Antithrombotic Therapy in People with Hemophilia—A Narrative Review

Abstract

As the life expectancy of individuals with hemophilia continues to increase, the complexity of balancing bleeding risks and thrombotic management has become increasingly critical in people with hemophilia with or at a high risk of thrombosis. Advances in hemophilia therapies such as extended half-life coagulation factors, non-factor therapies, rebalancing agents, and gene therapy have expanded treatment options for a variety of people with hemophilia. The thrombotic risk of people with hemophilia in general are relatively low as compared to those without hemophilia. However, antithrombotic therapy for prevention and treatment for thrombosis should still be considered in some situations, even in hemophilia. This clinical focus highlights the use of antithrombotic therapy in the management of thrombosis in people with hemophilia. A multidisciplinary, personalized approach is essential for optimizing the safety and efficacy of antithrombotic therapy in people with hemophilia with or at a high risk of thrombosis. High performance computer based multidimensional data analysis may help in establishing the personalized antithrombotic therapy in the future.

Keywords

hemophilia - antiplatelet therapy - anticoagulation - thrombosis - bleeding management - artificial intelligence

Publication History

Received: 13 January 2025

Accepted: 27 February 2025

Accepted Manuscript online:
28 February 2025

Article published online:
28 March 2025

• References

• 1 Gualtierotti R, Giachi A, Bitto N, La Mura V, Peyvandi F. Gene therapy in hemophilia: the dawn of a new era. Res Pract Thromb Haemost 2024; 9 (01) 102640
• 2 Español MG, Mistretta JN, Tarantino MD, Roberts JC. The evolution of hemophilia therapeutics: an illustrated review. Res Pract Thromb Haemost 2024; 8 (03) 102308
• 3 Hassan S, Monahan RC, Mauser-Bunschoten EP. et al. Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018. J Thromb Haemost 2021; 19 (03) 645-653
• 4 Liberale L, Badimon L, Montecucco F, Lüscher TF, Libby P, Camici GG. Inflammation, aging, and cardiovascular disease: JACC review topic of the week. J Am Coll Cardiol 2022; 79 (08) 837-847
• 5 Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens 1994; 7 (7 Pt 2): 7S-12S
• 6 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
• 7 Nagao A, Chikasawa Y, Sawada A. et al; ADVANCE Japan Working Group. Haemophilia and cardiovascular disease in Japan: low incidence rates from ADVANCE Japan baseline data. Haemophilia 2023; 29 (06) 1519-1528
• 8 Biere-Rafi S, Tuinenburg A, Haak BW. et al. Factor VIII deficiency does not protect against atherosclerosis. J Thromb Haemost 2012; 10 (01) 30-37
• 9 Goto S, Bhatt DL, Röther J. et al; REACH Registry Investigators. Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. Am Heart J 2008; 156 (05) 855-863 , 863.e2
• 10 Schutgens RE, 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
• 11 Benitez-Hidalgo O, Suito Alcántara M, Martinez Garcia MF. et al. Portal vein thrombosis in a patient with severe hemophilia B: a challenging balanced management. Clin Case Rep 2024; 12 (02) e8121
• 12 Ono K, Takedani H. Risk of deep venous thrombosis after total knee arthroplasty in patients with haemophilia A. Haemophilia 2020; 26 (05) 867-872
• 13 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
• 14 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
• 15 Mannucci PM, Agosti P, Lettino M. Guidance for the antithrombotic management of persons with haemophilia and cardiovascular disease. Haemophilia 2023; 29 (06) 1390-1393
• 16 Nagao A, Chikasawa Y, Hiroi Y, Ieko M. Treatment of thrombotic cardiovascular diseases in people with haemophilia: a Japanese consensus study. Haemophilia 2024; 30 (04) 933-942
• 17 Coppola A, Zani M, Quintavalle G, Focosi D, Franchini M. The evolution of hemophilia pharmacological treatments and therapeutic targets at the turn of the third millennium. Semin Thromb Hemost 2025; 51 (01) 10-17
