Factor XIa inhibition for the prevention of thrombosis: mechanism, clinical trial signals, and indication-specific positioning

PURPOSE OF REVIEW: Factor XI (FXI) and its activated form, factor XIa (FXIa), have emerged as a leading novel anticoagulant target of the past decade. This review summarizes mechanistic and clinical data from 2023 through 2026 and proposes an indication-specific framework for FXIa inhibitor positioning. RECENT FINDINGS: Three large randomized studies diverged by indication. Abelacimab reduced major and clinically relevant nonmajor bleeding by 62% versus rivaroxaban in atrial fibrillation (AZALEA-TIMI 71). Asundexian was inferior to apixaban for stroke prevention in atrial fibrillation (OCEANIC-AF) yet reduced recurrent stroke after noncardioembolic events (OCEANIC-STROKE). Milvexian entered a three-trial phase 3 program. FXIa has been found to drive platelet and endothelial activation in inflammation-associated thrombosis, whereas the FXI zymogen has noncoagulation roles that include activation of bone morphogenetic protein 7-SMAD1/5 cardioprotection. A fifth drug class of allosteric FXI activation inhibitors was further characterized. SUMMARY: FXIa contribution to thrombus formation varies by anatomic site, flow conditions, and inflammatory phenotype. The clinical data support indication-specific positioning for cancer-associated thrombosis, secondary stroke prevention, and patients at high bleeding risk, but provide weaker support for broad substitution for direct oral anticoagulants.