Beyond traditional anticoagulants: exploring the future of thromboembolism treatment with FXI inhibitors

Abstract

Thromboembolic diseases impose a significant burden on global health. However, the currently approved anticoagulant drugs, including heparin, vitamin K antagonists, and direct oral anticoagulants (DOACs), all carry certain bleeding risks. The proteases inhibited by these drugs play crucial roles in both pathological thrombosis formation and normal hemostasis. Therefore, how to effectively anticoagulate without increasing bleeding has become the core direction of clinical research. Factor XI (FXI) and activated factor XI (FXIa) are increasingly recognized as regulators at the interface between coagulation and immunothrombosis. Experimental studies suggest that FXI/FXIa may interact with neutrophil extracellular trap formation (NETosis), complement activation, and inflammatory signaling pathways, raising the possibility that FXI/FXIa inhibition could have broader effects beyond anticoagulation. However, the clinical relevance of these immunomodulatory functions remains to be established. Genetic evidence also supports this characteristic: FXI deficiency can reduce the risk of venous thromboembolism (VTE) and does not lead to spontaneous bleeding, whereas elevated FXI levels increase thrombotic events. Thus, FXI/FXIa have become promising targets due to their unique biological properties. Currently, FXI inhibitors have been developed in various formulations, including antisense oligonucleotides, monoclonal antibodies, and small - molecule synthetic drugs. The phase II clinical trials of FXI inhibitors have achieved positive results in the treatment of knee joint replacement surgery, end - stage renal disease, atrial fibrillation (AF), acute non - cardiogenic thromboembolic ischemic stroke, and high - risk transient ischemic attack (TIA). Phase III clinical trials of certain FXI inhibitors are also being actively conducted. The review focuses on the spatial structure of FXI, its role in the coagulation pathway and pathological thrombosis formation, immunothrombosis and gene polymorphisms. It introduces the current cutting - edge drugs in development, summarizes the results of completed clinical trials, and discusses the current research progress.