Challenges in Managing Acute Bleeding in Patients with Hemophilia

Presentation Outline

Hemophilia and Bleeding Disorders: 1. Epidemiology and genetics Diagnosis and Clinical Features 2. Clinical features of hemophilia

Mark T. Reding, MD 3. Inhibitors in congenital hemophilia Director, Center for Bleeding and Clotting Disorders 4. Acquired hemophilia University of Minnesota Medical Center, Fairview Associate Professor University of Minnesota Medical School Minneapolis, MN

Q1: How often do you manage acute What is Hemophilia? bleeding in patients with hemophilia? a. Quite often, I am associated with a • Congenital bleeding disorder hemophilia treatment center • Due to deficiency or absence of a b. Once a year coagulation cascade protein c. Every few years • Hemophilia A = factor VIII deficiency d. Never • Hemophilia B = factor IX deficiency • Others . . .

Rare Bleeding Disorders Hemophilia A Hemophilia B Protein Prevalence Genetics Specific Rx

Fibrinogen 1 : 1,000,000 AR Yes • Factor VIII deficiency • Factor IX deficiency Factor II 1 : 2,000,000 AR No • Classical hemophilia • Christmas disease Factor V 1 : 1,000,000 AR No • 1 in 5,000 to 10,000 • 1 in 30,000 male Factor VII 1 : 500, 000 AR Yes malbithle births birth s Factor X 1 : 1,000,000 AR No • 80% of total cases • 20% of total cases Factor XI 1 : 1,000,000 AD Yes # • Spontaneous • Spontaneous Factor XIII 1 : 2,000,000 AR Yes mutations = 30% mutations = 20% AR = autosomal recessive, AD = autosomal dominant # Not available in U.S.

• Account for 3 - 5% of all inherited coagulation disorders Clinical phenotypes are indistinguishable • Higher prevalence in areas of geographic or social isolation

1 Challenges in Managing Acute Bleeding in Patients with Hemophilia

• Hemophilia affects Age Distribution of the U.S. all racial and Hemophilia Population socioeconomic groups equally • There are ~ 20,000 Age (yr) Number Percent hemophiliacs in the 2 – 19 8584 48% United States • More than 500,000 20 – 44 6418 36% hemophiliacs 45 – 64 2274 13% worldwide 65+ 524 3%

Centers for Disease Control and Prevention. Summary report of UDC Activity (National). Report date May 30, 2011.

Genetics of Hemophilia Genetics of Hemophilia

• Genes for factors VIII and IX are located on the X chromosome • Females are carriers, males are affected Hig h rate o f spontaneous mutations • Unaware female carriers • New mutation in baby boy • ~30% have no family history of hemophilia

Genetics of Hemophilia Diagnosis of Hemophilia + Family History No Family History

• Identify carriers • Bleeding with birth trauma, circumcision, • Pre-conception immunizations counseling • Suspected child • Cord blood testing of abuse males • Joint bleeds and • Defer testing of hematomas start to females until sx or occur when learning considering pregnancy to walk

2 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Diagnosis of Hemophilia Clinical Features of Hemophilia

Laboratory testing Severity of bleeding tendency depends on the factor level

• Normal CBC Mild ( > 5% ) Moderate (1-5%) Severe ( < 1 %)

• Normal platelet function • Bleed only • Bleed after • Frequent after severe injury, surgery spontaneous • Normal PT / INR injury, trauma, bleeding • May have or surgery • Prolonged aPTT occasional • Diagnosis • May not be spontaneous made in early • Measure factor VIII and IX levels diagnosed until bleeding childhood adulthood

Clinical Features of Hemophilia: Joint bleed (hemarthrosis) The Clinical Problem of Joint Bleeding

• Hemarthrosis, primarily involving the ankles, knees, and elbows, is the most common complication of hemophilia • 45% experience first joint bleed within first year of life • Median age at first joint bleed: 17 – 26 months • 90% have at least one joint bleed by 4 years of age • 90% of those with severe hemophilia have chronic degenerative changes involving at least 1 joint by age 25 • 40% report restricted physical activities due to arthropathy

Lafeber et al. Haemophilia. 2008; 14(Suppl 4):3-9. Valentino et al. Semin Hematol. 2008; 45(Suppl 1):S50-S57. ©2009 Rush University Medical Center, used with permission.

