REFERENCES
1. Raskob G, Angchaisuksiri P, Blanco A, et al. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. 2014;34:2363-71.
2. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-128.
3. Zapata-Wainberg G, Ximénez-Carrillo Rico Á, Benavente Fernández L, et al. Epidemiology of intracranial haemorrhages associated with vitamin K antagonist oral anticoagulants in Spain: TAC registry. Intervent Neurol. 2015;4:52-8.
4. Wilson D, Charidimou A, Shakeshaft C, et al. Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type. Neurology. 2016;86:360-6.
5. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37:256-62.
6. Mulder FI, Bosch FTM, Young AM, et al. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Blood. 2020;136:1433-41.
7. Zhou S, Xiao Y, Zhou C, et al. Effect of rivaroxaban vs enoxaparin on major cardiac adverse events and bleeding risk in the acute phase of acute coronary syndrome: the H-REPLACE randomized equivalence and noninferiority trial. JAMA Netw Open. 2023;6:e2255709.
8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
9. Granger CB, Alexander JH, Mcmurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.
10. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104.
12. Van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124:1968-75.
13. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus Warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-14.
15. Mohammed BM, Matafonov A, Ivanov I, et al. An update on factor XI structure and function. Thromb Res. 2018;161:94-105.
16. Al-Horani RA, Afosah DK. Recent advances in the discovery and development of factor XI/XIa inhibitors. Med Res Rev. 2018;38:1974-2023.
17. Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis: insights from animal models. Arterioscler Thromb Vasc Biol. 2019;39:331-8.
18. Brummel Ziedins K, Branda R, Butenas S, Mann K. Discordant fibrin formation in hemophilia. J Thromb Haemost. 2009;7:825-32.
19. Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 2013;39:621-31.
20. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000;342:696-701.
21. Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372:232-40.
23. Visser M, Heitmeier S, Ten Cate H, Spronk HMH. Role of factor XIa and plasma kallikrein in arterial and venous thrombosis. Thromb Haemostasis. 2020;120:883-993.
24. Hsu C, Hutt E, Bloomfield DM, Gailani D, Weitz JI. Factor XI inhibition to uncouple thrombosis from hemostasis. J Am Coll Cardiol. 2021;78:625-31.
25. Lorentz CU, Tucker EI, Verbout NG, et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood. 2021;138:2173-84.
26. Lorentz CU, Verbout NG, Wallisch M, et al. Contact activation inhibitor and factor XI antibody, AB023, produces safe, dose-dependent anticoagulation in a phase 1 first-in-human trial. Arterioscler Thromb Vasc Biol. 2019;39:799-809.
27. Campello E, Simioni P, Prandoni P, Ferri N. Clinical pharmacology of factor XI inhibitors: new therapeutic approaches for prevention of venous and arterial thrombotic disorders. J Clin Med. 2022;11:6314.
28. Winkelmayer WC, Lensing AW, Thadhani RI, et al. A phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis. Kidney Int. 2024;106:145-53.
29. Liu Q, Bethune C, Dessouki E, Grundy J, Monia BP, Bhanot S. ISIS-FXIRx, a novel and specific antisense inhibitor of factor XI, caused significant reduction in FXI antigen and activity and increased aPTT without causing bleeding in healthy volunteers. Blood. 2011;118:209.
30. Verhamme P, Yi BA, Segers A, et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385:609-17.
31. Koch AW, Schiering N, Melkko S, et al. MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans. Blood. 2019;133:1507-16.
32. Yi BA, Freedholm D, Widener N, et al. Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of factor XI and factor XIa. J Thromb Haemost. 2022;20:307-15.
33. Perera V, Wang Z, Luettgen J, et al. First-in-human study of milvexian, an oral, direct, small molecule factor XIa inhibitor. Clin Transl Sci. 2021;15:330-42.
34. Piccini JP, Patel MR, Steffel J, et al. Asundexian versus Apixaban in patients with atrial fibrillation. N Engl J Med. 2025;392:23-32.
35. Decrem Y, Rath G, Blasioli V, et al. Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. J Exp Med. 2009;206:2381-95.
36. Thomas D, Thelen K, Kraff S, et al. BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: first evaluation of safety, pharmacodynamics, and pharmacokinetics. Res Pract Thromb Haemost. 2019;3:242-53.
