https://doi.org/10.4081/btvb.2024.118
Factor XI inhibitors: a new option for the prevention and treatment of cancer-associated thrombosis
Submitted: 17 January 2024
Accepted: 12 March 2024
Published: 16 May 2024
Accepted: 12 March 2024
Abstract Views: 332
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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
Venous thromboembolism (VTE) is a relatively common complication in cancer patients with potentially dire consequences. Anticoagulants are the mainstay of treatment of cancer-associated VTE. The anticoagulants most often used are low-molecular-weight heparin (LMWH) and direct oral factor (F) Xa inhibitors, which include apixaban, edoxaban, and rivaroxaban. Most guidelines recommend primary VTE prophylaxis with LMWH, apixaban, or rivaroxaban after abdominal or pelvic cancer surgery, or in high-risk ambulatory cancer patients. Both oral FXa inhibitors and LMWH have limitations. LMWH requires daily subcutaneous injections, and because of its renal clearance, its use may be problematic in patients with severe kidney disease. The risk of bleeding with oral FXa inhibitors may be higher than with LMWH in patients with intraluminal gastrointestinal or genitourinary cancers. Other problems with oral FXa inhibitors include potential drug-drug interactions and dosing issues in patients with thrombocytopenia or severe kidney or liver disease. Therefore, there remains a need for convenient and safer anticoagulants for VTE treatment in cancer patients. FXI has emerged as a potentially safer target for anticoagulants than FXa because FXI is essential for thrombosis, but mostly dispensable for hemostasis. This review summarizes the currently available therapeutic options for cancer-associated VTE, highlights knowledge gaps, and discusses the potential of FXI inhibitors to address key unmet clinical needs in this vulnerable patient population.
Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8:11.
DOI: https://doi.org/10.1038/s41572-022-00336-y
Mulder FI, Horváth-Puhó E, van Es N, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021;137:1959-69.
DOI: https://doi.org/10.1182/blood.2020007338
Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5: 632-4.
DOI: https://doi.org/10.1111/j.1538-7836.2007.02374.x
Lloyd AJ, Dewilde S, Noble S, et al. What impact does venous thromboembolism and bleeding have on cancer patients’ quality of life? Value Health 2018;21:449-55.
DOI: https://doi.org/10.1016/j.jval.2017.09.015
Sharp L, Carsin AE, Timmons A. Associations between cancer-related financial stress and strain and psychological well-being among individuals living with cancer. Psychooncology 2013;22:745-55.
DOI: https://doi.org/10.1002/pon.3055
Cohen AT, Katholing A, Rietbrock S, et al. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost 2017;117:57-65.
DOI: https://doi.org/10.1160/TH15-08-0686
Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8.
DOI: https://doi.org/10.1182/blood-2002-01-0108
Noble S, Prout H, Nelson A. Patients’ Experiences of LIving with CANcer-associated thrombosis: the PELICAN study. Patient Prefer Adherence 2015;9:337-45.
DOI: https://doi.org/10.2147/PPA.S79373
Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-24.
DOI: https://doi.org/10.1056/NEJMoa1711948
Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018;36:2017-23.
DOI: https://doi.org/10.1200/JCO.2018.78.8034
Planquette B, Bertoletti L, Charles-Nelson A, et al. Rivaroxaban vs dalteparin in cancer-associated thromboembolism: a randomized trial. Chest 2022;161:781-90.
DOI: https://doi.org/10.1016/j.chest.2021.09.037
McBane RD 2nd, Wysokinski WE, Le-Rademacher JG, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020;18:411-21.
DOI: https://doi.org/10.1111/jth.14662
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
Schrag D, Uno H, Rosovsky R, et al. Direct oral anticoagulants vs low-molecular-weight heparin and recurrent vte in patients with cancer: a randomized clinical trial. JAMA 2023;329:1924-33.
DOI: https://doi.org/10.1001/jama.2023.7843
Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021;5:927-74.
DOI: https://doi.org/10.1182/bloodadvances.2021004734
Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2020;38:496-520.
DOI: https://doi.org/10.1200/JCO.19.01461
Falanga A, Ay C, Di Nisio M, et al. Venous thromboembolism in cancer patients: ESMO clinical practice guideline. Ann Oncol 2023;34:452-67.
DOI: https://doi.org/10.1016/j.annonc.2022.12.014
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.
DOI: https://doi.org/10.1200/JCO.23.00294
Kraaijpoel N, Di Nisio M, Mulder FI, et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE cancer study. Thromb Haemost 2018;118:1439-49.
