Thrombotic Complications in Hemophilia: An Intricate Conundrum

Abstract

Hemophilia A and hemophilia B are rare genetic disorders characterized by low plasma levels of coagulation factor VIII or factor IX, resulting in a bleeding tendency with a clinical severity proportional to the degree of the clotting factor deficiency. Although rare, hemophilia patients can paradoxically experience thrombotic events that complicate the clinical picture and the management by physicians operating at hemophilia treatment centers. Such thromboembolic complications, which can involve either the arterial or the venous districts, recognize various causes, including aging (due to the progress of care during the last three decades) and inherited and acquired (treatment-related) risk factors. These determinants often interact with each other to increase patients' susceptibility to thrombosis. In this narrative review, we summarize the current knowledge on the mechanisms, clinical presentation, and management of thrombotic complications in hemophilia patients.

Keywords

hemophilia - thrombosis - cardiovascular disease - therapy

Authors' Contributions

M.F. and P.M.M. co-wrote the article. D.F. and P.M.M. revised the article.

Publication History

Received: 22 April 2025

Accepted: 08 May 2025

Accepted Manuscript online:
08 May 2025

Article published online:
23 May 2025

• References

• 1 Mannucci PM, Tuddenham EG. The hemophilias–from royal genes to gene therapy. N Engl J Med 2001; 344 (23) 1773-1779
• 2 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27 (04) 179-184
• 3 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7: 24
• 4 Franchini M, Mannucci PM. The more recent history of hemophilia treatment. Semin Thromb Hemost 2022; 48 (08) 904-910
• 5 Mannucci PM. Hemophilia treatment innovation: 50 years of progress and more to come. J Thromb Haemost 2023; 21 (03) 403-412
• 6 Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): A review of current therapeutic practice. Br J Clin Pharmacol 2011; 72 (04) 553-562
• 7 Faghmous I, Nissen F, Kuebler P, Flores C, Patel AM, Pipe SW. Estimating the risk of thrombotic events in people with congenital hemophilia A using US claims data. J Comp Eff Res 2021; 10 (18) 1323-1336
• 8 Shapiro S, Makris M. Haemophilia and ageing. Br J Haematol 2019; 184 (05) 712-720
• 9 Mauser-Bunschoten EP, Fransen Van De Putte DE, Schutgens RE. Co-morbidity in the ageing haemophilia patient: The down side of increased life expectancy. Haemophilia 2009; 15 (04) 853-863
• 10 Franchini M, Mannucci PM. Management of hemophilia in older patients. Drugs Aging 2017; 34 (12) 881-889
• 11 Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol 2010; 148 (04) 522-533
• 12 Badulescu OV, Badescu MC, Bojan IB. et al. Thrombotic disease in hemophilic patients: Is this a paradox in a state of hypocoagulability?. Diagnostics (Basel) 2024; 14 (03) 286
• 13 Shapiro S, Benson G, Evans G, Harrison C, Mangles S, Makris M. Cardiovascular disease in hereditary haemophilia: The challenges of longevity. Br J Haematol 2022; 197 (04) 397-406
• 14 Shapiro AD, Hardesty BM, Peyvandi F, Iorio A. Prevalence of selected bleeding and thrombotic events in persons with hemophilia versus the general population: A scoping review. Res Pract Thromb Haemost 2022; 7 (01) 100007
• 15 Chen H, Yang S. Acute coronary syndrome management in hemophiliacs: How to maintain balance?: A review. Medicine (Baltimore) 2023; 102 (11) e33298
• 16 Coppola A, Tagliaferri A, Franchini M. The management of cardiovascular diseases in patients with hemophilia. Semin Thromb Hemost 2010; 36 (01) 91-102
• 17 Franchini M, Focosi D, Mannucci PM. How we manage cardiovascular disease in patients with hemophilia. Haematologica 2023; 108 (07) 1748-1757