• 18 von Drygalski A, Chowdary P, Kulkarni R. et al; XTEND-1 Trial Group. Efanesoctocog alfa prophylaxis for patients with severe hemophilia A. N Engl J Med 2023; 388 (04) 310-318
• 19 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 (09) 811-822
• 20 Pasi KJ, Rangarajan S, Georgiev P. et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med 2017; 377 (09) 819-828
• 21 Matsushita T, Shapiro A, Abraham A. et al; explorer7 Investigators. explorer7 Investigators. Phase 3 trial of concizumab in hemophilia with inhibitors. N Engl J Med 2023; 389 (09) 783-794
• 22 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
• 23 Mahlangu J, Kaczmarek R, von Drygalski A. et al; GENEr8-1 Trial Group. Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. N Engl J Med 2023; 388 (08) 694-705
• 24 Pipe SW, Leebeek FWG, Recht M. et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N Engl J Med 2023; 388 (08) 706-718
• 25 Cuker A, Kavakli K, Frenzel L. et al; BENEGENE-2 Trial Investigators. Gene therapy with fidanacogene elaparvovec in adults with hemophilia B. N Engl J Med 2024; 391 (12) 1108-1118
• 26 Group I–C. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. J Am Coll Cardiol 1988; 12: A3-A13
• 27 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345 (07) 494-502
• 28 Vogel B, Claessen BE, Arnold SV. et al. ST-segment elevation myocardial infarction. Nat Rev Dis Primers 2019; 5 (01) 39
• 29 Levine GN, Jeong YH, Goto S. et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014; 11 (10) 597-606
• 30 Ferrer F, Moraleda JM, Vicente V. Antithrombotic therapy after coronary-artery stenting. N Engl J Med 1999; 340 (17) 1365 , author reply 1367
• 31 Kumar A, Lutsey PL, St Peter WL. et al. Comparative effectiveness of ticagrelor, prasugrel, and clopidogrel for secondary prophylaxis in acute coronary syndrome: a propensity score-matched cohort study. Clin Pharmacol Ther 2023; 113 (02) 401-411
• 32 Mohamed MO, Kontopantelis E, Alasnag M. et al. Impact of society guidelines on trends in use of newer P2Y12 inhibitors for patients with acute coronary syndromes undergoing percutaneous coronary intervention. J Am Heart Assoc 2024; 13 (09) e034414
• 33 Wallentin L, Becker RC, Budaj A. et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
• 34 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
• 35 Mauri L, Kereiakes DJ, Yeh RW. et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371 (23) 2155-2166
• 36 Bonaca MP, Bhatt DL, Cohen M. et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
• 37 Kuno T, Watanabe A, Shoji S. et al. Short-term DAPT and DAPT de-escalation strategies for patients with acute coronary syndromes: a systematic review and network meta-analysis. Circ Cardiovasc Interv 2023; 16 (09) e013242
• 38 Watanabe H, Domei T, Morimoto T. et al; STOPDAPT-2 Investigators. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial. JAMA 2019; 321 (24) 2414-2427
• 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 Mayfield JJ, Leavitt AD, Tanriverdi T, Soni K, Ports TA, Abraham MR. Acute coronary syndrome in patients with hemophilia: a delicate balancing act. J Thromb Thrombolysis 2022; 54 (02) 323-329
• 41 Kim D-K, Kim D-I, Kim M-S. et al. Successful percutaneous coronary intervention for acute coronary syndrome in a patient with severe hemophilia a. Korean Circ J 2010; 40 (10) 527-529
• 42 John J, Koshy SKG. Current oral antiplatelets: focus update on prasugrel. J Am Board Fam Med 2012; 25 (03) 343-349
• 43 Koo BK, Kang J, Park KW. et al; HOST-EXAM investigators. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet 2021; 397 (10293): 2487-2496
• 44 Bouget J, Balusson F, Viglino D. et al. Major bleeding risk and mortality associated with antiplatelet drugs in real-world clinical practice. A prospective cohort study. PLoS One 2020; 15 (08) e0237022
