The new in anticoagulation: factor XI inhibitors

Abstract

Haemostasis and thrombosis are closely linked, so that any anticoagulant strategy available today that reduces the thrombotic risk inevitably increases the bleeding risk. However, epidemiological and experimental evidence suggests that inhibiting the contact pathway—the first phase of the intrinsic coagulation pathway—and especially factor XI (FXI) achieves the objective of preventing thrombosis with minimal interference on the haemostatic process. Several pharmacological strategies that act by inhibiting FXI are being studied in clinical trials. Specifically, Phase 2 clinical trials in patients undergoing major orthopaedic surgery, end-stage renal disease, atrial fibrillation (AF), and acute coronary syndrome have shown promising results, allowing clinical research to advance into Phase 3 clinical trials. FXI inhibitors will not necessarily replace currently available direct oral anticoagulants: this would appear too ambitious as of today. However, it is possible to hypothesize that FXI inhibitors are a useful addition to our therapeutic armamentarium in contexts where current anticoagulants have failed or have not been adequately tested, as well as in categories of patients who are at a high risk of bleeding even with current direct oral anticoagulants.

Distinct pleiotropic effects of direct oral anticoagulants on cultured endothelial cells: a comprehensive review

“…The most promising class of compounds is FXIa inhibitors, which target the coagulation cascade upstream of the currently existing DOACs. Some of these compounds, such as asundexian and milvexian, are currently in phase 3 clinical trials, and there is evidence that they can inhibit thrombosis while preserving hemostasis ( Schumacher et al, 2010 ; Muscente and De Caterina, 2023 ; Wichaiyo et al, 2023 ). Emerging preclinical evidence suggests that FXIa inhibitors may exert pleiotropic effects, such as anti-inflammatory and anti-atherogenic ( Ngo et al, 2021 ).…”

Anticoagulation in the ICU: a future for contact pathway inhibition?

“…In recent decades, different parenteral and oral anticoagulants became available, almost all targeting the common pathway via effects on factor (F)IIa or FXa (except for citrate, which works through calcium chelation and pH alterations). [1,4] Unfortunately, all anticoagulants are limited by their associated bleeding risk. Recently, new kids on the block have appeared, as contact pathway inhibitors targeting FXI and FXII made their entrance, endorsed by epidemiological data from genetic disorders concerning these coagulation factors.…”

“…Recently, new kids on the block have appeared, as contact pathway inhibitors targeting FXI and FXII made their entrance, endorsed by epidemiological data from genetic disorders concerning these coagulation factors. [4] Individuals with congenital FXI-deficiency rarely exhibit spontaneous major bleeding and have a lower risk of venous thromboembolism (VTE) and possibly acute myocardial infarction (AMI). They however, might exhibit a higher risk of minor bleeding after trauma or surgery, especially when the trauma involves mucosal tissues rich in fibrinolytic activity, such as the oropharynx/nasopharynx and genitourinary tract.…”

“…Consequently, a contact pathway inhibitor could prevent thrombosis, without interfering with haemostasis. [4,8] On the ICU, contact pathway inhibition could even be a double-win, given the fact that FXI and FXII are strongly activated by negatively charged plastic surfaces of non-biological materials such as catheters, cannulas or devices, which are omnipresent in critically ill. Especially in patients on pMCS, contact pathway inhibition could be a real game changer, as it might tackle LIC and device-related thrombosis, without the increased major bleeding risk that accompanies other anticoagulants (Figure 1).…”