Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets

Abstract Thrombospondin-1 (TSP-1) is released by platelets upon activation and can increase platelet activation, but its role in hemostasis vivo unclear. We show that TSP-1 a critical mediator of promotes modulating inhibitory cyclic adenosine monophosphate (cAMP) signaling. Genetic deletion did not affect vitro, models thrombosis showed TSP-1–deficient mice had prolonged bleeding, defective thrombosis, increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer wild-type (WT) TSP-1−/− ameliorated thrombotic phenotype, suggesting key for platelet-derived TSP-1. In functional assays, an cAMP signaling, inhibition aggregation, arrest under flow (PGI2). Plasma swap experiments plasma correct PGI2 hypersensitivity platelets. By contrast, incubation with releasates from WT or purified TSP-1, platelets, reduced effects PGI2. Activation resulted diminished accumulation downstream which was associated activity hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A were unaffected mice. Platelets deficient CD36, receptor, PGI2/cAMP signaling activity, This scenario suggests release regulates through modulation at sites vascular injury.