n Review Article

Instructions 1. Review the stated learning objectives at the beginning cme ARTICLE of the CME article and determine if these objectives match your individual learning needs. 2. Read the article carefully. Do not neglect the tables and other illustrative materials, as they have been selected to enhance your knowledge and understanding. 3. The following quiz questions have been designed to Disorders in provide a useful link between the CME article in the issue and your everyday practice. Read each question, choose the correct answer, and record your answer on the CME Registration Form at the end of the quiz. Orthopedic 4. Type or print your full name and address and your date of birth in the space provided on the CME Registration Form. 5. Indicate the total time spent on the activity (reading John Mansour, DO; Kenneth Graf, MD; Paul Lafferty, MD article and completing quiz). Forms and quizzes cannot be processed if this section is incomplete. All participants are required by the accreditation agency to attest to the time spent completing the activity. 6. Complete the Evaluation portion of the CME Regi­stration Form. Forms and quizzes cannot be processed if the Evaluation portion is incomplete. The Evaluation portion of the CME Registration Form will be separated from the quiz upon receipt at Orthopedics. Your evaluation of this activity will in no way affect the scoring of your quiz. educational objectives 7. Send the completed form, with your $15 payment (check As a result of reading this article, physicians should be able to: or money order in US dollars drawn on a US bank, or credit card information) to: Orthopedics CME Quiz, PO Box 36, Thorofare, NJ 08086, OR take the quiz online. Visit www. 1. Possess a basic understanding of commonly encountered disorders of pri- Healio.com/EducationLab/Orthopedics for details. mary and secondary hemostasis. 8. Your answers will be graded, and you will be advised whether you have passed or failed. Unanswered questions will be considered incorrect. A score of at least 80% is required to 2. Identify the clinical presentation of patients with bleeding disorders. pass. If a passing score is achieved, Vindico Medical Education will issue an AMA PRA Category 1™ certificate within 4-6 weeks. 3. Understand the importance of the diagnoses, treatments, and potential 9. Be sure to mail the CME Registration Form on or before the deadline listed. After that date, the quiz will close. CME complications associated with commonly encountered bleeding disorders in Registration Forms received after the date listed will not be orthopedic surgery. processed. CME ACCREDITATION This activity has been planned and implemented 4. Understand the preoperative management of antiplatelet and anticoagu- in accordance with the Essential Areas and policies of the lant therapeutic agents. Accreditation Council for Continuing Medical Education through the sponsorship of Vindico Medical Education and Orthopedics. Vindico Medical Education is accredited by the ACCME to provide continuing medical education for physicians. Abstract qualitative and factor Vindico Medical Education designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. With increasing recognition of the compli- disorders and coagulation inhibitors. The Physicians should claim only the credit commensurate with the extent of their participation in the activity. cations related to , it is of management of these coagulopathies that This CME activity is primarily targeted to orthopedic paramount importance for all orthopedic can be encountered in elective and non- surgeons, hand surgeons, head and neck surgeons, trauma surgeons, physical medicine specialists, and rheumatologists. surgeons to possess a basic knowledge of elective practice is often ignored. With There is no specific background requirement for participants taking this activity. common bleeding disorders. The evalua- appropriate knowledge and a multidisci- FULL DISCLOSURE POLICY tion of the coagulopathic patient requires plinary approach with hematologists and In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support, all a careful history, physical examination, cardiologists, surgeons can perform minor CME providers are required to disclose to the activity audience and laboratory evaluation. Bleeding disor- and major orthopedic procedures safely the relevant financial relationships of the planners, teachers, and authors involved in the development of CME content. An ders commonly include quantitative and and effectively. individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which Drs Mansour and Graf are from the Department of Orthopaedic Trauma, Cooper University Hospi- the individual has control. tal, Camden, New Jersey; and Dr Lafferty is from the Department of Orthopaedic Surgery, University of Drs Mansour, Graf, and Lafferty have no relevant financial Minnesota Regions Hospital, St Paul, Minnesota. relationships to disclose. Dr Aboulafia, CME Editor, has no relevant financial relationships to disclose. Dr D’Ambrosia, The material presented in any Vindico Medical Education continuing education activity does not Editor-in-Chief, has no relevant financial relationships to necessarily reflect the views and opinions of rthopedicsO or Vindico Medical Education. Neither disclose. The staff of Orthopedics have no relevant financial Orthopedics nor Vindico Medical Education nor the authors endorse or recommend any techniques, relationships to disclose. commercial products, or manufacturers. The authors may discuss the use of materials and/or products UNLABELED AND INVESTIGATIONAL USAGE that have not yet been approved by the US Food and Drug Administration. All readers and continuing The audience is advised that this continuing medical education activity may contain references to unlabeled uses education participants should verify all information before treating patients or using any product. of FDA-approved products or to products not approved by the Correspondence should be addressed to: John A. Mansour, DO, Department of Orthopaedic Trau- FDA for use in the United States. The faculty members have ma, Cooper University Hospital, 2437 E York St, Philadelphia, PA 19125 ([email protected]). been made aware of their obligation to disclose such usage. doi: 10.3928/01477447-20121120-09

