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.