The Clinical Problem of Joint Bleeding Clinical Features of Hemophilia: Joint bleed (hemarthrosis) Blood in joint space • 26 yo with severe hemophilia A and fVIII Recurrent Inflammation inhibitor bleeding • Recurrent traumatic and spontaneous knee bleeds Acute and chronic synovitis • Left side surgically replaced

• Hemophilic arthropathy is characterized by cartilage and bone • Note severe muscular destruction, bone remodeling, and progressive loss of function atrophy • Prophylactic administration of clotting factor concentrates is essential for preventing hemophilic arthropathy SK

3 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Clinical Features of Hemophilia: Clinical Features of Hemophilia: Joint bleed (hemarthrosis) Joint bleed (hemarthrosis)

• 36 year old • 36 year old • Severe hemophilia A • Severe hemophilia A • Recurrent left knee bleeds • Recurrent left knee • Severe hemophilic bleeds arthropathy • Severe hemophilic arthropathy • Underwent total knee arthroplasty • Infected prosthesis had to be removed 3 months later TS TS

Patient: LF, 22-yo male with severe hemophilia A

March 2008 May 2010 June 2010 Severe hemophilia A, no inhibitor, morbidly obese RS

Clinical Features of Hemophilia: Joint bleed (hemarthrosis)

• Severe hemophilia A with inhibitor and • 36 year old, severe hemophilia A, followed by hemophilia advanced arthropathy treatment center since birth. No history of fVIII inhibitor.

• Required right total hip arthroplasty SK • Target joint in childhood, no longer bleeds (or moves). NJ

4 Challenges in Managing Acute Bleeding in Patients with Hemophilia

44-yo male with severe hemophilia A, right elbow fracture after fall (July 2010) DK December 2010 – 4 months s/p arthroplasty, doing well

Clinical Features of Hemophilia: Soft tissue bleeding

February 2012 – Resumed truck driving and heavy lifting. Acquired hemophilia, non-traumatic elbow bleed Not doing so well. DT

Clinical Features of Hemophilia: Clinical Features of Hemophilia: Soft tissue bleeding Deep muscle bleeds

• 56 year old with severe hemophilia A and inhibitor • 20 year old with • Fell on icy sidewalk mild hemophilia A • Did no t t rea t aggressi vel y • No trauma enough • Bled after light • Required transfusion of 6 jogging units RBCs

GR

5 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Clinical Features of Hemophilia: Clinical Features of Hemophilia: Deep muscle bleeds Intracranial bleeds

• 6 year old with severe hemophilia A • Bumped head on school playground equipment, did not appear to have any significant injury • Parents noted change in behavior later that • 52 year old with severe evening hemophilia B • Spontaneous bleed

Clinical Features of Hemophilia: Inhibitors in Congenital Hemophilia Soft tissue bleeding • Some hemophilia patients “see” factor VIII or factor IX as a foreign protein • Infusion of factor concentrate to prevent or treat bleeding triggers an immune response • Antibodies (“inhibitors”) directed against factor VIII or factor IX neutralize the procoagulant effect and render standard treatment useless Severe hemophilia A with inhibitor,

neck bleed provoked by coughing GR

Inhibitors in Congenital Hemophilia Inhibitors in Congenital Hemophilia

• Development of inhibitors is currently the most severe complication of factor replacement therapy Factor VIIIVIIIFactor Factor IXIXFactor • Typically seen in those with severe hemophilia • Common (~25%) • Rare (< 5%) • Hemophilia A – inhibitors develop in ~25% • Well-studied and • Risk factors poorly characterized defined •Hemophilia B – inhibitors developp% in < 5% • Eradicated in ~ 70% • ITT often fails • No longer associated with increased mortality with ITT (immune • Allergic reactions, tolerance therapy) However . . . nephrotic syndrome  Bleeding more difficult to control May develop following treatment with both  Devastating joint disease and disability plasma derived and recombinant factor products  Major clinical and economic challenges Similar bleeding patterns, diagnosis, and management

