitute risk factors rather and is therefore assumed to provide clinical benefit. than the unequivocal causes of haemorrhage. Most evidence supporting the clinical efficacy of desmo- PFA-100 has a high rate of false positive and false pressin in platelet disorders comes from case reports or 1356 negative results and does not predict bleeding risk.1356 small case series, and only one old placebo-controlled 1366 The C-EPI parameter is not sufficiently sensitive to be study. The latter study found that desmopressin recommended as a haemostasis screening test,1364 shortened bleeding time and was sufficient for periopera- although it correlates with severity of bleeding history.1327 tive management, dependent on the underlying platelet defect. Desmopressin has also been reported as haemos- Furthermore, no consensus currently exists regarding the tatically effective during obstetric delivery in patients standardisation and interpretation of in vitro platelet with mild platelet defects.1367 However, efficacy appears aggregation/secretion studies for the definitive diagnosis variable, both in mild and in severe platelet defects,1357 of a platelet defect. and has rarely been shown in Glanzmann thrombasthenia.1358 10.2.2.2 Perioperative management If desmopressin is contraindicated or is not effective, Recommendations patients should receive platelet transfusion or possibly We recommend that patients with severe inherited rFVIIa.1356 platelet disorders should be managed perioperatively Recommendation in collaboration with a haematologist.1C We suggest that antifibrinolytic drugs should be used as We suggest preoperative haemostatic correction in haemostatic adjuncts in procedures involving patients patients with inherited platelet disorders.2C with inherited platelet defects. 2C Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 344 Kozek-Langenecker et al.

Antifibrinolytic drugs are useful as adjunctive Platelet transfusions are appropriate in severe platelet therapy;1356,1357 minor bleeding (e.g. dental procedures) defects and when other options have failed. Due to may respond to these agents alone.1358 The use of anti- uncertainty concerning rFVIIa efficacy, platelets are fibrinolytic drugs in inherited platelet disorders is not recommended for major elective surgery in patients with evidence-based. However, tranexamic acid can partially Glanzmann thrombasthenia and Bernard–Soulier syn- reverse effects of clopidogrel in cardiac surgery.72 drome.1356,1365 First doses should be given preoperatively with further doses depending on clinical need. For emer- Recommendation gency procedures, random donor platelets may be given, We recommend that rFVIIa treatment should be con- albeit with a high risk of alloimmunisation which can sidered in patients with Glanzmann thrombasthenia limit future responses.1365 undergoing surgery. 1C Inherited thrombocytopaenias are generally managed rFVIIa is licensed for use in Glanzmann thrombasthenia, similarly to mild platelet disorders.1371 Thrombocytopae- in which platelet transfusion may be ineffective. Appro- nic patients without evidence of platelet dysfunction priate dosing may be 90 mgkg 1 immediately preopera- should be treated according to platelet count. Platelet tively, repeated every 2 h for 12 h, then every 3–4 h until transfusion guidelines recommend 50 000 ml 1 for liver the risk of rebleeding subsides.1356 An international biopsy, laparotomy, central line insertion and for major registry including 59 patients with Glanzmann throm- surgery, except ophthalmological and neurological basthenia showed that rFVIIa was effective in 29/31 surgery, when 100 000 ml 1 is recommended.929 Trans- surgical procedures and in 77/103 bleeding episodes, 1368 fusions are usually effective if platelet count is raised eight of which recurred. Increased success was above 20 000–30 000 ml 1. observed in severe bleeding episodes when a regimen including 80 mgkg 1 by injection, a dosing interval Although guidelines recommend a preoperative platelet 2.5 h and 3 doses before failure declaration, was used. transfusion threshold of <50 000 ml1, supporting evi- Patients receiving maintenance doses experienced fewer dence is weak.927 An old study of thrombocytopenic bleeding recurrences within 48 h than those not receiving patients with acute leukaemia showed that surgery is maintenance doses. One thromboembolic event and one safe even in patients with platelet counts <50 000 ml1, ureteral blood clot occurred with high-dose rFVIIa. provided that optimal supportive care is available.1372 Further thrombotic complications related to rFVIIa Central venous catheters can also be inserted safely therapy have been reported.1031 in acute leukaemia patients with platelet counts 20 000 ml1 without platelet transfusion, provided that No reliable data exist concerning rFVIIa in bleeding due to other coagulation abnormalities are absent.1373 platelet dysfunction and the drug is not licensed for other platelet disorders. In one study, rFVIIa was used in Recent data suggest also administering fewer platelet children with inherited platelet function disorders: Glanz- transfusions, at lower doses. However, a meta-analysis mann thrombasthenia (n ¼ 5); Bernard–Soulier syndrome showed that high-dose platelet transfusion (3.35–7.7 (n ¼ 1); and storage pool disease with severe phenotype 1011 l1) increased the transfusion interval compared with (n ¼ 1).1369 Variable results were seen in Glanzmann low-dose platelet transfusion (2.01–4.6 1011 l1).1374 thrombasthenia, although surgical procedures were suc- The increase in post-transfusion platelet count was cessfully covered. Importantly, good/excellent responses also higher in patients receiving the higher dose, with were observed in 10/14 bleeding episodes (71%) treated ABO-compatible transfusions. Although bleeding inci- within 12 h, but only 2/11 (18%) treated after 12 h. dence appeared to be independent of platelet count, the above data coming from haemato-oncology should not be In another study, patients with Glanzmann thrombasthe- extrapolated to inherited thrombocytopaenia. nia with bleeding episodes or undergoing dental surgery were treated with antifibrinolytic drugs, with or without 10.2.3 Haemophilia A and B additional rFVIIa. In most cases of mild/moderate muco- Haemophilia A is characterised by reduced plasma FVIII cutaneous bleeding, antifibrinolytic drugs and local coagulant activity (FVIII:C), and Haemophilia B by FIX measures were considered sufficiently effective, render- deficiency. The prevalence of haemophilia A is 1:10 000, ing rFVIIa unnecessary.1370 However, prophylactic compared with 1:60 000 for haemophilia B.1375 administration of rFVIIa was effective in avoiding bleeding during teeth extractions. Haemophilia patients may develop spontaneous bleeding into joints and bleed excessively after injury or Recommendations surgery. Clinical severity of the bleeding correlates with We recommend against routine platelet transfusion in the degree of deficiency.1376 Haemophilia A is classified patients with inherited platelet disorders.1C as mild, moderate or severe, depending on FVIII:C There is insufficient evidence to recommend a threshold concentration. Mildly affected patients bleed excessively for perioperative prophylactic platelet transfusion in only after trauma or surgery and may have normal routine thrombocytopaenic patients. C coagulation test results.1377 Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 345

Factor replacement therapy can induce anti-FVIII or postoperative week. The recommended concentrations anti-FIX antibodies, known as ’inhibitors’. These are for haemophilia B are slightly lower: 60–80%, 40–60%, more common in severe forms of haemophilia.1341 Devel- 30–50%, and 20–40%, respectively.1387 opment of inhibitors in mild haemophilia can change An appropriate factor concentration should be main- bleeding phenotype from mild to severe.1377 tained for 5–7 days or until wound healing after minor Some carrier females have reduced coagulation factor surgery, and for 10–14 days after major surgery. For concentrations1376 and this is important when specific minor invasive procedures (lumbar puncture, arterial replacement therapy may be required. blood gas determination, bronchoscopy with brushings or biopsy, and gastrointestinal endoscopy with biopsy), Acquired haemophilia is a rare but potentially life-threa- replacement therapy should only be given before the tening haemorrhagic disorder caused by the development procedure.1387 of autoantibodies against FVIII. It may be associated with malignancy, autoimmune disorders, drug reactions and A literature review and a survey of European practice pregnancy.1378 were published recently.1379 Although high-quality studies are lacking, replacement therapy appeared Haemophilia therapy involves infusion of coagulation efficacious in perioperative management of haemophilia factor concentrates, either prophylactically or during A. The recommendations formulated by the authors are bleeding. Mild haemophilia may be treated with desmo- similar to those formulated by the WFH. For liver biopsy, pressin and tranexamic acid rather than coagulation preoperative factor concentrations should be >80% and factors.1341 replacement therapy should continue for 3 days. For Recommendations children undergoing surgery, preoperative factor concen- We recommend that haemophilia patients should be trations should generally be >80% and therapy should be referred preoperatively to a haematologist for assess- maintained for 7–10 days after tonsillectomy, 3–4 days ment/intervention. 1C after circumcision, and 3 days after central venous access device insertion.1379 For dental extractions, treat- We recommend that surgery in haemophilia patients ment with clotting factor concentrate is recommended to should be performed in specialised centres with exper- obtain a minimum factor concentration of 50%. tise in coagulation disorders. 1C The European survey1379 also demonstrated extensive With adequate therapy provided in specialised centres, heterogeneity in clinical practice. However, in most set- haemophilia patients can safely undergo most surgical tings there was agreement between published data and 1379–1382 procedures. Retrospective cohort studies found clinical practice concerning the intensity and duration of 1382 the same outcome after orthopaedic surgery or gen- replacement therapy. eral surgery1381 compared to non-haemophilia controls. General surgical and endoscopic procedures were per- Clinical effects of different coagulation factor concen- formed with low morbidity (4% haemorrhagic compli- trations have not been investigated, and minimum cations) and mortality rates (1.4%) with appropriate factor haemostatic concentrations of individual factors cannot replacement and good support from the haemophilia be defined. Only one study showed that lower factor 1388 team.1380 Surgical procedures are also safe in children concentrations may be safe in surgical procedures. with haemophilia provided that a standard protocol is Conversely, a high–level clotting factor replacement followed.1383 regimen which maintains the preoperative high concentration for a longer period of time appeared to favour Recommendations wound healing and to decrease the infection rate in total We recommend adequate perioperative replacement knee arthroplasty.1389 therapy to ensure safe surgery in haemophilia patients. FFP and cryoprecipitate have relatively low clotting 1C factor concentrations and potential viral transmission We suggest that perioperative replacement therapy (tar- risks. These products are indicated only if concentrates get factor levels and duration) in haemophilia patients are not available.1379,1387 follows published guidelines.2C Few reviews of periprocedural replacement therapy have Recommendation We recommend either recombinant products or plasma- been published, and consensus recommendations are derived concentrates for perioperative replacement country-specific.1341,1384–1386 The World Federation of therapy in haemophilia patients. 1C Haemophilia (WFH) recommends that in patients undergoing major surgery, preoperative factor levels should be Both plasma-derived and recombinant FVIII products 80–100%. Postoperatively, factor concentrations should proved efficacious for preventing/treating bleeding epi- be maintained at 60–80% during days 1 to 3, 40–60% sodes in haemophilia patients.1390,1391 Although all during days 4 to 6 and 30–50% during the second plasma-derived coagulation factor concentrates have Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 346 Kozek-Langenecker et al.

excellent safety, UK guidelines recommend recombi- FVIII product showed similar surgical bleeding in severe nant, rather than plasma-derived, products.1341 haemophilia patients compared with non-haemophilia control patients.1408 Increased risk of inhibitor develop- The question of whether plasma-derived or recombinant ment has been linked with continuous infusion,1409 but products are preferable is still under discussion.1390,1391 It other data do not confirm this risk.1410 has been suggested that plasma-derived products induce fewer inhibitors than recombinant FVIII.1391 One study Continuous infusion is used in nearly half of patients showed that recombinant FVIII carries a 2.5–3-fold undergoing major orthopaedic surgery, a greater pro- higher risk of inhibitor development than plasma– portion than suggested by the literature1379.Ina derived FVIII/VFW.1392 In a paediatric study, increased cross–sectional study performed in 22 European centres risk of inhibitor formation was associated with early including 742 patients, continuous infusion was haemos- exposure to recombinant products.1393 Conversely, tatically very effective (median incidence of postopera- another study demonstrated no significant difference in tive bleeding 1.8%) without increasing the risk of risk of inhibitor development between plasma-derived inhibitor development.1411 Half of the centres aimed FVIII and recombinant FVIII.1394 In addition, the safety to maintain high FVIII levels of >0.8–1.0 IU ml1 during and efficacy of recombinant FVIII has been shown in a the early postoperative period, employing an initial infu- post-marketing observational study.1395 sion rate of 4.0–5.0 IU kg1 h1. Despite the high target Two systematic reviews reported discordant concentration, the impact of continuous infusion on over- results.1396,1397 A prospective cohort study showed that all cost was favourable. the degree of FVIII purity but not the source of the Continuous infusion of FIX has also been associated with product influences inhibitor development independently excellent haemostasis and safety.1412–1414 from other risk factors.1398 In this study there was an increased inhibitor risk with recombinant FVIII and Recommendation high-purity plasma-derived FVIII compared to low/inter- We suggest treatment with either rFVIIa or activated mediate-purity plasma-derived FVIII. PCCs for haemophilia patients with inhibitors.2C In haemophilia B, there is also evidence that both plasma- Bleeding in haemophilia patients with inhibitors is derived and recombinant products are effective in usually treated with bypassing agents such as PCC perioperative management,1399–1401 providing similar (either activated, which can produce thrombin without outcomes to those observed among non-haemophiliacs. any requirement for FVIII, or non-activated) or 1415,1416 If recombinant FIX is unavailable, FIX concentrate is rFVIIa. Large quantities of human factor concen- preferable to PCC, which carries thrombotic risks.1341 trates or porcine products and plasmapheresis are other options to overcome the inhibitors.1341 Two systematic reviews of thrombotic adverse events1402 and non-thrombotic, non-inhibitor-associated adverse A systematic review found that high-dose FVIII was highly reactions1403 to factor FVIII/FIX concentrates used for successful (100%) in patients with low-titre, low-respond- treatment of haemophilia and VWD confirm these pro- ing inhibitors undergoing surgery, although not reliable for ducts’ high degree of safety. Over a 20 year period, only high-responding inhibitors.1417 Porcine FVIII was effec- 20 thrombotic events (2 major and 18 superficial throm- tive for controlling bleeding in 60–90% of perioperative bophlebitis) and 12.3% allergic reactions were identified, bleeding in patients with high-titre or high-responding respectively. No differences were reported between the inhibitors. No evidence supported PCC use in surgery, plasma-derived and recombinant products in the inci- while APCCs controlled approximately 90% of surgical dence of these events. bleeding episodes. rFVIIa controlled 60–100% of surgical bleeding episodes in patients with high-responding inhibi- Recommendation tors; results were better when rFVIIa was used early. We suggest that coagulation factors should be given perioperatively by continuous infusion. 2C In a post-marketing surveillance study of patients with inhibitors, an APCC (FVIII inhibitor bypassing activity Continuous infusion of replacement factors may reduce [FEIBA]) showed efficacy of 82% and 91% in acute and ‘wasteful’ peaks followed by subtherapeutic concen- surgical treatments, respectively.1035 Additionally, pro- trations, compared with bolus infusion.1404 For severe phylactic treatment improved or stabilised clinical ortho- haemophilia A patients undergoing surgery, continuous paedic status in 11/13 patients (85%). With a small infusion has been shown to reduce FVIII dosage by 36% number of adverse events (<0.04%), FEIBA was judged compared with bolus infusion, while reducing major to be safe. No thrombotic complications were reported. bleeding complications to zero (compared with a 17% Further studies have since confirmed the efficacy of incidence in patients receiving bolus infusion; P ¼ 0.06). APCC.1036,1038,1418–1421 The efficacy of continuous infusion has been confirmed in other studies.1405–1407 The first study designed to The dose varied between 50 and 100 IU kg1 given obtain regulatory approval for continuous infusion of a before surgery and thereafter at 6–12-h intervals, Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 347

adjusted to an approximate maximum of 200 IU kg1 to APCC for mild/moderate bleeding in this patient day1 and tapered when postoperative haemostasis and population.1428 In addition, orthopaedic surgery with wound healing permitted. In one study, the median rFVIIa in haemophilia patients with inhibitors is perioperative dose was 130 IU kg1 day1 over 12 days generally cost-saving, relative to not having surgery.1429 for major surgical procedures and 87.5 IU kg1 day1 over However, a cost-minimisation analysis for major ortho- 2 days for minor procedures.1038 Haemostatic outcome paedic procedures showed that APCC, alone or alongside was excellent or good in 78% and 100% of cases, respect- rFVIIa, represents a cost-saving approach.1032 ively. Some haemophilia patients with inhibitors may become In a recent review, good efficacy was reported for rFVIIa in refractory to rFVIIa or APCC therapy. Management of haemophilia patients with inhibitors; rare instances of these patients is difficult. In a retrospective review, insufficient haemostasis were attributed to inadequate combined therapy with both agents was described.1430 rFVIIa dosing.1422 In RCT, a high–dose rFVIIa regimen Continuous infusion of low-dose rFVIIa (30–70 mgkg1) (bolus dose of 90 mgkg1, followed by a 90 mgkg1 dose and low-dose FEIBA (20–30 U kg1) appears safe, every 2 h for 48 h and then at 4–6 h intervals for 24 h) efficacious and economical in patients refractory to resulted in fewer postoperative bleeds and fewer extra rFVIIa.1431 However, a critical review of 17 reports doses needed than a lower dose regimen (35 mgkg1 at the regarding parallel use of bypassing agents in the same same hourly intervals).1423 Recently, a consensus protocol bleeding episode in 49 patients pointed to an increased for the use of rFVIIa in orthopaedic surgery in haemophilia risk of thrombosis in these patients.130 patients with inhibitors recommended an initial bolus of 1 1 Potential thromboembolic risks associated with rFVIIa 120–180 mgkg , followed by a 90 mgkg dose every 2 h 1031,1432 for 48 h. Thereafter, the intervals may be increased to 3 h and APCC have been discussed. However, the for another 48 h; at day 5 after surgery, the intervals may be methodology of a pharmacovigilance programme suggesting a higher frequency of thrombotic events further increased to 4 h for the next 3 days followed by 1031 further lengthening to 6 h until discharge.987 Adjunctive with rFVIIa over APCC has been criticised. A tranexamic acid is highly recommended. review article reported 3.67 thromboembolic events per 100 000 rFVIIa infusions in haemophilia patients,1433 An updated evaluation of rFVIIa in perioperative bleed- comparable to figures reported for FEIBA.1242 Both ing in patients with inhibitors reported an overall effec- rFVIIa1416 and APCC1242 administration in haemophilia tiveness of 84% and an incidence of thrombotic events of patients with inhibitors is therefore considered safe. 0.4%.1424 Recommendation The efficacy of continuous infusion of rFVIIa is contro- We suggest the use of antifibrinolytic drugs as peri- 1 versial. In an open-label randomised study, 90 mgkg operative adjunct therapy in haemophilia patients. 2C rFVIIa bolus infusion (initially every 2 h) was compared with continuous infusion (initially 50 mgkg1 h1)in In Europe, tranexamic acid is frequently reported inhibitor-expressing haemophilia A/B patients under- as perioperative adjunct therapy in haemophilia 1379 going surgery.1425 Haemostatic efficacy was comparable patients. Despite frequent use of tranexamic acid, between the groups, with efficacy demonstrated in 8/11 limited evidence supports its coadministration with 1434 (73%) and 9/12 (75%) subjects in the bolus infusion FVIII. A retrospective survey indicated that tranexa- and continuous infusion groups, respectively. Cumulat- mic acid used alongside coagulation factor replacement ive 72-h doses were 237.5 and 292.2 mg, respectively. reduces blood loss after orthopaedic surgery compared 1407 One patient in the bolus infusion group developed with coagulation factor substitution alone. In addi- venous thrombosis on day 10 after surgery. Better efficacy tion, adjuvant EACA may help to control bleeding in 1435 has been reported by others using rFVIIa continuous haemophilia patients with inhibitors. 986,1426,1427 infusion. However, most of these patients also Antibrinolytic drugs are not recommended for treatment received tranexamic acid. of patients with FIX deficiency already receiving large 1387 The relative effectiveness of rFVIIa and APCC for the doses of PCCs. treatment of acute bleeding in haemophilia patients with The antifibrinolytics are particularly indicated in dental inhibitors was investigated by a Cochrane review.1415 care, where the high fibrinolytic activity of saliva may Similar haemostatic effects for rFVIIa and APCC were more easily destabilise the relatively weak clot.1435 WFH reported, without increasing thromboembolic risk. In the recommends that EACA or tranexamic acid should absence of comparative studies carried out in the surgical be started before replacement therapy. The dose of setting, personal experience, availability and cost may 1033 EACA, which should be started the night before or on guide the choice of the bypassing agents. the morning of the procedure, is 50–100 mg kg 1 every The use of bypassing agents has a substantial economic 4–6 h for 5–10 days (maximum 24 g per 24 h). The dose impact. rFVIIa appears to be at least cost-neutral relative for tranexamic acid is 25–50 mg kg1 orally every 6–8 h

for 10 days. A liquid preparation of these drugs may be A retrospective survey in patients with hypo- or afibri- used as a mouthwash.1387 nogenaemia reported the mean incidence of bleeding episodes in patients receiving prophylaxis to be not much A small double-blind cross-over randomised controlled lower than for patients treated on-demand.1444 Unfortu- pilot trial including 16 patients with haemophilia showed nately, no data were reported describing plasma concen- that tranexamic acid mouthwash was as effective as factor trations of fibrinogen at the time of intracranial bleeding. replacement therapy prior to dental scaling.1436 Another study including 113 dental extractions in 50 patients with Risk of bleeding after surgery in patients with FXI inherited bleeding disorders performed without previous deficiency is particularly high if anatomical sites rich in administration of clotting factor concentrates showed that fibrinolytic activity are involved.1445 However, among no severe bleeding complications occurred during the FXI-deficient women giving birth, 69.4% experienced follow-up period of 8 days.1437 no postpartum haemorrhage, suggesting no relationship between FXI level and risk of postpartum haemorrhage. Recommendation We suggest individualised perioperative thromboprophy- Recommendations laxis in haemophilia patients. 2C We recommend that surgery in patients with rare bleeding disorders should be carried out in consultation with a When perioperative factor substitution is adequate, the haematologist with experience in factor deficiencies.1C risk of venous thrombosis might be considered. A small prospective study including 24 haemophiliac patients There is insufficient data to recommend routine perio- undergoing 29 major orthopaedic surgical procedures perative supplementation of deficient factors in patients and screened for VTE by compression ultrasonography with rare bleeding disorders.C showed that subclinical DVT occurred in up to 10% of Perioperative bleeding in patients with RBDs is treated cases.1438 No case of clinical DVT or PE was reported. by supplementing the deficient factor.1446 Coagulation Grade 1 compression above-knee stockings were used in factor supplementation is generally advisable for fibrino- all patients. Based on these findings, routine pharmaco- gen concentrations <1gl 1 and <20–30% of normal logical thromboprophylaxis may not be indicated in all concentrations for other coagulation factors. 1447,1359 haemophiliac patients undergoing major orthopaedic Thrombosis is a major concern with coagulation factor surgery. However, half of the comprehensive haemo- supplementation; thrombotic events have been reported philia centres in Europe reported using pharmacological following administration of fibrinogen and FXI concen- antithrombotic prophylaxis after major orthopaedic trate.1365,1441,1442 surgery1379 and one centre reported that 82% of haemophiliacs received VTE prophylaxis after the year 2000 with The best treatment options, doses and management no evidence of increased bleeding complications.1381 In a approaches for patients with RBDs were reviewed in study of open heart surgery in haemophilia patients, indi- 2004.1446 Evidence levels were low (descriptive studies vidualised antithrombotic measures were reported.1439 and expert opinion). Treatment is generally administered Individualised antithrombotic therapy, based on local on-demand, so data on preoperative prophylactic therapy clinical experience, guidelines for non-haemophilia are scarce. UK guidelines recommend specific factor patients and the patient’s clinical characteristics is recom- concentrates for fibrinogen and FXIII deficiencies.1341 mended.1440 An open, uncontrolled, retrospective study showed that fibrinogen concentrate was effective as preoperative pro- 10.2.4 Rare bleeding disorders phylaxis.1448 However, one high-risk patient developed Rare bleeding disorders (RBDs; congenital coagulation DVT and non-fatal pulmonary embolism; fibrinogen sub- factor deficiencies)1341 have low prevalence: between stitution could not be excluded as a contributing factor. 1:500 000 and 1:2 000 000.1365,1441 They account for Another open-label, uncontrolled, prospective study of 3–5% of inherited coagulation disorders,1442 and FVII patients with afibrinogenaemia showed that human fibri- deficiency is the most common. nogen concentrate can restore haemostasis with a good safety profile.1234 Recommendations We recommend that patients with rare bleeding dis- Supplementation is not always necessary in FVII orders should be referred preoperatively to a haemato- deficiency. In a retrospective analysis of surgical pro- logist for assessment/intervention. 1C cedures performed without replacement therapy in FVII-deficient patients, the median FVII level was 5% Bleeding risk in RBD patients is largely assessed using and the bleeding rate was 15%.1449 A threshold level for case reports and expert opinion.1365,1441,1442 Minimum FVII replacement of 10% was proposed. required coagulation factors concentrations are contro- versial1443 and correlations between factor concentrations FFP (preferably virally inactivated) is the only current and bleeding risk are generally poor.1441,1442 option for FV deficiency, and other deficiencies if the Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 349

