Bleeding phenotypes associated with P2Y12 inhibitor therapy in venoarterial extracorporeal membrane oxygenation

Background: Many patients requiring VA-ECMO for acute coronary syndromes receive P2Y12 inhibitor therapy to prevent stent thrombosis, yet existing literature reports only composite bleeding rates without stratification by anatomic site. Whether P2Y12 inhibitor use produces distinct bleeding patterns compared to standard heparin anticoagulation remains underexplored. Methods: Retrospective analysis of adult VA-ECMO patients at NewYork-Presbyterian Hospital (April 2011–January 2025). Patients receiving P2Y12 inhibitors plus heparin ( n = 36) were compared to those receiving standard heparin alone ( n = 129). Postcardiotomy patients were excluded. Primary outcomes were site-specific bleeding complications. Multivariate logistic regression adjusted for baseline differences in illness severity. Results: P2Y12 patients were older (63.0 vs 50.7 years, p < 0.001), had higher rates of cardiac arrest (83.3% vs 55.0%, p = 0.002), and elevated lactate (10.2 vs 7.1 mmol/L, p = 0.004). P2Y12 inhibitor use was associated with increased airway hemorrhage (19.4% vs 7.0%, p = 0.049) and reduced weaning success (44.4% vs 66.7%, p = 0.015). On multivariate analysis adjusting for illness severity, P2Y12 inhibitor use was not associated with bleeding complications or mortality, whereas lactate was an independent predictor of mortality (OR 1.11 per mmol/L, 95% CI 1.02–1.20, p = 0.020). Conclusions: Although not independently associated with bleeding complications, P2Y12 inhibitor therapy in VA-ECMO patients identifies a high-risk population with elevated airway hemorrhage. These findings support enhanced mucosal surveillance and individualized anticoagulation strategies in this vulnerable population.