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

Aburima, Ahmed; Berger, Martin; Spurgeon, Benjamin EJ; Webb, Beth A; Wraith, Katie S; Febbraio, Maria; Poole, Alastair W.; Naseem, Khalid M

Authors

Martin Berger

Benjamin EJ Spurgeon

Beth A Webb

Maria Febbraio

Alastair W. Poole

Khalid M Naseem



Abstract

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–deficient mice had prolonged bleeding, defective thrombosis, and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild-type (WT) but not TSP-1−/− platelets ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1–deficient 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−/− platelets. By contrast, incubation of TSP-1−/− platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1−/− 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−/− 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.

Citation

Aburima, A., Berger, M., Spurgeon, B. E., Webb, B. A., Wraith, K. S., Febbraio, M., …Naseem, K. M. (2021). Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets. Blood, 137(5), 678-689. https://doi.org/10.1182/blood.2020005382

Journal Article Type Article
Acceptance Date Jul 31, 2020
Online Publication Date Sep 3, 2020
Publication Date Feb 4, 2021
Deposit Date Feb 8, 2021
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 137
Issue 5
Pages 678-689
DOI https://doi.org/10.1182/blood.2020005382
Keywords Platelets and thrombopoiesis; Thrombosis and hemostasis
Public URL https://hull-repository.worktribe.com/output/3620589
Publisher URL https://ashpublications.org/blood/article-abstract/137/5/678/463620/Thrombospondin-1-promotes-hemostasis-through?redirectedFrom=fulltext
Related Public URLs http://eprints.whiterose.ac.uk/165667/

https://www.sciencedirect.com/science/article/pii/S0006497121002184