concentrates are not available;1442 non-virally inactivated Elsewhere, effective haemostasis was reported in 100% cryoprecipitate may be an option for minimising admin- of FXI-deficient patients receiving prophylactic rFVIIa istration volume. PCCs are recommended for FII or FX before dental procedures or minor and major opera- deficiencies, because specific concentrates are not avail- tions.1432 No alternative haemostatic agents or transfu- able. Evidence supporting prophylactic use of PCCs in sions were administered, except for tranexamic acid. An prothrombin1450,1451 or FX deficiency is scarce.1452,1453 acute cerebrovascular accident was reported in a patient rFX and rFXIII are currently being developed. Phase I with a history of cardiovascular disease. The authors data suggest that rFXIII may be safe and effective in concluded that rFVIIa was an effective alternative to patients with FXIII deficiency.1454 plasma-derived FXI, but that rFVIIa may not be suitable for patients with pre-existing thrombotic risk factors. For FXI deficiency, both FXI concentrate and virally inactivated FFP are reasonable, although tranexamic acid rFVIIa appears effective in patients with FV or FVIII alone may suffice for minor procedures.1341 However, deficiency and surgical bleeding resistant to supplement- there is evidence that prophylactic treatment is not ation therapy.1464 Registry data suggest that rFVIIa treat- mandatory in FXI deficiency.1455 ment may control or prevent bleeding in other RBDs, with a favourable safety profile.1465 Vitamin K is the mainstay treatment for vitamin K- dependent clotting factor deficiency.1456 However, peri- Recommendation operative supplementation using plasma or PCC may also There are insufficient data to recommend periprocedural be needed.1441 desmopressin or antifibrinolytic drugs in patients with mild rare bleeding disorders.C Recommendations Desmopressin has also been used in RBDs, especially We suggest that rFVIIa should be used in perioperative mild cases. Limited data suggest a potential role for bleeding due to inherited FVII deficiency.2C desmopressin in the treatment of bleeding episodes If rFVIIa is given to control perioperative bleeding in or prevention of postoperative bleeding in mild FXI inherited FVII deficiency, we suggest lower doses than defects. Such use is described in a systematic review in haemophilia patients.2C of 16 case reports.1466 There are insufficient data to recommend rFVIIa in peri- Antifibrinolytic agents may be given to patients with operative bleeding for patients with other rare bleeding RBDs, particularly for mucosal bleeding or bleeding disorders. C prevention following dental extractions.1341,1446 1446 rFVIIa is the treatment of choice for FVII deficiency. 11 FINAL REMARKS If rFVIIa is not available, plasma-derived FVII is The overall aim of this extensive document is to provide favoured over PCC because of PCC’s potential throm- clinicians with evidence-based and up-to-date guidelines bogenicity.1341 A wide rFVIIa dose range (1.2– for better clinical management of our patients. Great care 223.8 mgkg 1) has been reported in FVII deficiency.1457 has been taken by the task force and the steering com- Dosing intervals of 2–18 h and treatment durations of mittee to follow a transparent and comprehensive 30 h to 2 weeks are described.1458 Continuous infusion of approach in finding relevant literature and assessing rFVIIa has also been reported in FVII deficiency.1459 the existing evidence. The recommended dose of rFVIIa for FVII deficiency is Guided by expert assistance, our search strategy was 20–25 mgkg 1 every 4–6 h,1446 individualised according based on predefined criteria and broadly adhered to to bleeding phenotype. In surgery, the specific procedure, accepted methodologies, such as those advocated by tissue/organ involved and type of anaesthesia should be the Cochrane Collaboration. More than 20 000 abstracts taken into account. Supplementation is recommended were selected by a sensitive search strategy. As with all until wound healing is established (5–7 days).1446 database searches, it is possible that some relevant In a prospective study of subjects with FVII deficiency literature was not initially captured. Therefore, to make undergoing surgery, rFVIIa (3 doses of 13 mgkg 1) the process as robust as possible, the authors of each proved effective.1460 Bleeding occurred in three section were asked to conduct supplementary searches patients to whom rFVIIa was given at low doses. FVII and provide the committee with any additional relevant antibody was observed in one patient undergoing a literature. The authors subsequently assessed all publi- multiple dental extraction. No thromboses were reported. cations relevant to their sections. Low-dose rFVIIa (33–47 mgkg 1) also appears safe As initially required by the ESA Scientific and Guideline and effective for surgery in patients with severe committee, we applied the SIGN method, which places FXI deficiency and inhibitors.1461 Co-administration of emphasis on risk of bias when grading the quality of the tranexamic acid has also proved effective,1462,1463 evidence in publications such as systematic reviews or although it may increase thrombotic risks. RCTs. This approach is similar to that advocated by the Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. 350 Kozek-Langenecker et al.

Cochrane Collaboration for evaluating the quality of trials issues and our recommendations may need to be viewed and the various domains of bias. When assessing all differently in some countries and institutions until relevant publications, the authors were required to con- additional evidence to support routine use of these pro- sider important issues such as publication bias, incon- ducts and devices is published. This statement is in sistency, indirectness, imprecision and funding bias. accordance with the official position of the ESA Guide- Finally, the authors were requested to combine the above line Committee, and we emphasise that our recommen- with their own expert opinions in a transparent manner to dations can be adopted, modified or not implemented, generate appropriate and clinically meaningful recom- depending on institutional or national requirements. mendations. Many of the authors and experts involved in developing The team of authors acknowledges that, despite adhering this guideline have conflicts of interest. Each of these to common assessment tools such as SIGN and GRADE, individuals has provided a detailed disclosure statement, it is nearly impossible when creating a guideline to avoid as declared in this article. In order to minimise bias in our an element of subjectivity. Indeed, these guideline tools assessment of the literature, the entire guideline docu- provide room for subjectivity, for instance when weighing ment was subject to internal and external review and was risks versus benefits, considering preferences of patients open to critical input from colleagues and national organ- and evaluating resources and costs. Despite the universal isations. acceptance of its importance, evidence-based medicine is an ideal that is often very difficult to achieve. If guide- Acknowledgement lines had to be developed using a purely objective Assistance with the guidelines: Dr. Georgina Imberger (literature approach with no room for subjectivity, we would be left search). The various chapters were edited by the following authors: with very little of true value to recommend. Thus, chapters 4.1 (AS, CA), 4.2 (GI), 4.3 (AS); 5.1 (ML, AA), 5.2 (CS, AA), guidelines per se will always be subject to a degree of 6.1 (SK), 6.2 (PW, MJ, JM), 6.3 (PVdL), 7.1 (DF), 7.2 (EDR), 7.3 (KG, SK), 8.1 (NR), 8.2 (AW), 8.3 (KG, TH), 8.4 (SM), 8.5 (TH, subjectivity. What is essential is that readers are provided KG), 9 (CMS, PA, JL), 10 (DF). with sufficient information to assess the degree of trans- parency of the process by which a guideline has been Financial support and sponsorship: The literature search was developed. We believe that we have achieved this in this funded by the European Society of Anaesthesiology. Editorial assistance by Meridian HealthComms was funded by the Austrian detailed document. Society of Anaesthesiology, Resuscitation and Intensive Care. It comes as no surprise that there are variations in our Conflicts of interest: PA received honoraria for lecturing from practices across Europe. We acknowledge the importance Abbott, Bayer, Boehringer-Ingelheim, CSL Behring, Daiichi San- of guidelines as a steering tool but also appreciate the fact kyo, LFB, Fresenius and Pfizer-BMS. PA is on the advisory that recommendations should be evaluated locally. Some committees of Bayer, Boehringer-Ingelheim and Pfizer-BMS. countries and national societies may decide to assess the DFi received honoraria for lecturing and travel reimbursement evidence and recommendations differently. from Abbott, Bayer, B. Braun, Edwards, GlaxoSmithKline, Med- tronic, Fresenius Kabi, MSD, Novo Nordisk, Pfizer, Sanofi-Aventis, Some institutions may decide not to introduce devices, Schering AG, Servier and Vifor Pharma. DFi is co-author of the medications or strategies advocated in this guideline until trauma bleeding management guidelines which were supported by further supporting evidence is available. This might be unrestricted grants from CSL Behring (Germany) and LFB Bio- the case with point-of-care testing and products such as medicaments (France). KG received honoraria for lecturing and fibrinogen concentrate and prothrombin complex con- travel reimbursement from CSL Behring GmbH, Octapharma AG, Tem International GmbH and Verum Diagnostic GmbH. KG is centrate, for which the results of the many ongoing trials currently employed by Tem International GmbH but was in the are eagerly anticipated. sole employ of the University Hospital Essen at the time of writing. Furthermore, some institutions may consider it difficult DF received honoraria for lecturing, travel reimbursement, con- to justify funding the introduction, daily use and main- sulting fees and grants from AstraZeneca, Baxter, B. Braun, Biotest, CSL Behring, Delta Select, Dade Behring, Fresenius Kabi, Glax- tenance of point-of-care devices, and the higher direct oSmithKline, Haemoscope, Hemogen, Lilly, LFB, Mitsubishi costs of coagulation factor concentrates compared with Pharma, Novo Nordisk, Sangart, Tem Innovations and the US allogeneic blood products. We note, however, that Army. TH received honoraria for lecturing and travel reimburse- although allogeneic blood products are perceived as ment from CSL Behring and Octapharma AG. MJ received honor- low cost, substantial indirect and infrastructure costs aria for lecturing and travel reimbursement from Fresenius Kabi, B. mean that the actual cost of transfusion is high. There Braun, Serumwerk Bernburg and Baxter. MJ also received unrest- is evidence that use of coagulation factor concentrates ricted research grants from Fresenius Kabi, CSL Behring and guided by point-of-care testing may actually reduce costs Serumwerk Bernburg. SKL received honoraria for lecturing, travel reimbursement and consulting fees within the last 10 years from in some settings. However, cost analyses performed in Baxter, B. Braun, Biotest, Pfizer-BMS, CSL Behring, Fresenius studies will not reflect the local situation in every hospital Kabi, Mitsubishi Pharma, Novo Nordisk, Octapharma, TEM Inter- and prices for allogeneic blood products and coagulation national and Verum Diagnostics. JL received honoraria for lecturing factor concentrates vary among countries depending on within the last 3 years from Bayer, Baxter, Boehringer-Ingelheim, the local market. This task force acknowledges these CSL Behring, Fresenius Kabi, Pfizer-BMS, Rovi and Sanofi. JL is Eur J Anaesthesiol 2013; 30:270–382 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited. ESA guidelines: management of severe bleeding 351

on the advisory committees of Bayer, Baxter, Boehringer-Ingel- 15 Phan HH, Wisner DH. Should we increase the ratio of plasma/platelets heim, CSL Behring, Pfizer-BMS and Sanovi-Aventis. SMc is on the to red blood cells in massive transfusion: what is the evidence? Vox Sang 2010; 98:395–402. advisory committee of Haemonetics. JM received honoraria for 16 Roback JD, Caldwell S, Carson J, et al. Evidence-based practice lecturing from CSL Behring, Pulsion, Sorin Group and TEVA. guidelines for plasma transfusion. Transfusion 2010; 50:1227–1239. NR-M is a member of advisory boards for CSL Behring and MSD, 17 Afshari A, Wikkelso A, Brok J, Moller AM, Wetterslev J. and received unrestricted grants for clinical studies from these Thrombelastography (TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in patients with massive transfusion. companies. CMS received honoraria for lecturing from Abbott, Cochrane Database Syst Rev 2011; 3:CD007871. 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1350 Windyga J, von Depka-Prondzinski M, European Wilate Study G. 1373 Zeidler K, Arn K, Senn O, Schanz U, Stussi G. Optimal preprocedural Efficacy and safety of a new generation von Willebrand factor/factor VIII platelet transfusion threshold for central venous catheter insertions in concentrate (Wilate(R)) in the management of perioperative patients with thrombocytopenia. Transfusion 2011; 51:2269–2276. haemostasis in von Willebrand disease patients undergoing surgery. 1374 Cid J, Lozano M. Lower or higher doses for prophylactic platelet Thromb Haemost 2011; 105:1072–1079. transfusions: results of a meta-analysis of randomized controlled trials. 1351 Federici AB. The safety of plasma-derived von Willebrand/factor VIII Transfusion 2007; 47:464–470. concentrates in the management of inherited von Willebrand disease. 1375 Mannucci PM, Tuddenham EG. The hemophilias–from royal genes to Expert Opin Drug Saf 2009; 8:203–210. gene therapy. N Engl J Med 2001; 344:1773–1779. 1352 van Vliet HH, Kappers-Klunne MC, Leebeek FW, Michiels JJ. PFA-100 1376 White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. monitoring of von Willebrand factor (VWF) responses to desmopressin Recommendation of the scientific subcommittee on factor VIII and factor (DDAVP) and factor VIII/VWF concentrate substitution in von IX of the scientific and standardization committee of the International Willebrand disease type 1 and 2. Thromb Haemost 2008; 100:462– Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 468. 85:560. 1353 Makris M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis 1377 Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost following the use of intermediate purity FVIII concentrate to treat patients 2010; 8:421–432. with von Willebrand’s disease. Thromb Haemost 2002; 88:387–388. 1378 Franchini M, Zaffanello M, Lippi G. 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J Thromb Haemost 2001; 7:96–98. 2010; 8:2063–2065. 1386 Santagostino E, Mannucci PM, Bianchi Bonomi A. Guidelines on 1362 Biss TT, Blanchette VS, Clark DS, Wakefield CD, James PD, Rand ML. replacement therapy for haemophilia and inherited coagulation Use of a quantitative pediatric bleeding questionnaire to assess disorders in Italy. Haemophilia 2000; 6:1–10. mucocutaneous bleeding symptoms in children with a platelet function 1387 World Federation of Haemophilia. Guidelines for the management of disorder. J Thromb Haemost 2010; 8:1416–1419. haemophilia. http://www.wfh.org. [Accessed November 27 2011]. 1363 Quiroga T, Goycoolea M, Panes O, et al. High prevalence of bleeders of 1388 Srivastava A, Chandy M, Sunderaj GD, et al. Low-dose intermittent unknown cause among patients with inherited mucocutaneous bleeding. factor replacement for post-operative haemostasis in haemophilia. A prospective study of 280 patients and 299 controls. 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Prophylactic and therapeutic Haemophilia 2011; 17:625–629. recombinant factor VIIa administration to patients with Glanzmann’s 1394 Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related thrombasthenia: results of an international survey. J Thromb Haemost risk factors of inhibitor development in previously untreated patients with 2004; 2:1096–1103. hemophilia A: the CANAL cohort study. Blood 2007; 109:4648–4654. 1369 Almeida AM, Khair K, Hann I, Liesner R. The use of recombinant factor 1395 Musso R. Efficacy and safety of recombinant factor VIII products in VIIa in children with inherited platelet function disorders. Br J Haematol patients with hemophilia A. Drugs Today 2008; 44:735–750. 2003; 121:477–481. 1396 Franchini M, Tagliaferri A, Mengoli C, Cruciani M. Cumulative inhibitor 1370 Hennewig U, Laws HJ, Eisert S, Gobel U. Bleeding and surgery in incidence in previously untreated patients with severe hemophilia A children with Glanzmann thrombasthenia with and without the use of treated with plasma-derived versus recombinant factor VIII recombinant factor VII a. Klin Padiatr 2005; 217:365–370. concentrates: a critical systematic review. Crit Rev Oncol Hematol 1371 Blumberg N, Heal JM, Phillips GL. Platelet transfusions: trigger, dose, 2012; 81:82–93. benefits, and risks. F1000 Med Rep 2010; 2:5. 1397 Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor development in 1372 Bishop JF, Schiffer CA, Aisner J, Matthews JP, Wiernik PH. Surgery in previously untreated hemophilia A patients treated with plasma-derived acute leukemia: a review of 167 operations in thrombocytopenic or recombinant factor VIII concentrates: a systematic review. J Thromb patients. Am J Hematol 1987; 26:147–155. Haemost 2010; 8:1256–1265.

1398 Mancuso ME, Mannucci PM, Rocino A, Garagiola I, Tagliaferri A, 1420 Valentino LA. The benefits of prophylactic treatment with APCC in Santagostino E. Source and purity of factor VIII products as risk factors patients with haemophilia and high-titre inhibitors: a retrospective case for inhibitor development in patients with hemophilia A. J Thromb series. Haemophilia 2009; 15:733–742. Haemost 2012; 10:781–790. 1421 Tjonnfjord GE. Surgery in patients with hemophilia and inhibitors: a 1399 Lissitchkov T, Matysiak M, Zavilska K, et al. A clinical study assessing the review of the Norwegian experience with FEIBA. Semin Hematol 2006; pharmacokinetics, efficacy and safety of AlphaNine((R)), a high-purity 43 (2 Suppl 4):S18–21. factor IX concentrate, in patients with severe haemophilia B. 1422 Obergfell A, Auvinen MK, Mathew P. Recombinant activated factor VII Haemophilia 2011; 17:590–596. for haemophilia patients with inhibitors undergoing orthopaedic surgery: 1400 Ragni MV, Pasi KJ, White GC, et al. Use of recombinant factor IX in a review of the literature. Haemophilia 2008; 14:233–241. subjects with haemophilia B undergoing surgery. Haemophilia 2002; 1423 Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA. 8:91–97. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in 1401 Mauser-Bunschoten EP, Kleine Budde I, Lopaciuk S, et al. An ultrapure haemophilia patients with inhibitors undergoing surgery. Thromb plasma-derived monoclonal antibody-purified factor IX concentrate Haemost 1998; 80:773–778. (Nonafact(R)), results of phase III and IV clinical studies. Haemophilia 1424 Valentino LA, Cooper DL, Goldstein B. Surgical experience with rFVIIa 2011; 17:439–445. (NovoSeven) in congenital haemophilia A and B patients with inhibitors 1402 Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, to factors VIII or IX. Haemophilia 2011; 17:579–589. Mannucci PM. Thrombotic adverse events to coagulation factor 1425 Pruthi RK, Mathew P, Valentino LA, et al. Haemostatic efficacy and safety concentrates for treatment of patients with haemophilia and von of bolus and continuous infusion of recombinant factor VIIa are Willebrand disease: a systematic review of prospective studies. comparable in haemophilia patients with inhibitors undergoing major Haemophilia 2012; 18:e173–e187. surgery. Results from an open-label, randomized, multicenter trial. 1403 Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM. Non- Thromb Haemost 2007; 98:726–732. thrombotic-, non-inhibitor-associated adverse reactions to coagulation 1426 Santagostino E, Morfini M, Rocino A, Baudo F, Scaraggi FA, Gringeri A. factor concentrates for treatment of patients with hemophilia and von Relationship between factor VII activity and clinical efficacy of Willebrand’s disease: a systematic review of prospective studies. recombinant factor VIIa given by continuous infusion to patients with Haemophilia 2012; 18:e164–e172. factor VIII inhibitors. Thromb Haemost 2001; 86:954–958. 1404 Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion 1427 Smith MP, Ludlam CA, Collins PW, et al. Elective surgery on factor VIII of factor VIII in haemophilia patients undergoing major surgery. Br J inhibitor patients using continuous infusion of recombinant activated Haematol 2000; 110:715–720. factor VII: plasma factor VII activity of 10 IU/ml is associated with an 1405 Stieltjes N, Altisent C, Auerswald G, et al. Continuous infusion of B- increased incidence of bleeding. Thromb Haemost 2001; 86:949–953. domain deleted recombinant factor VIII (ReFacto) in patients with 1428 Knight C, Dano AM, Kennedy-Martin T. A systematic review of the cost- haemophilia A undergoing surgery: clinical experience. Haemophilia effectiveness of rFVIIa and APCC in the treatment of minor/moderate 2004; 10:452–458. bleeding episodes for haemophilia patients with inhibitors. Haemophilia 1406 Ne´grier C, Shapiro A, Berntorp E, et al. Surgical evaluation of a 2009; 15:405–419. recombinant factor VIII prepared using a plasma/albumin-free method: 1429 Lyseng-Williamson KA, Plosker GL. Recombinant factor VIIa (eptacog efficacy and safety of Advate in previously treated patients. Thromb alfa): a pharmacoeconomic review of its use in haemophilia in patients Haemost 2008; 100:217–223. with inhibitors to clotting factors VIII or IX. Pharmacoeconomics 2007; 1407 Schulman S, Loogna J, Wallensten R. Minimizing factor requirements for 25:1007–1029. surgery without increased risk. Haemophilia 2004; 10 (Suppl 4):35– 1430 Kraut EH, Aledort LM, Arkin S, Stine KC, Wong WY. Surgical 40. interventions in a cohort of patients with haemophilia A and inhibitors: an 1408 Martinowitz U, Luboshitz J, Bashari D, et al. Stability, efficacy, and safety experiential retrospective chart review. Haemophilia 2007; 13:508– of continuously infused sucrose-formulated recombinant factor VIII 517. (rFVIII-FS) during surgery in patients with severe haemophilia. 1431 Martinowitz U, Livnat T, Zivelin A, Kenet G. Concomitant infusion of low Haemophilia 2009; 15:676–685. doses of rFVIIa and FEIBA in haemophilia patients with inhibitors. 1409 Eckhardt CL, Menke LA, van Ommen CH, et al. Intensive peri-operative Haemophilia 2009; 15:904–910. use of factor VIII and the Arg593–>Cys mutation are risk factors for 1432 O’Connell NM, Riddell AF, Pascoe G, Perry DJ, Lee CA. Recombinant inhibitor development in mild/moderate hemophilia A. J Thromb factor VIIa to prevent surgical bleeding in factor XI deficiency. Haemost 2009; 7:930–937. Haemophilia 2008; 14:775–781. 1410 Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa 1433 Abshire T, Kenet G. Safety update on the use of recombinant factor VIIa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results and the treatment of congenital and acquired deficiency of factor VIII or of a pivotal study. Haemophilia 2010; 16:731–739. IX with inhibitors. Haemophilia 2008; 14:898–902. 1411 Batorova A, Holme P, Gringeri A, et al. Continuous infusion in 1434 Hvas AM, Sorensen HT, Norengaard L, Christiansen K, Ingerslev J, haemophilia: current practice in Europe. Haemophilia 2012; 18:753– Sorensen B. Tranexamic acid combined with recombinant factor VIII 759. increases clot resistance to accelerated fibrinolysis in severe hemophilia 1412 Morfini M. Secondary prophylaxis with factor IX concentrates: A. J Thromb Haemost 2007; 5:2408–2414. continuous infusion. Blood Transfus 2008; 6 (Suppl 2):s21–s25. 1435 Ghosh K, Shetty S, Jijina F, Mohanty D. Role of epsilon amino caproic 1413 Chowdary P, Dasani H, Jones JA, et al. Recombinant factor IX (BeneFix) acid in the management of haemophilic patients with inhibitors. by adjusted continuous infusion: a study of stability, sterility and clinical Haemophilia 2004; 10:58–62. experience. Haemophilia 2001; 7:140–145. 1436 Lee AP, Boyle CA, Savidge GF, Fiske J. Effectiveness in controlling 1414 Hoots WK, Leissinger C, Stabler S, et al. Continuous intravenous haemorrhage after dental scaling in people with haemophilia by using infusion of a plasma-derived factor IX concentrate (Mononine) in tranexamic acid mouthwash. Br Dent J 2005; 198:33–38. haemophilia B. Haemophilia 2003; 9:164–172. 1437 Hewson I, Makhmalbaf P, Street A, McCarthy P, Walsh M. 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REVIEW How do you treat bleeding disorders with desmopressin? Bu¨lent O¨ zgo¨nenel, Madhvi Rajpurkar, Jeanne M Lusher ......