6 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Factors Influencing Inhibitor Development Clinical Recognition of Inhibitors in Hemophilia A • Usually develop in small children, after only a small number of factor exposures Patient Variables Treatment Variables • Disease severity • Number and pattern of • Change in bleeding pattern fVIII exposures • FVIII gene defect • Type of fVIII product • Poor response to treatment with factor • Ethnicity InhibitorInhibitor • Concurrent immune • FH of inhibitors system challenges • Allergic reactions often herald the • HLA type • Frequency of development of factor IX inhibitors • Individual immune monitoring response traits • May develop later in life in those with mild or moderate hemophilia A complex interaction of many variables leads to  Often after intense factor exposure following inhibitor development in a particular individual surgery or trauma

Gouw SC. Semin Thromb Hemost. 2009; 35:723-34.

Measurement of Factor VIII Inhibitors: Treatment of Inhibitors Bethesda Assay • “Bypassing Agents” Reciprocal of - Prothrombin complex concentrates dilution at which - Recombinant factor VIIa 50% of normal FVIII activity is • Bypassing agents have unpredictable efficacy (50 – 90%) observed - More bleeding, more joint damage - SiikSurgery is risky • Immune Tolerance Therapy 1:1 1:2 1:5 1:10 1:20 1:50 11 - Expensive: ~ $1 million per patient P e r f o r m F V I I I a s s a y 1 / 551 - Only ~ 70% effective • Overall costs 6% 21% 50% 75% 86% 98% - Routine treatment: $200,000 – 250,000 per year Inhibitor Titer - Major bleed, surgery: $500,000 – 1,000,000 ++ = Patient plasma = Control plasma = 5 BU/mL

Acquired Hemophilia

• Inhibitors can develop in those who are not Why You Should Care About genetically deficient in factor VIII Acquired Hemophilia • Rare autoimmune condition  Morbidity: > 80% have serious bleeding • Occurs in 0.2 – 1 per million per year  Mortality: as high as 20% • Must have a high index of suspicion to make a timely diagnosis (Translation: 1 in 5 patients may bleed to death) • Delayed diagnosis and lack of appreciation of risk to patient are common mistakes

7 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Acquired Hemophilia: Acquired Hemophilia: Clinical Features Associated Conditions

• Median age at presentation: 60 - 67 yrs; range: 2 - 89 yrs • 50 – 60% of AH cases are idiopathic • Males and females both affected • 40 – 50% of AH cases are associated with • Bleeding pattern other underlying conditions . . . – Hemarthroses rare – Mucocutaneous bleeding common (epistaxis, PregnancyPregnancyPregnancy ecchymosis, gastrointestinal bleeding, hematuria) Autoimmune disorders – Severe intramuscular bleeding Malignancy – Intracranial hemorrhage Drugs – Postsurgical or postpartum bleeding Infections

Ma AD, Carrizosa D. Hematology Am Soc Hematol Educ Program. 2006:432-7. Ma AD, Carrizosa D. Hematology Am Soc Hematol Educ Program. 2006:432-7.

