Factor XI inhibition with gruticibart prevents mechanical valve thrombosis in a porcine pulmonary model.

Mechanical heart valves have excellent lifelong durability but require lifelong anticoagulation, traditionally with vitamin K antagonists, which increase bleeding risk and require monitoring. Factor XI (FXI) inhibitors may provide safer anticoagulation by targeting the intrinsic pathway while preserving hemostasis. This study evaluated whether FXI inhibition with the A2-domain-specific monoclonal antibody, gruticibart (AB023), could prevent thrombosis of mechanical valves after implantation in the pulmonary position of pigs, without causing bleeding or thromboembolic complications. Six juvenile pigs underwent pulmonary valve replacement with 21-mm On-X mechanical valves; 3 pigs received gruticibart, and 3 received no treatment. Animals were followed up for 3 months or until valve failure. Valve motion was assessed with serial fluoroscopy and cardiac ultrasonography. At termination, valves and lungs were examined macroscopically and histologically. Activated partial thromboplastin time (aPTT) was monitored to confirm the anticoagulant effect. Gruticibart more than doubled the baseline aPTT and maintained a stable prolongation to ∼40 seconds. All gruticibart-treated valves remained fully functional throughout the study, with unrestricted leaflet motion and normal gradients. No thrombus, hinge obstruction, or pulmonary emboli were identified at explantation. In contrast, all control animals developed severe valve thrombosis requiring early termination at 16, 24, and 49 days. No bleeding or thromboembolic events occurred in either group. Factor XI inhibition with gruticibart fully prevented mechanical valve thrombosis in this validated porcine model. Biweekly dosing produced stable anticoagulation without bleeding. These findings support FXI inhibition as a promising alternative to vitamin K antagonists for mechanical valve anticoagulation and justify larger, longer-term studies.