37. He X, Zhang J, Du Y, et al. BJTJ-1837, a novel FXI activation-blocking antibody. Res Pract Thromb Haemost. 2023;7:100067.
38. Nowotny B, Thomas D, Schwers S, et al. First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men. J Thromb Haemost. 2022;20:1684-95.
39. Xiang Q, Liu Z, Xie Q, et al. Pharmacokinetics, pharmacodynamics and safety profile of SKB336, a selective inhibitor of coagulation factor XI/XIa in healthy subjects. Br J Clin Pharmacol. 2025;91:2817-26.
40. Chen R, Guan X, Hu P, et al. First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a small-molecule factor XIa inhibitor in healthy subjects. Front Pharmacol. 2022;13:821363.
41. Ma T, Dong Y, Huang L, et al. SHR2285, the first selectively oral FXIa inhibitor in China: safety, tolerability, pharmacokinetics and pharmacodynamics combined with aspirin, clopidogrel or ticagrelor. Front Pharmacol. 2022;13:1027627.
42. Xu J, Zhao N, Huang J, et al. The safety, pharmacokinetics, and pharmacodynamics of SHR2285, an oral small molecule factor XIa inhibitor, in healthy chinese volunteers. Clin Drug Investig. 2023;43:435-45.
43. Thomas D, Kanefendt F, Schwers S, Unger S, Yassen A, Boxnick S. First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa. J Thromb Haemost. 2021;19:2407-16.
44. Chen H, Hashizume K, Kanefendt F, Brase C, Schmitz S, Liu T. Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data. Clin Transl Sci. 2024;17:e13895.
45. Beale D, Dennison J, Boyce M, et al. ONO-7684 a novel oral FXIa inhibitor: safety, tolerability, pharmacokinetics and pharmacodynamics in a first-in-human study. Br J Clin Pharmacol. 2021;87:3177-89.
46. Pollack CV, Kurz MA, Hayward NJ. EP-7041, a factor XIa inhibitor as a potential antithrombotic strategy in extracorporeal membrane oxygenation: a brief report. Crit Care Explor. 2020;2:e0196.
47. Zhou Y, Wang D, Wu J, et al. Discovery of the low-hemorrhagic antithrombotic effect of montelukast by targeting FXIa in mice. Arterioscler Thromb Vasc Biol. 2025;45:e150-62.
48. Perera V, Luettgen JM, Wang Z, et al. First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects. Br J Clin Pharmacol. 2018;84:876-87.
49. Zhang JY, Ruan ZR, Jiang B, et al. Pharmacokinetics, pharmacodynamics, and safety of frunexian in healthy Chinese volunteer adults: a randomized dose-escalation phase I study. Clin Transl Sci. 2024;17:e13787.
50. Roehrig S, Ackerstaff J, Jiménez Núñez E, et al. Design and preclinical characterization program toward asundexian (BAY 2433334), an oral factor XIa inhibitor for the prevention and treatment of thromboembolic disorders. J Med Chem. 2023;66:12203-24.
51. Piccini JP, Caso V, Connolly SJ, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399:1383-90.
52. Update on phase 3 librexia ACS trial. Available from: https://news.bms.com/news/details/2025/Update-on-Phase-3-Librexia-ACS-Trial/default.aspx [Last accessed on 13 Aug 2026].
53. Ruff CT, Patel SM, Giugliano RP, et al. Abelacimab versus rivaroxaban in patients with atrial fibrillation. N Engl J Med. 2025;392:361-71.
54. Weitz JI, Bauersachs R, Becker B, et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA. 2020;323:130.
55. Wong PC, Crain EJ, Bozarth JM, et al. Milvexian, an orally bioavailable, small-molecule, reversible, direct inhibitor of factor XIa: in vitro studies and in vivo evaluation in experimental thrombosis in rabbits. J Thromb Haemost. 2022;20:399-408.
56. Weitz JI, Strony J, Ageno W, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med. 2021;385:2161-72.
57. Pfeffer MA, Kohs TC, Vu HH, et al. Factor XI inhibition for the prevention of catheter-associated thrombosis in patients with cancer undergoing central line placement: a phase 2 clinical trial. Arterioscler Thromb Vasc Biol. 2024;44:290-9.
58. Weitz JI, Tankó LB, Floege J, et al. Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial. Nat Med. 2024;30:435-42.
