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

Abstract

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, hPPL 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, hPPL upregulated prostaglandin E synthase (PTGES), thereby increasing prostaglandin E2 (PGE₂) production and its receptor 3 (EP3)-mediated platelet activation, which reinforced PS-mediated clot formation. Our findings identified an apoptosis-driven PTGES/PGE₂/EP3 signaling axis that augmented PS-mediated coagulation in murine and porcine hemorrhage models, and established hPPL 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.