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Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in <jats:italic>Apoe<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (<jats:italic>Apoe<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice). Bone marrow from wild-type or <jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice was transplanted into irradiated <jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in <jats:italic>Apoe<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.<\/jats:p>","DOI":"10.1038\/s41598-020-78522-9","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T11:04:42Z","timestamp":1607425482000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Mild hyperlipidemia in mice aggravates platelet responsiveness in thrombus formation and exploration of platelet proteome and lipidome"],"prefix":"10.1038","volume":"10","author":[{"given":"Johanna P.","family":"van Geffen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke","family":"Swieringa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"van Kuijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibian M. 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