{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:21:39Z","timestamp":1790364099016,"version":"4.1.0"},"reference-count":52,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Thrombospondin-1 (TSP-1) is released by platelets upon activation and can increase platelet activation, but its role in hemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of hemostasis that promotes platelet activation by modulating inhibitory cyclic adenosine monophosphate (cAMP) signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of hemostasis and thrombosis showed that TSP-1\u2013deficient mice had prolonged bleeding, defective thrombosis, and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild-type (WT) but not TSP-1\u2212\/\u2212 platelets ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1\u2013deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation, and arrest under flow by prostacyclin (PGI2). Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1\u2212\/\u2212 platelets. By contrast, incubation of TSP-1\u2212\/\u2212 platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1\u2212\/\u2212 platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1\u2212\/\u2212 mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2\/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This scenario suggests that the release of TSP-1 regulates hemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.<\/jats:p>","DOI":"10.1182\/blood.2020005382","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T16:01:08Z","timestamp":1599148868000},"page":"678-689","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":80,"title":["Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets"],"prefix":"10.1182","volume":"137","author":[{"given":"Ahmed","family":"Aburima","sequence":"first","affiliation":[{"name":"Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Berger","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, RWTH Aachen University, Aachen, Germany;"},{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E. 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