DECEMBER 2012 | Volume 35 • Number 12 1053 n Review Article cme ARTICLE

hrombotic and bleeding compli- ily history.5 Given the variability in pa- the ability of coagulation factors II, V, VIII, cations occur in 5.8% and 5.4%, tients’ perceptions of bleeding, as well as IX, X, and XI, whereas the PT assesses the Trespectively, of patients undergo- their documentation in medical records,6 ability of factors II, V, VII, and X to form ing orthopedic surgery of the hip, knee, a comprehensive dialogue must ensue be- a clot.4,9,10 Although once part of the and spine.1 The management of acquired tween the patient and the physician. initial evaluation, the test has deep venous and pulmonary Patients with a suspected bleeding recently been omitted due to its nonspeci- embolism in orthopedic surgery is a con- disorder should also be questioned about ficity in the general clinical setting.11,12 troversial issue. However, the manage- past bleeding problems (eg, epistaxis, oral ment of other coagulopathies (bleeding , dental extractions, mennorhagia, Disorders of Primary Hemostasis events) that one may encounter in elective or parturition), a history of medical con- The disorders of primary hemostasis and nonelective practice is often ignored. ditions affecting hemostasis (eg, uremia, comprise quantitative and qualitative ab- Orthopedic surgery in patients with these hepatic cirrhosis, cancer, or collagen vas- normalities of or the vascular en- coagulopathies achieves pain relief, cor- cular disorders), previous operations and dothelium. Dysfunction of platelet adhe- rects contractures and angular deformi- the occurrence of prolonged bleeding or sion occurs in and ties, and controls recurrent bleeds into unusual postoperative bruising, history of Bernard-Soulier syndrome. Platelet acti- the joint, thus contributing significantly transfusions, family history of bleeding vation can be limited secondary to drugs, to the functional ability of the patients. disorders, and dietary habits or antibiotic such as aspirin, clopidogrel, nonsteroidal However, they are not without significant use that might predispose to vitamin K anti-inflammatory drugs (NSAIDs), and economic costs.2 With the increasing inci- deficiency. Disclosure of medication use certain herbals, or in uremia caused by dence of complications related to bleeding is also important, including prescribed kidney failure. disorders, it is critical for orthopedic sur- medications, over-the-counter medica- Primary immune , geons to possess a basic understanding of tions, and herbal products. formerly known as idiopathic immune their diagnoses, treatments, and potential The physical examination may also thrombocytopenia, is an acquired disease postoperative complications. yield clues to the origin of the bleed- of isolated thrombocytopenia, defined as Bleeding disorders are characterized ing. A mucocutaneous bleeding pattern a peripheral blood platelet count less than by defects in primary and secondary he- is the hallmark of primary hemostasis. 100,000 cells/µL with no clear initiating mostasis. Primary hemostasis involves Unexplained or extensive bruising, epi- or underlying cause of the low platelet the adherence of platelets to the injured staxis, oral cavity bleeding, easy bruis- count.13,14 The pathogenesis is now thought blood vessel via the ing, and menorrhagia are characteristic.4,7 to be due to autoantibodies that lead to anchor, creating a platelet plug. Second- Because the initial platelet plug has not premature destruction of platelets medi- ary hemostasis is the fibrin clot formation yet formed, persistent bleeding occurs. ated by impaired platelet production and process by way of tissue factor triggering Large-vessel bleeding associated with fac- T-cell–mediated effects.15 In addition to the coagulation cascade. The initial plate- tor deficiencies as characterized by bleed- increased platelet destruction, decreased let plug is strengthened by the fibrin clot, ing into muscles and is the result of platelet production by megakaryocytes in which serves as a matrix for fibroblasts as secondary hemostasis. Delayed bleeding the marrow has recently been prov- they migrate to repair the damaged vessel.3 occurs because the platelet plug gradually en.16 According to international consensus, succumbs to the pressures of blood flow treatment is rarely indicated in patients Approach to the Patient without reinforcement of fibrin strands to with platelet counts greater than 50,000 The clinical evaluation of a patient with strengthen the hemostatic plug.3,8 cells/µL in the absence of bleeding due to a bleeding disorder begins with a thor- Preoperative laboratory screening for platelet dysfunction or other hemostatic ough history assessment and can usually coagulation disorders is only necessary defect, trauma, or surgery.13,16 However, establish whether the disorder is inherited when the history and physical examination for patients undergoing major surgery, or acquired. Although an important part are suggestive of a bleeding disorder or the platelet counts should remain greater than of the preoperative evaluation, the bleed- patient is undergoing a moderate- to high- 80,000 cells/µL.17 ing history can have false-negative results risk procedure, such as elective orthopedic The treatment of idiopathic immune and should serve only as a screening guide surgery. In these situations, a complete thrombocytopenia has focused on prevent- to the selection of lab tests.4 An inherited blood count with the platelet count, pro- ing platelet destruction by using cortico- bleeding disorder is commonly associated thrombin time (PT), and activated partial steroids in 1 of 2 ways: prednisone (1 to 2 with the onset of bleeding symptoms in thromboplastin time (aPTT) are the screen- mg/kg per day until a response is seen) or infancy or childhood and a positive fam- ing assays warranted. The aPTT evaluates pulse dexamethasone (40 mg per day for