Treatment of Acquired Hemophilia Acquired Hemophilia: Diagnostic Barriers, Management Pitfalls 1. Stop Bleeding 1. Delay in establishing correct diagnosis Factor VIII • Dismissal of prolonged aPTT Prothrombin complex concentrates • Not included in differential diagnosis Recombinant factor VIIa • Requi res spec ilidialized coagu ltilation lbtlab tes ting 2. Eradicate inhibitor 2. Failure to recognize seriousness of diagnosis Plasma exchange • Immunosuppressive therapy should begin as Immunosuppression (steroids) soon as the diagnosis is established Cyclophosphamide • Optimal treatment requires expertise rarely found outside of a hemophilia treatment center Rituximab

Clinical Challenges in Managing Congenital Hemophilia with Inhibitors and Acquired Hemophilia

• Rare patients, higher risk of bleeding, increased morbidity •Unpppyredictable and incomplete efficacy of bypassing agents • No routine lab monitoring available • Extremely expensive • Optimal management of acute bleeding and surgery requires HTC expertise

8 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Timeline of Hemophilia Treatment

• Before 1940s: supportive care, transfusions of whole blood or fresh plasma Clinical Considerations in Managing – Average life expectancy 27 years Acute Bleeding in Patients with – Disabled by age 20 • 1960: transfusion medicine improved Hemophilia – Average lif e expect ancy 40 years – Still severely disabled and unemployed

Surabhi Palkimas, Pharm.D. • 1964: expanding treatment options with cryoprecipitate Pharmacy Clinical Coordinator, Hematology • 1968: development and availability of plasma-derived University of Virginia Health System factors products Charlottesville, Virginia – Average life expectancy 60 years – Hemophiliacs able to travel, work, and attend school with regularity

Timeline of Hemophilia Treatment Treatment of Hemophilia

• 1982: First reported case of AIDS in patients • Hemophilia A or B with hemophilia – Severity of factor deficiency • 1985: Virally inactivated factor concentrates – Past clinical course introduced • Develop an ongoing relationship with • 1992: Recombinant factor VIII regional hemophilia treatment center • 1997: Recombinant factor IX – Assist in day-to-day management and provide information on available therapeutic products

Q2: Prophylactic administration of clotting factor concentrate is recommended as Strategies for Bleeding Management standard of care by the World Federation • Goal is rapid and effective replacement of of Hemophilia. missing coagulation factor – Episodic or “on demand” a. True • Conventional treatment approach b. False – Proppyhylactic • Primary – Given at early age to prevent expected complication • Secondary – Begun after complication has occurred to prevent recurrence – Bolus vs. continuous infusion • Surgical procedures

Rodriguez NI et al. Pediatric Clin North Am. 2008; 55:357-76, viii.

9 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Q3: The choice of factor VIII product for Factor VIII Products hemostasis is usually based upon the safety, purity, cost and risk of inhibitory Plasma Derived antibodies. Products Containing Immunoaffinity Purified von Willebrand Factor a. True Alphanate® Hemofil M™ b. False Koate®-DVI Monoclate-P® Humate-P® Monarc-M™ Recombinant First Generation Second Generation Third Generation

Recombinate™ Kogenate® FS Advate® Kogenate® Helixate® FS Xyntha® Helixate® Refacto®

Wong T et al. Drugs. 2011; 71:305-20. Also see prescribing information (PI) in reference list.

Comparison of Recombinant Factor VIII Products: Factor VIII Products (rFVIII) Choice of Product • First generation • Safety and purity – Required bovine or human serum for stabilization – No documented cases of viral transmission • Second generation with any plasma-derived or recombinant factor – Reqqpuired plasma durin g manufacturin gp,g process, but concentrate in more than 25 years plasma is removed in final product – All rFVIII products are hemostatically • Third generation equivalent – Serum free during manufacturing process and final product – There is no difference in immunogenicity – Smaller infusion volumes between different generations of rFVIII – Safety advantage is theoretical only products

Wong T et al. Drugs. 2011; 71:305-20. Mannucci PM et al. Blood. 2012; 119:4108-14.

Factor VIII Products: Factor VIII Products: Choice of Product Dosing • Administration of 1 international unit per kg • Risk of occurrence of inhibitory antibodies increases plasma factor VIII level by 2% – Data suggest, but do not prove, that plasma- – Number of units depends upon derived products elicit fewer inhibitors than • Body weight rFVIII • Volume of distribution • Desired factor level •Cost • Half life approximately 8 to 12 hours • Check factor VIII level near end of 12-hour period

Mannucci PM et al. Blood. 2012; 119:4108-14.