DOI: https://doi.org/10.1055/s-0038-1667001
Moik F, Posch F, Zielinski C, et al. Direct oral anticoagulants compared to low-molecular-weight heparin for the treatment of cancer-associated thrombosis: updated systematic review and meta-analysis of randomized controlled trials. Res Pract Thromb Haemost 2020;4:550-61.
DOI: https://doi.org/10.1002/rth2.12359
Steffel J, Collins R, Antz M, et al. 2021 European heart rhythm association practical guide on the use of non-vitamin k antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021;23:1612-76.
DOI: https://doi.org/10.1093/europace/euab157
Wang TF. Drug-drug interactions: Implications for anticoagulation, with focus in patients with cancer. Thromb Res 2022;213:S66-s71.
DOI: https://doi.org/10.1016/j.thromres.2021.11.026
Hsu C, Hutt E, Bloomfield DM, et al Factor XI inhibition to uncouple thrombosis from hemostasis: jacc review topic of the week. J Am Coll Cardiol 2021;78:625-31.
DOI: https://doi.org/10.1016/j.jacc.2021.06.010
Cheng Q, Tucker EI, Pine MS, et al. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 2010;116:3981-9.
DOI: https://doi.org/10.1182/blood-2010-02-270918
Geddings JE, Hisada Y, Boulaftali Y, et al. Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice. J Thromb Haemost 2016;14:153-66.
DOI: https://doi.org/10.1111/jth.13181
Davila M, Amirkhosravi A, Coll E, et al. Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost 2008;6:1517-24.
DOI: https://doi.org/10.1111/j.1538-7836.2008.02987.x
Shim YJ, Chatterjee V, Swaidani S, et al. Polyphosphate expression by cancer cell extracellular vesicles mediates binding of factor XII and contact activation. Blood Adv 2021;5:4741-51.
DOI: https://doi.org/10.1182/bloodadvances.2021005116
Nickel KF, Ronquist G, Langer F, et al. The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis. Blood 2015;126:1379-89.
DOI: https://doi.org/10.1182/blood-2015-01-622811
Swystun LL, Mukherjee S, Liaw PC. Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost 2011;9:2313-21.
DOI: https://doi.org/10.1111/j.1538-7836.2011.04465.x
Fredenburgh JC, Gross PL, Weitz JI. Emerging anticoagulant strategies. Blood 2017;129:147-54.
DOI: https://doi.org/10.1182/blood-2016-09-692996
Long AT, Kenne E, Jung R, et al. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016;14:427-37.
DOI: https://doi.org/10.1111/jth.13235
Marin A, Bull L, Kinzie M, Andresen M. Central catheter-associated deep vein thrombosis in cancer: clinical course, prophylaxis, treatment. BMJ Support Palliat Care 2021;11: 371-80.
DOI: https://doi.org/10.1136/bmjspcare-2019-002106
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
Wang X, Cheng Q, Xu L, et al. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J Thromb Haemost 2005;3:695-702.
DOI: https://doi.org/10.1111/j.1538-7836.2005.01236.x
Wang X, Smith PL, Hsu MY, et al. Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice. J Thromb Haemost 2006;4:1982-8.
DOI: https://doi.org/10.1111/j.1538-7836.2006.02093.x
Ay C, Hisada Y, Cooley BC, Mackman N. Factor XI-deficient mice exhibit increased bleeding after injury to the saphenous vein. J Thromb Haemost 2017;15:1829-33.
DOI: https://doi.org/10.1111/jth.13766
Schumacher WA, Seiler SE, Steinbacher TE, et al. Antithrombotic and hemostatic effects of a small molecule factor XIa inhibitor in rats. Eur J Pharmacol 2007;570: 167-74.
DOI: https://doi.org/10.1016/j.ejphar.2007.05.043
Revenko AS, Gao D, Crosby JR, et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood 2011;118:5302-11.
DOI: https://doi.org/10.1182/blood-2011-05-355248
Renné T, Pozgajová M, Grüner S, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005;202:271-81.
DOI: https://doi.org/10.1084/jem.20050664
Renné T, Oschatz C, Seifert S, et al. Factor XI deficiency in animal models. J Thromb Haemost 2009;7:79-83.
DOI: https://doi.org/10.1111/j.1538-7836.2009.03393.x
Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol 2019;39: 331-8.
DOI: https://doi.org/10.1161/ATVBAHA.118.312130
Younis HS, Crosby J, Huh JI, et al. Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood 2012;119: 2401-8.
DOI: https://doi.org/10.1182/blood-2011-10-387134
Matafonov A, Leung PY, Gailani AE, et al. Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 2014;123:1739-46.
