Abstract
BACKGROUND: The development of anticoagulants that provide antithrombotic efficacy without a concomitant bleeding risk remains an unmet clinical need in thrombosis. Although direct oral anticoagulants (DOACs) have a reduced incidence of major bleeding compared with warfarin, they still carry a bleeding risk, resulting in a suboptimal therapeutic index. Epidemiologic data suggest that inhibiting activated factor XI (FXIa) may offer an improved safety profile with respect to bleeding risk compared with current-generation DOACs. Additionally, a phase II trial of milvexian in patients undergoing elective total knee replacement demonstrated robust dose-dependent efficacy with no statistically significant increase in bleeding. Nevertheless, the ability to rapidly and effectively correct FXIa inhibitor-induced anticoagulation may still be important in situations where patients experience uncontrolled bleeding or require emergency surgery. OBJECTIVES: We assessed the ability to normalize the anticoagulant effects of the novel small-molecule FXIa inhibitor milvexian (BMS-986177/JNJ-70033093) in vitro using commercially available prohemostatic agents. METHODS: Milvexian-associated anticoagulation and correction was evaluated in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. RESULTS: Activated prothrombin complex concentrates (PCCs) and recombinant factor (rF)VIIa corrected the anticoagulant effects of milvexian in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. In contrast, other agents, including PCCs, rFIX, and rFVIII, demonstrated either modest or no correction of milvexian-associated anticoagulation. CONCLUSION: This study demonstrated that currently available activated PCCs and rFVIIa normalize the anticoagulation induced by milvexian in vitro. The clinical utility of these agents remains to be established.