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Table 1 Antiplatelet Agents

GP IIb-IIIa Receptor Variable Aspirin NSAIDs ADP Receptor Antagonists Antagonists Action Inhibits platelet function via Inhibits platelet function via Inhibits platelet activation Inihibits platelet irreversible acetylation of reversible acetylation of aggregation platelet COX-1, indirectly platelet COX-1, indirectly inhibits TXA2 synthesis inhibits TXA2 synthesis Cessation 7-10 d 24-48 h 7-10 d (clopidogrel, prasurgel); 24-48 h (abciximab); preoperatively 14 d (ticlopidine) 10 h (eptifibatide); 2-4 h (tirofiban) Abbreviations: ADP, adenosine diphosphote; COX-1, cyclooxygenase-1; GP, glycoproteins; NSAIDs, nonsteroidal anti-inflammatory drugs; TXA2, thromboxane A2.

4 days) as first-line therapy. For patients Willebrand disease is classified based on gery found that, although the prevalence with low platelet counts and the presence severity: type I is the mildest form and of vWD was 0.6%, most could be pre- of bleeding, immunoglobulins such as in- presents as atraumatic bruising or fre- dicted from clinical evaluation, and those travenous immune globulin (0.5 to 2.0 g/ quent bleeding from the gums or nostrils; who were not had no difference in severe kg over 2 to 5 days) and Anti-Rho(D) (50 type II presents with increasing severity of bleeding risk.21 releases to 75 µg/kg intravenously over 2 to 5 min- these symptoms; and type III is the most stored vWF from the endothelium and is utes) have been proposed; however, much severe and presents similarly to severe he- the first line of therapy. For patients with of the morbidity and mortality is associ- mophilia with recurrent hemarthroses. mild bleeding or undergoing minor sur- ated with the side effects rather than the Because the pathophysiology of vWD gery, intravenous desmopressin can be bleeding. Second-line therapy includes is similar to that of hemophilia, joint administered as 0.3 µg/kg infused slowly immunosuppressive agents and splenec- bleeding is treated in the same manner. over 15 to 30 minutes at 12-hour intervals tomy. Von Willebrand factor (vWF) plays a vi- to achieve vWF:RCo of at least 30 IU/dL. Although all other treatments act by tal role in primary hemostasis by enabling Two to 4 repeat doses may be required, decreasing platelet destruction, the re- platelets to adhere to the sites of vascular but tachyphylaxis may occur.22-24 cently approved thrombopoietin recep- and then form platelet aggregates.19 For major surgical procedures, the tor agonists increase platelet production. It also contributes to fibrin clot formation vWF:RCo and factor VIII should increase However, they are not without side ef- by acting as a carrier protein by binding above 80 IU/dL and maintain more than fects, such as rebound thrombocytopenia, to and stabilizing factor VIII, which has a 50 IU/dL until hemostasis is confirmed. bone marrow fibrosis, thrombosis, hepato- greatly shortened half-life and an abnor- Factor VIII should also remain more toxicity and even progression of hemato- mally low concentration unless it is bound than 50 IU/dL until healing is logic malignancies.17 to vWF.20 Secondary hemostatic dysfunc- achieved.25 It is strongly recommended tion can occur due to low factor VIII lev- that patients with major bleeding or un- Von Willebrand Disease els in vWD and is important to understand dergoing major surgery be hospitalized at With a prevalence of 1% to 3 % in for treatment purposes. Initial laboratory a facility with expertise in managing vWD the general population, von Willebrand screenings show an elevated bleeding and laboratory monitoring of vWF levels. disease (vWD) is the most common in- time, and diagnosis is confirmed with herited bleeding disorder.18 Most cases vWF antigen level (Ag) (vWF:Ag,30 IU/ Bernard-Soulier Disease are transmitted as an autosomal dominant dL), vWF ristocetin cofactor activity level Bernard-Soulier Disease (BSD) is a trait affecting men and women equally.18 (RCo) (vWF:RCo,30 IU/dL), and factor qualitative defect of platelet binding to Clinically, patients may experience mild VIII (normal or decreased). collagen, as demonstrated by the absent to moderate bleeding evidenced by nose- Of note, despite the comparatively aggregation on exposure to ristocetin.23 bleeds, heavy menstrual flow, gingival high prevalence of vWD, studies have These platelets’ defect is in the platelet bleeding, easy bruising, and bleeding not shown value in preoperative screen- membrane glycoprotein GPIb-IX-V com- associated with surgery or trauma. Von ing. A study of patients undergoing sur- plex, resulting in the inability to adhere to

