Targeting factor XI as a compromise between thrombosis and bleeding.

Abstract

Thromboembolic diseases have long been a leading cause of morbidity and mortality, necessitating advances in anticoagulant drugs. Heparins, vitamin K inhibitors, and direct oral anticoagulants (DOACs) are well-established drug classes that help prevent thromboembolic complications. While effective, they pose significant risks during long-term therapy, including bleeding, osteoporosis, heparin-induced thrombocytopenia, and the need for frequent monitoring and dose adjustments. Factor XI (FXI) inhibitors represent an innovative approach in anticoagulation therapy, aiming to balance thromboembolic events with the risk of bleeding complications. They include: a) orally administered small molecule inhibitors such as milvexian and asundexian; b) monoclonal antibodies such as abelacimab, osocimab, and xisomab, which specifically bind and inactivate FXI; c) FXI-antisense oligonucleotide (FXI-ASO), which downregulate FXI synthesis at the mRNA level and reduce plasma FXI concentrations. Available data indicate that FXI inhibitors decrease the risk of thromboembolic events and are associated with a lower incidence of major bleeding than current gold standard methods. Hence, FXI inhibitors may become the preferred anticoagulant class, especially for patients with elevated bleeding risk. Their development is an important step in the history of anticoagulant therapy, striving to find a balance between preventing thromboembolism and reducing bleeding risk, ultimately improving patient outcomes. In this context, a discussion on the characteristics of FXI inhibitors, a summary on data regarding the efficacy and safety of FXI inhibitors based on preclinical and clinical studies, and an outline of future perspectives regarding therapeutic strategies of FXI inhibition in venous thrombosis are presented in this study.