• 18 Cayla G, Morange PE, Chambost H, Schved JF. Management of cardiovascular disease in haemophilia. Thromb Res 2013; 132 (01) 8-14
• 19 Badescu MC, Ciocoiu M, Rezus E. et al. Current therapeutic approach to acute myocardial infarction in patients with congenital hemophilia. Life (Basel) 2021; 11 (10) 1072
• 20 Schutgens RE, Klamroth R, Pabinger I, Dolan G. ADVANCE Working Group. Management of atrial fibrillation in people with haemophilia–a consensus view by the ADVANCE Working Group. Haemophilia 2014; 20 (06) e417-e420
• 21 Klamroth R, Ay C, De Moerloose P. et al. Applicability of the European Society of Cardiology Guidelines on the management of acute coronary syndromes to older people with haemophilia A - A modified Delphi consensus by the ADVANCE Working Group. Haemophilia 2023; 29 (01) 21-32
• 22 Escobar M, Lassila R, Bekdache C, Owaidah T, Sholzberg M. Use of antithrombotic therapy in patients with hemophilia: A selected synopsis of the European Hematology Association - International Society on Thrombosis and Haemostasis - European Association for Hemophilia and Allied Disorders - European Stroke Organization Clinical Practice Guidance document. J Thromb Haemost 2025; 23 (02) 745-749
• 23 Schutgens REG, Jimenez-Yuste V, Escobar M. et al. Antithrombotic treatment in patients with hemophilia: An EHA-ISTH-EAHAD-ESO clinical practice guidance. HemaSphere 2023; 7 (06) e900
• 24 Schutgens REG, Klamroth R, Pabinger I, Malerba M, Dolan G. ADVANCE Working Group. Atrial fibrillation in patients with haemophilia: A cross-sectional evaluation in Europe. Haemophilia 2014; 20 (05) 682-686
• 25 Van Der Valk P, Makris M, Fischer K. et al. Reduced cardiovascular morbidity in patients with hemophilia: Results of a 5-year multinational prospective study. Blood Adv 2022; 6 (03) 902-908
• 26 Mannucci PM. Management of antithrombotic therapy for acute coronary syndromes and atrial fibrillation in patients with hemophilia. Expert Opin Pharmacother 2012; 13 (04) 505-510
• 27 de Koning MLY, Fischer K, de Laat B, Huisman A, Ninivaggi M, Schutgens REG. Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists. J Thromb Haemost 2017; 15 (05) 868-875
• 28 Guillet B, Cayla G, Lebreton A. et al. Long-term antithrombotic treatments prescribed for cardiovascular diseases in patients with hemophilia: Results from the French Registry. Thromb Haemost 2021; 121 (03) 287-296
• 29 van der Valk PR, Mauser-Bunschoten EP, van der Heijden JF, Schutgens REG. Catheter ablation for atrial fibrillation in patients with hemophilia or von Willebrand disease. TH Open 2019; 3 (04) e335-e339
• 30 Toselli M, Bosi D, Benatti G, Solinas E, Cattabiani MA, Vignali L. Left atrial appendage closure: A balanced management of the thromboembolic risk in patients with hemophilia and atrial fibrillation. J Thromb Thrombolysis 2020; 50 (03) 668-673
• 31 Lim MY, Abou-Ismail MY. Left atrial appendage occlusion for management of atrial fibrillation in persons with hemophilia. Thromb Res 2021; 206: 9-13
• 32 Xu W, Lv M, Wu S. et al. Severe bleeding risk of direct oral anticoagulants versus vitamin K antagonists for stroke prevention and treatment in patients with atrial fibrillation: a systematic review and network meta-analysis. Cardiovasc Drugs Ther 2023; 37 (02) 363-377
• 33 Khan S, Krishnaswamy R, Malik BH. et al. Comparing safety and efficacy of dabigatran and factor Xa inhibitors for stroke prevention in hemophiliacs with non-valvular atrial fibrillation. J Atr Fibrillation 2019; 12 (04) 2157
• 34 van den Ham HA, Souverein PC, Klungel OH. et al. Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies. Pharmacoepidemiol Drug Saf 2021; 30 (10) 1339-1352
• 35 Van Gelder IC, Rienstra M, Bunting KV. et al.; ESC Scientific Document Group. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2024; 45 (36) 3314-3414
