Reprogrammed apoptotic platelets drive rapid hemostasis through phosphatidylserine and prostaglandin E2 signaling in preclinical models

Uncontrolled hemorrhage in trauma, surgical, organ-related, and endoscopic settings, particularly in patients receiving antiplatelet therapy, remains difficult to manage clinically. Here, we introduce hPPL, a reprogrammed procoagulant platelet derivative generated by calcium ionophore A23187-induced apoptosis, enriched in surface phosphatidylserine (PS) and capable of driving rapid hemostasis. Retaining a protein profile akin to resting platelets, hPPL robustly promotes platelet activation and aggregation, demonstrating superior hemostatic efficacy compared with clinical thrombin and hemostatic materials (MPH and FIBRILLAR™) in murine and porcine bleeding models, even under antiplatelet treatment. Mechanistically, hPPL uniquely upregulates prostaglandin E synthase (PTGES), thereby increasing prostaglandin E2 (PGE2) production and EP3 receptor-mediated platelet activation, which synergize with PS to amplify clot formation. Our findings uncover a previously unrecognized apoptosis-driven PTGES/PGE2/EP3 signaling axis that reinforces PS-mediated coagulation, establishing hPPL as a transformative, natural topical hemostatic agent with broad translational potential for organ-related bleeding and distinct advantages in managing complex endoscopic hemorrhages under both physiological and coagulopathic conditions.