Postgrad Med J 2007;83:159–163. doi: 10.1136/pgmj.2006.052118 Desmopressin is an analog of vasopressin that exerts a Finnish physician who, in 1926, first described a hereditary haemorrhagic disease with autosomal substantial haemostatic effect by inducing the release of von dominant inheritance pattern in a large kindred Willebrand factor from its storage sites in endothelial cells. It from the A˚land islands, an archipelago off the has proved useful in treating or preventing bleeding episodes in western coast of Finland.4 His index patient was a patients with von Willebrand disease, haemophilia A and young girl who died of menstrual haemorrhage soon after her menarche, clearly epitomising the platelet function defects. Its efficacy in achieving a satisfactory involvement of females in this bleeding disorder as level of haemostasis has reduced the use of blood products to opposed to that in haemophilia A or B. It was only treat bleeding episodes. Clinicians need to become familiar with years later, well into the late 20th century, that it the use of this drug that has become a home medication for was appreciated that the disease originated from a quantitative or qualitative deficiency of a plasma many patients with inherited bleeding disorders. protein of high importance in the normal haemo- ...... static mechanism. VWF is a complex multimeric glycoprotein with esmopressin is one of the several non- two important roles in haemostasis: it binds to transfusional pharmacological agents within platelet receptors, bridging them to other platelets Dthe clinician’s armamentarium for treating and subendothelial tissue that is exposed after bleeding episodes, which include, among others, vascular injury, and also acts as a carrier protein anti-fibrinolytic agents tranexamic acid, e-amino- for the coagulation factor VIII (FVIII), thus caproic acid and aprotinin; recombinant human preventing its proteolytic inactivation in the factor VIIa; and the conjugated oestrogens.1 Its plasma. Without the VWF, FVIII plasma levels properties of ease of use, low cost and versatility in decline rapidly; and depending on the severity of preventing and treating bleeding from various sites the disorder, a haemostatic defect similar to of the body in a variety of bleeding disorders make haemophilia A emerges.45 it a useful haemostatic drug. Importantly, it carries The gene for VWF is located on chromosome 12. no risk of transmitting bloodborne infectious During its synthesis in endothelial cells and agents. Since its introduction into clinical use in megakaryocytes, VWF undergoes extensive proces- 1977, it has revolutionised the treatment of sing in the Golgi apparatus of these cells, including bleeding disorders, leading to a marked reduction polymerisation into a large molecule with a in the use of blood products for the prevention and molecular weight of 20 000 kDa. Stored inside treatment of bleeding episodes.23 specialised storage organelles, the Weibel–Palade This review outlines the basic knowledge on bodies of endothelial cells and a-granules of desmopressin, and attempts to reintroduce it to the platelets, VWF is released into circulation both primary care clinician, who could be an emergency constitutively and on stimulation.5 Myriad sub- room physician treating epistaxis in a patient with stances act as secretagogues of the VWF, including mild haemophilia A, a nurse practitioner treating histamine, thrombin, epinephrine and vasopres- gum bleeding in a patient with end-stage renal sin.5 disease, a dentist anticipating wisdom tooth VWF is released into plasma as a large multimer, extraction in a patient with type 1 von which is instantaneously broken down by a Willebrand disease (VWD), or a paediatrician protease into several molecules of varying mole- treating a female adolescent patient with type 1 cular sizes: multimers with high, intermediate and VWD experiencing excessive menstrual bleeding. low molecular weight. The protease that cleaves See end of article for In these clinical scenarios, understanding the authors’ affiliations VWF immediately on its release into the plasma, ...... pathogenesis of the disease process and the ADAMTS13, has recently gained clinical relevance mechanism of action of desmopressin will enable when it was understood that its deficiency under- Correspondence to: the clinician to formulate a plan of action for the Dr Bu¨lent O¨ zgo¨nenel, lies the pathogenesis of thrombotic thrombocyto- 6 Children’s Hospital of patient in conjunction with the haematologist and penic purpura. In this disorder, platelet Michigan, Division of avoid delay in patient management. aggregation occurs around the unusually large Hematology/Oncology, VWF molecules in circulation, leading to dissemi- 3901 Beaubien Boulevard, Detroit, MI 48201-2196, PHYSIOLOGY OF THE VON WILLEBRAND nated thrombosis and multiorgan dysfunction. USA; bulentozgonenel@ FACTOR The high-molecular-weight multimers, by virtue yahoo.com Insight into the normal and pathological physiol- of their strong affinity to platelet receptors, are ogy of the von Willebrand factor (VWF) will considered more potent than the other multimers. Received 5 August 2006 Accepted facilitate understanding of the mechanism of 26 September 2006 action of desmopressin. Both the factor and the Abbreviations: FVIII, coagulation factor VIII; VWD, von ...... disease are named after Dr Erik von Willebrand, a Willebrand disease; VWF, von Willebrand factor

www.postgradmedj.com 160 O¨ zgo¨nenel, Rajpurkar, Lusher

Owing to presence of little or no VWF in the storage sites in Box 1: Synopsis of the physiology of the von type 3 VWD, desmopressin shows no therapeutic benefit in this Willebrand factor disease.4910Type 2 VWD is characterised by a qualitative defect in the VWF molecule. Some patients with type 2 VWD N Gene located on chromosome 12 will show absence of the high-molecular-weight multimers N Multimeric glycoprotein with molecular weight ranging (types 2A and 2B). Type 2B is characterised by a gain-of- from 500 to 20 000 kDa function type of interaction between platelets and VWF, N leading to spontaneous platelet aggregation and thrombocyto- Synthesis by endothelial cells and megakaryocytes penia due to clearance of the platelet–VWF complexes from N Storage in Weibel–Palade bodies of endothelial cells and circulation. Other patients with type 2 VWD will have a normal a-granules of platelets multimer pattern, but laboratory evaluation will detect either a N Release into plasma as a large molecule, followed by deficient interaction with the platelet receptors (type 2M) or a breakdown into varying sizes of multimeric molecules by deficient FVIII-carrying activity (type 2N). Type 2N is a plasma protease characterised by rapid proteolysis of FVIII, and the clinical N Functions include platelet adhesion and protecting picture is much like that of haemophilia A.4910 Theoretically, coagulation factor VIII from proteolytic inactivation in desmopressin is not expected to provide any haemostatic the plasma effect in type 2 VWD, because the VWF released from the storage sites will still be abnormal. Surprisingly, however, some patients with type 2 VWD will have a laboratory and clinical response to desmopressin.11 Notably, type 2B constitutes a The absence of these multimers leads to a defect in platelet theoretical contraindication to the use of desmopressin, as the adhesion, prolonging the bleeding time. Ristocetin is an release of abnormal VWF molecules with a gain-of-function antibiotic that enhances the interaction between the VWF defect is expected to trigger spontaneous platelet aggregation and the platelet receptors. On the basis of this effect, ristocetin and thrombocytopenia.10 Table 1 shows a synopsis of the cofactor activity test is used as a surrogate marker of the types of VWD and the response to desmopressin in individual 4 functional activity of the VWF. Box 1 summarises the types. physiology of VWF. Haemophilia A MECHANISM OF ACTION OF DESMOPRESSIN FVIII has a critical role in the coagulation cascade by acting as a Vasopressin is a secretagogue of VWF. This hormone functions cofactor for factor IXa in the activation of factor X, the through two receptors, termed V1 and V2, which activate common-pathway protease that will subsequently activate different intracellular second messengers.7 Agonist activity at thrombin, the real propeller of the coagulation machine. In V2 receptors leads to a rise in intracellular concentrations of the absence of FVIII, the activation of factor X is sluggish, cyclic adenosine monophosphate, which in turn induces leading to an intolerable delay in coagulation. Many different exocytosis of VWF from its storage sites (ie, Weibel–Palade mutations of the FVIII gene on the X chromosome, but most bodies of endothelial cells) into the circulation. Interestingly, commonly inversion of one of the introns of the FVIII gene, tissue plasminogen activator, a molecule involved in fibrinolysis disrupt the synthesis of the product molecule. Patients with and therefore in opposition to the effects of VWF, is also such mutations have no detectable levels of FVIII, and are released into circulation along with VWF. Desmopressin (1- clinically at the most severe end of the spectrum, exhibiting desamino-8-D-arginine vasopressin, also abbreviated DDAVP) potentially crippling or fatal, spontaneous bleeding episodes. is a synthetic analogue of vasopressin, which activates only V2 Unfortunately, these patients do not benefit from administra- receptors and thus lacks its vasoconstrictor and uterotonic tion of desmopressin, because increases in plasma levels of properties. Intravenous or intranasal administration of desmo- VWF alone without its precious cargo, the FVIII molecule, will pressin to healthy individuals is followed by a rise in levels of not translate into a haemostatic effect. Some patients with both VWF and its precious cargo, FVIII.2 Individuals who lack haemophilia A, however, have detectable FVIII levels because a V2 receptors—that is, patients with nephrogenic diabetes single nucleotide substitution in the FVIII gene will still allow insipidus—expectedly do not show this increase in VWF and the translation of a mutant FVIII molecule, albeit with FVIII levels.1378 diminished factor activity. These patients are classified into Although originally designed for the treatment of diabetes the category of mild or moderate haemophilia, and may insipidus, desmopressin emerged as a haemostatic agent, with fortunately respond to desmopressin.12 the appreciation of its effects on coagulation and the lack of the severe side effects associated with vasopressin. The next section Other bleeding disorders discusses the bleeding disorders amenable to treatment with Various acquired or inherited disorders of bleeding have been this drug. documented to respond to desmopressin.3 The exact mechanism underlying this therapeutic effect is not known but may be BLEEDING DISORDERS TREATED WITH related to several events associated with the release of VWF. DESMOPRESSIN First of all, sheer increase in FVIII levels will accelerate the von Willebrand disease activation of factor X, thus providing a faster coagulation. von Willebrand disease (VWD) is categorised into three major Secondly, unlike its constitutive release into the lumen of types. Mild quantitative deficiency of VWF molecule with a vessels, stimulated release of VWF is thought to occur on the normal multimer pattern is the cause of type 1 VWD, the most abluminal surface of the endothelial cell, directly bringing VWF common inherited bleeding disorder, affecting up to 1% of the into contact with the subendothelial tissues. This may in turn population. Total or near-total absence of VWF leads to type 3 provide a more efficient platelet adhesion, a process that is VWD, which is the most severe but fortunately a rare type.5 possible only through interaction between platelets and VWF. Understandably, desmopressin is a useful therapeutic agent in Finally, desmopressin induces the release of the unusually large type 1 VWD, where there is residual VWF in the endothelial VWF molecules, which are more adhesive than the regular- storage sites to provide haemostasis, at least temporarily. sized VWF molecules in circulation.3 www.postgradmedj.com Treat bleeding disorders with desmopressin 161

Table 1 Desmopressin use in various types of von Willebrand disease

Type of VWD Characteristic features Desmopressin use

Type 1 Mild to moderate decrease in plasma VWF levels with a normal multimer pattern Trial needed before use Type 2A Absence of multimers with high and intermediate molecular weight Trial needed before use Type 2B Increased affinity for platelet receptors, ultimately leading to excessive platelet activation and Trial needed before use? Contraindicated thrombocytopenia Type 2N Mutation in FVIII-binding region of the VWF, disrupting FVIII-carrying function Trial needed before use Type 2M Mutation in the region of the VWF that binds to platelet receptors, disrupting platelet adhesion Trial needed before use Type 3 Undetectable levels of the VWF with severe bleeding diathesis Not useful

FVIII, coagulation factor VIII; VWD, von Willebrand disease; VWF, von Willebrand factor.

USE OF DESMOPRESSIN IN THE TREATMENT OF DOSING AND ADMINISTRATION BLEEDING DISORDERS Desmopressin can be given through intravenous, subcutaneous Desmopressin has been successfully used in the prophylaxis and intranasal routes. The dose for both intravenous and and treatment of bleeding episodes in some patients with VWD subcutaneous routes is 0.3 mg/kg. When giving intravenously, types 1 and 2, mild to moderate haemophilia A, platelet the drug is diluted in normal saline and infused over function defects related to aspirin use, uraemia and inherited 15–30 min. The dilution volume of normal saline is 15–30 ml platelet disorders, bleeding related to cirrhosis (excluding acute for children and 50–100 ml for adults. The intranasal dose is gastrointestinal bleeding), or heparin use.136 Patients with 150 mg for patients weighing ,50 kg (one puff into one nostril) inherited disorders should undergo a trial to document an and 300 mg for patients weighing >50 kg (one puff into each improvement in laboratory parameters, which could be an nostril). The intranasal solution of desmopressin used in the increase in VWF and ristocetin cofactor activity levels for treatment of bleeding disorders (Stimate, Ferring AB, patients with VWD, increase in FVIII levels for patients with Limhamn, Sweden) is more concentrated than that used in haemophilia A, and normalisation of bleeding time or platelet the treatment of nocturnal enuresis or diabetes insipidus. The function analysis test for patients with inherited platelet peak effect is achieved 30–60 min after intravenous infusion, disorders. Before starting treatment, it is important to inquire and 60–90 min after an intranasal or subcutaneous dose. This about response to desmopressin trial, and the patient’s timing should be taken into account when desmopressin is haematologist should be contacted if in doubt. The haematol- given as prophylaxis before procedures. Owing to the shorter ogist should definitely be consulted for the management of a time required to achieve the haemostatic effect, intravenous patient with bleeding disorders who has never used desmo- route is preferred to subcutaneous and intranasal routes when pressin before. treating acute bleeding episodes. High levels of FVIII and VWF Desmopressin can raise VWF and FVIII levels by 3–5-fold. As are maintained for 6–8 h.110 Table 2 provides a summary of the response to desmopressin in an individual patient is dosing of desmopressin. consistent on different occasions, knowledge of the expected The dose can be repeated every 12–24 h depending on the response and baseline levels of factor is essential to determine type and severity of bleeding; however, most patients with the optimal mode of treatment. For example, for a patient with moderate haemophilia A (and to a lesser extent, those with haemophilia with baseline FVIII levels of 10% that responds to VWD) respond less with each consecutive dose (tachyphylaxis) desmopressin by a fourfold increase, a combination of because of exhaustion of VWF stores. Therefore, to achieve desmopressin and oral antifibrinolytics could be sufficient longlasting haemostasis during recovery from major trauma or prophylaxis before a simple dental extraction. The same patient surgery, specific factor concentrates or platelet transfusions would need to be treated with FVIII concentrates for the should be provided, depending on the underlying disease. treatment of a limb or life-threatening haemorrhage, or in The response to desmopressin can be monitored using preparation for major surgery. laboratory tests specific for the bleeding disorder. Platelet The efficacy of desmopressin in preventing or treating function analyzer PFA-100 (Dade International, Miami, menorrhagia in patients with bleeding disorders is not clear Florida, USA), which has been introduced as an alternative to because of conflicting results from studies in which desmo- bleeding time, is a new in vitro tool to test platelet function pressin was used in the treatment of menorrhagia in women globally. The results are given as closure times representing with VWD.13 Desmopressin paradoxically causes release of the formation of a platelet aggregate within its two cartridges that tissue plasminogen activator, a fibrinolytic substance, along contain either adenosine diphosphate or epinephrine, agonists with the VWF, and thus may actually increase menstrual for platelet activation.18 PFA-100 may be a be a useful adjunct bleeding. A therapeutic trial can be undertaken for each to monitor response to desmopressin in patients with type 1 individual woman to gauge the clinical response, as a guide for future plan of action. Pictorial chart assessment can be used Table 2 Doses and preparations of desmopressin to estimate menstrual blood loss. It is important to exclude other causes of menorrhagia, such as dysfunctional uterine Mode of bleeding, before the use of haemostatic agents. delivery Dose and preparation Both intranasal and subcutaneous desmopressin was found Intranasal Stimate 150 mg for body weight ,50 kg (one spray into to be effective in the treatment of menorrhagia in women with one nostril) VWD.14–16 Unfortunately, the optimal dosing schedule to 300 mg for body weight .50 kg (one spray into each prevent menstrual bleeding is not known, although a tentative nostril) Intravenous 0.3 mg/kg body weight diluted in normal saline (15–30 ml approach would be a dose at the onset of menses followed by for children, 50–100 ml for adults) and given over 15– two subsequent doses every 24 h.15 Alternative treatment 30 min strategies would include oral tranexamic acid, oral contra- Subcutaneous 0.3 mg/kg body weight ceptives, levonorgesterel-releasing intrauterine systems and endometrial ablations.17

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VWD.19 As PFA-100 is an expensive test and knowledge FVIII work together to activate factor X, so artificially regarding its utility in monitoring haemostasis is yet evolving, increasing the levels of one factor is not expected to compensate at the time of writing this manuscript, the general practitioner for the lack of the other. Nevertheless, response to desmopres- is advised only to become familiar with the interpretation of its sin has been reported in patients with mild to moderate results but not to use it as a routine test to monitor response to haemophilia B, perhaps because of a generalised haemostatic desmopressin. effect.25 Box 2 summarises the guidelines for the use of desmopressin in bleeding disorders. ADVERSE EFFECTS, PRECAUTIONS, AND CONTRAINDICATIONS CONCLUSION The most common side effects encountered with the use of Desmopressin has revolutionised the treatment of bleeding desmopressin are tachycardia (mild), flushing and headache disorders since its introduction to haematology in 1977. The (mild).3 As desmopressin is a potent antidiuretic agent, it can resultant avoidance of blood products has saved numerous lives cause hyponatraemia and even seizures in patients receiving since then. Intranasal and subcutaneous routes render it generous amounts of hypotonic intravenous or oral fluids, convenient for treatment at home, avoiding emergency room necessitating fluid restriction during desmopressin treatment. or office visits for simple bleeding problems. Clinicians in This fact is especially important in the context of treatment of primary care should familiarise themselves with the indica- minor bleeding episodes at home, and the patients or care tions, dosing, side effects and contraindications of this versatile givers should be instructed to observe fluid restriction after giving desmopressin. For young children who are inpatients (ie, postoperative patients), hypotonic intravenous fluids should be Key references avoided and total fluid intake should be reduced to 75% of maintenance requirements in the 24 h after use of desmopres- N Mannucci PM. Hemostatic drugs. NEnglJMed sin. Monitoring serum sodium levels and osmolality before and after desmopressin use would be prudent in young children, 1998;339:245–53. especially if more than one dose is used over a 24-h period.20 N Mannucci PM. Desmopressin (DDAVP) in the treatment of A rare but serious side effect in patients receiving desmo- bleeding disorders: the first 20 years. Blood pressin is the occurrence of arterial thrombotic events, such as 1997;90:2515–21. stroke or acute myocardial infarction.21 22 Caution should be N Mannucci PM. Treatment of von Willebrand’s Disease. N exercised, therefore, with the use of desmopressin in elderly Engl J Med 2004;351:683–94. patients with atherosclerotic disease. Venous thrombosis is N Lee CA, Abdul-Kadir R. von Willebrand disease and likewise rare after desmopressin administration, and has been women’s health. Semin Hematol 2005;42:42–8. observed only in patients who had received desmopressin after N Scott H. Use of desmopressin, antifibrinolytics, and transfusion of FVIII/VWF concentrates.22 Patients with throm- conjugated estrogens in hemostasis. In: Goodnight J, bocytopenic purpura should not receive desmopressin because Hathaway WE, eds. Disorders of Hemostasis & further release of the unusually large VWF molecules into plasma is thought to add more fuel to the ongoing thrombotic Thrombosis: a clinical guide. 2nd edn. Philadelphia: event in these patients.23 Thrombocytopenia can easily develop McGraw-Hill, 2001: 528–42. in patients with type 2B VWD after desmopressin use, and this disease represents a classic contraindication to the use of tool for haemostasis. desmopressin; however, some patients with type 2B VWD have had a therapeutic response to desmopressin without developing thrombotic complications.24 Therefore, desmopressin should be SELF-ASSESSMENT QUESTIONS; ANSWERS AT THE used in patients with type 2B VWD only under the guidance of END OF REFERENCES a haematologist. 1. Desmopressin exerts its haemostatic effect by: It is also important to recognise disorders where desmopressin will not be effective, such as type 3 VWD and severe A. Inducing synthesis of the von Willebrand factor (VWF) by haemophilia A. Recombinant or plasma-derived factor concen- endothelial cells trates and other non-transfusional agents, such as conjugated B. Stimulating release of the VWF from its storage sites in oestrogens or antifibrinolytics, can be helpful in the manage- endothelial cells ment of patients with such bleeding problems. C. Cleaving the large VWF multimers circulating in plasma Desmopressin does not provide any haemostatic benefit in into smaller multimers severe haemophilia B, deficiency of factor IX. Factor IX and D. Enhancing interaction between platelets and the VWF E. Binding to VWF receptors on platelets Box 2: Guidelines for the use of desmopressin in 2. Desmopressin is not expected to show any haemostatic bleeding disorders effect in patients with:

N Inquire about response to trial A. Uraemia N Administer 30–60 min before procedure B. Type 1 von Willebrand disease (VWD) N Restrict fluid intake C. Type 3 VWD N Monitor serum sodium level and osmolality in young D. Mild haemophilia A children E. Platelet function defect secondary to aspirin use N Anticipate tachyphylaxis after repeated doses N Monitor therapeutic response with an appropriate test for 3. A 2-year-old boy with mild haemophilia A, known to be the individual bleeding disorder responsive to desmopressin, is hospitalised for elective surgery. He receives a single intravenous dose before and www.postgradmedj.com Treat bleeding disorders with desmopressin 163

two more doses 12 h apart after surgery, which proceeds 2 Warrier AI, Lusher JM. DDAVP: a useful alternative to blood components in moderate hemophilia A and von Willebrand disease. J Pediatr without any haemorrhagic complications. To thwart 1983;102:228–33. serious side effects of desmopressin, postoperative care 3 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the should include: first 20 years. Blood 1997;90:2515–21. 4 Ginsburg D. von Willebrand disease. In: Beutler E, Coller BS, Lichtman MA, Kipps TJ, eds. Williams hematology.6th edn. Philadelphia: McGraw-Hill, A. Monitoring serum sodium levels 2001:1813–28. B. Serial electrocardiograms 5 Castaman G, Federici AB, Rodeghiero F, et al. Von Willebrand’s disease in the year 2003: towards the complete identification of gene defects for correct C. Chest radiograph diagnosis and treatment. Haematologica 2003;88:94–108. D. Prothrombin time and partial thromboplastin time 6 Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood 2005;106:11–17. 7 Thibonnier M. Vasopressin agonists and antagonists. Horm Res 1990;34:124–8. E. Platelet count 8 Scott H. Use of desmopressin, antifibrinolytics, and conjugated estrogens in hemostasis. In: Goodnight J, Hathaway WE, eds. Disorders of hemostasis & 4. A 20-year-old woman (weight 54 kg) with type 1 VWD is thrombosis:a clinical guide. 2nd edn. USA: McGraw-Hill, 2001:528–42. going to have wisdom tooth extraction. The appropriate 9 Lusher JM. Response to 1-deamino-8-D-arginine vasopressin in von Willebrand disease. Haemostasis 1994;24:276–84. dose and timing for the intranasal solution is: 10 Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med 2004;351:683–94. A. One puff (150 mg) to one nostril 10 min before the 11 Federici AB, Mazurier C, Berntorp E, et al. Biologic response to desmopressin in procedure patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004;103:2032–8. B. One puff to each nostril (total dose 300 mg) 10 min before 12 Kaufman RJ, Antonarakis SE. Structure, biology, and genetics of factor VIII. In: the procedure Hoffman R, Edward J, Benz J, Shattil SJ, Furie B, Cohen HJ, et al, eds. Hematology:basic principles and practice.3rd edn. Philadelphia: Churchill C. One puff (150 mg) to one nostril 60 min before the Livingstone, 2000:1850–68. procedure 13 Kujovich JL. von Willebrand’s disease and menorrhagia: prevalence, diagnosis, and management. Am J Hematol 2005;79:220–8. D. One puff to each nostril (total dose 300 mg) 60 min before 14 Leissinger C, Becton D, Cornell C Jr, et al. High-dose DDAVP intranasal spray the procedure (Stimate) for the prevention and treatment of bleeding in patients with mild E. Two puffs to each nostril (total dose 600 mg) 60 min before haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia 2001;7:258–66. the procedure 15 Amesse LS, Pfaff-Amesse T, Leonardi R, et al. Oral contraceptives and DDAVP nasal spray: patterns of use in managing vWD-associated menorrhagia: a 5. Which of the following is NOT part of the guidelines for single-institution study. J Pediatr Hematol Oncol 2005;27:357–63. the use of desmopressin in children for the treatment of 16 Rodeghiero F, Castaman G, Mannucci PM. Prospective multicenter study on subcutaneous concentrated desmopressin for home treatment of patients with von bleeding episodes? Willebrand disease and mild or moderate hemophilia A. Thromb Haemost 1996;76:692–6. 17 Lee CA, Abdul-Kadir R. von Willebrand disease and women’s health. Semin A. Inquiry about response to a previous trial of desmopressin Hematol 2005;42:42–8. B. Generous use of intravenous fluids 18 Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005;130:3–10. C. Anticipation of reduced haemostatic effect after repeated 19 Franchini M, Gandini G, Manzato F, et al. Evaluation of the PFA-100 system for doses monitoring desmopressin therapy in patients with type 1 von Willebrand’s disease. Haematologica 2002;87:670. D. Monitoring serum sodium and osmolality in patients 20 Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young children. receiving multiple doses J Pediatr Hematol Oncol 2005;27:330–2. 21 Mannucci PM, Lusher JM. Desmopressin and thrombosis. Lancet 1989;2:675–6. E. Monitoring the therapeutic response with appropriate tests 22 Girolami A, Tezza F, Scapin M, et al. Arterial and venous thrombosis in patients with von Willebrand’s disease: a critical review of the literature. J Thromb Thrombolysis 2006;21:175–8...... 23 Overman M, Brass E. Worsening of thrombotic thromboctyopenic purpura Authors’ affiliations symptoms associated with desmopressin administration. Thromb Haemost Bu¨lent O¨ zgo¨nenel, Madhvi Rajpurkar, Jeanne M Lusher, Carman and 2004;92:886–7. Ann Adam’s Department of Pediatrics, Division of Hematology/Oncology, 24 McKeown LP, Connaghan G, Wilson O, et al. 1-Desamino-8-arginine- vasopressin corrects the hemostatic defects in type 2B von Willebrand’s disease. Children’s Hospital of Michigan, Wayne State University, Detroit, Am J Hematol 1996;51:158–63. Michigan, USA 25 Ehl S, Severin T, Sutor AH. DDAVP (desmopressin; 1-deamino-cys-8-D-arginine- Competing interests: None. vasopressin) treatment in children with haemophilia B. Br J Haematol 2000;111:1260–2.