• 36 Sagris D, Leventis I, Georgiopoulos G. et al. Bleeding risk comparison between direct oral anticoagulants at doses approved for atrial fibrillation and aspirin: Systematic review, meta-analysis and meta-regression. Eur J Intern Med 2020; 79: 31-36
• 37 Staritz P, de Moerloose P, Schutgens R, Dolan G. ADVANCE Working Group. Applicability of the European Society of Cardiology guidelines on management of acute coronary syndromes to people with haemophilia - An assessment by the ADVANCE Working Group. Haemophilia 2013; 19 (06) 833-840
• 38 Lawton JS, Tamis-Holland JE, Bangalore S. et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145 (03) e18-e114
• 39 Valgimigli M, Frigoli E, Heg D. et al.; MASTER DAPT Investigators. Dual antiplatelet therapy after PCI in patients at high bleeding risk. N Engl J Med 2021; 385 (18) 1643-1655
• 40 Agostoni P, Biondi-Zoccai GG, de Benedictis ML. et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004; 44 (02) 349-356
• 41 Mannucci PM, Mauser-Bunschoten EP. Cardiovascular disease in haemophilia patients: A contemporary issue. Haemophilia 2010; 16 (Suppl. 03) 58-66
• 42 Agosti P, Siboni SM, Ciavarella A. et al. Safety and efficacy of combined dual antiplatelet therapy and factor VIII prophylaxis in patients with haemophilia A after acute coronary syndrome. Haemophilia 2024; 30 (02) 336-344
• 43 Hermans C. Thrombosis and hemophilia: Little more evidence, much more guidance. HemaSphere 2023; 7 (06) e918
• 44 Uminski K, Xu Y, Zahrai A. et al. Management strategies in persons with inherited haemophilia requiring antithrombotic therapy: A scoping review. Haemophilia 2024; 30 (01) 16-50
• 45 Girolami A, Bertozzi I, de Marinis GB, Tasinato V, Sambado L. Discrepant ratios of arterial versus venous thrombosis in hemophilia A as compared with hemophilia B. J Thromb Thrombolysis 2014; 37 (03) 293-297
• 46 Srivastava A, Santagostino E, Dougall A. et al.; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26 (Suppl. 06) 1-158
• 47 Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 2016; 388 (10042): 365-375
• 48 Berge E, Whiteley W, Audebert H. et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021; 6 (01) I-LXII
• 49 Franchini M, Mannucci PM. Modifiers of clinical phenotype in severe congenital hemophilia. Thromb Res 2017; 156: 60-64
• 50 Franchini M, Montagnana M, Targher G. et al. Interpatient phenotypic inconsistency in severe congenital hemophilia: A systematic review of the role of inherited thrombophilia. Semin Thromb Hemost 2009; 35 (03) 307-312
• 51 Lee DH, Walker IR, Teitel J. et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83 (03) 387-391
• 52 Escuriola Ettingshausen C, Halimeh S, Kurnik K. et al. Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost 2001; 85 (02) 218-220
• 53 Kurnik K, Kreuz W, Horneff S. et al. Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children–results of a multicenter studys. Haematologica 2007; 92 (07) 982-985
• 54 Tizzano EF, Soria JM, Coll I. et al. The prothrombin 20210A allele influences clinical manifestations of hemophilia A in patients with intron 22 inversion and without inhibitors. Haematologica 2002; 87 (03) 279-285
• 55 Schulman S, Eelde A, Holmström M, Ståhlberg G, Odeberg J, Blombäck M. Validation of a composite score for clinical severity of hemophilia. J Thromb Haemost 2008; 6 (07) 1113-1121
• 56 Arbini AA, Mannucci PM, Bauer KA. Low prevalence of the factor V Leiden mutation among “severe” hemophiliacs with a “milder” bleeding diathesis. Thromb Haemost 1995; 74 (05) 1255-1258
• 57 Arruda VR, Annichino-Bizzacchi JM, Antunes SV, Costa FF. Association of severe haemophilia A and factor V Leiden: Report of three cases. Haemophilia 1996; 2 (01) 51-53
• 58 Di Perna C, Franchini M, Riccardi F, Rivolta GF, Angeri F, Tagliaferri A. Association between haemophilia and inherited thrombophilia: A single centre survey. Haemophilia 2011; 17 (01) 161-162