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Table 2 Herbal Medications

Variable Garlic Ginger Ginseng Ginkgo Biloba Kava Kava Fish Oil Vitamin E Action Dose-dependent Prolonged Inhibits in May inhibit Platelet Increased Antioxidant; may irreversible bleeding vitro platelet platelet- dysfunction; bleeding increase effects inhibition time aggregation activating hepatotoxicity risk at high of anticoagulants of platelet and prolongs factor and alter doses and antiplatelets aggregation coagulation platelet function times Cessation 7 d 2 wk 7 d 36 h 2 wk preoperatively

vWF. However, this complex site is not tinal and other sites is observed with the plasma proteins, primarily fibrinogen.35 associated with a platelet-specific antigen combined use of aspirin and clopidogrel Abciximab, eptifibatide, and tirofiban block site; therefore, repeated transfusion with or of aspirin and warfarin.28 The effects this final common pathway and are consid- platelet concentrate will not result in the of aspirin on platelets remain for the lifes- ered the most powerful platelet inhibitors. acquisition of specific antibodies.22 First- pan of the platelet, which is 8 to 10 days. Time to normal platelet aggregation is 24 to line treatment for any platelet disorder in a Therefore, patients taking aspirin alone are 48 hours after administration of abciximab, patient undergoing major surgery consists advised to stop the medicine 7 to 10 days and eptifibatide and tirofiban require 4 to 8 of either 8 U of platelet concentrate or 90 preoperatively to allow for reversal of the hours.36 Eptifibatide and tirofiban interrupt- µg/kg intravenously of recombinant acti- effect.29,30 In contrast to aspirin, NSAIDs ed 10 hours preoperatively should allow for vated factor VII (rFVIIa) followed by 2 or reversibly inhibit COX-1, generally to a restoration of platelet function.37 According more injections every 2 hours as needed.26 lesser degree than aspirin, and platelet to a recent study evaluating the use of ti- function is restored within 24 to 48 hours rofiban in patients undergoing urgent or Therapeutic Antiplatelet Agents after discontinuation of the drug.31 emergent coronary artery bypass grafting, The most common clinical circum- no delay in treatment is necessary; the au- stances leading to disordered platelet Antagonize Adenosine Diphosphote thors concluded that discontinuation of the function include a desired therapeutic Receptor Antagonists GP IIb-IIIa inhibitor within 2 to 4 hours of effect or an adverse medication effect. Clopidogrel, ticlodipine, and prasugrel elective surgery appears sufficient to ensure With the expanding use of anticoagulants are thienopyridines that selectively and irre- a safe surgical procedure.34,38 and platelet inhibitor drugs, a substantial versibly antagonize adenosine diphosphote amount of the population is at risk for ab- (ADP) stimulation. Platelets subjected to Herbal Preparations normal bleeding (Table 1). clopidogrel are normally affected for 5 to Important herbal preparations that can 7 days, but recent studies have shown no interfere with blood clotting include garlic, Aspirin and Nonsteroidal Anti- serious complications or increased transfu- ginkgo biloba, and ginseng. All of these inflammatory Drugs sion requirements in patients undergoing agents affect platelet function. Therefore, Aspirin is the most common and most nonelective orthopedic surgery who are garlic and ginseng should be stopped at extensively studied of the antiplatelet drugs taking clopidogrel.32 However, to reverse least 7 days preoperatively, whereas ginkgo due to its role in prevention of thrombotic the anticoagulant effects, clopidogrel and biloba should be stopped 36 hours preop- cardiovascular events. Aspirin inhibits prasurgel should be discontinued 7 to 10 eratively.39 Other medications affecting platelet function via irreversible acetyla- days preoperatively. Ticlodipine is longer normal clotting function include feverfew, tion of platelet cyclooxygenase-1 (COX-1) acting and requires 14 days.33,34 ginger, kava kava, clove, and white willow and the resulting inhibition of thrombox- bark and should be discontinued 2 weeks ane A2 (TXA2) synthesis. A 5% to 10% Glycoprotein IIb-IIIa Receptor Antagonists preoperatively.40 Other supplements that incidence of minor bleeding and a 1% to The final common pathway of platelet pose a concern are fish oil and vitamins A 2% incidence of major bleeding exist fol- aggregation leading to coronary thrombo- and E. These dietary supplements may per- lowing aspirin ingestion.27 An associated sis involves cross-linking of platelet recep- pentuate the effects of anticoagulants and increased rate of bleeding at gastrointes- tor glycoprotein (GP) IIb-IIIa by adhesive antiplatelet drugs (Table 2).

