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 a high phosphatidylserine (PS)–exposed procoagulant platelet (hPPL) derivative reprogrammed from isolated platelets via calcium ionophore A23187–induced apoptosis, enriched in surface PS and capable of driving rapid hemostasis. Retaining a protein profile akin to resting platelets, hPPLs robustly promoted platelet activation and aggregation in human- and rat-derived plasma and whole blood in vitro and demonstrated superior hemostatic efficacy compared with clinical thrombin and commercial hemostatic materials [microporous polysaccharide hemispheres (MPH) and FIBRILLAR] in murine liver injury and porcine gastric ulcer bleeding models, even under antiplatelet treatment. Mechanistically, hPPLs up-regulated prostaglandin E synthase (PTGES), thereby increasing prostaglandin E2 (PGE 2 ) production and its receptor 3 (EP3)–mediated platelet activation, which reinforced PS-mediated clot formation. Our findings identified an apoptosis-driven PTGES-PGE 2 -EP3 signaling axis that augmented PS-mediated coagulation in murine and porcine hemorrhage models and established the hPPL derivative as a topical hemostatic agent with translational potential for organ-related bleeding and distinct advantages in managing complex endoscopic hemorrhages under both physiological and coagulopathic conditions.