REFERENCES ANSWERS 1 Mannucci PM. Hemostatic drugs. N Engl J Med 1998;339:245–53. 1. (B) 2. (C) 3. (A) 4. (D) 5. (B)

www.postgradmedj.com Haemophilia (2014), 20, 158–167 DOI: 10.1111/hae.12254

REVIEW ARTICLE Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders

C. LEISSINGER,* M. CARCAO,† J. C. GILL,‡ J. JOURNEYCAKE,§¶ T. SINGLETON** and L. VALENTINO*** *Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA; †Division of Haematology/ Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; ‡Pediatric Hematology, Medicine and Epidemiology, The Medical College of Wisconsin and the Blood Center of Wisconsin, Milwaukee, WI; §Pediatrics, University of Texas Southwestern Medical Center; ¶Bleeding Disorders and Thrombosis Program, Children’s Medical Center, Dallas, TX; **Section of Pediatric Hematology/Oncology, Tulane University, New Orleans, LA; and ***Section of Pediatric Hematology/Oncology, Rush Hemophilia & Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA

Summary. Bleeding disorders, including haemophilia, in a variety of clinical settings. However, despite the von Willebrand disease, and platelet function widespread use of DDAVP, the available clinical abnormalities pose a substantial, ongoing management evidence on its efﬁcacy and safety in these settings is challenge. Patients with these disorders not only require limited, and there has not been a recent comprehensive treatment during bleeding events but also need effective review of its role in the clinical management of patients management strategies to prepare for events ranging with bleeding disorders. As such, this article provides a from minor dental procedures to major surgery and review of the mechanism of action and pharmacokinetic childbirth. Moreover, women with bleeding disorders properties of DDAVP, followed by a concise summary often require ongoing treatment to prevent menorrhagia of the available evidence for its use in the treatment and during childbearing years. Desmopressin (DDAVP), a prevention of bleeding. synthetic derivative of the antidiuretic hormone L- arginine vasopressin, has become a well-established tool Keywords: DDAVP, desmopressin, haemophilia A, von for the management of patients with bleeding disorders Willebrand disease

Introduction desmopressin sulfate; CSL Behring, King of Prussia, PA, USA) over the past two decades, the role of DDAVP Exogenously administered desmopressin (DDAVP), a further expanded to include its routine use in the home synthetic derivative of the antidiuretic hormone L-argi- setting, where self-administration facilitates the timely nine vasopressin, raises plasma levels of factor VIII treatment of bleeding episodes. DDAVP use has also (FVIII) and von Willebrand factor (VWF). The ability been reported to successfully prevent or treat bleeding of intravenously (IV) administered DDAVP to treat in patients with other bleeding disorders, including mild selected patients with haemophilia A and von platelet function defects and vascular abnormalities Willebrand disease (VWD) was ﬁrst described by such as Ehlers-Danlos syndrome (EDS) [2]. Mannucci in 1977 [1]. With the introduction of a high- Despite the widespread use of DDAVP, there is a â dose intranasal (IN) formulation in Europe (Minirin paucity of clinical trial data available to guide treat- desmopressin acetate; Ferring Pharmaceuticals, Saint- ment, and few comprehensive reviews have been â Prex, Switzerland) and the United States (Stimate published. The purpose of this article was to conduct a systematic review of the MEDLINE and Embase data- Correspondence: Cindy Leissinger, MD, Chief of the Hematol- bases, and concisely summarize data from available ogy/Oncology Section, Department of Medicine, Tulane Univer- peer-reviewed articles pertaining to the efﬁcacy and sity School of Medicine, 1430 Tulane Avenue, SL78 New safety of DDAVP in the management of patients with Orleans, LA 70112, USA. congenital bleeding disorders. The review was restricted Tel.: 504 988 5433; fax: 504 988 3508; to articles published in English. Studies evaluating both e-mail: [email protected] paediatric and adult patient populations were included, Accepted after revision 15 July 2013 and this review includes all relevant articles.

DDAVP mechanism of action and FVIII, and there is more inter-patient variability [11]. In studies evaluating the effect of IV DDAVP in patients pharmacokinetics with congenital or acquired platelet disorders, a specific Desmopressin (1-deamino-8-D-arginine vasopressin) platelet effect appears within 30 min of administration acts through antidiuretic type 2 vasopressin receptors and dissipates within 3–4 h [12–14]. and is nearly devoid of activity through type 1 recep- While the pharmacokinetics of SC-administered tors, which reduces undesirable vasoactive side effects DDAVP is similar to that of IV dosing, IN administra- and prolongs its half-life when compared to native tion is associated with greater variability in absorp- vasopressin [3–5]. Following DDAVP administration, tion, time to peak activity and peak and duration of cyclic adenosine monophosphate signals the secretion activity [10]. A response is generally seen within 1– of VWF and tissue plasminogen activator (t-PA) from 4 h after IN dosing, and the duration of activity is Weibel-Palade bodies in endothelial cells into plasma typically 6–8 h. Decreased absorption of IN DDAVP [2,6]. The released VWF is highly multimerized, which can occur in patients with nasal obstruction or allergic enhances binding to the subendothelial matrix and rhinitis [15]. Because of this, many prefer the IV for- platelets, and increases haemostatic efficacy [6]. FVIII, mulation for a DDAVP challenge, although IN which co-localizes with VWF, is also released from DDAVP can be suitable in patients who have shown a storage sites following DDAVP administration. consistent response to DDAVP in this formulation. DDAVP-induced increases in plasma VWF may pro- A summary of pharmacokinetic properties of tect FVIII from proteolytic degradation, contributing DDAVP by administration route is provided in to additional, sustained increases in FVIII activity [6]. Table 1. DDAVP-induced release of t-PA briefly increases fibrinolysis, but does not interfere with DDAVP’s overall Response to DDAVP and challenge testing haemostatic efficacy. DDAVP increases the expression of glycoprotein Ib/ DDAVP is most effective in patients with mild haemo- IX and CD62 (P-selectin) on platelet surfaces, leading philia A (FVIII:C > 5%) and patients with type 1 VWD to increased platelet rolling, activation and adhesion who have functionally normal VWF. Overall, about [7,8]. Collectively, these actions can shorten the bleed- 80–90% of these individuals will have a clinically ing time and normalize shear-induced platelet aggrega- meaningful haemostatic response to DDAVP [14,16]. tion [2,4,7,9]. Although there is no standard criterion for defining a DDAVP has a biphasic half-life that contributes to response, most investigators define a response as a rise rapid onset of antidiuretic activity. The terminal half- in FVIII and VWF of at least twofold to threefold, with À life of DDAVP is 3.5 h in healthy volunteers and FVIII and VWF levels ≥0.3 IU dL 1 1–2 h after increases to 9 h in patients with renal insufficiency; it DDAVP administration [16,17]. For patients with rapid is primarily excreted in the urine. VWF-clearance forms of type 1 VWD (i.e. ‘Vincenza’ DDAVP is currently available in IV, subcutaneous variants), response to DDAVP may appear to be sub- (SC) IN, and oral formulations. The oral formulation of stantial, with an increase in baseline VWF and FVIlI:C DDAVP has insufficient efficacy in patients with con- levels of fivefold to 10-fold; however, there is a rapid genital bleeding disorders, so this discussion will focus decline in levels, with a terminal half-life as short as on the IV, SC and IN routes of administration. IV 60 min, which may limit its usefulness in such patients DDAVP shows peak activity within 30 min of infusion, for most clinical situations [18]. In addition, in patients raising FVIII:C levels twofold to fourfold in patients with type 2B VWD, VWF levels may increase following with bleeding disorders (levels return to baseline 24 h DDAVP administration, only to precipitate a worsening after a single dose) [10]. IV DDAVP also increases VWF of thrombocytopenia [19], leading most clinicians to activity, but the impact is not as dramatic as it is on avoid its use in this type of VWD.

Table 1. FVIII and VWF responses resulting from different routes of DDAVP administration.

IV SC IN À À Standard/recommended ‘ 0.3 lgkg 1 body weight 0.3 lgkg 1 body weight 150 lg (1 puff) ≤50 kg dose (VWD) Maximum of 20–30 lg 300 lg (2 puffs) >50 kg (given over 30 min) Peak activity Three- to fourfold rise in Two- to fourfold rise in VWF Two- to threefold rise in VWF and FVIII levels and FVIII levels VWF and FVIII:C levels Time to peak activity 30–60 min 60–90 min 1–4h Half-life of haemostatic 8h 6–8h 6–8h effect Dosing considerations Magniﬁed antidiuretic effect Variable absorption due to (in relation to SC and IN routes) nasal obstruction IV, intravenous; SC, subcutaneous; IN, intranasal; VWD, von Willebrand disease; VWF, von Willebrand factor; FVIII, factor VIII.

DDAVP is not recommended for children under mild platelet function disorders, DDAVP is used 2 years of age because of decreased responsiveness empirically because there is no reliable laboratory and increased toxicity; however, children typically assay to monitor response. become more responsive as they age. In a study of 74 boys with mild or moderate haemophilia A, 10 of 11 DDAVP dosing who underwent DDAVP challenge testing at a median of 2 years of age had an improved response (i.e. The standard IV or SC dose of DDAVP is À attained higher FVIII:C levels) when retested at a med- 0.3 lgkg 1. Some guidelines suggest a maximum ian of 5 years of age. In fact, retesting resulted in dose of 20 lg to avoid untoward effects [20]; how- nearly half of these patients being reclassified as ever, such a restriction may lead to a diminished clini- DDAVP responders [20]. For patients with more cal response in patients weighing over 70 kg. In severe forms of haemophilia A or VWD, responsive- addition, young children tend not to respond as well ness to DDAVP is variable (Table 2), and such treat- to DDAVP as do adults, possibly the result of dosing ment is not advised [2,31]. based on body weight rather than surface area [20]. A DDAVP challenge test is recommended before The recommended IN dose of DDAVP is 150 lg first use in patients with haemophilia A or VWD to (one puff) for patients weighing ≤50 kg, and 300 lg document response and assess tolerability. For patients (two puffs) for those weighing >50 kg, which trans- with platelet disorders or other congenital bleeding lates to a potential twofold difference in dose for indi- disorders (e.g. EDS), demonstrating a quantitative lab- viduals close to the cut-off weight [11]. IN DDAVP oratory response to DDAVP is more difficult. The has been shown to be equally as effective as the IV PFA-100 (Siemens Ag, Deerfield, IL, USA) and the formulation in raising VWF and FVIII:C levels [11]. Simplate bleeding time assay (BioMerieux Inc., Dur- Repeated DDAVP dosing leads to the phenomenon ham, NC, USA) have been proposed as laboratory of tachyphylaxis, the loss of therapeutic effect after measures to gauge the haemostatic effect of DDAVP repeated dosing [4,6]. This development, which is in these patients, but their clinical usefulness remains more pronounced in patients with haemophilia A than uncertain [14,32,33]. For the majority of patients with with VWD [24], relates to depletion of VWF and

Table 2. Prospective studies of IV DDAVP and laboratory response by VWD disease subtype.

Mean increase (fold)*

VWD subtype N Response rate† VWF:RCo VWF:Ag FVIII Type of evidence Type 1 Mannucci et al. [21] 15 N/A N/A 3.6 5.5 Prospective cohort de la Fuente et al. [22] 13 94% 5.0 4.5 5.7 Prospective cohort Mannucci et al. [23] 7 N/A 9.5 9.0 10.3 Prospective cohort Mannucci et al. [24] 15 N/A 5.1 4.8 4.3 Prospective cohort Federici et al. [17] 26 27% 3.1 N/A 3.3 Prospective cohort Type 1 Vincenza (rapid-clearing type) Mannucci et al. [23] 6 N/A 9.1 8.3 10.2 Prospective cohort Rodeghiero et al. [25] 5 N/A N/A N/A 10 Prospective cohort ‡ ‡ ‡ Castaman et al. [18] 22 N/A 11.4 , 13.8§ 5.3 ,8.5§ 5.2 , 10.4§ Prospective cohort Type 2A de la Fuente et al. [22] 7 86% 6.4 4.9 4.9 Prospective cohort ¶ Revel-Vilk et al. [16] 5 40% 4.2 N/A 2.9 Retrospective case series Federici et al. [17] 15 7% 2.6 N/A 3.4 Prospective cohort Type 2B Casonato et al. [26] 4 N/A 2.3 3.5 3.0 Prospective cohort McKeown et al. [27] 3 N/A 3.2 3.2 3.6 Prospective cohort Castaman et al. [28] 33 N/A Normalized in 18/33 Normalized in 33/33 Normalized in 33/33 Literature review Type 2M Federici et al. [17] 21 14% 3.3 N/A 3.0 Prospective cohort Type 2N Mazurier et al. [29] 8 N/A 1.4 2.2 9.7 Prospective cohort Federici et al. [17] 4 75% 3.8 N/A 6.6 Prospective cohort Adapted from: U.S. Department of Health and Human Services. National Institutes of Health. The Diagnosis, Evaluation and Management of von Wille- brand Disease. NIH Publications No. 08-5832. December 2007. http://www.nhlbi.nih.gov/guidelines/vwd/vwd.pdf. Accessed July 1, 2013 [30]. VWD, von Willebrand disease; VWF, von Willebrand factor; IV, intravenous; FVIII, factor VIII. *Data are given as mean fold increase in plasma factor compared to baseline after a single administration of DDAVP. Mean fold increases were calculated from original data, where possible, if not included in the manuscript. † À Response deﬁned as twofold increase and to at least 30 IU dL 1 VWF:RCo and FVIII. ‡ C1130F VWF mutation. §R1205H VWF mutation. ¶Results given for responders only.

FVIII stores and to desensitization of vasopressin type DDAVP administration; over a 6-year period, more 2 receptors. On average, the response to a second dose than 80 patients were treated with SC DDAVP for of DDAVP is about 30% less than that of the first bleeding with adequate efficacy [18]. Nevertheless, dose [24]. Because of this effect, DDAVP is not patients with rapid clearance variants of VWD may expected to be effective when given at intervals less not benefit when prolonged elevations of FVIII:C or than 24 h or when repeated doses are given for more VWF are needed. than 2–4 days. Treatment may need to be periodically stopped to restore effectiveness. DDAVP for surgical haemostasis

DDAVP in the treatment of bleeding A number of both prospective and retrospective studies have described DDAVP use in the surgical setting Small, single-institution series initially reported effi- (Table 4); IV DDAVP was used in nearly all reported cacy with the use of one to three doses of IV DDAVP surgical cases. While the majority of surgeries were for the treatment of typical bleeding events, including adenotonsillar procedures or minor oral and dental epistaxis, oral and soft tissue bleeding and rarely surgeries, some reports of major surgery have been haemarthrosis [34,35]. One prospective clinical trial identified (Table 4) [1,18,22,35,38–45]. evaluated the treatment of bleeding with IV DDAVP Early single-institution reports described the success- in 18 patients with HA and three patients with VWD ful use of IV DDAVP in the management of patients who had epistaxis, haemarthrosis, or intramuscular with VWD or mild haemophilia A undergoing adeno- bleeding and other soft tissue bleeding. [22] Nine of tonsillar procedures, with the adjunctive use of tranexa- 18 patients with haemophilia responded to DDAVP mic acid or epsilon-aminocaproic acid. Vasomotor (one to three doses) without other infusion therapy, reaction (skin flushing) was the only appreciable AE while the remaining patients had follow-up infusions reported in these series [17,25,28]. of cryoprecipitate or FVIII concentrate. Six of eight Subsequently, larger studies (including one prospec- patients who had an increase in baseline FVIII to tive trial) of patients with VWD have reported data À ≥0.3 IU dL 1 after DDAVP did not require additional on more than 150 patients undergoing adenotonsillar FVIII therapy for the treatment of bleeding. All three procedures and have shown that DDAVP is generally VWD patients had a good response to IV DDAVP to effective and safe; most patients were children, control minor bleeding episodes [22]. although some adults were included as well. Treat- Subsequently, two prospective studies were done to ment dosing regimens varied widely, ranging from a À evaluate DDAVP use in the outpatient setting to allow single dose (usually 0.3 lgkg 1; although in some À for the rapid treatment of bleeding (Table 3). These cases, 0.5 lgkg 1 doses were used) to as many as five studies evaluated the efficacy of IN and SC DDAVP doses, and usually included adjunctive antifibrinolytic used to treat spontaneous bleeding in over 500 outpa- therapy (Table 4). Early postoperative bleeding was tients with bleeding disorders (276 with VWD, 216 well controlled in patients who received two to four with HA, and 10 with other bleeding disorders) doses of DDAVP during the first week postoperatively; [36,37]. Both studies included children and adults, however, approximately 5–25% of patients experi- with a median age of 28 years in one study and a enced breakthrough bleeding 5–10 days postopera- mean age of 23.9 years in the other. Haemostatic tively, suggesting that additional treatment may be responses (efficacy rating of good or excellent) were needed prior to and at the time of eschar separation. achieved in 91–96% of all bleeding episodes, and no Hyponatremia was more likely to occur with multiple significant adverse events (AEs) were reported, DDAVP doses, and was minimized by careful atten- suggesting that DDAVP is effective in home-based tion to fluid restriction [38–41]. therapy. Other studies with larger patient populations One other prospective study was performed in a reported good haemostasis in patients undergoing hospital setting for patients with VWD who were invasive dental procedures when one to three doses of genetically typed to have rapid clearance of VWF after DDAVP were used in conjunction with antifibrinolytic

Table 3. Prospective studies of SC or IN DDAVP to treat bleeding in the homecare setting.

Mode of DDAVP Bleeding frequency Citation Patient population Age range (years) delivery, dose (lg) (haemorrhages/patient/year) Efﬁcacy Rodeghiero VWD (n = 100) 10–65 (median, 28) SC VWD: 1.27 Excellent: 64% et al. [36] HA (n = 69) 20 (<70 kg) HA: 1.33 Good: 27% 40 (≥70 kg) Ineffective: 9% Leissinger VWD (n = 176) 5.3–64.7 (mean, 23.9) IN ~3.5 Excellent: 75% et al. [37] HA (n = 147) 150 (≤50 kg) Good: 21% Other (n = 10) 300 (>50 kg) Ineffective: 5% VWD, von Willebrand disease; HA, haemophilia A; SC, subcutaneous; IN, intranasal.

(2014), DDAVP Type of treatment Adjunctive Post-op Surgery type Study type N patients Age (years) and dose Doses (n) Days with doses* therapies Monitoring bleeding Adverse events

20 Adenotonsillar Prospective [38] 40 VWD Type 1 1.3–13 (5.2) IV 2–4 0-1, 2, 3 and/or 4 TA Daily sodium Early: 2/40 Mild hyponatremia:

158--167 , À procedures 0.3 lgkg 1 97 days Late: 0/40 27/40 (67.5%) Severe hyponatremia:

2/40 (5%) al. et Seizure: 1/40 (2.5%) Retrospective [39] 12 VWD 2.5–9IVDaily until 0–0 EACA or TA Daily sodium Early: 1/12 Mild hyponatremia: À Type 1 0.3 lgkg 1 eschar falls Daily until Late: 2/12 2/12 (16.7%) off eschar falls off Severe hyponatremia: 3/12 (25%) Retrospective [40] 69 VWD 1.5–17.3 (7.3) IV 1 0 Not reported Sodium (in Early: 7/69 Mild hyponatremia: À 0.3 lgkg 53 patients) Late: 9/69 27/69 (39.1%) Severe hyponatremia: 3/69 (4.3%) Seizure: 1/69 (1.4%) Retrospective [41] 41 VWD <18 (5.9) IV 30–0 and 5, 6, 7 or 8 EACA None noted Early: 0/41 Mild hyponatremia: À Type 1 0.3 lgkg 1 95 days Late: 7/41 1/41 (2.4%) Dental Prospective [22] 12 VWD (5) 8–60 IV 1–70 EACA None noted 1/12 None noted À extractions HA (7) 0.3 lgkg 1 0–0 93–5 days 0–1–3–4–7–10–12 Prospective [18] 20 VWD Unk SC 11 TANone noted None None noted À 0.3 lgkg 1 95 days Retrospective [1] 8 Mild HA (7) Unk IV 20–1 TA None noted None None À Moderate HA (1) 0.5 lgkg 1 Retrospective [35] 25 VWD (9) Unk IV 1–30 TA None noted 3/25 None noted À HA (16) 0.3 lgkg 1 0–1–7or8 Retrospective [42] 27 VWD Type 1 (20) 5–87 IV 10 TANone noted None None noted À VWD Type 2a (7) 0.3 lgkg 1 97 days Thoracotomy Retrospective [1] 1 Mild HA Unk IV 20–1 TA None noted None None À 0.5 lgkg 1 Retrospective [43] 1 VWD Unk IV 1 0 EACA None noted None None noted À 0.5 lgkg 1 Palate repair Prospective [22] 1 HA 46 IV 1 0 None None noted None None noted

© À 0.5 lgkg 1 03Jh ie osLtd Sons & Wiley John 2013 Retrospective [43] 1 VWD Unk IV 1 0 EACA None noted None None noted À 0.5 lgkg 1 Cholecystectomy Retrospective [1] 1 VWD Unk IV 20–1 TA None noted None None À 0.5 lgkg 1 Retroperitoneal Retrospective [35] 1 VWD Unk IV 50–2–4–6–8 TA None noted None None noted À ganglioma 0.3 lgkg 1

(continued) DDAVP IN THE MANAGEMENT OF BLEEDING DISORDERS 163

therapy [1,35]. In a prospective study of 83 patients with a speciﬁc rapid VWF-clearance form of VWD, 20 patients underwent 28 dental extractions, with 24 receiving a single infusion of SC DDAVP followed by antiﬁbrinolytic therapy for 5 days. No cases of immediate or delayed bleeding events were observed in these patients [18]. As previously noted, published experience on the use of DDAVP in major surgery is rare, with a few Post-op bleeding Adverse events anecdotal case reports [1,35,43,44]. Due to DDAVP’s limited usefulness over a prolonged duration, it is not expected to be effective in major surgeries.

DDAVP in the management of gynaecological

s; SC, subcutaneous. and obstetrical bleeding

Menorrhagia therapies Monitoring Adjunctive

Not reported None noted None None noted Menorrhagia, deﬁned as the passage of >80 mL of blood per month, is the most common complication that affects women with congenital bleeding disorders [46]. Several treatment modalities are available to con- 3 TA None noted None None noted

– trol heavy menstrual bleeding, with selection deter- day of surgery. 2 2 TA None noted None None noted – – =

1 21 2 TA TA None noted None None noted None noted Nonemined None noted by a patient’s age and whether preservation of – – – – 0 1 0 1 0 2

– – – – – – fertility is a concern. Hormonal therapies, including 0 0 oral contraceptives, cutaneous patches, vaginal rings

) Days with doses* and some types of oestrogen-containing intrauterine n devices, reduce menstrual blood ﬂow and also raise

20 FVIII:C and VWF levels [47]. DDAVP is an alternative – 50 30 40 30 1 approach for women who cannot take hormonal ther- 1 1 1 1 1

À À À À À apy or who are actively attempting to become pregnant. Two prospective studies in women with VWD or mild gkg gkg gkg gkg gkg l l l l l

DDAVP haemophilia A (i.e. haemophilia A carriers) have shown and dose Doses ( treatment 0.3 0.3 0.3 0.3 0.3 responses to DDAVP and antifibrinolytic therapy that were good or excellent in 86% and 92% of patients respectively (Table 5) [36,37]. Although no studies have investigated the relative efficacy of DDAVP and 66 IV – antifibrinolytic therapy, the combination may be more 13 effective than either drug used individually.

Obstetrical bleeding

Type of patients Age (years) The use of DDAVP during pregnancy is controversial because of the theoretical risk for intrauterine growth VWD (2) retardation, uterine contraction and premature labour.

N Nonetheless, a systematic review of case reports and small case series reported good safety and efficacy with DDAVP [48]. DDAVP administered to pregnant women in their first and second trimesters before invasive procedures (i.e. chorionic villus sampling, amniocentesis, cervical cerclage, termination) and for the Retrospective [35] 1 HA Unk IV Prospective [22] 8 HA (6) treatment of a first-trimester subchorionic haemorrhage did not cause neonatal complications, and only mild maternal side effects were reported [48]. When administered peripartum to women with bleeding disorders, DDAVP prevented postpartum haemorrhage in 167 of repair surgeries Bilateral hernia Table 4. (continued). Surgery type Study type Appendectomy RetrospectiveHydrocoele [35] 1Meniscectomy HA Retrospective [35]Other Retrospective minor [35] 1 1 VWD HAEACA, epsilon-aminocaproic acid; HA, haemophilia A; TA, Unk tranexamic acid; Unk, unknown or not reported; VWD, von Unk Willebrand disease; IV, intravenou Unk IV IV IV *Numbers listed denote days on which doses were given; numbers listed twice indicate two doses were given on that day. 0 172 deliveries (97%) [48]. Of the five pregnancies in

Table 5. Reports of DDAVP in the management of menorrhagia.