10 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Factor VIII Products: Factor VIII Products: Control and Prevention of Bleeding Monitoring Parameters Type of Bleeding Factor VIII Dosage and Episode Level Required Frequency (% of normal) Concept Factor VIII Minor 20 - 40 • 10 – 20 units/kg Early hemarthrosis • Repeat dose every 12 - 24 Blood pressure and heart rate  Minor muscle or oral bleed hours or add antifibrinolytic Moderate 50 - 80 • 25 – 40 units/kg every 12 - Partial thromboplastin time ()(PTT)  24 hours until bleeding Bleeding into muscles or oral Factor levels cavity, definite hemarthrosis, resolved  known trauma Development of factor inhibitors  Major 80 - 100 • Initial dose: 40 – 50 units/kg • Repeat dose 20 – 50 Signs of bleeding (hemoglobin, GI, intracranial, intra-abdominal, hemocrit)hematocrit)  intrathoracic, CNS, or units/kg every 8 - 12 hours retroperitoneal bleeding until bleeding resolved

Advate (antihemophilic factor [recombinant], plasma/albumin-free method) PI; 2012 Jul. Helixate FS (antihemophilic factor [recombinant], formulated with sucrose) PI; 2011 Apr.

Adjuvant Therapy: Desmopressin Acetate Adjuvant Therapy: Antifibrinolytics • Increase circulating level of factor VIII by 2 to 10 • Used for mild bleeding episodes fold (mild to moderate hemophiliac) • Stabilizes clot and discourages re-bleeding • Dose 0.3 mcg/kg IV over 30 min or 150-300 mcg • Aminocaproic acid intranasal – Adult dose: 5 g orally or IV during the first hour then – Repeated at 12-24 hour interval 1g/hr for 8 hours or until bleeding is controlled • Limited use – Pediatric dose: 50 – 100 mg/kg orally or IV every 6 • Adverse effects hours – Flushing, headache, tachycardia, nausea, abdominal • Tranexamic acid cramping – Adult and pediatric dose: 10 mg/kg IV every 8 hours for 2 to 8 days Stimate (desmopressin acetate nasal spray) PI; 2011 Sep. Amicar (aminocaproic acid) PI; 2012 Jan. Desmopressin acetate injection PI; 2012 Apr. Cyklokapron (tranexamic acid injection) PI; 2011 Jan.

Adjuvant Therapy: Adjuvant Therapy: Cryoprecipitate Fresh Frozen Plasma (FFP) • Same factor VIII and IX concentrations as • Prepared from FFP: contains high levels of normal plasma factor VIII, XIII, vWF, and fibrinogen – 1 unit of FFP contains 200-250 units of factors VIII, IX • One unit of cryo contains 80-150 units of and XI factor VIII • Each unit increases patient’s factor VIII level by – 30-fold more concentrated compared with FFP only 5-10% – Large volumes needed to get factor levels above 50% • Limited use • Complications • Limited use – Allergic reactions, transmission of viral • Complications infections – Allergic reactions, transmission of viral infections vWF = von Willebrand factor

11 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Factor IX Products: Factor IX Products Dosing Plasma Derived • Administration of 1 international unit per kg AlphaNine® SD Mononine® increases plasma factor IX level by 1% Recombinant – Number of units depends upon: BeneFix® PthbiCProthrombin Comp lex Concen tttrates (PCC)(PCCs) • BdBody wei ihtght ® ® Profilnine SD Bebulin VH • Volume of distribution Activated Prothrombin Complex Concentrates • Desired factor level Factor VIII inhibitor bypassing activity (FEIBA® NF) • Half life approximately 18 to 24 hours • Check factor IX level near the end of 24-hour Wong T et al. Drugs. 2011; 71:305-20. period Also see prescribing information (PI) in reference list.

