Targeting Factor XI for Safer Anticoagulation: Emerging Data and Future Directions

: Despite major advances with direct oral anticoagulants (DOACs), the clinical challenge of minimizing bleeding without losing efficacy remains unresolved. Factor XI (FXI) plays a pivotal role in thrombosis with limited contribution to hemostasis, making it an attractive target for novel anticoagulant therapy. Inhibition of FXI or its active form, FXIa, may therefore achieve effective antithrombotic protection while reducing the risk of bleeding. This review summarizes the biological rationale for targeting FXI, key pharmacological features of different inhibitor classes, and the main results from phase I-II trials of antisense oligonucleotides, monoclonal antibodies, and small-molecule FXIa inhibitors. It also discusses the ongoing phase III programs evaluating these agents across clinical settings, including atrial fibrillation, venous thromboembolism, and secondary prevention after acute coronary syndromes. Early phase studies have demonstrated robust and reproducible benefits in preventing venous thromboembolism after major orthopedic surgery, whereas efficacy in atrial fibrillation and secondary stroke prevention has been more variable. Key uncertainties persist regarding the most suitable indications, patient selection criteria, and how FXI inhibitors should be positioned alongside existing DOACs, particularly in high-bleeding-risk groups unsuitable for oral therapy, such as those with severe kidney failure, on dialysis, or facing cancer-related thrombosis.