DOI: https://doi.org/10.1182/blood-2013-04-499111
Gruber A, Hanson SR. Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates. Blood 2003;102:953-5.
DOI: https://doi.org/10.1182/blood-2003-01-0324
Meijers JC, Tekelenburg WL, Bouma BN, et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000;342:696-701.
DOI: https://doi.org/10.1056/NEJM200003093421004
Cushman M, O’Meara ES, Folsom AR, Heckbert SR. Coagulation factors IX through XIII and the risk of future venous thrombosis: the longitudinal investigation of thromboembolism etiology. Blood 2009;114:2878-83.
DOI: https://doi.org/10.1182/blood-2009-05-219915
Georgi B, Mielke J, Chaffin M, et al. Leveraging human genetics to estimate clinical risk reductions achievable by inhibiting factor XI. Stroke 2019;50:3004-12.
DOI: https://doi.org/10.1161/STROKEAHA.119.026545
Preis M, Hirsch J, Kotler A, et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017;129:1210-5.
DOI: https://doi.org/10.1182/blood-2016-09-742262
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, 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
Stavrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res 2010;125:210-5.
DOI: https://doi.org/10.1016/j.thromres.2009.11.028
Weitz JI. Factor XI and factor XII as targets for new anticoagulants. Thromb Res 2016;141:S40-5.
DOI: https://doi.org/10.1016/S0049-3848(16)30363-2
Yuan S, Burgess S, Laffan M, et al. Genetically proxied inhibition of coagulation factors and risk of cardiovascular disease: a mendelian randomization study. J Am Heart Assoc 2021;10:e019644.
DOI: https://doi.org/10.1161/JAHA.120.019644
Key NS. Epidemiologic and clinical data linking factors XI and XII to thrombosis. Hematol Am Soc Hematol Educ Program 2014;2014:66-70.
DOI: https://doi.org/10.1182/asheducation-2014.1.66
Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991;325:153-8.
DOI: https://doi.org/10.1056/NEJM199107183250303
Weitz JI, Chan NC. Advances in antithrombotic therapy. Arterioscler Thromb Vasc Biol 2019;39:7-12.
DOI: https://doi.org/10.1161/ATVBAHA.118.310960
Johnson CY, Tuite A, Morange PE, et al. The factor XII -4C>T variant and risk of common thrombotic disorders: A HuGE review and meta-analysis of evidence from observational studies. Am J Epidemiol 2011;173:136-44.
DOI: https://doi.org/10.1093/aje/kwq349
Doggen CJ, Rosendaal FR, Meijers JC. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: Opposite and synergistic effects of factors XI and XII. Blood 2006;108:4045-51.
DOI: https://doi.org/10.1182/blood-2005-12-023697
Mäder J, Rolling CC, Voigtländer M, et al. Effect of factor XI inhibition on tumor cell-induced coagulation activation. J Thromb Haemost 2023;22:199-212.
DOI: https://doi.org/10.1016/j.jtha.2023.09.015
Dilger AK, Pabbisetty KB, Corte JR, et al. Discovery of milvexian, a high-affinity, orally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. J Med Chem 2022;65:1770-85.
DOI: https://doi.org/10.1021/acs.jmedchem.1c00613
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.
DOI: https://doi.org/10.1111/jth.15588
Kubitza D, Heckmann M, Distler J, et al. Pharmacokinetics, pharmacodynamics and safety of BAY 2433334, a novel activated factor XI inhibitor, in healthy volunteers: a randomized phase 1 multiple-dose study. Br J Clin Pharmacol 2022;88:3447-62.
DOI: https://doi.org/10.1111/bcp.15230
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.
DOI: https://doi.org/10.1056/NEJMoa1405760
Weitz JI, Bauersachs R, Becker B, et al. Effect of osocimabin 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
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
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
Nopp S, Kraemmer D, Ay C. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med 2022;9:903029.
DOI: https://doi.org/10.3389/fcvm.2022.903029
van Es N, De Caterina R, Weitz JI. Reversal agents for current and forthcoming direct oral anticoagulants. Eur Heart J 2023;44:1795-806.
DOI: https://doi.org/10.1093/eurheartj/ehad123
Pfeffer MA, Kohs TCL, 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.
DOI: https://doi.org/10.1161/ATVBAHA.123.319692
How to Cite
Di Nisio, M., Candeloro, M., Potere, N., Porreca, E., & Weitz, J. I. (2024). Factor XI inhibitors: a new option for the prevention and treatment of cancer-associated thrombosis. Bleeding, Thrombosis and Vascular Biology, 3(s1). https://doi.org/10.4081/btvb.2024.118
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