Factor IX Products: Factor VIII and Factor IX Products: Control and Prevention of Bleeding Monitoring Parameters Type of Bleeding Episode Factor IX Dosage and Frequency Level Required Concept Factor VIII Factor IX (% of normal) Minor 15 – 30 • Initial dose: 15 – 30 units/kg Blood pressure and heart rate  Uncomplicated hemarthrosis • Maintenance dose: 20 Superficial muscle or soft tissue units/kg every 12 - 24 hours Partial thromboplastin time (PTT)  bleed Factor levels Moderate 25 – 50 • Initial dose: 30 – 60 units/kg  Bleeding into muscles or oral cavity, • Maintenance dose: 30 Development of factor inhibitors  definite hemarthrosis, and known units/kg every 12 - 24 hours trauma Signs of bleeding (hemoglobin, hematocrit)hemocrit)  Major 50 – 100 • Initial dose: 60 – 100 GI, intrathoracic, CNS, or units/kg Signs of hypersensitivity reactions  retroperitoneal bleeding • Maintenance dose: 60 units/kg every 12- 24 hours

BeneFIX (coagulation factor IX [recombinant]) PI; 2011 Nov.

Comparison of Factor VIII and IX Products Inhibitors in Hemophilia Factor VIII Factor IX Concept Plasma Plasma Derived Recomb Derived Recomb • Antibody against factor VIII or factor IX Easy to store and prepare   – Most serious treatment-related complication in Straightforward dosing   hemophilia May contain immunomodulatory proteins  Contains vWF  • Hig her inc idence in hemop hilia A than Biologically identical to human factor  hemophilia B No risk of pathogen transmission ? ?  More expensive*  • Appear following median of 8 to 12 exposure Increase dose up to 1.5x vs. plasma derived  days *Compared with plasma-derived products.

Makris M et al. Haemophilia. 2012; 18(Suppl 4):48-53.

12 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Management of Acute Bleeding in Inhibitors in Hemophilia Patients with High Inhibitor Titer • Risk factors – Type of mutation in the factor VIII or factor IX gene • Goal: to “bypass” the need for factor VIII or – Human leukocyte antigen types and polymorphisms in gene IX in coagulation cascade that codes for cytokines – Led to exploring the efficacy and safety of – rFVIII products pose increased risk? PCCs • Low inhibitor titer is <5 BU/mL • Two bypass products – May have historically had higher titers – Factor VIII inhibitor bypassing agent (FEIBA) – Higher (4-5 times) doses of exogenous factor may be required • Activated PCC • High inhibitor titer is ≥ 5 BU/mL – Recombinant factor VIIa (rFVIIa) – Control of acute bleeding episodes – Reduction of inhibitor titer BU = Bethesda unit Makris M et al. Haemophilia. 2012; 18(Suppl 4):48-53.

FEIBA® NF Recombinant Factor VIIa (rFVIIa) • Consists of – Factors II, IX, X (mainly non-activated) • Complexed with tissue factor can activate – Factor VII (activated form) coagulation factor X and factor IX • Provides both factor II and Xa at site of the bleed • Minimizes risk of systemic coagulation •Dose seen with FEIBA – 50 – 100 units/kg every 6 to 12 hours (not to exceed daily dose 200 units/kg) •Dose • Risk of DIC or thromboembolism – 90 mcg/kg every 2 hours until hemostasis is • Cannot monitor clinical efficacy achieved – Thrombin generation time (TGT)? FEIBA NF (anti-inhibitor coagulant complex, nanofiltered and vapor heated) PI; 2011 Feb. NovoSeven RT (coagulation factor VIIa [recombinant] room temperature stable) PI.; 2012 Jan.

Review of Literature Formulary Considerations

• FEIBA vs. rFVIIa1 • Product considerations – Both had an efficacy rate of 80 to 90% – Dosage and storage – Neither product was superior to the other – Safety and purity • Availability • FEIBA plus rFVIIa2 – Hemostatic efficacy appears to be satisfactory • Physician’s experience – Higher incidence of thrombotic complications •Cost – Reserved for life-threatening bleed

1Astermark J et al. Blood. 2007; 109:546-51. 2Ingerslev J et al. Br J Haematol. 2011; 155:256-62.