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Disorders of Secondary Hemostasis episodes, according to the type and sever- tions to prevent the progression of chronic Deficiencies of coagulation factors ei- ity of bleeds and until complete resolution synovitis.51 Radiosynovectomy remains ther inherited or acquired characterize the of bleeding or surgical wound healing.46 the preferred initial treatment option for disorders of secondary hemostasis. These Although resolution of bleeding is accom- chronic hemophilic synovitis, with success include inherited thombophilias, liver dis- plished, progressive joint destruction is rates of approximately 80%. However, skin ease, vitamin k deficiency, and antibodies. undeterred. Once thought to be the hall- burns have been reported if the material is Medications such as warfarin, heparin, mark of hemophilia, recent data on the use injected outside the joint,51 and 2 case re- low-molecular-weight heparin, and direct of prophylactic clotting factor replace- ports exist of acute lymphoblastic leuke- thrombin inhibitors also interfere with ment has been shown to slow the natural mia.52,53 After 3 unsuccessful attempts to secondary hemostasis. course of hemophiliac arthropathy. prevent progression, an arthroscopic syno- In a recent prospective, randomized vectomy is indicated. The Hemophilias study, continuous prophylactic clotting During the second and fourth decades, Factor VIII (hemophilia A) and factor factor replacement of 25 to 40 units/kg of progression to advanced arthropathy is IX (hemophilia B) deficiency are X-linked factor VIII 3 times weekly or factor IX 2 commonly encountered. Possible treatment recessive disorders with clinical mani- to 3 times weekly in patients with hemo- options include realignment osteotomies, festations seen exclusively in men. These philia A and B, respectively, was shown joint fusion, and joint arthroplasty. With re- X-linked disorders represent the majority to slow the natural course of hemophiliac peated episodes of hemarthroses, leg-length of inherited deficiencies of clotting factors, arthropathy.47.48 Significant reductions in discrepancies and angular deformities may occurring in approximately 1 per 5000 and severity and frequency of spontaneous occur during childhood as a result of the 1 per 50,000 male births, respectively, with bleeds and arthropathy, hospitalizations, increased vascularity leading to asym- no racial predilection.41-43 The hemophilias missed school or work days lost, and over- metrical hypertrophy of the epiphyseal are classified by the baseline level of per- all higher levels of quality of life have led growth plates.45 Realignment osteotomies centage of clotting factor activity as mild to the consensus of prophylaxis.46 provide a solution to the varus or valgus (more than 5%), moderate (1%-5%), or se- Primary prophylaxis is defined as the strain imparted on the knee joint and thus vere (less than 1%). This classification di- infusion of concentrates started after the prevent the progression of joint destruc- rectly reflects