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The aim of this study was to compare two direct\u2010acting, reversible P2Y<jats:sub>12<\/jats:sub>antagonists,<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 and ticagrelor, in a rat thrombosis model by simultaneous quantification of their antithrombotic efficacy and surgery\u2010induced blood loss. Blood flow velocity was assessed in the carotid artery after FeCl<jats:sub>3<\/jats:sub>\u2010induced thrombus formation using a Doppler flow probe. At the same time, blood loss after surgical wounding of the spleen was quantified. Continuous infusions of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 and ticagrelor prevented the injury\u2010induced reduction of blood flow in a dose\u2010dependent manner. High doses of both antagonists normalized blood flow and completely abolished thrombus formation as confirmed by histology. Intermediate doses restored baseline blood flow to \u226565%. However,<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 caused significantly less increase of blood loss than ticagrelor; the difference in blood loss was 2.6\u2010fold (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) at high doses and 2.7\u2010fold (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) at intermediate doses. Potential reasons for this unexpected difference were explored by measuring the effects of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 and ticagrelor on vascular tone. At concentrations needed to achieve maximal antithrombotic efficacy, ticagrelor compared with<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 significantly increased carotid blood flow velocity in\u00a0vivo (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.003), induced vasorelaxation of precontracted rat femoral arteries, and inhibited contraction of femoral artery induced by electrical field stimulation or by phenylephrine. Overall,<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 showed a significantly wider therapeutic window than ticagrelor. The absence of vasodilatory effects due to high selectivity of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 for P2Y<jats:sub>12<\/jats:sub>provides potential arguments for the observed safety advantage of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010246475 over ticagrelor.<\/jats:p>","DOI":"10.1002\/prp2.338","type":"journal-article","created":{"date-parts":[[2017,8,14]],"date-time":"2017-08-14T03:02:40Z","timestamp":1502679760000},"source":"Crossref","is-referenced-by-count":29,"title":["The reversible P2Y<sub>12<\/sub>antagonist ACT\u2010246475 causes significantly less blood loss than ticagrelor at equivalent antithrombotic efficacy in rat"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5391-4872","authenticated-orcid":false,"given":"Markus","family":"Rey","sequence":"first","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd. 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