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However, the non\u2010platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet\u2010COX\u20101\u2010ko mice to define the platelet and non\u2010platelet eicosanoids affected by aspirin. Mass\u2010spectrometry analysis demonstrated blood from platelet\u2010COX\u20101\u2010ko and global\u2010COX\u20101\u2010ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA\n                    <jats:sub>2<\/jats:sub>\n                    , prostaglandin (PG) F\n                    <jats:sub>2\u03b1<\/jats:sub>\n                    , 11\u2010hydroxyeicosatraenoic acid (HETE), and 15\u2010HETE was absent in both platelet\u2010 and global\u2010COX\u20101\u2010ko mice. Conversely, in vivo\n                    <jats:italic>,<\/jats:italic>\n                    platelet\u2010COX\u20101\u2010ko mice had a distinctly different profile from global\u2010COX\u20101\u2010ko or aspirin\u2010treated control mice, notably significantly higher levels of PGI\n                    <jats:sub>2<\/jats:sub>\n                    metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet\u2010COX\u20101\u2010ko mice would be protected from thrombosis, forming less pro\u2010thrombotic TxA\n                    <jats:sub>2<\/jats:sub>\n                    and PGE\n                    <jats:sub>2<\/jats:sub>\n                    . Conversely, aspirin or lack of systemic COX\u20101 activity decreased the synthesis of anti\u2010aggregatory PGI\n                    <jats:sub>2<\/jats:sub>\n                    and PGD\n                    <jats:sub>2<\/jats:sub>\n                    at non\u2010platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX\u20101 in platelets and in the remainder of the cardiovascular system and linked them to anti\u2010 and pro\u2010thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.\n                  <\/jats:p>","DOI":"10.1096\/fj.202000312r","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T14:16:54Z","timestamp":1596032214000},"page":"10027-10040","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Profiling the eicosanoid networks that underlie the anti\u2010 and pro\u2010thrombotic effects of aspirin"],"prefix":"10.1096","volume":"34","author":[{"given":"Marilena","family":"Crescente","sequence":"first","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul C.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, 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University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Mein","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Gaston\u2010Massuet","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme S.","family":"Cottrell","sequence":"additional","affiliation":[{"name":"Reading School of Pharmacy and ICMR University of Reading Reading UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"National Heart &amp; 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