59. Walsh M, Bethune C, Smyth A, et al. Phase 2 study of the factor XI antisense inhibitor IONIS-FXIRx in patients with ESRD. Kidney Int Rep. 2022;7:200-9.
60. Brase C, Schmitz S, Sommer K, Halabi A, Kanefendt F. Effect of age, sex, renal impairment and hepatic impairment on the safety, pharmacokinetics and pharmacodynamics of asundexian. Clin Pharmacokinet. 2024;63:1631-48.
61. Rao SV, Kirsch B, Bhatt DL, et al. A multicenter, phase 2, randomized, placebo-controlled, double-blind, parallel-group, dose-finding trial of the oral factor XIa inhibitor asundexian to prevent adverse cardiovascular outcomes after acute myocardial infarction. Circulation. 2022;146:1196-206.
62. Gibson CM, Bahit MC, Mehran R, et al. Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: rationale and design of the phase 3 (Librexia ACS). Am Heart J. 2025;285:21-8.
63. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. 2022;400:997-1007.
64. Sharma M, Molina CA, Toyoda K, et al. Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2024;23:46-59.
65. Samaha E, Schwameis M, Schranz S, et al. The factor XIa antibody osocimab strongly inhibits clotting in extracorporeal circuits with human blood and in baboons. Res Pract Thromb Haemost. 2025;9:102932.
66. Bentley R, Hardy LJ, Scott LJ, Sharma P, Philippou H, Lip GYH. Drugs in phase I and II clinical development for the prevention of stroke in patients with atrial fibrillation. Expert Opin Investig Drugs. 2021;30:1057-69.
67. Alexander JH, Lydon EJ, Piccini JP, et al. Asundexian or apixaban in patients with atrial fibrillation according to prior oral anticoagulant use: a subgroup analysis of the OCEANIC-AF randomized clinical trial. JAMA Cardiol. 2025;10:555.
68. Al Said S, Patel SM, Giugliano RP, et al. Abelacimab versus rivaroxaban in patients with atrial fibrillation on antiplatelet therapy: a prespecified analysis of the AZALEA-TIMI 71 trial. Circulation. 2025;152:290-6.
69. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:338S-400S.
70. Weitz JI, Kithcart AP, O'brien MP, et al. Efficacy and safety of REGN9933A2 and REGN7508Cat for preventing postoperative venous thromboembolism (ROXI-VTE-I and ROXI-VTE-II): two randomised, open-label, phase 2 trials. Lancet. 2025;406:2551-63.
71. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022;8:11.
72. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO guideline update. J Clin Oncol. 2023;41:3063-71.
73. Ageno W, Caramelli B, Donadini MP, Girardi L, Riva N. Changes in the landscape of anticoagulation: a focus on direct oral anticoagulants. Lancet Haematol. 2024;11:e938-50.
74. Van Cutsem E, Mahé I, Felip E, et al. Treating cancer-associated venous thromboembolism: a practical approach. Eur J Cancer. 2024;209:114263.
75. Ades M, Simard C, Vanassche T, Verhamme P, Eikelboom J, Mavrakanas TA. Factor XI inhibitors: potential role in end-stage kidney disease. Semin Nephrol. 2023;43:151484.
76. Winkelmayer W. Factor XI inhibition is not useful for end-stage kidney disease patients receiving haemodialysis. Medical Conferences. 2026. Available from: https://conferences.medicom-publishers.com/specialisation/nephrology/era-2025/factor-xi-inhibition-is-not-useful-for-end-stage-kidney-disease-patients-receiving-haemodialysis/ [Last accessed on 13 Aug 2026].
77. Moon JY, Nagaraju D, Franchi F, Rollini F, Angiolillo DJ. The role of oral anticoagulant therapy in patients with acute coronary syndrome. Ther Adv Hematol. 2017;8:353-66.
78. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52:e364-467.
79. Galli M, Gragnano F, Berteotti M, et al. Antithrombotic therapy in high bleeding risk, part I: percutaneous cardiac interventions. JACC Cardiovasc Interv. 2024;17:2197-215.
80. Galli M, Gragnano F, Berteotti M, et al. Antithrombotic therapy in high bleeding risk, part II: noncardiac percutaneous interventions. JACC Cardiovasc Interv. 2024;17:2325-36.