Patient population DDAVP Days/cycle treated Efficacy Citation VWD SC Unknown Excellent: 65% Rodeghiero et al. [36] N = 14 20 lg(<70 kg) Good: 21% 40 lg(≥70 kg) Ineffective: 14% VWD and HA carriers IN 1–8 days Excellent + good: 92% Leissinger et al. [37] N = 90 150 lg(≤50 kg) avg: 1.7 days 300 lg(>50 kg) 51% used 1 day 25% used 2 days 14% used 3 days 10% used four or more days HA, haemophilia A; VWD, von Willebrand disease; IN, intranasal; SC, subcutaneous. which adverse bleeding events were reported, there headache, facial flushing, mild hypotension and tachy- were four cases of postpartum haemorrhage and one cardia) [2,4]. The incidence of these effects is highly case of SC haematoma. The underlying bleeding disor- variable [37,38,40,41,52] and differs with the mode ders in these women who developed bleeding complica- of administration, with more vasoactive AEs likely to tions despite treatment included two cases of occur with IV administration. In one study of IV À Hermansky-Pudlak syndrome and a single case each of DDAVP 0.3 lgkg 1 in children with congenital platelet storage pool disorder, EDS and VWD [48]. bleeding disorders, mild cases of flushing and head- Other AEs associated with the use of DDAVP during ache were reported in some patients [14]. However, pregnancy in the studies reviewed included one case of infusing DDAVP over a 30- to 60-min period can premature labour in the ninth month and one case of attenuate these vasomotor effects. In a prospective maternal seizure resulting from hyponatremia, both in study of the home use of SC DDAVP in 169 patients patients with VWD. No neonatal complications or signs with VWD and mild or moderate haemophilia A, of intrauterine growth retardation were reported in the 30% reported mild flushing with or without headache, studies reviewed [48]. but these effects generally did not affect patient com- There have been no reports of teratogenic effects in pliance [36]. Meanwhile, in a large prospective study foetuses exposed to DDAVP in the first trimester of of IN DDAVP in 278 patients with mild haemophilia pregnancy, and in vitro placental models show that A or mild or moderate type 1 VWD, or who were DDAVP does not cross the placental barrier in detect- symptomatic carriers of haemophilia A, 172 (8%) able amounts [49,50]. DDAVP is released into breast doses were associated with AEs, with headache milk in very small quantities, but there is negligible oral (3.6%) and flushing (3.2%) being most frequently absorption, suggesting that maternal use during breast- reported, followed less frequently by dizziness (1.5%) feeding is safe [50,51]. Nonetheless, the manufacturer and nausea (1.1%) [37]. advises against use of DDAVP by nursing mothers. Mild to severe hyponatremia and hyponatremia- related seizures are the most serious AEs linked to the DDAVP safety use of DDAVP and are caused by its antidiuretic effect, which is 10 times greater with IV than with IN Most AEs associated with DDAVP are mild and administration. Large case series suggest that hyponat- related to the vasomotor effects of the drug (e.g. remia in otherwise healthy adults is uncommon, and

Table 6. Important safety considerations with DDAVP.

Potential severity Safety concerns Potential clinical effects of effects Frequency Comments Vasomotor effects Manucci et al. [4] Facial flushing, mild Mild Common Can usually be attenuated by slowing the infusion Franchini et al. [2] hypotension, and tachycardia rate of DDAVP; it is recommended to give IV DDAVP over 30–60 min Antidiuretic effects Dunn et al. [52] Hyponatremia, volume Serious Less Particularly a problem in very young children, patients Das et al. [59] overload, and seizures common on diuretics, or patients who cannot control their Jimenez-Yuste et al. [38] fluid intake (those on IV fluids); more likely when Smith et al. [55] patients receive multiple doses of DDAVP Thrombotic complications Bond et al. [57] Myocardial infarction and stroke Life-threatening Rare DDAVP is generally avoided in patients with known Byrnes et al. [58] atherosclerotic coronary artery disease, or poorly Franchini et al. [60] controlled hypertension IV, intravenous.

Haemophilia (2014), 20, 158--167 © 2013 John Wiley & Sons Ltd DDAVP IN THE MANAGEMENT OF BLEEDING DISORDERS 165 that incidence increases in young children with surgery, with reports confirming good efficacy, espe- repetitive dosing or with overly aggressive fluid cially when combined with antifibrinolytic therapy replacement during surgery [53–56]. Consequently, [42,50]. It is clear that a major risk period for bleed- DDAVP is not recommended in children under 2 years ing occurs five or more days after the procedure at of age, and fluid intake should be closely regulated in the time of eschar separation, and should serve as a all patients [53,54]. In addition, DDAVP should be reminder that additional therapy may be needed to used with caution in persons with medical disorders prevent late postoperative bleeding. Although there associated with sodium abnormalities, such as cystic are several case reports of its use in major surgery, fibrosis, heart failure and renal disorders. DDAVP is not an appropriate treatment choice in Because type 1 vasopressin receptors are minimally most major surgical procedures requiring prolonged affected by DDAVP, the risk of uterine or gastroin- haemostasis because tachyphylaxis and concern over testinal contractions or hypertension with treatment fluid retention precludes effective use over multiple is low [4]. Rare instances of thrombotic complica- days [24]. tions (i.e. myocardial infarction, stroke) have been DDAVP is an important drug in the haemostatic reported after DDAVP administration in elderly armamentarium for patients with bleeding disorders. patients with cardiovascular and/or cerebrovascular It has been successfully used in a wide variety of clini- risk factors, and the drug should be used cautiously cal settings in selected patients who have demon- in this patient population [57,58], as well as those strated responsiveness either by laboratory testing (in with important risk factors for cardiovascular disease, patients with VWD or haemophilia A) or clinical such as poorly controlled hypertension. Table 6 pro- observation (in patients with other bleeding disorders). vides a summary of potential safety concerns with Compared to factor concentrates, DDAVP has the DDAVP. advantage of ease of administration (particularly with the IN formulation), convenience, low cost and avoid- Conclusions ance of blood derivatives. In addition, responses can be readily monitored by following VWF or FVIII:C Clinical experience with DDAVP has greatly expanded levels in patients with VWD and haemophilia A. over the past three decades. A recent study of practice DDAVP has also demonstrated a favourable safety patterns of a representative sampling of US haematolo- profile, with most reported AEs being mild and related gists caring for VWD patients showed that DDAVP was to its vasomotor effects. prescribed to treat over 80% of bleeding events, and While the collective clinical experience with DDAVP used in over 85% of surgical procedures in patients is largely based on anecdotal reports and small case with type 1 VWD, and in approximately 50% of bleed- series, the number of prospective and retrospective ing events and 40% of surgical procedures in type 2 reports is accumulating. Our review of the published VWD [61]. This collective clinical experience with literature affirms the efficacy and safety of DDAVP DDAVP is largely based on a growing literature of rela- for prevention and treatment of bleeding in selected tively small case series and a limited number of prospec- patients with haemophilia A, VWD and other congen- tive non-randomized clinical trials. ital bleeding disorders. When used in the treatment of bleeding, including menorrhagia in women, efficacy is good and signifi- Disclosures cant AEs are rare, particularly when the number of doses is limited and there is attention to fluid restric- CL has acted as a paid consultant to Baxter, Bayer, Biogen Idec, CSL tion. Overall, given the potential benefits of rapid Behring, Kedrion, NovoNordisk, and Pfizer, and has received research treatment of haemorrhages and the high level of safety funding from Baxter, Bayer, CSL Behring and NovoNordisk. MC has and tolerability of DDAVP in older children and received honoraria/speaking fees from Baxter, Bayer, CSL Behring, Novo Nordisk, Octapharma, and Pfizer. MC has received research funds from adults, the weight of evidence favours making DDAVP Baxter, Bayer, Bio Sea, Novo Nordisk, and Pfizer. JCG has acted as a readily available for home use, with appropriate paid advisory board member to CS Behring, Octapharma, and Biogen precautions regarding fluid restriction. Most patients Idec. JJ has received honoraria from Baxter Healthcare and Biogen Idec. JC has been on a grant review panel for Pfizer Hemophilia. TS has acted are asked to limit their outpatient use to no more than as a paid consultant for Kedron, Pfizer, and CSL Behring. She is a speaker two doses over a 24-h period, and to call their for Grifols, Baxter, and Novo Nordisk. She has received grant funding physician’s office if additional therapy is needed. from Baxter. Rush University Medical Center receives grant support on Surgery in patients with haemostatic disorders can behalf of LV from Baxter Bioscience, Bayer Healthcare, Biogen, CSL Behring, GTC Biotherapeutics, Inspiration Bioscience, NovoNordisk, and be challenging and requires a deliberate and collabo- Pfizer; and Rush University Medical Center also receives payments on rative approach to achieve a successful outcome. Pub- behalf of LV for his participation in advisory boards and as a consultant lished studies of DDAVP for prevention of surgical for Baxter Bioscience, Bayer Healthcare, Biogen, CSL Behring, GTC bleeding have largely focused on ENT and dental Biotherapeutics, Inspiration Bioscience, NovoNordisk, and Pfizer.

References in children with von Willebrand disease. 30 National Heart, Lung, and Blood Institute. J Pediatr Hematol Oncol 2003; 25: 874–9. The Diagnosis, Evaluation, and Manage- 1 Mannucci PM, Ruggeri ZM, Pareti FI, 17 Federici AB, Mazurier C, Berntorp E et al. ment of von Willebrand Disease. Bethesda, Capitanio A. DDAVP: a new pharmacolog- Biologic response to desmopressin in MD: US Department of Health and Human – ical approach to the management of hemo- patients with severe type 1 and type 2 von Services, 2008; Table 11: 39 40. philia and von Willebrand disease. Lancet Willebrand disease: results of a multicenter 31 Mannucci PM. Treatment of von Wille- – 1977; 1: 869–72. European study. Blood 2004; 103: 2032 8. brand’s Disease. N Engl J Med 2004; 351: – 2 Franchini M. The use of desmopressin as a 18 Castaman G, Tosetto A, Federici AB, 683 94. hemostatic agent: a concise review. Am J Rodeghiero F. Bleeding tendency and effi- 32 Mast K, Nunes M, Ruymann F, Kerlin B. Hematol 2007; 82: 731–5. cacy of anti-haemorrhagic treatments in Desmopressin responsiveness in children 3 Mannucci PM, Aberg M, Nilsson IM, Rob- patients with type 1 von Willebrand disease with Ehlers-Danlos syndrome associated ertson B. Mechanism of plasminogen activa- and increased von Willebrand factor clear- bleeding symptoms. Br J Haematol 2008; – – tor and factor VIII increase after vasoactive ance. Thromb Haemost 2011; 105: 647 54. 144: 230 3. drugs. Br J Haematol 1975; 30:81–93. 19 Kyrle PA, Niessner H, Dent J et al. IIB von 33 Yasui H, Adachi Y, Minami T, Ishida T, 4 Mannucci PM, Vicente V, Alberca I et al. Willebrand’s disease: pathogenetic and Kato Y, Imai K. Combination therapy of Intravenous and subcutaneous administra- therapeutic studies. Br J Haematol 1988; DDAVP and conjugated estrogens for a – tion of desmopressin (DDAVP) to hemo- 69:55 9. recurrent large subcutaneous hematoma in philiacs: pharmacokinetics and factor VIII 20 Seary ME, Feldman D, Carcao MD. Ehlers-Danlos syndrome. Am J Hematol – responses. Thromb Haemost 1987; 58: DDAVP responsiveness in children with 2003; 72:71 2. 1037–9. mild or moderate haemophilia A correlates 34 Warrier AI, Lusher JM. DDAVP: a useful 5 Ozgonenel€ B, Rajpurkar M, Lusher JM. with age, endogenous FVIII:C level and alternative to blood components in moder- How do you treat bleeding disorders with with haemophilic genotype. Haemophilia ate hemophilia A and von Willebrand dis- – – desmopressin? Postgrad Med J 2007; 83: 2012; 18:50 5. ease. J Pediatr 1983; 102: 228 33. 159–63. 21 Mannucci PM, Canciani MT, Rota L, 35 Mariana G, Ciavarella N, Mazzucconi MG 6 Kaufmann JE, Vischer UM. Cellular mech- Donovan BS. Response of factor VIII/von et al. Evaluation of the effectiveness of anisms of the hemostatic effects of desmo- Willebrand factor to DDAVP in healthy DDAVP in surgery and bleeding episodes in pressin (DDAVP). J Thromb Haemost subjects and patients with haemophilia A hemophilia and von Willebrand’s disease. 2003; 1: 682–9. and von Willebrand’s disease. Br J Haema- A study of 43 patients. Clin Lab Haematol – – 7 Leithauser€ B, Zielske D, Seyfert UT, Jung tol 1981; 47: 283 93. 1984; 6: 229 38. F. Effects of desmopressin on platelet mem- 22 de la Fuente B, Kasper CK, Rickles FR, 36 Rodeghiero F, Castaman G, Mannucci PM. brane glycoproteins and platelet aggrega- Hoyer LW. Response of patients with mild Prospective multicenter study on subcutane- tion in volunteers on clopidogrel. Clin and moderate hemophilia A and von Wille- ous concentrated desmopressin for home Hemorheol Microcirc 2008; 39: 293–302. brand’s disease to treatment with desmo- treatment of patients with von Willebrand – 8 Coppola A, Di Minno G. Desmopressin in pressin. Ann Intern Med 1985; 103:6 14. disease and mild or moderate hemophilia – inherited disorders of platelet dysfunction. 23 Mannucci PM, Lombardi R, Castaman G A. Thromb Haemost 1996; 76: 692 6. Haemophilia 2008; 14:31–9. et al. von Willebrand disease “Vicenza” 37 Leissinger C, Becton D, Cornell C Jr, Cox 9 Cattaneo M, Lombardi R, Bettega D, Lec- with larger than-normal (supranormal) von Gill J. High-dose DDAVP intranasal spray chi A, Mannucci PM. Shear-induced plate- Willebrand factor multimers. Blood 1988; (Stimate) for the prevention and treatment – let aggregation is potentiated by 71:65 70. of bleeding in patients with mild haemo- desmopressin and inhibited by ticlopidine. 24 Mannucci PM, Bettega D, Cattaneo M. philia A, mild or moderate type 1 von Arterioscler Thromb 1993; 13: 393–7. Patterns of development of tachyphylaxis in Willebrand disease and symptomatic carri- 10 Kohler€ M, Harris A. Pharmacokinetics and patients with haemophilia and von Wille- ers of haemophilia A. Haemophilia 2001; – haematological effects of desmopressin. Eur brand disease after repeated doses of des- 7: 258 66. J Clin Pharmacol 1988; 35: 281–5. mopressin (DDAVP). Br J Haematol 1992; 38 Jimenez-Yuste V, Prim MP, De Diego JI – 11 Gill JC, Ottum M, Schwartz B. Evaluation 82:87 93. et al. Otolaryngologic surgery in children of high dose intranasal and intravenous 25 Rodeghiero F, Castaman G, Di Bona E, with von Willebrand disease. Arch Otolar- – desmopressin in pediatric patients with Ruggeri M. Consistency of responses to yngol Head Neck Surg 2002; 128: 1365 8. mild hemophilia A and mild to moderate repeated DDAVP infusions in patients with 39 Derkay CS, Werner E, Plotnick E. Manage- type 1 von Willebrand disease. J Pediatr von Willebrand’s disease and hemophilia ment of children with von Willebrand dis- – 2002; 140: 595–9. A. Blood 1989; 74: 1997 2000. ease undergoing adenotonsillectomy. Am J – 12 Reiter RA, Mayr F, Blazicek H et al. Des- 26 Casonato A, Sartori MT, de Marco L, Otolaryngol 1996; 17: 172 7. mopressin antagonizes the in vitro platelet Girolami A. 1-Desamino-8-D-arginine vaso- 40 Allen GC, Armfield DR, Bontempo FA, dysfunction induced by GPIIb/IIIa inhibi- pressin (DDAVP) infusion in type IIB von Kingsley LA, Goldstein NA, Post JC. Ade- tors and aspirin. Blood 2003; 102: 4594–9. Willebrand’s disease: shortening of bleeding notonsillectomy in children with von Wille- 13 Lethagen S, Olofsson L, Frick K, Berntorp time and induction of a variable pseudo- brand disease. Arch Otolaryngol Head – E, Bjorkman€ S. Effect kinetics of desmo- thrombocytopenia. Thromb Haemost 1990; Neck Surg 1999; 125: 547 51. – pressin-induced platelet retention in healthy 64: 117 20. 41 Witmer CM, Elden L, Butler RB, Manno volunteers treated with aspirin or placebo. 27 McKeown LP, Connaghan G, Wilson O, CS, Raffini LJ. Incidence of bleeding compli- Haemophilia 2000; 6:15–20. Hansmann K, Merryman P, Gralnick HR. cations in pediatric patients with type 1 von 14 Hanebutt FL, Rolf N, Loesel A, Kuhlisch 1-Desamino-8-arginine-vasopressin corrects Willebrand disease undergoing adenotonsil- – E, Siegert G, Knoefler R. Evaluation of des- the hemostatic defects in type 2B von lar procedures. J Pediatr 2009; 155:68 72. mopressin effects on haemostasis in chil- Willebrand’s disease. Am J Hematol 1996; 42 Federici AB, Sacco R, Stabile F, Carpenedo – dren with congenital bleeding disorders. 51: 158 63. M, Zingaro E, Mannucci PM. Optimising Haemophilia 2008; 14: 524–30. 28 Castaman G, Rodeghiero F. Desmopressin local therapy during oral surgery in patients 15 Greiff L, Andersson M, Svensson C, Lundin and type II B von Willebrand disease. Hae- with von Willebrand disease: effective – S, Wollmer P, Persson CG. Reduced airway mophilia 1996; 2:73 7. results from a retrospective analysis of 63 – absorption in seasonal allergic rhinitis. Am 29 Mazurier C, Gaucher C, Jorieux S, Goude- cases. Haemophilia 2000; 6:71 7. J Respir Crit Care Med 1997; 156: 783–6. mand M. Biological effect of desmopressin 43 Kobrinsky NL, Israels ED, Gerrard JM et al. 16 Revel-Vilk S, Schmugge M, Carcao MD, in eight patients with type 2N (‘Normandy’) Shortening of bleeding time by 1-deamino-8- Blanchette P, Rand ML, Blanchette VS. von Willebrand disease. Collaborative D-arginine vasopressin in various bleeding – – Desmopressin (DDAVP) responsiveness Group. Br J Haematol 1994; 88: 849 54. disorders. Lancet 1984; 1: 1145 8.

44 Nitu-Whalley IC, Griffioen A, Harrington pregnancy—a systematic review. Haemo- 55 Smith TJ, Gill JC, Ambruso DR, Hathaway C, Lee CA. Retrospective review of the philia 2012; 18:25–33. WE. Hyponatremia and seizures in young management of elective surgery with des- 49 Ray JG. DDAVP use during pregnancy: an children given DDAVP. Am J Hematol mopressin and clotting factor concentrates analysis of its safety for mother and child. 1989; 31: 199–202. in patients with von Willebrand disease. Obstet Gynecol Surv 1998; 53: 450–5. 56 Humphries JE. Significant hyponatremia fol- Am J Hematol 2001; 66: 280–4. 50 Burrow GN, Wassenaar W, Robertson GL, lowing DDAVP administration in a healthy 45 Kreuz W, Mentzer D, Becker S, Scharrer I, Sehl H. DDAVP treatment of diabetes insipi- adult. Am J Hematol 1993; 44:12–5. Kornhuber B. Haemate P in children with dus during pregnancy and the postpartum 57 Bond L, Bevan D. Myocardial infarction von Willebrand’s disease. Haemostasis period. Acta Endocrinol 1981; 97:23–5. in a patient with hemophilia treated with 1994; 24: 304–10. 51 Hale T. Medications and Mother’s Milk DDAVP. N Engl J Med 1988; 318: 121. 46 James AH, Kouides PA, Abdul-Kadir R (15th edn). Amarillo, TX: Hale Publishing, 58 Byrnes JJ, Larcada A, Moake JL. Thrombosis et al. Evaluation and management of acute 2012: 310–1. following desmopressin for uremic bleeding. menorrhagia in women with and without 52 Dunn AL, Cox Gill J. Adenotonsillectomy Am J Hematol 1988; 28:63–5. underlying bleeding disorders: consensus in patients with desmopressin responsive 59 Das P, Carcao M, Hitzler J. DDAVP- from an international expert panel. Eur J mild bleeding disorders: a review of the lit- induced hyponatremia in young children. J Obstet Gynecol Reprod Biol 2011; 158: erature. Haemophilia 2010; 16: 711–6. Pediatr Hematol Oncol 2005; 27: 330–2. 124–34. 53 Dunn AL, Powers JR, Ribeiro MJ, Rickles 60 Franchini M, Krampera M, Veneri D. Deep 47 Byams VR, Kouides PA, Kulkarni R et al.; FR, Abshire TC. Adverse events during use vein thrombosis after orthopedic surgery in Haemophilia Treatment Centres Network of intranasal desmopressin acetate for hae- a patient with type 1 von Willebrand dis- Investigators. Surveillance of female patients mophilia A and von Willebrand disease: a ease and mutations in the MTHFR and with inherited bleeding disorders in United case report and review of 40 patients. Hae- beta-fibrinogen genes. Thromb Haemost States Haemophilia Treatment Centres. mophilia 2000; 6:11–4. 2003; 90: 963–4. Haemophilia 2011; 17(Suppl. 1): 6–13. 54 Weinstein RE, Bona RD, Altman AJ et al. 61 Leissinger C, Nugent D. Treatment and 48 Trigg DE, Stergiotou I, Peitsidis P, Kadir Severe hyponatremia after repeated intrave- management patterns of patients with von RA. The use of desmopressin for treatment nous administration of desmopressin. Am J Willebrand disease in the United States. and prophylaxis of bleeding disorders in Hematol 1989; 32: 258–61. J Blood Disord Transfus 2013. In press.

1997 90: 2515-2521

Desmopressin (DDAVP) in the Treatment of Bleeding Disorders: The First 20 Years

Pier Mannuccio Mannucci

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The Journal of BLOOD The American Society of Hematology

VOL 90, NO 7 OCTOBER 1, 1997

REVIEW ARTICLE Desmopressin (DDAVP) in the Treatment of Bleeding Disorders: The First 20 Years

By Pier Mannuccio Mannucci

N 1977 DESMOPRESSIN (1-deamino-8-D-arginine va- the enhancement of blood clotting associated with stress was I sopressin, abbreviated DDAVP), a derivative of the anti- caused by the liberation of adrenaline in plasma.6,7 In 1957, diuretic hormone, was used for the ®rst time to treat patients a possible mechanism for faster clotting after adrenaline was with hemophilia A and von Willebrand disease (vWD), the provided by Marciniak,8 who found a transient increase in most frequent congenital bleeding disorders.1 After the origi- coagulation factor VIII after injection in rabbits. Reports of nal clinical study performed in Italy, desmopressin was used raised factor VIII after adrenaline infusion in humans soon in many other countries and the World Health Organization followed: the average increase was to about twice the starting included it in the list of essential drugs. A drug that could level, with no measurable change in other clotting factors.9 raise the plasma levels of factor VIII and von Willebrand In patients with mild hemophilia the magnitude of the factor factor (vWF) without the need of blood products was espe- VIII increase induced by adrenaline was similar to that elic- cially attractive in the late 1970s and early 1980s, a time ited in healthy individuals.9,10 when the human immunode®ciency virus began to be trans- These ®ndings stimulated further research, with the goal mitted by infected coagulation factor concentrates to patients to identify a factor VIII±increasing agent that would be free with congenital coagulation disorders. of the side effects of adrenaline and could be administered The clinical indications for desmopressin quickly ex- to hemophilic patients as autologous replacement therapy. panded beyond hemophilia and vWD. The compound was Vasopressin and insulin also induced an increase of factor shown to be ef®cacious even in bleeding disorders not in- VIII,11 but their side effects were not milder than those of volving a de®ciency or dysfunction of factor VIII or vWF, adrenaline, making clinical use unrealistic. An important step including congenital and acquired defects of platelet function forward was made with the observation that desmopressin, and such frequent abnormalities of hemostasis as those asso- a synthetic analogue of vasopressin, increased factor VIII ciated with chronic kidney and liver diseases. Desmopressin and vWF in healthy individuals.12,13 Unlike the natural antidi- has also been used prophylactically in patients undergoing uretic hormone, desmopressin produced little or no vasocon- surgical operations characterized by large blood loss and striction, no increase in blood pressure, and no contraction transfusion requirements. of the uterus or gastrointestinal tract, so that it was well Twenty years of clinical experience have now established tolerated when administered to humans.12,13 more ®rmly the clinical indications of desmopressin. Some A big step forward was taken when desmopressin was of these indications have been strengthened by the experi- used in patients for the prevention and treatment of bleeding, ence accumulated, others have not been supported by rigor- ®rst during dental extractions and then during major surgical ous clinical trials or have been overcome by the advent of procedures with mild hemophilia A or vWD.1 Surgery was more ef®cacious treatments. This report reviews the spec- performed without blood products, demonstrating that autol- trum of indications in bleeding disorders, in the attempt to ogous factor VIII and vWF increased in patient plasma by establish which indications remain valid and which do not. desmopressin could effectively replace homologous factors Topics such as pharmacokinetics, pharmacodynamics, and contained in blood products.1 These clinical results were side effects of desmopressin will not be dealt with because soon con®rmed.14-16 they are covered in previous reviews.2-4

