Mustafa Akkaya, Adolfo Llinás, Juan Sebastian Sanchez-Osorio, Mustafa Citak.
Response/Recommendation: Mechanical venous thromboembolism (VTE) prophylaxis is most appropriate for patients with bleeding disorders undergoing orthopaedic surgery. However, the addition of mild pharmacologic VTE prophylaxis should be considered for select patient groups that may express a higher prothrombotic phenotype, and in those using clotting factor concentrates bypassing agents or monoclonal antibodies that may increase the risk of thrombosis.
Strength of Recommendation: Limited.
Rationale: The normal clotting mechanism of blood is altered in patients with bleeding disorders. These patients most frequently exhibit musculoskeletal bleeding including hemarthrosis as a symptom of their condition, thereby resulting in progressive joint damage, especially when they are not administered a clotting factor replacement regimen for early prophylaxis1. Ultimately, the presence of resulting arthropathy usually necessitates major orthopaedic surgery such as total knee arthroplasty (TKA) and total hip arthroplasty (THA) in patients with bleeding disorders2-4. In theory, perioperative administration of coagulation factor concentrates in order to correct a hemostatic defect leads to a normalized risk of VTE, and therefore such patients would then have a similar risk of VTE as the general population5. Various practices for VTE prophylaxis have emerged as a result of the bleeding complications encountered in this patient population6. However, evidence-based results cannot be obtained due to the lack of controlled studies.
Hemophilia is an inherited bleeding disorder and has two main types, i.e., hemophilia A that stems from factor VIII deficiency, and hemophilia B that stems from factor IX deficiency. Many (90%) of the patients with hemophilia develop hemophilic arthropathy before the age of 30 due to recurrent hemarthroses7,8. Despite the high rate of surgical complications including infection, the number of patients undergoing total joint arthroplasty (TJA) has been rising with increased availability of factor replacement therapy3,9,10. The risk of VTE complications is decreased in patients with hemophilia due to the deficiency of coagulation factors11. On the other hand, these patients are perioperatively administered clotting factor replacement therapy in order to correct the hemostatic defect, leading potentially, to an increased risk of postoperative VTE12. In this patient group, prolonged use of central venous catheters, which are frequently utilized in treatment , as well as the use of intensive replacement therapy and bypassing agents, immobilization and malignancies are known to cause an increased risk of VTE2,14-18. According to the literature, while the risk of VTE ranges between 1 – 2% in the general population19,20, the incidence of symptomatic VTE after major orthopaedic surgery (THA or TKA) has been reported to be 0.5-1% in patients with hemophilia2,5,9. Studies conducted with hemophilic patient groups have shown that short-term therapy (two weeks) with low-molecular-weight heparin (LMWH) can be administered to the patients who develop thrombosis17,21. In an extensive survey study including centers that provide treatment for patients with hemophilia in Europe, it was found that pharmacologic VTE was preferred in more than half of these centers22. According to another USA-based survey study, 67% of the participants thought that some type of VTE prophylaxis could be required in patients with hemophilia undergoing TJA, whereas only 37% of the participants actually used VTE prophylaxis as part of routine practice6.
Considering the risk of VTE in patients with rarer bleeding disorders, it was reported that patients with Von Willebrand Disease (VWD) had increased risk of thrombosis compared to those with hemophilia23,24, and thrombotic events were frequently associated with surgery18. Thrombotic events have also been reported in patients with congenital factor VII deficiency, afibrinogenemia, and factor XI deficiency25,26. In such patients, coagulation factor replacement therapy for surgery, immobilization, and advanced age were reported to be risk factors for VTE2. Therefore, VTE prophylaxis is also recommended for these patient group as in patients with hemophilia A and B.
Recent studies have shown that compression stockings and intermittent sequential compression devices can be recommended as part of routine practice and are beneficial for the mechanical prophylaxis for VTE prevention in patients with hemophilia. On the other hand, the use of pharmacologic agents for VTE prophylaxis, i.e., LMWH, warfarin, unfractionated heparin, fondaparinux, and aspirin, should be based on the individualized risk according to the choice and level factor replacement or bypassing agents like prothrombin complex concentrates in combination with monoclonal antibodies (emicizumab), and prothrombotic risk factors5,7,27. Antifibrinolytics can be used with standard doses of clotting factor concentrates, including bypassing agents. However, they should not be used with prothrombin complex concentrates due to the increased risk of thromboembolism27.