• 59 Franchini M, Mannucci PM. Interactions between genotype and phenotype in bleeding and thrombosis. Haematologica 2008; 93 (05) 649-652
• 60 Franchini M, Lippi G, Factor V. Factor V Leiden and hemophilia. Thromb Res 2010; 125 (02) 119-123
• 61 Franchini M. Thrombotic complications in patients with hereditary bleeding disorders. Thromb Haemost 2004; 92 (02) 298-304
• 62 Franchini M, Mannucci PM. The safety of pharmacologic options for the treatment of persons with hemophilia. Expert Opin Drug Saf 2016; 15 (10) 1391-1400
• 63 van Vulpen LF, Saccullo G, Iorio A, Makris M. The current state of adverse event reporting in hemophilia. Expert Rev Hematol 2017; 10 (02) 161-168
• 64 Scharrer I. The need for highly purified products to treat hemophilia B. Acta Haematol 1995; 94 (Suppl. 01) 2-7
• 65 Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM. 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 (03) e173-e187
• 66 Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39 (07) 772-778
• 67 Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus FVIII bypassing activity. J Thromb Haemost 2004; 2: 1700-1708
• 68 Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) - addressing safety issues. Haemophilia 2008; 14 (01) 39-43
• 69 Jiménez-Yuste V. Non-factor therapies for hemophilia: Achievements and perspectives. Semin Thromb Hemost 2025; 51 (01) 23-27
• 70 Franchini M, Marano G, Pati I. et al. Emicizumab for the treatment of haemophilia A: A narrative review. Blood Transfus 2019; 17 (03) 223-228
• 71 Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42 (05) 526-532
• 72 Olasupo OO, Noronha N, Lowe MS, Ansel D, Bhatt M, Matino D. Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B. Cochrane Database Syst Rev 2024; 2 (02) CD014544
• 73 Hemlibra. Accessed May 12, 2025 at: https://www.ema.europa.eu/en/medicines/human/EPAR/hemlibra
• 74 Oldenburg J, Mahlangu JN, Kim B. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
• 75 Alcedo Andrade PE, Mannucci PM, Kessler CM. Emicizumab: The hemophilia A game-changer. Haematologica 2024; 109 (05) 1334-1347
• 76 Chowdary P, Carcao M, Kenet G, Pipe SW. Haemophilia. Lancet 2025; 405 (10480): 736-750
• 77 Muniz RL, Camelo RM, Araújo MS. et al. Efficacy/effectiveness and safety of emicizumab prophylaxis of people with hemophilia A: A systematic review and meta-analysis. Expert Rev Hematol 2023; 16 (12) 1087-1097
• 78 Young G, Lenting PJ, Croteau SE, Nolan B, Srivastava A. Antithrombin lowering in hemophilia: A closer look at fitusiran. Res Pract Thromb Haemost 2023; 7 (04) 100179
• 79 FDA News Release. FDA Approves Novel Treatment for Hemophilia A or B, with or without Factor Inhibitors. Accessed May 12, 2025 at: https://www.fda.gov/news-events/press-announcements/fda-approves-novel-treatment-hemophilia-or-b-or-without-factor-inhibitors
• 80 Hoffman M. Thrombosis and novel hemophilia therapies: the fine line between clotting and bleeding. Blood Adv 2021; 5 (18) 3736
• 81 World Federation of Hemophilia. Alnylam Suspends Fitusiran Dosing due to Thrombotic Event in Phase 2 open-label extension study. 2017 . Accessed May 12, 2025 at: https://news.wfh.org/alnylam-suspends-fitusirandosing-due-thrombotic-event-phase-2-open-label-extension-study/
• 82 World Federation of Hemophilia. . Global dosing hold in fitusiran trials initiated by Sanofi Genzyme to investigate new adverse events; 2020: A joint statement of the World Federation of Hemophilia (WFH), European Haemophilia Consortium (EHC) and National Hemophilia Foundation (NHF). Accessed May 12, 2025 at: https://wfh.org/article/global-dosing-hold-in-fitusiran-trials-initiated-by-sanofi-genzyme-to-investigate-new-adverse-events/