the severity of clinical symp- first joint bleed or before age 2 years and tion. Arthrodesis has proven to be a reliable toms. The of the mild is now the first line of treatment in chil- procedure in the shoulder, hip, and ankle; form may only present during , dren with severe hemophilia.49 Secondary however, it is contraindicated in the knee dental extractions, and injuries, whereas prophylaxis aims to delay the progres- joint. Because of the systemic pathology spontaneous joint and muscle bleeds are sion of joint damage and occurs after age of hemophilia, it is common for patients largely confined to patients with severe 2 years or after 2 or more joint bleeds.49 to present with involvement of the hip or hemophilia. The knee, ankle, and elbow Before undergoing elective surgery, the ankle. A double fusion leads to significant account for approximately 80% of the in- patient’s clotting factor level is brought to problems with ambulating and activities volved joints.44 Although a consensus has 100% of normal activity and confirmed by of daily living. Total knee arthroplasty has not been reached on the exact mechanism factor assay. A continuous infusion of fac- been proven to restore function and relief of blood-induced joint damage, it has been tor to maintain more than 60% is contin- of pain but can be technically challenging postulated that hemosiderin deposition in ued intraoperatively and maintained until due to arthrofibrosis, joint surface erosions, the joint cavity leads to a viscous patho- discharge from the hospital. A level of and bony synovial cysts. Current recom- logical cycle of synovial inflammation and 30% to 60% is recommended for at least 2 mendations are for a posterior-stabilized cartilage degeneration, ultimately resulting weeks postoperatively.50 cemented design.51 Total hip arthroplasty in the destruction of cartilage and bone. If prophylaxis is not a possibility, due with a press-ft uncemented design remains With recurrent hemarthroses, iron deposits in part to high costs or intravenous access, an option; however, a high rate of loosening elucidate synovial hypertrophy character- the prevention of hemophilic arthropathy of the acetabular and femoral components ized by villous sinuses, neovascularization, begins with the successful management has been reported in the literature.51,54 and infiltration of lymphocytes.45 A multi- of joint bleeds. Arthrocentesis, regular re- To ensure a prompt recovery from or- factorial process then ensues, occurring in placement of factor concentrate to 50% ev- thopedic surgery, rehabilitation is of vital parallel and sequentially leading to chronic ery 48 hours, splinting of the involved joint importance. A strong focus on increasing arthropathy and arthrofibrosis. for 48 hours, physical therapy to maintain range of motion and muscle strengthening Replacement of the deficient factor adequate range of motion, and strengthen- around the joint should be the main goal is the mainstay of treatment for bleeding ing exercises are all first-line treatment op- of each session.

