https://doi.org/10.4081/btvb.2023.76
The new era of anticoagulation: factor XI and XII inhibitors
Submitted: 30 March 2023
Accepted: 22 May 2023
Published: 7 June 2023
Accepted: 22 May 2023
Abstract Views: 2023
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
The two last decades have witnessed a revolution in the field of anticoagulation, mainly due to the advent of direct anticoagulant with targeted action against single coagulation proteins. However, the residual risk of cardio- and cerebrovascular events, particularly in some critical settings, and the risk of major bleeding still represent unmet medical needs. Preclinical studies and experience from families with genetic deficiencies of factor XI or XII (FXI and FXII) allowed to identify these factors involved in the contact pathway of coagulation as potential targets for new anticoagulant approaches. To date, several pharmacological classes of FXI and FXII inhibitors have been developed, including antisense oligonucleotides, monoclonal antibodies, small molecules, natural inhibitors, and aptamers, and various molecules are currently under phase 2 or 3 clinical investigation. Particularly, promising results have been obtained in patients undergoing major orthopedic surgery, in those with end-stage kidney disease, atrial fibrillation and acute coronary syndrome. This review summarizes current knowledge on FXI and FXII inhibitors, with a particular focus on their pharmacological properties and potential clinical indications.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
DOI: https://doi.org/10.1056/NEJMoa0905561
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
DOI: https://doi.org/10.1056/NEJMoa1009638
Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
DOI: https://doi.org/10.1056/NEJMoa1310907
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
DOI: https://doi.org/10.1056/NEJMoa1107039
Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021;398:64-77.
DOI: https://doi.org/10.1016/S0140-6736(20)32658-1
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-62.
DOI: https://doi.org/10.1016/S0140-6736(13)62343-0
Lippi G, Mattiuzzi C, Cervellin G, Favaloro EJ. Direct oral anticoagulants: analysis of worldwide use and popularity using Google Trends. Ann Transl Med 2017;5:322.
DOI: https://doi.org/10.21037/atm.2017.06.65
Shmyr D, Van der Merwe V, Yakiwchuk E, et al. Triple antithrombotic therapy for atrial fibrillation and coronary stents. Can Fam Physician 2017;63:375-81.
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.
DOI: https://doi.org/10.1056/NEJMoa1300615
Dufrost V, Wahl D, Zuily S. Direct oral anticoagulants in antiphospholipid syndrome: meta-analysis of randomized controlled trials. Autoimmun Rev 2021;20:102711.
DOI: https://doi.org/10.1016/j.autrev.2020.102711
Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330-93.
DOI: https://doi.org/10.1093/eurheartj/ehy136
Weitz JI, Fredenburgh JC. Factors XI and XII as targets for new anticoagulants. Front Med (Lausanne) 2017;4:19.
DOI: https://doi.org/10.3389/fmed.2017.00019
Kluge KE, Seljeflot I, Arnesen H, Jensen T, et al. Coagulation factors XI and XII as possible targets for anticoagulant therapy. Thromb Res 2022;214:53-62.
DOI: https://doi.org/10.1016/j.thromres.2022.04.013
Donadini MP, Ageno W. Milvexian and other drugs targeting Factor XI: a new era of anticoagulation? Bleed Thromb Vasc Biol 2022;1:22.
DOI: https://doi.org/10.4081/btvb.2022.22
Weidmann H, Heikaus L, Long AT, et al. The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity. Biochim Biophys Acta Mol Cell Res 2017;1864:2118-27.
DOI: https://doi.org/10.1016/j.bbamcr.2017.07.009
Engel R, Brain CM, Paget J, et al. Single-chain factor XII exhibits activity when complexed to polyphosphate. J Thromb Haemost 2014;12:1513-22.
DOI: https://doi.org/10.1111/jth.12663
Smith SA, Choi SH, Davis-Harrison R, et al. Polyphosphate exerts differential effects on blood clotting, depending on polymer size. Blood 2010;116:4353-9.
DOI: https://doi.org/10.1182/blood-2010-01-266791
Oehmcke S, Morgelin M, Herwald H. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun 2009;1:225-30.
DOI: https://doi.org/10.1159/000203700
Jaffer IH, Fredenburgh JC, Hirsh J, Weitz JI. Medical device-induced thrombosis: what causes it and how can we prevent it? J Thromb Haemost 2015;13:S72-81.
DOI: https://doi.org/10.1111/jth.12961
Karthikeyan G, Connolly SJ, Ntsekhe M, et al. The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation. Am Heart J 2020;225:69-77.
DOI: https://doi.org/10.1016/j.ahj.2020.03.018
Schmaier AH, Stavrou EX. Factor XII - What's important but not commonly thought about. Res Pract Thromb Haemost 2019;3:599-606.
DOI: https://doi.org/10.1002/rth2.12235
Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 1991;266:7353-8.
