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We show here that Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>mice, but not Epac2<jats:sup>\u2212\/\u2212<\/jats:sup>mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding. The Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>mice had deficient<jats:italic>in vitro<\/jats:italic>secondary hemostasis. Quantitative comprehensive proteomics analysis revealed that Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>mouse platelets (thrombocytes) had unbalanced expression of key components of the glycoprotein Ib-IX-V (GPIb-IX-V) complex, with decrease of GP1b\u03b2 and no change of GP1b\u03b1. This complex is critical for platelet adhesion under arterial shear conditions. Furthermore, Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>mice have reduced levels of plasma coagulation factors and fibrinogen, increased size of circulating platelets, increased megakaryocytes (the GP1b\u03b2 level was decreased also in Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>bone marrow) and higher abundance of reticulated platelets. Viscoelastic measurement of clotting function revealed Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>mice with a dysfunction in the clotting process, which corresponds to reduced plasma levels of coagulation factors like factor XIII and fibrinogen. We propose that the observed platelet phenotype is due to deficient Epac1 activity during megakaryopoiesis and thrombopoiesis, and that the defects in blood clotting for Epac1<jats:sup>\u2212\/\u2212<\/jats:sup>is connected to secondary hemostasis.<\/jats:p>","DOI":"10.1038\/s41598-017-08975-y","type":"journal-article","created":{"date-parts":[[2017,8,14]],"date-time":"2017-08-14T10:41:35Z","timestamp":1502707295000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIb\u03b2 expression"],"prefix":"10.1038","volume":"7","author":[{"given":"Gyrid","family":"Nygaard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Herfindal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrine S.","family":"Asrud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronja","family":"Bj\u00f8rnstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reidun K.","family":"Kopperud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2206-1480","authenticated-orcid":false,"given":"Eystein","family":"Oveland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frode S.","family":"Berven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene","family":"Myhren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erling A.","family":"Hoivik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Turid Helen Felli","family":"Lunde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marit","family":"Bakke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stein O.","family":"D\u00f8skeland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frode","family":"Selheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,18]]},"reference":[{"key":"8975_CR1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.blre.2011.03.002","volume":"25","author":"K Broos","year":"2011","unstructured":"Broos, K., Feys, H. 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