HISTORICAL BACKGROUND From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Institute of Internal Medicine, IRCSS Maggiore Hospital It was in 1772 when William Hewson noted that blood 5 and University of Milan, Milan, Italy. collected under conditions of stress clotted rapidly. Hew- Submitted February 20, 1997; accepted May 15, 1997. son's observations, described in detail in An Inquiry into Address reprint requests to Pier Mannuccio Mannucci, MD, Via the Properties of the Blood, triggered a series of animal Pace 9, 20122 Milano, Italy. experiments performed by the physiologist Cannon and his ᭧ 1997 by The American Society of Hematology. associates at the beginning of this century. They showed that 0006-4971/97/9007-0001$3.00/0

Blood, Vol 90, No 7 (October 1), 1997: pp 2515-2521 2515

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2516 PIER MANNUCCIO MANNUCCI

MECHANISMS OF ACTION OF DESMOPRESSIN Table 1. Recommended Dosages of Desmopressin and Factor VIII With vWF Responses in Patients With Hemophilia and vWD Despite 20 years of clinical use of desmopressin, mechanisms of action are still not completely understood. The Single dose Intravenous and subcutaneous: 0.3 mg/kg increases in the plasma levels of factor VIII and vWF occur Intranasal: 300 mg/kg not only in de®cient patients, but also in healthy individuals Mean factor increase 3-5 times and in patients who already have high levels of these factors. over baseline (range: 1.5-20 times) Time to peak levels 30-60 min after intravenous injection Desmopressin shortens the prolonged activated partial 90-120 min after subcutaneous injection 17 thromboplastin time and the bleeding time. These effects and intranasal application probably result from the increases in factor VIII and vWF, Plasma half-life 5-8 hours for factor VIII which play a rate-accelerating role in these global tests of 8-10 hours for vWF intrinsic coagulation and primary hemostasis. Desmopressin has no effect on platelet count or aggregation, but enhances platelet adhesion to the vessel wall.18,19 Release into plasma ef®cacious in bleeding disorders other than hemophilia and of large amounts of tissue plasminogen activator is another vWD, in patients who have normal or even high levels of short-lived effect of desmopressin.12,13 Plasminogen activator factor VIII and vWF. The favorable effects of the compound generates plasmin in vivo, but most of the plasmin is quickly may be mediated by increased platelet adhesion to the vessel complexed to a -antiplasmin and does not produce ®brin(o- 2 wall,18,19 due not only to the rise of plasma vWF but also to gen)olysis in circulating blood.20 Accordingly, it is usually the abluminal secretion of the protein toward the subendo- unnecessary to inhibit ®brinolysis when desmopressin is thelium22; by heightened coagulability, due to supranormal used for clinical purposes. levels of factor VIII, a rate-accelerating factor in the process How do factor VIII and vWF increase in plasma? Because of ®brin formation27; and by the fresh appearance in plasma these factors increase rapidly and transiently, it is most likely of ultralarge vWF multimers.28 These are hemostatically very that desmopressin causes them to be released from storage effective because they support to a higher degree platelet sites. The storage site(s) of factor VIII and the interaction adhesion to the vascular subendothelium and induce platelet between released factor VIII and concomitantly released aggregation under conditions of high shear.29 Other putative vWF are not well established. The vascular endothelium is mechanisms or mediators have been proposed to explain presumably the main source of vWF. This view is supported the hemostatic ef®cacy of desmopressin. For instance, the by the observation that in rats injections of desmopressin compound induces the adhesion of erythrocytes to the endo- elicit biological responses that are clearly related to the acti- thelium30 and decreases the endothelial production of 13- vation of endothelial cells, like surface expression of P selec- hydroxyoctadecadienoic acid (HODE), a derivative of lino- 21 tin and subsequent margination of leukocytes. In normal leic acid that powerfully inhibits platelet adhesion to the individuals, desmopressin infusion produces important vessel wall.31 The role of these mechanisms is uncertain and changes in the content and localization of vWF in vascular the search for additional or alternative mechanisms of action 22 endothelial cells. There is a reduction in the amount of has been unfruitful so far. the protein and a change in its localization, which causes a tendency for the protein to move abluminally toward the DESMOPRESSIN IN THE MANAGEMENT OF cellular basement membrane.22 Notwithstanding these data CONGENITAL BLEEDING DISORDERS focusing on the endothelial cell as the most likely source of In hemophilia and vWD, desmopressin is ef®cacious be- vWF, addition of desmopressin to cultured endothelial cells cause it provides a form of autologous replacement therapy. 23 in vitro does not release vWF. Even though cultured cells Table 1 summarizes the routes of administration, the recom- may not be identical to native cells and might have lost mended dosages, and the pharmacokinetic properties of des- speci®c receptors during culture, these observations suggest mopressin-induced factor VIII and vWF. an indirect action of desmopressin through a second messen- The prototypes of patients who respond to desmopressin ger. In the search of such a second messenger, it was shown and avoid the use of coagulation factor concentrates are those that release of vWF from endothelial cells occurred after the with measurable levels of factor VIII and vWF, ie, patients 24 addition of desmopressin to monocytes. These data, and with mild hemophilia A and type 1 vWD,1,14-16 whereas pa- those implicating monocyte-derived platelet activating factor tients with unmeasurable levels do not respond at all.17 In as the second messenger acting upon endothelial cells,25 need mild hemophilia A the ef®cacy of desmopressin usually con®rmation. Desmopressin acts on storage sites via its correlates with the postinfusion plasma levels of factor 1,14-16 strong V2 agonist activity, since patients with nephrogenic VIII. Accordingly, therapeutic indications are de®ned diabetes insipidus, who are unresponsive to V2 agonists, do by the nature of the bleeding episode, the baseline factor VIII not have increased factor VIII and vWF levels after treatment levels, and the levels that must be attained and maintained for with desmopressin.26 Anephric patients respond normally,13 hemostasis. Clinical failures of desmopressin can usually be indicating that the site of the V2 -like receptors involved in explained by the attainment of factor VIII levels in plasma the hemostatic properties of desmopressin is not in the kid- that are insuf®cient to control bleeding.1,14-16 For instance, a ney. Their location is currently unknown. major surgical procedure in a patient with factor VIII levels A puzzling, unresolved question is how desmopressin is of 10 U/dL may not be successfully managed with desmo-

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DESMOPRESSIN: THE FIRST 20 YEARS 2517

Table 2. Indication for Desmopressin in Different Types of vWD Subcutaneous and intranasal desmopressin are at least as

Established Type 1, ‘‘platelet normal’’ ef®cacious as intravenous desmopressin and can be self- Type 2N administered. Although intravenous desmopressin is recom- Possible Type 1, ‘‘platelet low’’ and types 2A and 2B mended before surgery or for treating severe hemorrhages, Doubtful Type 3 (severe) because very consistent responses are required in these situa- ‘‘Established’’ indications are those in which desmopressin normal- tions, subcutaneous desmopressin can be used at home to izes the bleeding time and factor VIII levels, and is clinically effica- prevent or treat minor bleeding episodes and in women with 36 cious; ‘‘Possible’’ indications, those in which the effect on the bleeding vWD who have excessive bleeding at menstruation. Others time is absent or inconsistent, with little data on clinical efficacy; prefer to use intranasal desmopressin as spray in these situa- ‘‘Doubtful’’ indications, those in which desmopressin does not nor- tions, even to handle major bleeding episodes and surgical malize factor VIII levels or the bleeding time, and is not clinically operations.37 efficacious. Despite the fact that neither in vitro nor in vivo studies have clearly proved a direct stimulatory effect of desmopres- 38 pressin because the expected posttreatment levels of 30 to sin on platelets (reviewed by Wun et al ), the drug shortens 50 U/dL are not high enough for hemostasis. On the other or normalizes the bleeding time of some patients with con- 39,40 hand, these levels should be suf®cient for the patient to have genital defects of platelet function. Defects associated a minor procedure, such as circumcision or dental extrac- with normal dense granule stores bene®t more from the com- 40 tions. pound. Accordingly, there is usually a good response in Most patients with type 1 vWD respond to desmopressin patients with defects of the release reaction, with cyclooxy- with increases in factor VIII and vWF that are larger than genase de®ciency, and in those with isolated and unexplained those seen in hemophiliacs.32 In addition to factor VIII, in prolongations of the bleeding time. Most patients with stor- these patients a determinant of the clinical ef®cacy of the age pool de®ciency respond to desmopressin but a few do 40 compound is its capacity to shorten or normalize the bleeding not, so a test dose is recommended to select responders. time. Although in type 1 vWD this effect is usually achieved Whether the effect on a laboratory test such as the bleeding in proportion to the levels of normally functioning vWF time corresponds to a hemostatic effect is not well estab- attained in plasma,28 the bleeding times of patients with type lished. On the other hand, the data obtained from a few well- 3, characterized by complete de®ciency of vWF, and of those conducted but nonrandomized studies would indicate that with dysfunctional molecules are usually not shortened.17,28 desmopressin can be a useful alternative to blood products There are, however, a few patients with type 2A vWD in during or after surgery or delivery, assuring satisfactory he- 39,40 whom desmopressin does shorten the bleeding time.33 The mostasis. reasons for these different behaviors are not clear and a To sum up, desmopressin is ef®cacious in mild hemophilia test dose is the only way to differentiate responders from and type 1 vWD and usually permits the avoidance of con- nonresponders. In theory, the administration of desmopressin centrates, with signi®cant reductions in costs. In the United to patients with heightened interactions between platelet gly- States, for instance, an average dose of factor VIII concen- coprotein Ib and vWF (type 2B and platelet-type or trate (2,000 IU) costs between $800 and $2,000, depending ``pseudo'' vWD) might be potentially dangerous, because it on the source (plasma-derived or recombinant). An average is followed by platelet aggregation and, in most instances, dose of desmopressin (21 mg) is much cheaper ($100) and by thrombocytopenia.34 Although there is some evidence that is even less expensive in Europe (the equivalent of $20 to desmopressin is clinically ef®cacious in these patients (re- $40). The bene®ts of desmopressin are not limited to cost viewed by Castaman and Rodeghiero35), most hematologists savings. The compound may be needed to meet religious would be reluctant to use it. Table 2 summarizes the indica- requests, such as the avoidance of blood products in Jeho- tions for desmopressin in patients with different types of vah's Witnesses. More importantly, it is likely to have spared vWD. many patients from infection with the human immunode®- Patients treated repeatedly with desmopressin may be- ciency virus type 1 (HIV). In Italy, where desmopressin was come less responsive, perhaps because stores are ex- used earlier and more extensively than in other countries, the hausted.32 Some experimental data support this hypothesis prevalence of HIV infection in patients with mild hemophilia because repeated infusions of desmopressin lower the (2.1%) is much lower than in patients with mild hemophilia amount of vWF contained in vascular endothelial cells.22 The B (13.5%).41 The latter is a suitable comparison group, be- average factor VIII responses obtained when desmopressin is cause these patients need treatment at least as frequently as repeated three to four times at 24-hour intervals are approxi- hemophilia A patients, but are unresponsive to desmopressin. mately 30% less than those obtained after the ®rst dose.32 Hence, they could only be treated with plasma concentrates The clinical implications are that the ef®cacy of desmopres- during the critical years between 1977 (when desmopressin sin may be limited when factor VIII levels must be main- was ®rst used clinically and the HIV outbreak started) and tained above the baseline levels for a prolonged period of 1985 (when the outbreak was halted by the development of time. In these situations, which occur relatively seldom in the virus-inactivation methods and their application to plasma clinical management of mild hemophilia and type 1 vWD, it concentrates). Additional evidence of the HIV-sparing effect may become necessary to use plasma-derived or recombinant of desmopressin stems from the comparison of the preva- factors, or to supplement desmopressin with them. lence of HIV infection in Italian patients with mild hemo-

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2518 PIER MANNUCCIO MANNUCCI philia A to the corresponding patients from other countries a possible treatment for patients with liver cirrhosis and where the compound was used later. In the United States, prolonged bleeding time who need invasive diagnostic pro- for instance, where in the period 1977-1985 mild hemophili- cedures such as liver biopsies. There is as yet little clinical acs were mainly treated with plasma concentrates because evidence that desmopressin prevents or stops bleeding com- desmopressin was not licensed until 1984, anti-HIV preva- plications that develop in association with the use of anti- lence is 18.4%, nine times higher than in Italy.41 thrombotic agents. The compound may provide an opportunity to control drug-induced bleeding without stopping DESMOPRESSIN IN ACQUIRED AND DRUG-INDUCED treatment and perhaps avoiding recurrence or progression of BLEEDING DISORDERS thrombosis. The hemostatic defect in uremia is characterized by a prolonged bleeding time, a laboratory abnormality that corre- DESMOPRESSIN AS A BLOOD-SAVING AGENT lates strongly with the hemorrhagic symptoms of these pa- The broadening indications of desmopressin, since the ®rst tients, mainly epistaxis and bleeding from the gastrointesti- use in hemophilia and vWD in 1977, led several investigators nal tract. Dialysis may improve the bleeding time and the to evaluate whether the compound was bene®cial during bleeding tendency, but this is not always the case. In the surgical operations in which blood loss is large and for which search for pharmacological agents that could improve he- multiple blood transfusions are needed. mostasis in uremia, intravenous desmopressin was consid- Open heart surgery with extracorporeal circulation is the ered, despite the fact that factor VIII and vWF are normal epitome of operations that warrant the adoption of blood- in uremic patients.42 The postinfusion bleeding time became saving measures. In addition to techniques such as presurgi- normal in about 75% of them, and returned to baseline values cal removal of autologous blood for postsurgical retransfu- after approximately 8 hours.42 Well-conducted but noncon- sion, returning all oxygenator and tubing contents to the trolled clinical studies have shown that desmopressin can patient, and autotransfusion of the mediastinal shed blood, be used successfully to prevent bleeding before invasive prophylaxis with pharmacological agents might help reduce procedures (biopsies and major surgery) and to stop sponta- blood transfusion further. Since 1986, desmopressin has been neous bleeding.42 Conjugated estrogens are a long-acting al- evaluated for this purpose. In the ®rst controlled randomized ternative to desmopressin, because they shorten the bleeding study carried out in patients undergoing complex cardiac time with a more sustained effect lasting for 10 to 15 days.43 operations associated with large blood losses, results were The two products can be given together, exploiting the differ- impressive.52 Given at the time of chest closure, desmopres- ent timings of their maximal effects. Currently, most patients sin reduced dramatically perioperative and early (12 hours) with chronic renal insuf®ciency are regularly treated with postoperative blood loss and transfusion requirements by erythropoietin. This practice has led to the sustained im- about one third.52 On the other hand, in two subsequent large provement not only of anemia but also of the hemostatic studies of patients undergoing less complex operations with defect,44 so that short-acting compounds such as desmopres- lesser blood loss, there were no signi®cant differences be- sin and conjugated estrogens are now less frequently needed. tween desmopressin- and placebo-treated patients in either The bleeding time is prolonged in some patients with liver total blood loss or transfusion requirements.53,54 Other stud- cirrhosis. There is usually mild or moderate thrombocyto- ies, mainly in patients undergoing coronary artery bypass penia, but platelet counts do not correlate negatively with grafting and uncomplicated valve replacement, failed to ®nd the bleeding time. Factor VIII and vWF are in the high any bene®t of desmopressin.55,56 normal range, or even higher, yet intravenous desmopressin The con¯icting results of desmopressin in open heart sur- shortens the bleeding time of cirrhotic patients.45,46 However, gery might be due to the fact that most studies were of a controlled clinical trial has shown that desmopressin is small size and had insuf®cient statistical power to detect true not useful in the management of acute variceal bleeding in differences in blood loss. A meta-analysis of 17 randomized, cirrhotic patients.47 Because this is the most frequent and double-blind, placebo-controlled trials, which included 1,171 serious hemorrhagic problem the overall clinical impact of patients undergoing open heart surgery, has attempted to desmopressin in liver cirrhosis is relatively small. overcome this pitfall.57 Overall, desmopressin reduced post- Desmopressin counteracts the effects on hemostasis mea- operative blood loss by 9%, a value that is statistically sig- surements of some antithrombotic drugs. It shortens the pro- ni®cant but of little clinical impact. Although desmopressin longed bleeding time of individuals taking widely used anti- had no blood-saving effect when the total blood loss in pla- platelet agents such as aspirin and ticlopidine,46 the cebo-treated patients decreased in the lower and middle prolonged bleeding time and activated partial thromboplastin thirds of distribution (687 to 1,108 mL), the compound re- time of patients receiving heparin,48 and the bleeding time duced blood losses by 34% when blood loss was larger.57 of rabbits treated with streptokinase49 or hirudin50 (without Therefore, desmopressin seems bene®cial only in cardiac corresponding human data). It also counteracts the antihemo- operations associated with large blood loss (ú1 L). It is not static effects of dextran, with no apparent impairment of the easy to predict which patient will bleed more, but situations antithrombotic properties.51 such as reoperation, presurgical use of antiplatelet agents, In summary, in chronic renal disease desmopressin re- preexisting coagulation defects, and sepsis might help to mains indicated only for those patients with renal failure not identify the cases suitable for prophylaxis. Lower preopera- treated or unresponsive to erythropoietin. Desmopressin is tive plasma levels of factor VIII and vWF may also help to

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DESMOPRESSIN: THE FIRST 20 YEARS 2519

Table 3. Indications for Desmopressin in the Treatment THERAPEUTIC GUIDELINES of Bleeding Disorders The main therapeutic guidelines for desmopressin are Grading of Level of summarized in Table 3 and are graded upon the criteria Recommendation Evidence proposed by the Agency for Health Care Policy and Research Established Mild hemophilia A B III Publications of the US Department of Health and Human vWD (see Table 2) B III Services.66 Twenty years after the ®rst clinical application, Possible Congenital defects of C IV the compound is still the treatment of choice for patients platelet function Uremia C IV with mild hemophilia A and type 1 vWD (grade B recom- Liver cirrhosis C IV mendation). The evidence of its ef®cacy as autologous re- Drug-induced bleeding C IV placement of the de®cient factors is so clear that no random- (heparin, hirudin, ized controlled clinical trial was ever necessary (level III antiplatelet agents, evidence). In patients with congenital defects of platelet dextran, function, with the hemostatic abnormalities associated with streptokinase) chronic liver disease and with those induced by the therapeu- Doubtful Cardiac surgery A I tic use of antiplatelet and anticoagulant agents, desmopressin General surgery A I has been used successfully to prevent or stop bleeding. How- ‘‘Established’’ indications are those in which the hemostatic efﬁcacy ever, there is still no well-designed clinical trial that truly of desmopressin has been demonstrated clinically; ‘‘Possible’’ indica- shows ef®cacy of the compound in these conditions (grade tions, those in which clinical data are too preliminary or inconclusive; C recommendation based on level IV evidence). Currently, ‘‘Doubtful’’ indications, those in which desmopressin is not efﬁca- the widespread use of erythropoietin and the resulting sus- cious clinically. Grading of recommendations and levels of evidence tained correction of the hemostatic defect make the use of are those proposed by the Agency for Health Care Policy and Research Publications of the US Department of Health and Human Services. desmopressin unnecessary in the majority of patients with chronic renal insuf®ciency. Anti®brinolytic amino acids and aprotinin should be preferred to desmopressin in reducing blood loss and transfusion requirements during cardiac sur- 52,53 identify patients most at risk of bleeding. However, the gery with extracorporeal circulation (grade A recommenda- overlap of values is so large that it is not possible to use tion based on level I evidence). The use of desmopressin in these measurements to select patients with the most to gain surgical operations other than cardiac surgery is not war- from the use of desmopressin. ranted at the moment. On the whole, more than 200 years Desmopressin is not the only blood-saving agent that can of research have provided an agent that makes the blood clot be used in cardiac surgery. The synthetic anti®brinolytic faster, and William Hewson, who so ingeniously inquired amino acids epsilon-aminocaproic acid (EACA) and tranexa- into the properties of blood in the 18th century, perhaps mic acid and the broad-spectrum protease inhibitor aprotinin would be content with the outcome of his pioneer studies. have also been used, particularly after the recognition that acquired immunode®ciency syndrome (AIDS) could result REFERENCES from blood transfusions contaminated with HIV. A few di- 1. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A: DDAVP: rect comparison studies58-60 and a meta-analysis61 have A new pharmacological approach to the management of hemophilia shown that the order of ef®cacy of these hemostatic agents and von Willebrand disease. Lancet 1:869, 1977 (greatest to least) is aprotinin, tranexamic acid, EACA, and 2. Mannucci PM: Desmopressin: A non transfusional agent. Annu desmopressin.61 On the other hand, the order of drug cost is Rev Med 41:55, 1990 also the same. Cost-effectiveness analysis is necessary to 3. Schulman S: DDAVP: The multipotent drug in patients with help the clinicians in making a choice that currently would coagulopathies. Transf Med Rev 5:132, 1991 4. Lethagen S: Desmopressin (DDAVP) and haemostasis. Ann be directed to aprotinin, but with formidable costs. Hematol 69:173, 1994 The ef®cacy of desmopressin has also been evaluated in 5. Hewson W: Experimental inquiries. Part I. An inquiry into noncardiac surgical operations characterized by large blood the properties of the blood, with remarks on some of its morbid loss. When administered to hemostatically normal children appearances, in Gulliver G (ed): The Works of William Hewson, before spinal fusion for idiopathic scoliosis, desmopressin FRS. London, UK, The Sydenham Society, 1846 reduced their average operative blood loss by about one 6. Cannon WB, Gray H: Factors affecting the coagulation time third,62 but these favorable results were not con®rmed in a of blood. II. The hastening or retarding of coagulation by adrenaline subsequent study.63 Desmopressin did not reduce blood loss injections. Am J Physiol 34:231, 1914 or transfusion requirement after total hip or knee arthro- 7. Cannon WB, Mendenhall WL: Factors affecting the coagula- plasty.64 Preoperative desmopressin failed to reduce blood tion time of blood. IV. The hastening of coagulation in pain and emotional excitement. Am J Physiol 34:251, 1914 loss in patients undergoing debridement and grafting of burn 8. Marciniak E: The in¯uence of adrenaline in blood coagulation. wounds, a procedure in which extreme blood loss is a fre- 65 Acta Physiol Pol 8:224, 1957 quent occurrence. 9. Ingram GIC: Increase in antihemophilic globulin activity fol- In summary, the ef®cacy of desmopressin as a blood- lowing infusion of adrenaline. J Physiol 156:217, 1961 saving agent in cardiac and noncardiac surgical operations 10. Ingram GIC, Vaughan Jones R, Hershgold EJ, Denson KWE, appears doubtful at the moment. Perkins JR: Factor VIII activity and antigen, platelet count and bio-