DOI: https://doi.org/10.1016/S0021-9258(20)89453-8
Shpilberg O, Peretz H, Zivelin A, et al. One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 1995;85:429-32.
DOI: https://doi.org/10.1182/blood.V85.2.429.bloodjournal852429
De Caterina R, Prisco D, Eikelboom JW. Factor XI inhibitors: cardiovascular perspectives. Eur Heart J 2023;44:280-92.
DOI: https://doi.org/10.1093/eurheartj/ehac464
Salomon O, Steinberg DM, Zucker M, et al. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb Haemost 2011;105:269-73.
DOI: https://doi.org/10.1160/TH10-05-0307
Salomon O, Steinberg DM, Koren-Morag N, et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008;111:4113-7.
DOI: https://doi.org/10.1182/blood-2007-10-120139
Salomon O, Steinberg DM, Dardik R, et al. Inherited factor XI deficiency confers no protection against acute myocardial infarction. J Thromb Haemost 2003;1:658-61.
DOI: https://doi.org/10.1046/j.1538-7836.2003.00195.x
Endler G, Marsik C, Jilma B, et al. Evidence of a U-shaped association between factor XII activity and overall survival. J Thromb Haemost 2007;5:1143-8.
DOI: https://doi.org/10.1111/j.1538-7836.2007.02530.x
Zeerleder S, Schloesser M, Redondo M, et al. Reevaluation of the incidence of thromboembolic complications in congenital factor XII deficiency--a study on 73 subjects from 14 Swiss families. Thromb Haemost 1999;82:1240-6.
DOI: https://doi.org/10.1055/s-0037-1614368
Girolami A, Ferrari S, Cosi E, et al. Thrombotic events in severe FXII deficiency in comparison with unaffected family members during a long observation period. J Thromb Thrombolysis 2019;47:481-5.
DOI: https://doi.org/10.1007/s11239-019-01819-8
Liu Q, Bethune C, Dessouki E, et al. 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.
DOI: https://doi.org/10.1182/blood.V118.21.209.209
Liu J, Cooley BC, Akinc A, et al. Knockdown of liver-derived factor XII by GalNAc-siRNA ALN-F12 prevents thrombosis in mice without impacting hemostatic function. Thromb Res 2020;196:200-5.
DOI: https://doi.org/10.1016/j.thromres.2020.08.040
Liu J, Qin J, Borodovsky A, et al. An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema. RNA 2019;25:255-63.
DOI: https://doi.org/10.1261/rna.068916.118
Fredenburgh JC, Weitz JI. Factor XI as a target for new anticoagulants. Hamostaseologie 2021;41:104-10.
DOI: https://doi.org/10.1055/a-1384-3715
Buller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015;372:232-40.
DOI: https://doi.org/10.1056/NEJMoa1405760
Bentley R, Hardy LJ, Scott LJ, et al. 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.
DOI: https://doi.org/10.1080/13543784.2021.1897786
Eikelboom J, Floege J, Thadhani R, et al. Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target. Kidney Int 2021;100:1199-207.
DOI: https://doi.org/10.1016/j.kint.2021.08.028
Walsh M, Bethune C, Smyth A, et al. Phase 2 Study of the factor XI antisense inhibitor IONIS-FXI(Rx) in patients with ESRD. Kidney Int Rep 2022;7:200-9.
DOI: https://doi.org/10.1016/j.ekir.2021.11.011
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.
DOI: https://doi.org/10.1002/rth2.12186
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.
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.
DOI: https://doi.org/10.1161/ATVBAHA.118.312328
McKenzie A, Roberts A, Malandkar S, et al. A phase I, first-in-human, randomized dose-escalation study of anti-activated factor XII monoclonal antibody garadacimab. Clin Transl Sci 2022;15:626-37.
DOI: https://doi.org/10.1111/cts.13180
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 2021.
DOI: https://doi.org/10.1111/jth.15577
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;323:130-9.
DOI: https://doi.org/10.1001/jama.2019.20687
Verhamme P, Yi BA, Segers A, et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med 2021;385:609-17.
DOI: https://doi.org/10.1056/NEJMoa2105872
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.
DOI: https://doi.org/10.1182/blood.2021011725
Skaistis J, Tagami T. Risk of fatal bleeding in episodes of major bleeding with new oral anticoagulants and vitamin K antagonists: a systematic review and meta-analysis. PLoS One 2015;10:e0137444.
DOI: https://doi.org/10.1371/journal.pone.0137444
Katsanos AH, Schellinger PD, Kohrmann M, et al. Fatal oral anticoagulant-related intracranial hemorrhage: a systematic review and meta-analysis. Eur J Neurol 2018;25:1299-302.
DOI: https://doi.org/10.1111/ene.13742
Katsanos AH, Kamel H, Healey JS, Hart RG. Stroke prevention in atrial fibrillation: looking forward. Circulation 2020;142:2371-88.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.049768
Chan N, Sobieraj-Teague M, Eikelboom JW. Direct oral anticoagulants: evidence and unresolved issues. Lancet 2020;396:1767-76.