13 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Conclusion

• Patients with hemophilia require life-long integrated care • Use of either plasma or recombinant factor product for the treatment or prevention of bleeding in patients with hemophilia • A serious complication of hemophilia is the development of an inhibitor

14 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Patient Scenarios: Innovative Could this occur on your watch? Strategies for Managing Patients • A 26 yo male with factor IX deficiency with Hemophilia in the presents to the ED with trauma, including a Hospital Setting fractured leg after crashing his motorcycle

William E. Dager, Pharm.D., BCPS (AQ-Cardiology) • A 50 yo male with factor VIII deficiency is Pharmacist Specialist scheduled for surgery UC Davis Medical Center Sacramento, California

Changes in the Hemophilia The Hemophilia Management Team Population Needs • Multidisciplinary • Established management considerations – Medicine (primary physician, hematologist, surgeon, …) – Younger population – Nursing (bedside, hematology program,…) – Hemarthrosis – Pharmacy – GtiGenetics Clinicians who are current on hemophilia • New challenges – population getting older – Coagulation laboratory management • Diseases of older populations – Social work considerations – Atrial fibrillation – Physical therapy – Coronary artery disease • Coordinated – Cancer • Easy to notify

• Communication Escobar M et al. Haemophilia. 2012; 18:971-81.

Skill: Assess the Situation Surgical Considerations • Is the center familiar with hemophilia • Active bleeding vs. planned procedure – Multidisciplinary team present – Confirm type of hemophilia – Experience • Insights from patient’s hemophilia treatment center • Surgical procedure or hematologist • Hemophilia as a special population • In hibitors presen t – Site: risk of a complication – Laboratory assay – What additional or related therapies may be • Discuss with the patient and family necessary • Type of anesthesia • Urgency of situation – General preferred over epidural or spinal block • Preoperative - Intraoperative - Postoperative Plan

Kulkarni R. Haemophilia. 2012 Aug 27 [Epub ahead of print].

15 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Avoiding Complications Pharmacology Considerations • Frequent bleeding a concern • Hemostatic agents – Consider minimally invasive procedure – Recombinant vs. pooled sources • Advanced age – rFVIIa, PCC, FEIBA – More conservative procedures – Is supply adequate? • Risk assessment – Reimbursement evaluated and handled accordingly – Scar tissue from multiple procedures • Antifibrinolytic agents – Other non-invasive options – Patient’s physical and clinical presentation – Tranexamic acid – Aminocaproic acid • Simplify agents used – Singular therapies vs. multiple agents • Topical therapies • Clinical support nearby or easy to contact • Immunomodulators – Consider when scheduling

Preoperative Management Perioperative Management Considerations Considerations • Consider ability to perform the procedure before • Maintaining hemostasis accepting the case – Hemostatic agents • Develop plan in advance of surgery – Antifibrinolytic agents – Adequate hemoglobin • Catheter insertion • Arrange availability of the agents • Antibiotic prophylaxis • Determine what should be withheld • Prophylactic hemostatic agent pre-op – Pre-surgical factor concentration (level) – Type of surgery – Type of hemophilia Escobar M et al. Haemophilia. 2012; 18:971-81. Escobar M et al. Haemophilia. 2012; 18:971-81. Kulkarni R. Haemophilia. 2012 Aug 27 [Epub ahead of print]. Kulkarni R. Haemophilia. 2012 Aug 27 [Epub ahead of print].

