Abstract 4359691: Factor XI Inhibition with AB023 Prevents Mechanical Valve Thrombosis in a Porcine Pulmonary Model Without Bleeding Events

Background: Mechanical heart valves offer lifelong durability but require continuous anticoagulation to prevent thrombosis. Vitamin K antagonists (VKAs) remain the standard of care despite bleeding risks and monitoring challenges, as direct oral anticoagulants failed to demonstrate efficacy. Factor XI (FXI) inhibitors that offer targeted anticoagulation without increased bleeding risk may provide a safer alternative. Hypothesis: We hypothesized that factor XI inhibition using the monoclonal antibody AB023 (gruticibart) would effectively prevent thrombosis of mechanical heart valves implanted in the pulmonary position of pigs, without causing bleeding or thromboembolic complications. Methods: Six juvenile pigs underwent pulmonary valve replacement with 21-mm On-X mechanical valves. Three pigs (test group) received AB023 (4 mg/kg IV every 2 weeks); three (control group) received placebo. Follow-up was 3 months or until terminal valve thrombosis. Valve performance was evaluated with serial fluoroscopy and cardiac ultrasound, alongside postmortem macroscopic analysis of the valve and histopathological examination of the lungs. Activated partial thromboplastin time (aPTT) was monitored to confirm anticoagulation. Results: All test group valves maintained normal function until study termination at 3 months, with no thromboembolism or bleeding. Explanted valves showed no thrombi on leaflets or hinges, and lungs exhibited no signs of thromboembolism or bleeding. AB023 consistently prolonged aPTT to ~40 seconds (> 2-fold elevation from baseline), confirming therapeutic anticoagulation. In contrast, all control group valves thrombosed after 16, 24, and 49 days. Conclusion: This is the first preclinical study using a validated in vivo model demonstrating that targeting FXI can successfully prevent mechanical valve thrombosis. Biweekly AB023 dosing preserved valve function in all test animals without bleeding complications, supporting its potential as a safer alternative to VKA therapy. These findings warrant further investigation in larger, longer-term studies and may form the basis for future clinical translation.