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Intramuscular bleeds occur less fre- bin complex concentrates, major elective and aPTT, particularly if these parameters quently than joint bleeding in hemophiliacs orthopedic surgery in hemophilia patients do not correct with the administration of but can be associated with complications with inhibitors has now become a reality. vitamin K or fresh-frozen plasma. Failure such as infection, compartment syndrome, Preoperatively, a bolus dose of 90 µg/kg-1 to correct with a plasma mixing study sug- and pseudotumors. An iliopsoas rFVIIa should be given every 2 hours for gests the diagnosis of an inhibitor present. is a common and serious of at least 48 hours and may be increased With the recent availability of hu- muscular bleeds that can imitate an acute based on response, whereas activated pro- man thrombin products, the incidence appendicitis.55 Hemophilic pseudotumors thrombin complex concentrates should be of bleeding related to the use of bovine consist of a hematoma encased in a fibrous administered at 50 to 75 units/kg-1 preop- thrombin is expected to decline. A recent calcific capsule that will invade and destroy eratively by bolus infusion and every 6 to phase 3, randomized, double-blind com- the surrounding soft tissue, bone, and neu- 8 hours thereafter, not to exceed 200 units/ parative study of recombinant thrombin rovascular structures. With a mortality rate kg-1 per day.62 These bypassing agents are vs bovine-derived thrombin demonstrated of approximately 20%,56 surgical removal recommended to be given at least 10 to 14 human thrombin-based products pos- should only be performed in specialized days postoperatively, with prophylactical sess equivalent efficacy and safety, with hemophiliac treatment centers. consideration during the patient’s reha- an improved immunogenicity profile. bilitative course.62 Forty-three (21.5%) patients exposed to Acquired Inhibitors of Anticoagulation Rehabilitation management of hemo- the bovine-derived thrombin product de- The most common and serious compli- philia patients with or without inhibitors veloped antibovine thrombin antibodies, cation of replacement therapy in patients follows a near equivocal path, with a few compared with 3 (1.5%) patients exposed with hemophilia is the development of an specific and important details. Careful to recombinant human thrombin who de- inhibitor against factor VIII or factor IX. monitoring and daily assessment by the veloped antihuman thrombin antibodies.71 This acquired autoantibody inactivates physical therapist with a gradual progres- the specific factor concentrate, result- sion of activity is crucial in preventing Liver Disease ing in complete preclusion of therapy. postoperative bleeding into the affected With the exceptions vWF and tissue Approximately 30% of patients with he- joint or other site.63,64 Any associated lim- plasminogen activator, the liver is the pro- mophilia A and 5% of patients with he- itation in active range of motion accom- duction site for almost all of the coagula- mophilia B generate antibodies during the panied with increased swelling or pain tion factors. The PT is a sensitive indica- first 20 to 50 days of exposure.57 Inhibitor should warrant a short period of rest, el- tor of hepatic synthetic function due to detection is quantified using Bethesda units evation, and ice, with resumption of activ- the short half-life (6 hours) of factor VII, (BU), where 1 unit is associated with the ity at a lower level at allow adequate heal- which the failing liver cannot maintain. inactivation of 50% of factor concentrate.58 ing. Other common causes of acquired in- Both the PT and aPTT tests are prolonged Because high-dose replacement therapy for hibitors include the use of fibrin sealants with more severe hepatic synthetic dys- major surgical procedures is generally only during surgical procedures, antiphospho- function. Ten to 15 mL/kg of fresh-frozen appropriate for the treatment of patients lipid antibodies, antibiotics, pregnancy, plasma intermittently replaces all coagu- with titers at or below 1 to 2 BU/mL, these and lymphoid malignancies. lation factors but is short lived and may patients have been denied all but essential Since the mid-1980s, topical hemostat- predispose the patient to volume overload. surgery due to the fear of inadequacy with ic agents, such as topical thrombin, have Desmopressin (0.3 µg/kg) may help by obtaining and maintaining hemostasis. been commonly used to control surgical improving platelet function, and vitamin Furthermore, an anamnestic rise in inhibi- bleeding by promoting the formation of a K administration (1 to 25 mg) excludes tor titer associated with high-dose replace- stable fibrin clot.65 First reported in 1989, concurrent vitamin K deficiency.72 ment therapy in as little as 1 to 2 days has bovine thrombin has been associated with been reported in the literature.59 Recent considerable safety concerns regarding Vitamin K Deficiency studies have shown greater morbidity and the development of autoimmune iatrogen- Clotting factors II, VII, IX, and X, as mortality and poorer quality of life in re- ic coagulopathies.66,67 This acquired co- well as proteins C and S, require vitamin gard to orthopedic status partially due to agulopathy results from the formation of K–dependent gamma carboxylation for the increased lifespan of inhibitor patients antibodies directed against bovine throm- full activity.73 Dietary forms are obtained with the accompanying degenerative, age- bin and coagulation factors, mainly fac- primarily from the intake of dark green associated orthopedic conditions.60,61 tor V.68-70 The diagnosis should always be vegetables and modified by gut flora to With the introduction of bypassing suspected in postoperative patients who the active form. Interruption of bile flow agents, rFVIIa, and activated prothrom- present with simultaneously abnormal PT will prevent absorption. Antibiotic-related