• 83 Fitusiran. Accessed May 12, 2025 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219019s000lbl.pdf
• 84 Pipe SW, Lissitchkov T, Georgiev P. et al. Long-term safety and efficacy of fitusiran prophylaxis, and perioperative management, in people with hemophilia A or B. Blood Adv 2025; 9 (05) 1147-1158
• 85 Young G, Kavakli K, Klamroth R. et al. Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: The ATLAS-OLE study. Blood 2025;blood.2024027008
• 86 Seremetis SV, Cepo K, Skovgaard Rasmussen J. et al. Risk mitigation strategy for concizumab clinical trials after pause due to non-fatal thrombotic events. Blood 2020; 136 (Suppl. 01) 40
• 87 Matsushita T, Shapiro A, Abraham A. et al.; explorer7 Investigators. Phase 3 trial of concizumab in hemophilia with inhibitors. N Engl J Med 2023; 389 (09) 783-794
• 88 Chowdary P, Angchaisuksiri P, Apte S. et al. Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): A prospective, multicentre, open-label, randomised, phase 3a trial. Lancet Haematol 2024; 11 (12) e891-e904
• 89 Chowdary P. Anti-tissue factor pathway inhibitor (TFPI) therapy: a novel approach to the treatment of haemophilia. Int J Hematol 2020; 111 (01) 42-50
• 90 Mahlangu JN, Lamas JL, Morales JC. et al. A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia. Br J Haematol 2023; 200 (02) 229-239
• 91 Mahlangu J, Luis Lamas J, Cristobal Morales J. et al. Long-term safety and efficacy of the anti-tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results. Br J Haematol 2023; 200 (02) 240-248
• 92 Matino D, Acharya S, Palladino A. et al. Efficacy and safety of the anti-tissue factor pathway inhibitor marstacimab in participants with severe hemophilia without inhibitors: results from the phase 3 BASIS Trial. Paper presented at: ASH Meeting 2023; December 9, 2023 . Abs 285.
• 93 Bala NS, Thornburg CD. Gene therapy in hemophilia A: Achievements, challenges, and perspectives. Semin Thromb Hemost 2025; 51 (01) 28-40
• 94 Deshpande SR, Joseph K, Tong J, Chen Y, Pishko A, Cuker A. Adeno-associated virus-based gene therapy for hemophilia A and B: A systematic review and meta-analysis. Blood Adv 2024; 8 (23) 5957-5974
• 95 Miesbach W, Batty P, Chowdary P. et al. Adeno-associated virus-based gene therapy for hemophilia-addressing the gaps. Res Pract Thromb Haemost 2024; 9 (01) 102673
• 96 von Drygalski A, Gomez E, Giermasz A. et al. Completion of Phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years. Blood Adv 2025;bloodadvances.2024015291
• 97 Leavitt AD, Mahlangu J, Raheja P. et al. Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial. Res Pract Thromb Haemost 2024; 8 (08) 102615
• 98 Franchini M, Mannucci PM. Coagulation abnormalities in chronic liver disease. Semin Thromb Hemost 2025; (e-pub ahead of print).
• 99 von Drygalski A, Kolaitis NA, Bettencourt R. et al. Prevalence and risk factors for hypertension in hemophilia. Hypertension 2013; 62 (01) 209-215
• 100 Siboni SM, Mannucci PM, Gringeri A. et al.; Italian Association of Haemophilia Centres (AICE). Health status and quality of life of elderly persons with severe hemophilia born before the advent of modern replacement therapy. J Thromb Haemost 2009; 7 (05) 780-786
• 101 Esposito P, Rampino T, Gregorini M, Fasoli G, Gamba G, Dal Canton A. Renal diseases in haemophilic patients: pathogenesis and clinical management. Eur J Haematol 2013; 91 (04) 287-294
• 102 El Maamari J, Amid A, Pelland-Marcotte MC, Tole S. Between Scylla and Charybdis: thrombosis in children with hemophilia. Front Pediatr 2023; 11: 1173549
• 103 Valentino LA, Kawji M, Grygotis M. Venous access in the management of hemophilia. Blood Rev 2011; 25 (01) 11-15
• 104 Journeycake JM, Quinn CT, Miller KL, Zajac JL, Buchanan GR. Catheter-related deep venous thrombosis in children with hemophilia. Blood 2001; 98 (06) 1727-1731