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Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI<jats:sub>2<\/jats:sub> could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI<jats:sub>2<\/jats:sub> over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI<jats:sub>2<\/jats:sub> reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI<jats:sub>2<\/jats:sub> on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI<jats:sub>2<\/jats:sub> caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI<jats:sub>2<\/jats:sub> can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis.<\/jats:p>","DOI":"10.1038\/s41598-017-05817-9","type":"journal-article","created":{"date-parts":[[2017,7,11]],"date-time":"2017-07-11T10:54:36Z","timestamp":1499770476000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability"],"prefix":"10.1038","volume":"7","author":[{"given":"M. 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