Thrombosis Complicating Non-Factor Therapy for Hemophilia

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Margaret V Ragni


This is an exciting time in hemophilia treatment with the unprecedented development of novel non-factor therapies. These agents have re-balanced hemostasis in patients with hemophilia A and B, with and without inhibitors, tipping the balance toward hemostasis and improved thrombin generation. While there have been numerous publications about the beneficial hemostatic effects and significant bleed reduction possible with these novel non-factor agents, little has been written about the less well-recognized thrombotic complications. Yet, the latter underscores the fine balance between hemostasis and thrombosis and the fact these agents prevent but do not treat bleeds, requiring clotting factor requirement to treat acute bleeds. The purpose of this Commentary is to review thrombotic complications that have occurred with non-factor therapies, risk factors for thrombosis, potential mechanisms, and potential mitigation approaches.

Keywords: hemophilia, non-factor therapy, rebalanced hemostasis, thrombosis

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How to Cite
RAGNI, Margaret V. Thrombosis Complicating Non-Factor Therapy for Hemophilia. Medical Research Archives, [S.l.], v. 9, n. 11, nov. 2021. ISSN 2375-1924. Available at: <>. Date accessed: 23 apr. 2024. doi:
Review Articles


1. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017;377(9):809-18. [PubMed: 28691557]
2. Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med 2018;379(9):811-822. [PubMed: 30157389]
3. Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of anti-thrombin in hemophilia A or B with RNAi therapy. N Engl J Med 2017;377(9):819-828. [PubMed: 28691885]
4. Shapiro A, Angshaisuksiri P, Astermark J, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A and hemophilia B with inhibitors: phase 2 trial results. Blood 2019;134(22):1973-1982. [PubMed: 314144162]
5. Mahlangu JN. Progress in the development of anti-tissue factor pathway inhibitors for hemophilia management. Frontiers in Med 2021;8:670526. [PubMed: 34026796]
6. Sampei Z, Igawa T, Soeda T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS One 2013;8(2):e57479. [PubMed: 23468998]
7. Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in hemophilia A with and without inhibitors. Haemophilia 2020;26(1):41-46. [PubMed: 31746522]
8. Seghal A, Barros S, Ivanciu L, et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nature Med 2015;21(5):492-499. [PubMed: 25849132]
9. Machin N, Ragni MV. An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. J Blood Med 2018;9:135-140. [PubMed: 30174468]
10. Pasi KJ, Lissitchkov T, Mamonov V, et al. Targeting of antithrombin in hemophilia A or B with an investigational siRNA therapeutic fitusiran – results of the phase 1 inhibitor cohort. J Thromb Haemost 2021;19(6):1436-1446. [PubMed: 33587824]
11. Broze GJ, Girard TJ. Tissue factor pathway inhibitor: structure-function. Front Biosci 2012;17:262-280. [PubMed: 22201743]
12. Hilden I, Lauritzen B, SØrensen BB, et al. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood 2012;119(24):5871-5878. [PubMed: 22563084]
13. Chowdary P. Inhibition of tissue factor pathway inhibitor (TFPI) as a treatment for haemophilia: rationale with focus on concizumab. Drugs 2018;78(9):881-890. [PubMed: 29845491]
14. Patel-Hett S, Martin EJ, Mohammed BM, et al. Martacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed hgemophilic blood and plasmas. Haemophilia 2019;25(5):797-806. [PubMed: 31336410]
15. Martin EJ, Nolte M, Kuhn J, Schmidt N, Pfaff, Brophy DF. An in vitro pharmacodynamic spiking study of befovacimab, a tissue factor pathway inhibitor monoclonal antibody, in blood samples from patients with severe FVIII deficiency. Haemophilia 2021;27(4):690-698. [PubMed: 33915599]
16. Dargaud Y, Beguin S, Lienhart A, Al Dieri R, Trzeciak C, Bordet JC, et al. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost. 2005;93(3):475-480. [PubMed: 15735797]
17. Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation. Sem Thromb Haemost 2006;32(Suppl 1):32-38. [PubMed: 16673264]
18. Brummel-Ziedins KE. Developing individualized coagulation profiling of disease risk: thrombin generation dynamic models of the pro and anticoagulant balance. Thromb Res 2014; 133(Suppl 1):S9-S11. [PubMed: 24759148]
19. Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: does it actually compare to factor VIII? Blood 2017;130(23):2463-2468. [PubMed: 29042366]
20. Qian K, Huang S, Akinc A, Liu J. Thrombin generation response with the addition of bypassing agents in plasma of patients treated with fitusiran, an investigational RNAi therapeutic targeting antithrombin for treatment of hemophilia. Haemophilia 2018;24: T55:MP 219 (141). [PubMed: 29749037]
21. Kjalke M, Kjelgaard-hansen M, Andersen S, Hilden S. Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: in vitro and ex vivo analyses. J Thromb Haemost 2021;19(7):1687-1696. [PubMed: 33819375]
22. Tiede A. Thromboembolic risks of non-factor replacement therapies in hemophilia. Hämostaseologie 2017;37(4):307-310. [PubMed: 29582931]
23. Makris M, Iorio A, Lenting PJ. Emicizumab and thrombosis: The story so far. J Thromb Haemost 2019;17(8):1269-1272. [PubMed: 31368220]
24. Negrier C, Pasi KJ, Ragni MV, et al. Fitusiran, an siRNA therapeutic targeting antithrombin for the treatment of hemophilia: Proposed revision to dose and regimen as a risk mitigation for vascular thrombosis. International Society of Thrombosis and Haemostasis (ISTH), July 2021 (abstract).
25. Negrier C, Pasi K, Ragni M, et al. Long-term efficacy and safety of fitusiran in participants with haemophilia A or B: An Interim analysis of the phase 1/2 open-label extension study. European Association for Haemophilia and Allied Disorders (EAHAD) February 2021 (abstract).