Targeting Factor XI and Factor XIa to Prevent Thrombosis

Abstract

Direct oral anticoagulants (DOACs) that inhibit the coagulation proteases thrombin or factor Xa have replaced warfarin and other vitamin K antagonists (VKA) for most indications requiring long-term anticoagulation. In many clinical situations, DOACs are as effective as VKAs, cause less bleeding, and do not require laboratory monitoring. However, because DOACs target proteases that are required for hemostasis, their use increases the risk of serious bleeding. Concerns over therapy-related bleeding undoubtedly contribute to under-treatment of many patients who would benefit from anticoagulation therapy. There is considerable interest in the plasma zymogen factor XI (FXI) and its protease form factor XIa (FXIa) as drug targets for treating and preventing thrombosis. Laboratory and epidemiologic studies support the conclusion that FXI contributes to venous and arterial thrombosis. Based on seventy years of clinical observations of patients lacking FXI, it is anticipated that drugs targeting this protein will cause less severe bleeding than warfarin or DOACs. In phase 2 studies, drugs that inhibit FXI or FXIa prevent venous thromboembolism after total knee arthroplasty as well as, or better than, low molecular weight heparin. Patients with heart disease on FXI/XIa inhibitors experienced less bleeding than patients on DOACs. Based on these early results, phase 3 trials have been initiated that compare drugs targeting FXI and FXIa to standard treatments or placebo. Here we review the contributions of FXI to normal and abnormal coagulation and discuss results from pre-clinical, nonclinical, and clinical studies of FXI and FXIa inhibitors.