DOI: https://doi.org/10.1016/S0140-6736(20)32439-9
Yau JW, Liao P, Fredenburgh JC, et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 2014;123:2102-7.
DOI: https://doi.org/10.1182/blood-2013-12-540872
Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382:1599-607.
DOI: https://doi.org/10.1056/NEJMoa1915103
Agnelli G, Munoz A, Franco L, et al. Apixaban and dalteparin for the treatment of venous thromboembolism in patients with different sites of cancer. Thromb Haemost 2022;122:796-807.
DOI: https://doi.org/10.1055/s-0041-1735194
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.
DOI: https://doi.org/10.1111/bcp.13520
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 2022;15:330-42.
DOI: https://doi.org/10.1111/cts.13148
Kubitza D, Heckmann M, Distler J, et al. Pharmacokinetics, pharmacodynamics and safety of BAY 2433334, a novel activated factor XI inhibitor, in healthy volunteers: arandomized phase 1 multiple-dose study. Br J Clin Pharmacol 2022;88:3447-62.
DOI: https://doi.org/10.1111/bcp.15230
Korff M, Imberg L, Will JM, et al. Acylated 1H-1,2,4-triazol-5-amines targeting human coagulation factor XIIa and thrombin: conventional and microscale synthesis, anticoagulant properties, and mechanism of action. J Med Chem 2020;63:13159-86.
DOI: https://doi.org/10.1021/acs.jmedchem.0c01635
Kalinin DV. Factor XII(a) inhibitors: a review of the patent literature. Expert Opin Ther Pathol 2021;31:1155-76.
DOI: https://doi.org/10.1080/13543776.2021.1945580
Weitz JI, Strony J, Ageno W, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med 2021;385:2161-72.
DOI: https://doi.org/10.1056/NEJMoa2113194
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.
DOI: https://doi.org/10.1016/S0140-6736(22)00456-1
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.
DOI: https://doi.org/10.1016/S0140-6736(22)01588-4
Sharma M, Molina CA, Toyoda K, et al. Rationale and design of the AXIOMATIC-SSP phase II trial: antithrombotic treatment with factor XIa inhibition to optimize management of acute thromboembolic events for secondary stroke prevention. J Stroke Cerebrovasc Dis 2022;31:106742.
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106742
Moon JY, Nagaraju D, Franchi F, et al. The role of oral anticoagulant therapy in patients with acute coronary syndrome. Ther Adv Hematol 2017;8:353-66.
DOI: https://doi.org/10.1177/2040620717733691
Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
DOI: https://doi.org/10.1056/NEJMoa1112277
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.
DOI: https://doi.org/10.1161/CIR.0000000000001115
Perera V, Abelian G, Li D, et al. Single-dose pharmacokinetics of milvexian in participants with normal renal function and participants with moderate or severe renal impairment. Clin Pharmacokinet 2022;61:1405-16.
DOI: https://doi.org/10.1007/s40262-022-01150-1
Pollack CV, Jr., 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.
DOI: https://doi.org/10.1097/CCE.0000000000000196
Campos IT, Amino R, Sampaio CA, et al. Infestin, a thrombin inhibitor presents in Triatoma infestans midgut, a Chagas' disease vector: gene cloning, expression and characterization of the inhibitor. Insect Biochem Mol Biol 2002;32:991-7.
DOI: https://doi.org/10.1016/S0965-1748(02)00035-8
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.
DOI: https://doi.org/10.1084/jem.20091007
de Maat S, Sanrattana W, Mailer RK, et al. Design and characterization of alpha1-antitrypsin variants for treatment of contact system-driven thromboinflammation. Blood 2019;134:1658-69.
DOI: https://doi.org/10.1182/blood.2019000481
Donkor DA, Bhakta V, Eltringham-Smith LJ, et al. Selection and characterization of a DNA aptamer inhibiting coagulation factor XIa. Sci Rep 2017;7:2102.
DOI: https://doi.org/10.1038/s41598-017-02055-x
Woodruff RS, Ivanov I, Verhamme IM, et al. Generation and characterization of aptamers targeting factor XIa. Thromb Res 2017;156:134-41.
DOI: https://doi.org/10.1016/j.thromres.2017.06.015
Liu M, Zaman K, Fortenberry YM. Overview of the therapeutic potential of aptamers targeting coagulation factors. Int J Mol Sci 2021;22.
DOI: https://doi.org/10.3390/ijms22083897
How to Cite
Prisco, D., Mattioli, I., De Caterina, R., & Bettiol, A. (2023). The new era of anticoagulation: factor XI and XII inhibitors. Bleeding, Thrombosis and Vascular Biology, 2(2). https://doi.org/10.4081/btvb.2023.76
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