Targeting coagulation factor XI/XIa for anticoagulation therapy: from mechanism to drug development

Coagulation Factor XI (FXI) and its activated form FXIa have been identified as important regulators of thrombin amplification, contributing substantially to pathological thrombosis while exerting a relatively limited role in physiological hemostasis, making it an attractive target for low-hemorrhagic antithrombotic therapy. In recent years, FXI/FXIa-targeted therapeutics have rapidly advanced in clinical trials and represent a promising strategy for precision anticoagulation. This review systematically summarizes the structural features, biological functions, and mechanistic roles of FXI/FXIa in thrombosis, followed by structure-guided drug design, major therapeutic modalities, and clinical translation. Clinical evidence is critically evaluated to highlight both the opportunities and limitations of FXI/FXIa-targeted therapies across different thrombotic indications. Furthermore, key challenges, including selectivity optimization, disease-dependent efficacy, and the physiological functions of FXI beyond coagulation, are discussed. A more comprehensive understanding of FXI biology will be essential for defining the long-term safety, therapeutic window and clinical positioning of FXI/FXIa-targeted anticoagulants.