1. Rodriguez-Merchan, E.C., et al., Joint protection in haemophilia. Haemophilia, 2011. 17 Suppl 2: p. 1-23.
2. Ozelo, M.C., Surgery in patients with hemophilia: Is thromboprophylaxis mandatory? Thrombosis Research, 2012. 130: p. S23-S26.
3. Goddard, N.J., H.A. Mann, and C.A. Lee, Total knee replacement in patients with end-stage haemophilic arthropathy: 25-year results. J Bone Joint Surg Br, 2010. 92(8): p. 1085-9.
4. Goddard, N.J., E.C. Rodriguez-Merchan, and J.D. Wiedel, Total knee replacement in haemophilia. Haemophilia, 2002. 8(3): p. 382-6.
5. Perez Botero, J., et al., Incidence of symptomatic venous thromboembolism in patients with hemophilia undergoing joint replacement surgery: A retrospective study. Thrombosis Research, 2015. 135(1): p. 109-113.
6. Pradhan, S.M., et al., Venous thrombosis prophylaxis in haemophilics undergoing major orthopaedic surgery: a survey of haemophilia treatment centres. Haemophilia, 2009. 15(6): p. 1337-8.
7. Peng, H.m., et al., Incidence of Symptomatic Venous Thromboembolism in Patients with Hemophilia Undergoing Hip and Knee Joint Replacement without Chemoprophylaxis: A Retrospective Study. Orthopaedic Surgery, 2019. 11(2): p. 236-240.
8. Morais, S.A., et al., Musculoskeletal complications of haematological disease. Rheumatology (Oxford), 2016. 55(6): p. 968-81.
9. Silva, M. and J.V. Luck, Jr., Long-term results of primary total knee replacement in patients with hemophilia. J Bone Joint Surg Am, 2005. 87(1): p. 85-91.
10. Sikkema, T., A.L. Boerboom, and K. Meijer, A comparison between the complications and long-term outcome of hip and knee replacement therapy in patients with and without haemophilia; a controlled retrospective cohort study. Haemophilia, 2011. 17(2): p. 300-3.
11. Giampaolo, A., et al., Consumption of clotting factors in severe haemophilia patients undergoing prophylaxis and on-demand treatment in Italy. Transfus Med, 2011. 21(4): p. 280-4.
12. Stein, M.I., J. Park, and S. Raterman, Prevention of VTE Following total hip and knee arthroplasty in Hemophilia patients. Orthopedics, 2011. 34(5): p. 389-392.
13. Journeycake, J.M., et al., Catheter-related deep venous thrombosis in children with hemophilia. Blood, 2001. 98(6): p. 1727-31.
14. Kasper, C.K., Postoperative thromboses in hemophilia B. N Engl J Med, 1973. 289(3): p. 160.
15. Ritchie, B., R.C. Woodman, and M.C. Poon, Deep venous thrombosis in hemophilia A. Am J Med, 1992. 93(6): p. 699-700.
16. Pruthi, R.K., et al., Venous thromboembolism after hip fracture surgery in a patient with haemophilia B and factor V Arg506Gln (factor V Leiden). Haemophilia, 2000. 6(6): p. 631-4.
17. Girolami, A., et al., Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases. J Thromb Thrombolysis, 2006. 21(3): p. 279-84.
18. Coppola, A., et al., Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia, 2012. 18(3): p. e173-87.
19. Falck-Ytter, Y., et al., Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e278S-e325S.
20. Bjornara, B.T., T.E. Gudmundsen, and O.E. Dahl, Frequency and timing of clinical venous thromboembolism after major joint surgery. J Bone Joint Surg Br, 2006. 88(3): p. 386-91.
21. Hermans, C., et al., Subclinical deep venous thrombosis observed in 10% of hemophilic patients undergoing major orthopedic surgery. J Thromb Haemost, 2010. 8(5): p. 1138-40.
22. Hermans, C., et al., Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations. Haemophilia, 2009. 15(3): p. 639-58.
23. Mannucci, P.M., Venous thromboembolism in von Willebrand disease. Thromb Haemost, 2002. 88(3): p. 378-9.
24. Makris, M., et al., Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost, 2002. 88(3): p. 387-8.
25. Girolami, A., et al., Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature. J Thromb Thrombolysis, 2010. 30(2): p. 172-8.
26. Ruiz-Saez, A., Thrombosis in rare bleeding disorders. Hematology, 2012. 17 Suppl 1: p. S156-8.
27. Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug;26 Suppl 6:1-158. doi: 10.1111/hae.14046. Epub 2020 Aug 3. Erratum in: Haemophilia. 2021 Jul;27(4):699. PMID: 32744769.