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2520 PIER MANNUCCIO MANNUCCI chemical changes after adrenoceptor stimulation. Br J Haematol factor following administration of DDAVP: Implications for patho- 35:81, 1977 physiology and therapy of von Willebrand's disease subtypes. Blood 11. Mannucci PM, Gagnatelli G, D'Alonzo R: Stress and blood 58:1272, 1982 coagulation, in Brinkhous KM, Hinnom S (eds): Thrombosis: Risk 29. Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hel- factors and diagnostic approaches. Stuttgart, Germany, Schattauer lum JD: Involvement of large plasma von Willebrand factor (VEF) Verlag, 1972, p 105 multimers and unusually large VWF forms derived from endothelial 12. Cash JD, Gader AMA, de Costa J: The release of plasminogen cells in shear-stress induced platelet aggregation. J Clin Invest activator and factor VIII by LVP, AVP, DDAVP, AT III, and OT 78:1456, 1986 in man. Br J Haematol 27:363, 1974 30. Tsai J-M, Sussman II, Nagel RL, Kaul DK: Desmopressin 13. Mannucci PM, Aberg M, Nilsson IM, Robertson B: Mecha- induces adhesion of normal human erythrocytes to the endothelial nism of plasminogen activator and factor VIII increase after vaso- surface of a perfused microvascular preparation. Blood 75:261, 1990 active drugs. Br J Haematol 30:81, 1975 31. Setty BNY, Dampier CD, Stuart MJ: 1-Deamino-8-D-argi- 14. Warrier L, Lusher JM: DDAVP: A useful alternative to blood nine vasopressin decreases the production of 13-hydroxyoctadeca- components in moderate hemophilia A and von Willebrand's dis- dienoic acid by endothelial cells. Thromb Res 67:545, 1992 ease. J Pediatr 102:228, 1983 32. Mannucci PM, Bettega D, Cattaneo M: Patterns of develop- 15. Mariani G, Ciavarella N, Mazzucconi MG, Antoncecchi S, ment of tachyphylaxis in patients with hemophilia and von Wille- Solinas S, Ranieri P, Pettini P, Agrestini F, Mandelli F: Evaluation brand disease after repeated doses of desmopressin (DDAVP). Br J of the effectiveness of DDAVP in surgery and bleeding episodes in Haematol 82:87, 1992 hemophilia and von Willebrand's disease. A study of 43 patients. 33. Gralnick HR, William SB, McKeon LP, Rick ME, Maison- Clin Lab Hematol 6:229, 1984 neuve P, Jenneau C, Sultan Y: DDAVP in type IIa von Willebrand's 16. de la Fuente B, Kasper CK, Rickles FR, Hoyer LW: Response disease. Blood 67:465, 1986 of patients with mild and moderate hemophilia A and von Willebrand 34. Holmberg L, Nilsson IM, Borge L, Gunnarson M, Sjorin E: disease to treatment with desmopressin. Ann Intern Med 103:6, 1985 Platelet aggregation induced by 1-deamino-8-D-arginine vasopressin 17. Mannucci PM, Pareti FI, Holmberg L, Ruggeri ZM, Nilsson (DDAVP) in type IIB von WIllebrand's disease. N Engl J Med IM: Studies on the prolonged bleeding time in von Willebrand dis- 309:816, 1983 ease. J Lab Clin Med 88:62, 1976 35. Castaman G, Rodeghiero F: Desmopressin and type IIB von 18. Barnhart MI, Chen S, Lusher JM: DDAVP: Does the drug Willebrand disease. Hemophilia 2:73, 1996 have a direct effect on the vessel wall. Thromb Res 31:239, 1983 36. Rodeghiero F, Castaman G, Mannucci PM: Prospective 19. Sakariassen KS, Cattaneo M, van der Berg A, Ruggeri ZM, multicenter study of subcutaneous concentrated desmopressin for Sixma JJ: DDAVP enhances platelet adherence and platelet aggre- home treatment of patients with von Willebrand disease and mild gate growth on human artery subendothelium. Blood 64:229, 1984 or moderate hemophilia A. Thromb Haemost 76:692, 1996 20. Levi M, de Boer JP, Roem D, ten Cate JH, Hack CE: Plasmin- 37. Rose EH, Aledort LM: Nasal spray desmopressin (DDAVP) ogen activation in vivo upon intravenous infusion of DDAVP. Quan- for mild hemophilia A and von Willebrand disease. Ann Intern Med titative assessment of plasmin-alpha2-antiplasmin complex with a 114:563, 1991 novel monoclonal antibody based radioimmunoassay. Thromb 38. Wun T, Paglieroni TG, Lachant NA: Desmopressin stimulates Haemost 67:111, 1992 the expression of P-selectin on human platelets in vitro. J Lab Clin 21. Kanwar S, Woodman RC, Poon MC, Murohara T, Lefer AM, Med 125:40, 1995 Davenpeck KL, Kubus P: Desmopressin induces endothelial P-selec- 39. Di Michele DM, Hathaway WE: Use of DDAVP in inherited tin expression and leukocyte rolling in post-capillary venules. Blood and acquired platelet dysfunction. Am J Hematol 33:39, 1990 86:2760, 1995 40. Rao AK, Ghosh S, Sum L, Yang X, Disa J, Pickens P, Polan- 22. Takeuchi M, Naguza H, Kanedu T: DDAVP and epinephrine ski M: Mechanisms of platelet dysfunction and response to DDAVP induce changes in the localization of von Willebrand factor antigen in patients with congenital platelet function defects. A double-blind in endothelial cells of human oral mucosa. Blood 72:850, 1981 placebo controlled trial. Thromb Haemost 74:1071, 1995 23. Booyse EM, Osikowicz G, Fedr S: Effects of various agents 41. Mannucci PM, Ghirardini A: Desmopressin twenty years on ristocetin-Willebrand factor activity in long-term cultures of von after. Thromb Haemost 78:958, 1997 Willebrand and normal human umbilical vein endothelial cells. 42. Mannucci PM, Remuzzi G, Pusineri F, Lombardi R, Valsec- Thromb Haemost 46:668, 1981 chi C, Mecca G, Zimmerman TS: Deamino-8-D-arginine vasopressin 24. Hashemi S, Tackaberry ES, Palmer DS, Rock G, Ganz PR: shortens the bleeding time in uremia. N Engl J Med 308:8, 1983 DDAVP-induced release of von Willebrand factor from endothelial 43. Livio M, Mannucci PM, ViganoÁ G, Mingardi G, Lombardi cells in vitro: The effect of plasma and blood cells. Biochim Biophys R, Mecca G, Remuzzi G: Conjugated estrogens for the management Acta 1052:63, 1990 of bleeding associated with renal failure. N Engl J Med 315:731, 25. Hashemi S, Palmer DS, Aye MT, Ganz PR: Platelet activating 1986 factor secreted by DDAVP-treated monocytes mediates von Wille- 44. Moia M, Mannucci PM, Vizzotto L, Casati S, Cattaneo M, brand factor release from endothelial cells. J Cell Physiol 154:496, Ponticelli C: Improvement in the hemostatic defect of uremia after 1993 treatment with recombinant human erythropoietin. Lancet 2:1227, 26. Kobrinsky ML, Doyle JJ, Israel ED, Winter JSD, Chenay 1987 MS, Walker RD, Bishop AJ: Absent factor VIII response to synthetic 45. Burroughs AK, Matthews K, Qadiri M, Thomas N, Kernoff vasopressin analogue (DDAVP) in nephrogenic diabetes insipidus. PBS, Tuddenham EGD, McIntyre N: Desmopressin and bleeding Lancet 1:1293, 1985 time in patients with cirrhosis. Br J Med 291:1377, 1985 27. Ibbotson SH, Davies JA, Grant PJ: The in¯uence of infusions 46. Mannucci PM, Vicente V, Vianello L, Cattaneo M, Alberca of 1-desamino-8-D-arginine vasopressin (DDAVP) in vivo on I, Coccato MP, Faioni E, Mari D: Controlled trial of desmopressin thrombin generation in vitro. Thromb Haemost 68:37, 1992 (DDAVP) in liver cirrhosis and other conditions associated with a 28. Ruggeri ZM, Mannucci PM, Lombardi R, Federici AB, Zim- prolonged bleeding time. Blood 67:1148, 1986 merman TS: Multimeric composition of factor VIII/von Willebrand 47. de Franchis F, Arcidiacono PG, Carpinelli PG, Andreoni B,

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DESMOPRESSIN: THE FIRST 20 YEARS 2521

Cestari L, Brunati S, Zambelli A, Battaglia G, Mannucci PM: Ran- effect of desmopressin on reducing blood loss in cardiac surgery. domized controlled trial of desmopressin plus terlipressin and terli- A meta-analysis of double-blind, placebo-controlled trials. Thromb pressin alone for the treatment of acute variceal hemorrhage in cir- Haemost 74:1064, 1988 rhotic patients: A multicenter, double blind study. Hepatology 58. Horrow JC, van Riper DF, Strong MD, Brodsky I, Parmet 18:1102, 1993 JL: Hemostatic effects of tranexamic acid and desmopressin during 48. Schulman S, Johnsson H: Heparin, DDAVP and the bleeding cardiac surgery. Circulation 84:2063, 1991 time. Thromb Hemost 65:242, 1991 59. Rocha E, Hidalgo F, Llorens R, Melero JM, Arroyo SL, Par- 49. Johnstone MT, Andrews T, Ware JA, Rudd MA, George D, amo JA: Randomized trial of aprotinin and DDAVP to reduce post- Weinstein M, Loscalzo J: Bleeding time prolongation with streptoki- operative bleeding after cardiopulmonary surgery. Circulation nase and its reduction with 1-deamino-8-D-arginine vasopressin. Cir- 90:921, 1994 culation 82:2142, 1990 60. Aron KV, Emery RW: Decreased postoperative drainage with 50. Bove CM, Casey B, Marder VJ: DDAVP reduces bleeding addition of epsilonaminocaproic acid before cardiopulmonary by- during continued hirudin administration in the rabbit. Thromb pass. Ann Thorac Surg 57:1108, 1994 Haemost 75:471, 1996 61. Fremes SE, Wong BI, Lee E, Mai R, Christakis GT, McLean 51. Flordal PA, Ljungstrom KG, Svensson J: Desmopressin re- RF, Goldman BS, Naylor CD: Meta-analysis of prophylactic drug verses effects of dextran on von Willebrand factor. Thromb Hemost treatment in the prevention of postoperative bleeding. Ann Thorac 61:541, 1989 Surg 58:1580, 1994 52. Salzman EW, Weinstein MJ, Weintraub RM, Ware JA, 62. Kobrinsky NL, Letts RP, Patel R, Israels ED, Monson RC, Thurer RL, Robertson L, Donovan A, Gaffney T, BerteleÂ V, Troll Schwetz N, Cheang MS: DDAVP shortens the bleeding time and J: Treatment with desmopressin acetate to reduce blood loss after decreases blood loss in hemostatically normal subjects undergoing cardiac surgery. N Engl J Med 314:1402, 1986 spinal fusion surgery. Ann Intern Med 107:446, 1987 53. Rocha E, Llorens R, Paramo JA, Arcas R, Cuesta B, Trenor 63. Guay J, Rainberg C, Poitras B, David M, Mathews S, Lortie A: Does desmopressin acetate reduce blood loss after surgery in L, Rivard GE: A trial of desmopressin to reduce blood loss in patients patients on cardiopulmonary bypass? Circulation 77:1319, 1988 undergoing spinal fusion for idiopathic scoliosis. Anesth Analg 54. Hackmann T, Gascoyne R, Naiman SC, Growe GH, Burchill 75:405, 1992 LD, Jamieson WR, Sheps SB, Schechter MT, Townsend GE: A 64. Karnezis TA, Stulberg SD, Wixson RL, Reilly P: The hemo- trial of desmopressin to reduce blood loss in uncomplicated cardiac static effects of desmopressin on patients who had total joint arthro- surgery. N Engl J Med 321:1437, 1989 plasty. A double-blind randomized trial. J Bone Joint Surg Am 55. Anderson TL, Solem JO, Tengborn L, Vinge E: Effects of 76:1545, 1994 desmopressin acetate on platelet aggregation, von Willebrand factor 65. Haith LR, Patton ML, Goldman WT, McCutchan KM: Dimin- and blood loss after cardiac surgery with extracorporeal circulation. ishing blood loss after operation for burns. Surg Gynaecol Obstet Circulation 81:872, 1990 176:119, 1993 56. Sean MD, Wadsworth LD, Rogers PC: The effect of desmo- 66. AHCPR: Acute Pain Management: Operative or Medical Pro- pressin acetate (DDAVP) on postoperative blood loss after cardiac cedures and Trauma (Agency for Health Care Policy and Research operations in children. J Thorac Cardiovasc Surg 48:217, 1988 Publications). Bethesda, MD, US Department of Health and Human 57. Cattaneo M, Harris AS, Stromberg U, Mannucci PM: The Services, 1992

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November 2012 · No. 11

DESMOPRESSIN (DDAVP) IN THE TREATMENT OF BLEEDING DISORDERS Revised edition

Pier Mannuccio Mannucci Angelo Bianchi Bonomi Hemophilia and Thrombosis Center IRCCS Cà Granda Maggiore Policlinico Foundation Milan, Italy Table of Contents

Introduction...... 1

Historical background...... 1

Mechanism of action...... 2

Desmopressin in the management of congenital bleeding disorders...... 3

Desmopressin in acquired and drug-induced bleeding disorders...... 4

Desmopressin as a blood-saving agent...... 5

Therapeutic guidelines...... 6

References...... 7

This document was originally published byBlood , Vol. 90, No. 7, 1997 and is reprinted with their permission; revised 2012. The WFH encourages redistribution of its publications for educational purposes by not-for-profit hemophilia organizations. In order to obtain permission to reprint, redistribute, or translate this publication, please contact the Communications Department at the address below. This publication is accessible from the World Federation of Hemophilia’s web site at www.wfh.org. Additional copies are also available from the WFH at: World Federation of Hemophilia 1425, boul. René-Lévesque O. Bureau 1010 Montréal, Québec H3G 1T7 Canada Tel. : (514) 875-7944 Fax : (514) 875-8916 E-mail: [email protected] Internet: www.wfh.org TheTreatment of Hemophilia series is intended to provide general information on the treatment and management of hemophilia. The World Federation of Hemophilia does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. Dose schedules and other treatment regimes are continually revised and new side effects recognized. WFH makes no representation, express or implied, that drug doses or other treatment recommendations in this publication are correct. For these reasons it is strongly recommended that individuals seek the advice of a medical adviser and/or to consult printed instructions provided by the pharmaceutical company before administering any of the drugs referred to in this monograph. Statements and opinions expressed here do not necessarily represent the opinions, policies, or recommendations of the World Federation of Hemophilia, its Executive Committee, or its staff. Treatment of Hemophilia Series Editor: Dr. Johnny Mahlangu DESMOPRESSIN (DDAVP) IN THE TREATMENT OF BLEEDING DISORDERS Revised edition

Introduction disorders, in an attempt to establish which indications remain valid and which do not. The pharmacokinetics, In 1977 desmopressin (1-deamino-8-D-arginine pharmacodynamics, and side effects of desmopressin have vasopressin, abbreviated DDAVP), a synthetic deriv- been dealt with in previous reviews [2-4]. ative of the antidiuretic hormone, was used for the first time to treat patients with hemophilia A and von Willebrand disease (VWD), the most frequent Historical background congenital bleeding disorders [1]. After the original clinical study performed in Italy, desmopressin was In 1772, William Hewson noticed that blood collected used in many other countries and the World Health under conditions of stress clotted rapidly [5]. Hewson’s Organization included it in the list of essential drugs. observations, described in detail in An Inquiry into the A drug that could raise plasma levels of factor VIII Properties of the Blood, triggered a series of animal exper- and von Willebrand factor (VWF ) without the need iments performed by the physiologist Cannon and his of blood products was especially attractive in the late associates at the beginning of the 20th century. They 1970s and early 1980s, a time when the human immu- showed that the enhancement of blood clotting associ- nodeficiency virus (HIV) began to be transmitted by ated with stress was caused by the liberation of adrenaline infected coagulation factor concentrates to patients in plasma [6,7]. In 1957, a mechanism for faster clotting with congenital coagulation disorders. after adrenaline was provided by Marciniak [8], who found a transient increase in coagulation factor VIII after The potential clinical indications for desmopressin injection in rabbits. Reports of raised factor VIII after quickly expanded beyond hemophilia and VWD. The adrenaline infusion in humans soon followed: the average compound was claimed to be efficacious in bleeding increase was to about twice the starting level, with no disorders not involving a deficiency or dysfunction of measurable change in other coagulation factors [9]. In factor VIII or VWF, including congenital and acquired patients with mild hemophilia, the magnitude of factor defects of platelet function and such frequent abnor- VIII increase induced by adrenaline was similar to that malities of hemostasis as those associated with chronic elicited in healthy individuals [9,10]. These findings stimu- kidney and liver disease. Desmopressin has also been lated further research, with the goal of identifying a factor used prophylactically in patients undergoing surgical VIII-increasing agent free of the side effects of adrenaline procedures characterized by significant blood loss that could be administered to people with hemophilia as and transfusion requirements, especially cardiac and autologous replacement therapy. orthopedic surgery. Vasopressin and insulin were shown to induce an increase Thirty-five years of clinical experience have now of factor VIII [11], but their side effects were not milder established more firmly the clinical indications of desmo- than those of adrenaline, making clinical use unrealistic. pressin. Some of these indications have been strengthened An important step forward was made with the observation by the experience accumulated, while others have not been that desmopressin, a synthetic analogue of vasopressin, supported by rigorous clinical trials or have been over- increased factor VIII and VWF in healthy individuals come by the advent of more efficacious treatments. This [12,13]. Unlike the natural antidiuretic hormone, desmo- report reviews the spectrum of indications in bleeding pressin produces little or no vasoconstriction, no increase 2 Treatment of Hemophilia No. 11

in blood pressure, and no contraction of the uterus or in vascular endothelial cells [22]. There is a reduction in gastrointestinal tract, so that it is well tolerated when the amount of the protein and a change in its localization, administered to humans [12,13]. which causes a tendency for the protein to move abluminally toward the cellular basement membrane [22]. A big step forward was made when desmopressin was used for the prevention and treatment of bleeding, Notwithstanding these data focusing on the endothelial first during dental extractions and then during major cell as the most likely source of VWF, addition of desmo- surgical procedures in patients with mild hemophilia pressin to cultured endothelial cells in vitro does not A or VWD [1]. Surgery was performed without blood release VWF [23]. This apparent paradox was solved by products, demonstrating that autologous factor VIII and the demonstration that the lack of direct effect of desmo- VWF increased in patient plasma and that desmopressin pressin on human vascular endothelial cells (HUVEC) could effectively replace homologous factors contained is attributable to the fact that these cells do not express in blood products [1]. These clinical results were soon the V2 receptor (V2R) [24]. When desmopressin was confirmed 14-16[ ]. added to cultured HUVEC transfected to express V2R or to lung microvascular endothelial cells (which natu- rally express V2R), the compound did elicit a release of Mechanism of action VWF, which was mediated by an increase in intracellular cAMP [24]. The increase in plasma levels of factor VIII and VWF occur not only in deficient patients, but also in healthy The interactions between released factor VIII and concom- individuals and in patients who already have high levels itantly released VWF and tPA are not well established. The of these factors. Desmopressin shortens the prolonged observation that patients with VWD type 3 treated with activated partial thromboplastin time and the bleeding desmopressin not only fail to release VWF (which is not time [17]. These effects probably result from the rise in synthesized in these patients), but also factor VIII and tPA factor VIII and VWF, which plays a rate-accelerating role (which are normally synthesized), supports the hypoth- in these global tests of intrinsic coagulation and primary esis that these effects are regulated by a single mechanism hemostasis. Desmopressin has no dramatic effect on defective in type 3 VWD [25]. platelet count or aggregation, but enhances platelet adhesion to the vessel wall [18,19]. Release into plasma of large The site of cellular storage and release of factor VIII is less amounts of tissue plasminogen activator is another short- well established than that of VWF [26]. Desmopressin did lived effect of desmopressin 12[ ,13]. Plasminogen activator elicit the expected VWF rise but no factor VIII rise in dogs generates plasmin in vivo, but most of the plasmin is with hemophilia A after hepatocyte-driven neonatal gene

quickly complexed to α2 –antiplasmin, so that it does therapy [27]. This observation suggests that the increase not produce fibrin(ogen)olysis in circulating blood [20]. of factor VIII induced by desmopressin in normal dogs Accordingly, it is usually unnecessary to inhibit fibrino- and perhaps in humans is due to its release from cells lysis when desmopressin is used for clinical purposes. other than the hepatocyte, perhaps endothelial cells where factor VIII is co-localized and complexed with VWF [27]. How do factor VIII and VWF increase in plasma? Because the increase is rapid and transient, it is most likely that That the cellular co-localization of factor VIII and VWF desmopressin causes these factors to be released from is required for the plasma rise in factor VIII after desmo- storage sites. The vascular endothelium is presumably pressin is also demonstrated by the observation that, the main source of VWF. This view is supported by the following liver transplantation, patients with hemophilia observation that, in rats, injections of desmopressin elicit A infused with desmopressin showed the expected VWF biological responses that are clearly related to the acti- rise but no change in plasma factor VIII [28]. Because vation of endothelial cells, such as surface expression of factor VIII is synthesized only in the transplanted liver, P-selectin and subsequent margination of leukocytes [21]. this observation supports the views that co-localization In normal individuals, desmopressin infusion produces of factor VIII and VWF in extrahepatic cells is necessary important changes in the content and localization of VWF for in vivo release of factor VIII after desmopressin [28]. Desmopressin (DDAVP) in the Treatment of Bleeding Disorders 3

TABLE 1. Recommended dosages of desmopressin Most patients with type 1 VWD, who have a functionally and factor VIII/VWF responses in patients with normal VWF but reduced plasma levels, respond to desmo- hemophilia and VWD pressin with plasma increases in factor VIII and VWF that are usually larger than those seen in people with hemophilia Intravenous and subcutaneous: [29,30]. Hence, desmopressin should be the first choice 0.3 μg/kg Single dose for treatment of these patients. There is, however, some Intranasal: 300 μg/kg variability in response to desmopressin between patients Mean factor increase 2-4 times with type 1 VWD [31-33]. The reasons for these different over baseline (range: 1.5-20 times) behaviours are not clear and a test dose is the only way to 30-60 min after intravenous injection distinguish good responders from poor or non-responders. The defects of patients with type 3 VWD and of those with Time to peak levels 90-120 min after subcutaneous injection and intranasal application dysfunctional molecules (type 2 VWD) are usually not corrected by desmopressin, with some exceptions [34,35]. 5-8 hours for factor VIII Plasma half-life 8-10 hours for VWF General guidelines for the use of desmopressin or plasma product in the different subtypes of VWD are given in Table 2, which shows the schedule of desmopressin administration Desmopressin in the management of and blood sampling recommended to evaluate the degree of congenital bleeding disorders laboratory response to a test dose. On the basis of the results obtained, one can predict whether the attained factor levels In hemophilia and VWD, desmopressin is efficacious and the duration of their persistence in plasma are sufficient because it provides a form of autologous replacement to successfully manage a given clinical situation. therapy. Table 1 summarizes the routes of administration, the recommended dosages, and the pharmacokinetic TABLE 2. Indication for desmopressin in different properties of desmopressin-induced factor VIII and VWF. types of VWD

The patients who respond to desmopressin and avoid Type 1, “platelet normal” Established the use of coagulation factor concentrates are those with Type 2N measurable levels of factor VIII and VWF, i.e. patients with mild hemophilia A and type 1 VWD, [14-16], Possible Type 1, “platelet low” and types 2A and 2B whereas patients with unmeasurable levels do not respond Doubtful Type 3 (severe) at all [17]. In mild hemophilia A, the efficacy of desmopressin usually correlates with the post-infusion plasma levels of factor VIII [14-16]. Accordingly, therapeutic indi- Patients treated repeatedly with desmopressin may become cations are defined by the nature of the bleeding episode, less responsive, perhaps because stores are exhausted [29]. the baseline factor VIII levels, and the levels that must be Some experimental data support this hypothesis, because attained and maintained for hemostasis. repeated infusions of desmopressin lower the amount of VWF contained in vascular endothelial cells [22]. The Clinical failures of desmopressin can usually be explained average factor VIII responses obtained if desmopressin is by the attainment of factor VIII levels in plasma that are repeated at 24-hour intervals are approximately 30% less insufficient to control bleeding. For instance, a major than those obtained after the first dose [29]. The clinical surgical procedure in a patient with factor VIII levels of implications are that the efficacy of desmopressin may be 10 U/dL may not be successfully managed with desmo- limited when factor VIII levels must be maintained above pressin, because the expected post-treatment levels of 30 the baseline levels for a prolonged period of time. In these to 50 U/dL are not high enough to secure hemostasis. On situations, which occur relatively seldom in the clinical the other hand, these levels should be sufficient for the management of mild hemophilia and type 1 VWD, it may patient to have a minor procedure, such as circumcision become necessary to use plasma-derived or recombinant or dental extraction. factors, or to supplement desmopressin with them. 4 Treatment of Hemophilia No. 11