• 45 Gundabolu K, Goldsweig A, Bhatt VR, Koepsell SA, Harper JL. ST-segment elevation myocardial infarction (STEMI) and pulmonary embolism in a hemophilia A patient receiving emicizumab and recombinant activated factor VII. Haemophilia 2020; 26 (01) e5-e8
• 46 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
• 47 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
• 48 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
• 49 Camm AJ, Accetta G, Ambrosio G. et al; GARFIELD-AF Investigators. Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation. Heart 2017; 103 (04) 307-314
• 50 Liao J-N, Chan Y-H, Kuo L. et al. Temporal trends of prescription rates, oral anticoagulants dose, clinical outcomes and factors associated with non-anticoagulation in patients with incident atrial fibrillation. Eur Heart J Qual Care Clin Outcomes 2025; qcaf002
• 51 Chao T-F, Chiang C-E, Lin Y-J. et al. Evolving changes of the use of oral anticoagulants and outcomes in patients with newly diagnosed atrial fibrillation in Taiwan. Circulation 2018; 138 (14) 1485-1487
• 52 Alkhezi OS, Buckley LF, Fanikos J. Trends in oral anticoagulant use and individual expenditures across the United States from 2014 to 2020. Am J Cardiovasc Drugs 2024; 24 (03) 433-444
• 53 Eikelboom JW, Connolly SJ, Brueckmann M. et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13) 1206-1214
• 54 Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353 (22) 2373-2383
• 55 Aggarwal R, Ruff CT, Virdone S. et al. Development and validation of the DOAC score: a novel bleeding risk prediction tool for patients with atrial fibrillation on direct-acting oral anticoagulants. Circulation 2023; 148 (12) 936-946
• 56 Hijazi Z, Lindbäck J, Alexander JH. et al; ARISTOTLE and STABILITY Investigators. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J 2016; 37 (20) 1582-1590
• 57 Hijazi Z, Oldgren J, Lindbäck J. et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
• 58 Dix C, McFadyen JD, Tran HA. Exploring the effects of factor Xa inhibitors on thrombin generation in people with haemophilia. Thromb Res 2024; 237: 148-153
• 59 Okumura K, Akao M, Yoshida T. et al; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med 2020; 383 (18) 1735-1745
• 60 Goto S, Goto S, Pieper KS. et al. New artificial intelligence prediction model using serial prothrombin time international normalized ratio measurements in atrial fibrillation patients on vitamin K antagonists: GARFIELD-AF. Eur Heart J Cardiovasc Pharmacother 2020; 6 (05) 301-309
• 61 Goto S, Kimura M, Katsumata Y. et al. Artificial intelligence to predict needs for urgent revascularization from 12-leads electrocardiography in emergency patients. PLoS One 2019; 14 (01) e0210103
• 62 Goto S, Mahara K, Beussink-Nelson L. et al. Artificial intelligence-enabled fully automated detection of cardiac amyloidosis using electrocardiograms and echocardiograms. Nat Commun 2021; 12 (01) 2726
• 63 Miura K, Yagi R, Miyama H. et al. Deep learning-based model detects atrial septal defects from electrocardiography: a cross-sectional multicenter hospital-based study. EClinicalMedicine 2023; 63: 102141
• 64 Goto S, Solanki D, John JE. et al. Multinational federated learning approach to train ECG and echocardiogram models for hypertrophic cardiomyopathy detection. Circulation 2022; 146 (10) 755-769
• 65 Nakayama M, Goto S, Sakano T, Goto S. Detection of the relationship between the multi-dimensional data sets of serially measured blood pressure and the future risk of death in healthy elderly Japanese population. J Atheroscler Thromb 2023; 30 (08) 1002-1009
• 66 Dunois C. Laboratory monitoring of direct oral anticoagulants (DOACs). Biomedicines 2021; 9 (05) 445
• 67 Müller J, Pekrul I, Pötzsch B, Berning B, Oldenburg J, Spannagl M. Laboratory monitoring in emicizumab-treated persons with hemophilia A. Thromb Haemost 2019; 119 (09) 1384-1393