Intraoperative Management Considerations Postoperative Management • Monitor hemostasis Considerations – Thromboelastograms • Minimizing bleeding – Consider ability to perform the procedure before accepting – Wound care (healing slower) • Control bleeding (expected vs. non-expected) – Timing of concentrated clotting factors – Avoid diluting clotting factors •Drains • Suture removal – Mechanical • Physical therapy – Topical • Monitoring and maintaining hemostasis – Systemic therapy – Avoid excessive blood draws – Cooling patient – Monitor for inhibitor development • Consider thromboembolism vs. bleeding risks – Hemostatic agents • Determine what should be withheld – Antifibrinolytic agents • Transfusing to maintain HgB/Hct • Prophylactic hemostatic agent pre-op Escobar M et al. Haemophilia. 2012; 18:971-81. Escobar M et al. Haemophilia. 2012; 18:971-81. Kulkarni R. Haemophilia. 2012 Aug 27 [Epub ahead of print]. Kulkarni R. Haemophilia. 2012 Aug 27 [Epub ahead of print].

16 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Postoperative Management Managing Acute Bleeding Considerations (cont) • Increasing blood loss → ↑ morbidity and mortality • Unexpected bleeding • Supportive and preventive therapy • Patients at risk for catastrophic bleeds • VTE prophylaxis – Trauma ((jmajor or to a vital location) – CitkiCompression stockings – Gastrointestinal bleeding – Pharmacologic: caution in patients with inhibitors – Vascular injury (aneurysms, graft failure, postoperative) – Cerebral vascular bleed – Congenital or acquired coagulopathy

Escobar M et al. Haemophilia. 2012; 18:971-81. Kulkarni R. Haemophilia. 2012 Aug 27 [Epub ahead of print].

Q4: For a given concentrated clotting Hemostatic Agent Considerations factor (hemostatic agent), the dose is • Dosing: Prophylaxis vs. active bleeding the same no matter what type of – Baseline factor levels hemophilia is present. – Presence of inhibitors a. True – Type of hemophilia (rFVIIA dose < in factor VII deficiency vs. Hemophilia A or B with inhibitors) b. False • Administration – Bolus – Continuous Infusion – Inhibitors • < 5 BU/mL – High dose factor replacement • ≥ 5 BU/mL – Agent bypassing the inhibitor (rFVIIa or FEIBA) • Single or combined therapies

Berntorp E et al. Lancet. 2012; 379:1447-56.

Q5: What laboratory measure may be Monitoring Hemostatic Agent useful to determine if internal bleeding is occurring? • Titrating infusion a. Bleeding time – Time assessment with revised dose b. Factor level <60% • Change rate or dosing interval just prior to physician assessment c. Hemoglobin • Factor levels d. Prothrombin time – Establish targets – Inhibitors developing?

17 Challenges in Managing Acute Bleeding in Patients with Hemophilia

Assessing Hemostasis with Adjunctive Therapies Hemostatic Agent in Use • Antifibrinolytic agents • Desmopressin • Assessing hemostasis •Steroids – Onsite expert • Cytotoxic immunosuppressants – Risk for undesirable clotting – IVIG • Severity of bleeding – Cyclophosphamide – Assessing wound (site, packing removed, etc.) – Rituximab – Hgb for internal bleeding • Topical agents – Improving or limited/no progress • Plasma exchange • Thrombosis risks • Single or combined therapies

Toschi V et al. Intern Emerg Med. 2010; 5:325-33.

Systems Support Key Pharmacy Considerations • Keep key personnel current • Is the right agent being sent out? • 24/7 process • Is the dose correct? • Identify necessary hemostatic agents and labs • Who and how is the dose being determined? • Is it safe? • Guidelines on using available therapies • Is it working? – Easy for clinicians to locate and follow • Do we have enough clotting factor concentrates available? – Adapted for patients with hemophilia • Is a change in therapy being considered? • Rapid ability to implement management • Is the dose going to be adjusted? • How can we minimize cost and wastage? • Periodic review and quality improvement • Was the correct pre-authorization or billing done?

Escobar M et al. Haemophilia. 2012; 18:971-81.

18 Challenges in Managing Acute Bleeding in Patients with Hemophilia

APPENDIX: COAGULATION CASCADE

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