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Table 3 Anticoagulants

Variable Factor Xa Inhibitors Unfractionated Heparin LMWH Warfarin Action Directly inhibits (rivaroxaban, Binds antithrombin Inactivates factor Inhibits vitamin K–dependent apixaban); indirectly inhibits III; indirectly inhibits Xa; less effect on y-carboxylation of via binding to antithrombin thrombin and factors thrombin procoagulant factors II, VII, III (fondaparinux) VIIa, IXa, Xa, and XIa IX, X and anticoagulant proteins C and S Cessation 2-4 da 6 h 12 h Approximately 5 d to achieve preoperatively target INR of 1.5 Abbreviations: INR, international normalized ratio; LMWH, low-molecular-weight heparin. aAnticoagulant effect can persist for 2 to 4 days, depending on renal and hepatic function.

elimination of enteric bacteria limits in- elimination from the body, they should be bocytopenia. Although several antibody testinal sources of vitamin K, whereas stopped at least 2 days preoperatively for detection tests have been proposed, the warfarin directly antagonizes its activity. patients without a high risk of bleeding diagnosis is made clinically. Immediate is first to prolong, but and 4 days preoperatively in patients with cessation of heparin with the addition of the aPTT will also increase with further a high risk of bleeding.75-77 If truly warrant- danaparoid or lepirudin is recommended factor deficiencies.73 In adults with nor- ed, recombinant factor VIIa can partially as parenteral therapy when beginning mal hepatic function, oral or subcutane- reverse the anticoagulant effects of these warfarin.80,81 ous vitamin K usually corrects within inhibitors.76,78 24 hours; however, if a patient is already Low-molecular-weight Heparin receiving warfarin, doses of vitamin K Heparin Low-molecular-weight heparin, such should be minimized to prevent refracto- Unfractionated heparin (UFH) indirect- as enoxaparin, inactivates factor Xa but riness to further anticoagulation. ly inactivates thrombin and factors VIIa, has a lesser effect on thrombin and does IXa, Xa, and XIa.76,79 The anticoagulant not prolong the aPTT. If monitoring is re- Parenteral Anticoagulants response to UFH is most frequently moni- quired, antifactor Xa assays can be used. Knowledge of the risks associated tored through the aPTT. The last preopera- These should be stopped at least 12 to 24 with particular drugs and combinations of tive dose of UFH should be no later than 6 hours preoperatively.74,79 Unlike its effi- them, their advantages, and the complica- hours preoperatively. If urgent reversal of cacy with UFH, protamine does not com- tions associated with the interruption of the effect of UFH is required, slow intra- pletely eradicate the anti-Xa activity of drug use for interventional procedures are venous protamine sulfate infusion will nor- low-molecular-weight heparin. However, essential for the orthopedic surgeon to re- malize the aPTT. The neutralization effect for patients who experience bleeding duce the incidence of iatrogenic bleeding is achieved with a dose of 1 mg protamine while receiving low-molecular-weight (Table 3). sulfate per 100 units of heparin. Protamine heparin, protamine sulfate (1 mg/100 anti- administration may also lead to allergic re- Xa units of low-molecular-weight heparin) Factor Xa Inhibitors actions and anaphylaxis.79 may reduce clinical bleeding.78 Factor Xa inhibitors block factor Xa Heparin-induced thrombocytopenia either directly or indirectly. Fondaparinux may result from the administration of Warfarin inhibits thrombin formation indirectly by UFH from the induction of heparin plate- Warfarin’s effects are mediated through selectively binding to antithrombin III, thus let antibodies. A 5% incidence of heparin- inhibition of the vitamin K–dependent neutralizing factor Xa.74 Rivaroxaban and induced thrombocytopenia has been dem- gamma-carboxylation of procoagulant apixaban act via direct inhibition and bind onstrated in the literature for orthopedic factors II, VII, IX, X and anticoagulant directly to the active binding site of fac- surgery patients who received UFH for proteins C and S.79 The major clinical ef- tor Xa blocking the interaction with sub- more than 2 weeks.3,79 A 50% decrease in fect is through the suppression of throm- strates.75 No clinical trials have evaluated the baseline platelet count or thrombocy- bin generation from the nonfunctional the length of time required for preoperative topenia less than 100,000 µL constitutes prothrombin and factor X.3,82 Normal discontinuation; however, based on time of the diagnosis of heparin-induced throm- monitoring takes place by following the

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PT/international normalized ratio level. a multidisciplinary approach with hema- and outcome criteria in immune thrombocy- topenic of adults and children: report For fully elective surgery in patients with tologists and cardiologists, patients can from an international working group. Blood. an international normalized ratio of 2 to 3, undergo minor and major orthopedic pro- 2009; 113(11):2386-2393. simple cessation of warfarin for approxi- cedures safely and effectively. 15. Olsson B, Andersson PO, Jernas M, et al. mately 5 days is enough time to allow the T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic pur- international normalized ratio to drop to References pura. Nat Med. 2003; 9(9):1123-1124. 1.5 or less. Once surgical hemostasis has 1. Oberweis S, Nukala S, Rosenberg A, Stuchin 16. McMillan R, Wang L, Tomer A, Nichol J, been achieved, warfarin therapy may be S, Radford M, Berger J. New study shows Pistillo J. 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