Subcutaneous and intranasal desmopressin are at least in Jehovah’s witnesses. More importantly, it is likely to as efficacious as intravenous desmopressin and can be have spared many patients from infection of the type 1 self-administered. Although intravenous desmopressin human immunodeficiency virus (HIV). In Italy, where is recommended before surgery or for treating severe desmopressin was used earlier and more extensively than hemorrhages, because very consistent responses are in other countries, the prevalence of HIV infection in required in these situations, subcutaneous desmopressin patients with mild hemophilia (2.1%) was much lower can be used at home to prevent or treat minor bleeding than in patients with mild hemophilia B (13.5%) [41]. episodes and in women with VWD who have exces- The latter is a suitable comparison group, because these sive bleeding at menstruation [36]. Others prefer to patients need treatment as frequently as hemophilia A use intranasal desmopressin in these situations, even patients, but are unresponsive to desmopressin. Hence, to handle major bleeding episodes and surgical oper- they could only be treated with plasma concentrates ations [37]. during the critical years between 1977 (when desmopressin was first used clinically and the HIV outbreak Despite the fact that neither in vitro nor in vivo studies started) and 1985-1987 (when the outbreak was halted by have clearly proved a direct stimulatory effect of desmo- the development of virus-inactivation methods and their pressin on platelets (reviewed by Wun et al) [38], the application to plasma concentrates). Additional evidence drug shortens or normalizes the bleeding time of some of the HIV-sparing effect of desmopressin stems from the patients with congenital defects of platelet function comparison of the prevalence of HIV infection in Italian [39,40]. Defects associated with normal dense granule patients with mild hemophilia A to the corresponding stores benefit more from the compound 40[ ]. Accordingly, patients from other countries where the compound was there is usually a good response in patients with defects used later. In the United States, for instance, where in of the release reaction, with cyclooxygenase deficiency, the period 1977-1985 people with mild hemophilia were and in those with isolated and unexplained prolongations mainly treated with plasma concentrates because desmo- of the bleeding time. pressin was not yet licensed, anti-HIV prevalence is 18.4%, nine times higher than in Italy [41]. Most patients with storage pool deficiency respond to desmopressin but a few do not [40], so a test dose is recommended to select responders. Whether the effect Desmopressin in acquired and on a laboratory test such as the bleeding time corre- drug-induced bleeding disorders sponds to a hemostatic effect is not well-established. On the other hand, the data obtained from a few well- The hemostatic defect in uremia is characterized by a conducted but non-randomized studies would indicate prolonged bleeding time, a laboratory abnormality that that desmopressin can be a useful alternative to blood correlates with the hemorrhagic symptoms of these products during or after surgery or delivery, assuring patients, mainly epistaxis and bleeding from the gastro- satisfactory hemostasis [39,40]. intestinal tract. Dialysis may improve the bleeding time and the bleeding tendency, but this is not always the To sum up, desmopressin is efficacious in mild hemo- case. In the search for pharmacological agents that could philia and type 1 VWD and usually permits the avoidance improve hemostasis in uremia, desmopressin was consid- of concentrates, with significant reductions in costs. In ered, despite the fact that factor VIII and VWF are normal the United States, for instance, an average dose of factor or even high in uremic patients [42]. The post-infusion VIII concentrate (2,000 IU) costs between US$1,000 and bleeding time became normal in about 75%, and returned $2,000. An average dose of desmopressin (21 μg) is much to baseline values after approximately 8 hours 42[ ]. cheaper (US$100) and is even less expensive in Europe (the equivalent of US$20-$40). Well-conducted but non-controlled clinical studies have shown that desmopressin can be used successfully to The benefits of desmopressin are not limited to cost prevent bleeding before invasive procedures (biopsies savings. The compound may be needed to meet reli- and major surgery) and to stop spontaneous bleeding gious requests, such as the avoidance of blood products [42]. Conjugated estrogens are a long-acting alternative Desmopressin (DDAVP) in the Treatment of Bleeding Disorders 5 to desmopressin, because they shorten the bleeding time Desmopressin as a blood-saving agent with a more sustained effect lasting for 10 to 15 days 43[ ]. The two products can be given together, exploiting the The broadening indications of desmopressin led several different timings of their maximal effects. Currently, most investigators to evaluate whether or not the compound patients with chronic renal insufficiency are regularly was beneficial during surgical operations in which blood treated with erythropoietin. This practice has led to the loss is great and for which multiple blood transfusions sustained improvement not only of anemia but also of the are needed. hemostatic defect [44], so that short-acting compounds such as desmopressin and conjugated estrogens are unusu- Open-heart surgery with extracorporeal circulation is ally needed. the epitome of operations that warrant the adoption of blood-saving measures. In addition to techniques such The bleeding time is prolonged in some patients with liver as pre-surgical removal of autologous blood for post- cirrhosis. There is usually mild or moderate thrombocy- surgical retransfusion, returning all oxygenator and tubing topenia, but platelet counts do not correlate negatively contents to the patient, and autotransfusion of the medias- with the bleeding time. Factor VIII and VWF are in tinal shed blood, prophylaxis with pharmacological agents the high-normal range, or even higher, yet intravenous might help reduce blood transfusion further. desmopressin shortens the bleeding time of cirrhotic patients [45,46]. However, a controlled clinical trial has Since 1986 desmopressin has been evaluated for this shown that desmopressin is not useful in the manage- purpose. In the first controlled randomized study carried ment of acute variceal bleeding in cirrhotic patients [47]. out in patients undergoing complex cardiac operations Because this is the most frequent and serious hemorrhagic associated with large blood losses, results were impres- problem, the overall clinical impact of desmopressin in sive [52]. On the other hand, in subsequent large studies liver cirrhosis is relatively small. of patients undergoing less complex operations with lesser blood loss, there were no significant differences between Desmopressin counteracts the effects of some antithrom- desmopressin- and placebo-treated patients in either total botic drugs on hemostasis measurements. It shortens the blood loss or transfusion requirements [53,54]. Other prolonged bleeding time of individuals taking antiplatelet studies, mainly in patients undergoing coronary artery agents, the prolonged bleeding time and activated partial bypass grafting and uncomplicated valve replacement, thromboplastin time of patients receiving heparin [48], failed to find any benefit of desmopressin55 [ ,56]. and the bleeding time of rabbits treated with streptokinase [49] or hirudin [50] (without corresponding human data). The conflicting results of desmopressin in open-heart It also counteracts the antihemostatic effects of dextran, surgery might be due to the fact that most studies were with no apparent impairment of the antithrombotic prop- of small size and had insufficient statistical power to erties [51]. detect true differences in blood loss. A meta-analysis of 17 randomized, double-blind, placebo-controlled trials, which In summary, in chronic renal disease desmopressin included 1,171 patients undergoing open-heart surgery, remains indicated only for those patients with renal has attempted to overcome this pitfall [57]. Overall, failure not treated or unresponsive to erythropoietin. desmopressin reduced post-operative blood loss by 9%, Desmopressin is a possible treatment for patients with a value that is statistically significant but of little clinical liver cirrhosis and prolonged bleeding time who need impact. Although desmopressin had no blood-saving invasive diagnostic procedures such as liver biopsies. effect when the total blood loss in placebo-treated patients Notwithstanding the fact that there is only preliminary decreased in the lower- and middle-thirds of distribution evidence that desmopressin prevents or stops bleeding (687 to 1,108 ml), the compound reduced blood losses by complications that develop in association with the use of 34% when blood loss was larger [57]. The modest results antithrombotic agents, the compound may provide an obtained with desmopressin were substantially confirmed opportunity to control drug-induced bleeding without in a more recent meta-analysis of 38 randomized, placebo- stopping treatment and perhaps avoiding recurrence or controlled trials on 2,488 undergoing various surgical progression of thrombosis. procedures (mainly cardiac surgery) [58]. 6 Treatment of Hemophilia No. 11

TABLE 3. Indications for desmopressin in the treatment of bleeding disorders

Grading of Level of recommendation evidence Mild hemophilia A B III Established VWD (see Table 2) B III Congenital defects of platelet function C IV Uremia C IV Possible Liver cirrhosis C IV Drug-induced bleeding (heparin, hirudin, C IV antiplatelet agents, dextran, streptokinase) Cardiac surgery A I Doubtful Orthopedic surgery A I

Therefore, desmopressin seems beneficial only in oper- blood loss. When administered to hemostatically normal ations associated with large blood loss (>1 l). It is not children before spinal fusion for idiopathic scoliosis, easy to predict which patient will bleed more, but situa- desmopressin reduced their average operative blood loss tions such as re-operation, pre-surgical use of antiplatelet by about one third [63], but these favorable results were agents, pre-existing coagulation defects, and sepsis might not confirmed in a subsequent study [64]. Desmopressin help to identify the cases suitable for prophylaxis. Lower did not reduce blood loss or transfusion requirement after pre-operative plasma levels of factor VIII and VWF may total hip or knee arthroplasty [65]. also help to identify patients most at risk of bleeding [52,53]. However, the overlap of values is so large that it In summary, the efficacy of desmopressin as a blood- is not possible to use these measurements to select patients saving agent in cardiac and noncardiac surgical operations with the most to gain from the use of desmopressin. appears doubtful at the moment.

Desmopressin is not the only blood-saving agent that can be used in cardiac surgery. The synthetic antifibri- Therapeutic guidelines nolytic amino acids aminocaproic acid (EACA) and tranexamic acid, and the broad-spectrum protease The main therapeutic guidelines for desmopressin are inhibitor aprotinin have also been used, particularly summarized in Table 3. It is the treatment of choice for after the recognition that acquired immunodeficiency patients with mild hemophilia A and type 1 VWD (grade syndrome (AIDS) could result from blood transfusions B recommendation). The evidence of its efficacy as autol- contaminated with HIV. A few direct comparison studies ogous replacement of the deficient factors is so clear that [59,60] and a meta-analysis [61] have shown that the no randomized controlled clinical trial was ever neces- order of efficacy of these hemostatic agents (greatest to sary (level III evidence). least) is aprotinin, tranexamic acid, EACA, and desmopressin [61]. The order of drug cost is also the same. In patients with congenital defects of platelet function, However, aprotinin has been withdrawn from use in with the hemostatic abnormalities associated with chronic cardiac surgery because it was shown to be associated liver disease, and with those induced by the therapeutic with an increased death rate associated with cardiovas- use of antiplatelet and anticoagulant agents, desmopressin cular complications [62]. has been used successfully to prevent or stop bleeding. However, there is still no well-designed clinical trial that The efficacy of desmopressin has also been evaluated in truly shows efficacy of the compound in these conditions noncardiac surgical operations characterized by large (grade C recommendation based on level IV evidence). Desmopressin (DDAVP) in the Treatment of Bleeding Disorders 7

Currently, the widespread use of erythropoietin and the The use of desmopressin in surgical operations other than resulting sustained correction of the hemostatic defect cardiac surgery is not warranted at the moment. On the make the use of desmopressin unnecessary in the majority whole, more than 200 years of research have provided of patients with chronic renal insufficiency. Antifibrinolytic an agent that makes the blood clot faster, and William amino acids should be preferred to desmopressin in Hewson, who so ingeniously inquired into the properties reducing blood loss and transfusion requirements during of blood in the 18th century, perhaps would be content cardiac surgery with extracorporeal circulation (grade A with the outcome of his pioneer studies. recommendation based on level I evidence).

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Blood of uremia after treatment with recombinant human 1982;59:1272-1278. erythropoietin. Lancet 2: 1227,1987. 31. Federici AB, Mazurier C, Berntorp E et al. Biologic 45. Burroughs AK, Matthews K, Qadiri M, Thomas response to desmopressin in patients with severe N, Kernoff PBS, Tuddenham EGD, McIntyre N. type 1 and type 2 von Willebrand disease: results of a Desmopressin and bleeding time in patients with multicenter European study. Blood 2004;103:2032-2038. cirrhosis. Br J Med 291:1377, 1985. 32. Castaman G, Lethagen S, Federici AB et al. Response 46. Mannucci PM, Vicente V, Vianello L, Cattaneo M, to desmopressin is influenced by the genotype and Alberca I, Coccato MP, Faioni E, Mari D. Controlled phenotype in type 1 von Willebrand disease (VWD): trial of desmopressin (DDAVP) in liver cirrhosis and results from the European Study MCMDM-1VWD. other conditions associated with a prolonged bleeding Blood 2008;111:3531-3539. time. Blood 67:1148,1986. 33. Haberichter SL, Castaman G, Budde U et al. 47. de Franchis F, Arcidiacono PG, Carpinelli PG, Identification of type 1 von Willebrand disease patients Andreoni B, Cestari L, Brunati S, Zambelli A, Battaglia with reduced von Willebrand factor survival by G, Mannucci PM. Randomized controlled trial of assay of the VWF propeptide in the European study: Desmopressin (DDAVP) in the Treatment of Bleeding Disorders 9

desmopressin plus terlipressin and terlipressin alone for 58. Crescenzi G, Landoni G, Biondi-Zoccai G et al. the treatment of acute variceal hemorrhage in cirrhotic Desmopressin reduces transfusion needs after patients: A multicenter, double blind study. Hepatology surgery: a meta-analysis of randomized clinical trials. 18:1102, 1993. Anesthesiology 2008;109:1063-1076. 48. Schulman S, Johnsson H. Heparin, DDAVP and the 59. Rocha E, Hidalgo F, Llorens R, Melero JM, Arroyo SL, bleeding time. Thromb Hemost 65:242, 1991. Paramo JA. Randomized trial of aprotinin and DDAVP 49. Johnstone MT, Andrews T, Ware JA, Rudd MA, George to reduce postoperative bleeding after cardiopulmonary D, Weinstein M, Loscalzo J. Bleeding time prolongation surgery. Circulation 90;921,1994. with streptokinase and its reduction with 1-deamino-8- 60. Aron KV, Emery RW. Decreased postoperative D-arginine vasopressin. Circulation 82:2142, 1990. drainage with addition of epsilonaminocaproic acid 50. Bove CM, Casey B, Marder VJ. DDAVP reduces bleeding before cardiopulmonary bypass. Ann Thorac Surg during continued hirudin administration in the rabbit. 57;1108, 1994. Thromb Haemost 75:471, 1996. 61. Fremes SE, Wong BI, Lee E, Mai R, Christakis GT, 51. Flordal PA, Ljungstrom KG, Svensson J. Desmopressin McLean RF, Goldman BS, Naylor CD. Meta- analysis reverses effects of dextran on von Willebrand factor. of prophylactic drug treatment in the prevention of Thromb Hemost 61:541, 1989. postoperative bleeding. Ann Thorac Surg 58;1580, 1994. 52. Salzman EW, Weinstein MJ, Weintraub RM, Ware JA, 62. Fergusson DA, Hébert PC, Mazer CD, Fremes S, Thurer RL, Robertson L, Donovan A, Gaffney T, Bertelé V, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano Troll J. Treatment with desmopressin acetate to reduce blood R, Blajchman MA, Bussières JS, Côté D, Karski J, loss after cardiac surgery.N Engl J Med 314:1402, 1986. Martineau R, Robblee JA, Rodger M, Wells G, Clinch 53. Rocha E, Llorens R, Paramo JA, Arcas R, Cuesta B, J, Pretorius R. BART Investigators. A comparison of Trenor A. Does desmopressin acetate reduce blood loss aprotinin and lysine analogues in high-risk cardiac after surgery in patients on cardiopulmonary bypass? surgery. N Engl J Med 358:2319, 2008. Circulation 77:1319, 1988. 63. Kobrinsky NL, Letts RP, Patel R, Israels ED, Monson RC, 54. Hackmann T, Gascoyne R, Naiman SC, Growe GH, Schwetz N, Cheang MS. DDAVP shortens the bleeding Burchill LD, Jamieson WR, Sheps SB, Schechter MT, time and decreases blood loss in hemostatically normal Townsend GE. A trial of desmopressin to reduce blood subjects undergoing spinal fusion surgery. Ann Intern loss in uncomplicated cardiac surgery. N Engl J Med Med 107:446, 1987. 321:1437, 1989. 64. Guay J, Rainberg C, Poitras B, David M, Mathews S, 55. Anderson TL, Solem JO, Tengborn L, Vinge E. Effects Lortie L, Rivard GE. A trial of desmopressin to reduce of desmopressin acetate on platelet aggregation, von blood loss in patients undergoing spinal fusion for Willebrand factor and blood loss after cardiac surgery idiopathic scoliosis. Anesth Analg 75;405, 1992. with extracorporeal circulation. Circulation 81:872, 1990. 65. Karnezis TA, Stulberg SD, Wixson RL, Reilly P. The 56. Sean MD, Wadsworth LD, Rogers PC. The effect of hemostatic effects of desmopressin on patients who had desmopressin acetate (DDAVP) on postoperative total joint arthroplasty. A double-blind randomized trial. blood loss after cardiac operations in children.J Thorac J Bone Joint Surg Am 76:1545,1994. Cardiovasc Surg 48:217, 1988. 57. Cattaneo M, Harris AS, Stromberg U, Mannucci PM. The effect of desmopressin on reducing blood loss in cardiac surgery . A meta-analysis of double-blind, placebo- controlled trials. Thromb Haemost 74;1064, 1988. TREATMENT OF HEMOPHILIA

November 2012 · No. 11

DESMOPRESSIN (DDAVP) IN THE TREATMENT OF BLEEDING DISORDERS Revised edition

Pier Mannuccio Mannucci Angelo Bianchi Bonomi Hemophilia and Thrombosis Center IRCCS Cà Granda Maggiore Policlinico Foundation Milan, Italy Table of Contents

Introduction...... 1

Historical background...... 1

Mechanism of action...... 2

Desmopressin in the management of congenital bleeding disorders...... 3

Desmopressin in acquired and drug-induced bleeding disorders...... 4

Desmopressin as a blood-saving agent...... 5

Therapeutic guidelines...... 6

References...... 7

TABLE 3. Indications for desmopressin in the treatment of bleeding disorders

References

Apply separately to the plate as 10 mm bands 5 μLofeach B. Amino acid analysis (2.2.56). For hydrolysis use Method 1 solution. Develop immediately over a path of 15 cm using a and for analysis use Method 1. mixture of 3 volumes of water R,36volumesofmethanol R Express the content of each amino acid in moles. Calculate and 130 volumes of methylenechlorideR.Drytheplatein the relative proportions of the amino acids, taking 1/6 of the a current of warm air, spray with a mixture of 5 volumes of sum of the number of moles of aspartic acid, glutamic acid, sulfuric acid R and 95 volumes of alcohol R and heat at 140 °C proline, glycine, arginine and phenylalanine as equal to 1. for 15 min. Examine in daylight. In the chromatogram obtained The values fall within the following limits: aspartic acid: 0.90 with test solution (a), any band, apart from the principal band, is to1.10;glutamicacid:0.90to1.10;proline:0.90to1.10; not more intense than the band in the chromatogram obtained glycine: 0.90 to 1.10; arginine: 0.90 to 1.10; phenylalanine: with reference solution (b) (2.5 per cent) and at most two such 0.90 to 1.10; tyrosine: 0.70 to 1.05; half-cystine: 0.30 to 1.05. bands are more intense than the band in the chromatogram Lysine, isoleucine and leucine are absent; not more than obtained with reference solution (c) (1.0 per cent). traces of other amino acids are present. Loss on drying (2.2.32). Not more than 5.0 per cent, determined TESTS on 0.500 g by drying in vacuo at 105 °C. Specific optical rotation (2.2.7): − 72 to − 82 (anhydrous and Sulfated ash (2.4.14). Not more than 0.1 per cent, determined acetic acid-free substance). on the residue obtained in the test for loss on drying. Dissolve 10.0 mg in a 1 per cent V/V solution of glacial acetic ASSAY acid R and dilute to 5.0 mL with the same acid. Dissolve 50.0 mg in alcohol R and dilute to 50.0 mL with the Related substances. Liquid chromatography (2.2.29): usethe same solvent. Dilute 5.0 mL of this solution to 100.0 mL with normalisation procedure. alcohol R. Prepare a reference solution in the same manner, Test solution. Dissolve 1.0 mg of the substance to be examined using 50.0 mg of deslanoside CRS (undried). To 5.0 mL of each in 2.0 mL of water R. solution add 3.0 mL of alkaline sodium picrate solution R and Resolution solution. Dissolve the contents of a vial of allow to stand protected from bright light in a water-bath at oxytocin/desmopressin validation mixture CRS in 500 μLof 20±1°Cfor40min.Measuretheabsorbance(2.2.25)ofeach water R. solution at the maximum at 484 nm, using as the compensation liquid a mixture of 3.0 mL of alkaline sodium picrate solution R Column: and 5.0 mL of alcohol R prepared at the same time. — size: l =0.12m,Ø=4.0mm; — stationary phase: octadecylsilyl silica gel for Calculate the content of C47H74O19 from the absorbances measured and the concentrations of the solutions. chromatography R (5 μm). Mobile phase: STORAGE — mobile phase A: 0.067 M phosphate buffer solution Store in an airtight, glass container, protected from light, at a pH 7.0 R; filter and degas; temperature below 10 °C. — mobile phase B: acetonitrile for chromatography R,mobile phase A (50:50 V/V); filter and degas. Time Mobile phase A Mobile phase B 07/2009:0712 (min) (per cent V/V) (per cent V/V) 0-4 76 24 DESMOPRESSIN 4 - 18 76 → 58 24 → 42 18 - 35 58 → 48 42 → 52 Desmopressinum 35 - 40 48 → 76 52 → 24 40 - 50 76 24 Flow rate:1.5mL/min. Detection: spectrophotometer at 220 nm. Injection:50μL. C46H64N14O12S2 Mr 1069 [16679-58-6] Retention time:desmopressin=about16min;oxytocin=about 17 min. DEFINITION System suitability: resolution solution: (3-Sulfanylpropanoyl)-L-tyrosyl-L-phenylalanyl-L-glutaminyl- — resolution: minimum 1.5 between the peaks due to L-asparaginyl-L-cysteinyl-L-prolyl-D-arginylglycinamide cyclic desmopressin and oxytoxin. (1→6)-disulfide. Limits: Synthetic cyclic nonapeptide, available as an acetate. — unspecified impurities:foreachimpurity,maximum0.5per Content: 95.0 per cent to 105.0 per cent (anhydrous and acetic cent; acid-free substance). — total:maximum1.5percent; CHARACTERS — disregard limit:0.05percent. Appearance: white or almost white, fluffy powder. Acetic acid (2.5.34): 3.0 per cent to 8.0 per cent. Solubility: soluble in water, in ethanol (96 per cent) and in Test solution.Dissolve20.0mgofthesubstancetobeexamined glacial acetic acid. in a mixture of 5 volumes of mobile phase B and 95 volumes of mobile phase A and dilute to 10.0 mL with the same mixture IDENTIFICATION of mobile phases. A. Examine the chromatograms obtained in the assay. Water (2.5.32): maximum 6.0 per cent, determined on 20.0 mg. Results: the retention time and size of the principal peak Bacterial endotoxins (2.6.14): lessthan500IU/mg,ifintended in the chromatogram obtained with the test solution are for use in the manufacture of parenteral preparations without approximately the same as those of the principal peak in the a further appropriate procedure for the removal of bacterial chromatogram obtained with the reference solution. endotoxins.

General Notices (1) apply to all monographs and other texts 1803 Desogestrel EUROPEAN PHARMACOPOEIA 7.0

ASSAY DEFINITION Liquid chromatography (2.2.29) as described in the test for 13-Ethyl-11-methylidene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol. related substances with the following modifications. Content: 98.0 per cent to 102.0 per cent (dried substance). Reference solution. Dissolve the contents of a vial of desmopressin CRS in water R to obtain a concentration of CHARACTERS 0.5 mg/mL. Appearance: white or almost white, crystalline powder. Mobile phase: mobile phase B, mobile phase A (40:60 V/V). Solubility: practically insoluble in water, very soluble in Flow rate:2.0mL/min. methanol, freely soluble in anhydrous ethanol and in methylene chloride. Retention time: desmopressin = about 5 min. IDENTIFICATION Calculate the content of desmopressin (C46H64N14O12S2)fromthe declared content of C46H64N14O12S2 in desmopressin CRS. A. Infrared absorption spectrophotometry (2.2.24). STORAGE Comparison: desogestrel CRS. In an airtight container, protected from light, at a temperature B. Specific optical rotation (see Tests). of 2 °C to 8 °C. If the substance is sterile, store in a sterile, TESTS airtight, tamper-proof container. Specific optical rotation (2.2.7): + 53 to + 57 (dried substance). LABELLING Dissolve 0.250 g in anhydrous ethanol R and dilute to 25.0 mL The label states: withthesamesolvent. — the mass of peptide per container; Related substances. Liquid chromatography (2.2.29). — where applicable, that the substance is suitable for use in the Test solution.Dissolve20.0mgofthesubstancetobeexamined manufacture of parenteral preparations. in 25 mL of acetonitrile R1 and dilute to 50.0 mL with water R. Reference solution (a). Dissolve 4 mg of desogestrel for system IMPURITIES suitability CRS (containing impurities A, B, C and D) in 5 mL of Other detectable impurities (the following substances would, acetonitrile R1 and dilute to 10.0 mL with water R. if present at a sufficient level, be detected by one or other of Reference solution (b).Dilute1.0mLofthetestsolutionto the tests in the monograph. They are limited by the general 100.0 mL with a mixture of equal volumes of acetonitrile R1 acceptance criterion for other/unspecified impurities and/or and water R. by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities Reference solution (c). Dilute 1.0 mL of reference solution (b) for demonstration of compliance. See also 5.10. Control of to 10.0 mL with a mixture of equal volumes of acetonitrile R1 impurities in substances for pharmaceutical use):A,B,C,D, and water R. E, F, G. Reference solution (d).Dissolve20.0mgofdesogestrel CRS in 25 mL of acetonitrile R1 and dilute to 50.0 mL with water R. Column: — size: l =0.25m,Ø=4.6mm, — stationary phase: sterically protected octadecylsilyl silica A. X = Gln, Y = Asp, Z = D-Arg: [5-L-aspartic acid]desmopressin, gel for chromatography R (5 μm), B. X = Glu, Y = Asn, Z = D-Arg: [4-L-glutamic acid]desmopressin, — temperature:50°C. Mobile phase: water R, acetonitrile R1 (27:73 V/V). D. X = Gln, Y = Asn, Z = L-Arg: [8-L-arginine]desmopressin, Flow rate:1.0mL/min. Detection: spectrophotometer at 205 nm. Injection:15μL of the test solution and reference solutions (a), (b) and (c). Run time: 2.5 times the retention time of desogestrel. C.R=OH,R4=R5=H:[9-glycine]desmopressin, Identification of impurities:usethechromatogram 5.4 E.R=NH2,R4=CH2-NH-CO-CH3,R5=H:N - supplied with desogestrel for system suitability CRS and the [(acetylamino)methyl]desmopressin, chromatogram obtained with reference solution (a) to identify 4.5 thepeaksduetoimpuritiesA,B,CandD. F.R=NH2,R4=H,R5=CH2-NH-CO-CH3 : N - [(acetylamino)methyl]desmopressin, Relative retention with reference to desogestrel (retention time = about 22 min): impurity E = about 0.2; 1.9 1.9 G.R=N(CH3)2,R4=R5=H:N ,N -dimethyldesmopressin. impurity D = about 0.25; impurity B = about 0.7; impurity A = about 0.95; impurity C = about 1.05. 01/2008:1717 System suitability: reference solution (a): — peak-to-valley ratio: minimum 2.0, where Hp =heightabove thebaselineofthepeakduetoimpurityCandHv = height DESOGESTREL above the baseline of the lowest point of the curve separating this peak from the peak due to desogestrel. Desogestrelum Limits: — correction factors: for the calculation of content, multiply the peak area of the following impurities by the corresponding correction factor: impurity A = 1.8, impurity D = 1.5; — impurities A, B, C:foreachimpurity,notmorethantwice the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent); — impurity D: not more than the area of the principal peak C22H30O Mr 310.5 in the chromatogram obtained with reference solution (c) [54024-22-5] (0.1 per cent);

1804 See the information section on general monographs (cover pages)