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At advanced stages, myocardial infarction, ischaemic stroke, and peripheral artery disease, including major adverse limb events, are caused either by acute occlusive atherothrombosis or by thromboembolism. Endothelial dysfunction, vascular smooth muscle cell activation, and vascular inflammation are essential in the development of acute cardiovascular events. Effects of the coagulation system on vascular biology extend beyond thrombosis. Under physiological conditions, coagulation proteases in blood are pivotal in maintaining haemostasis and vascular integrity. Under pathological conditions, including atherosclerosis, the same coagulation proteases (including factor Xa, factor VIIa, and thrombin) become drivers of atherothrombosis, working in concert with platelets and vessel wall components. While initially atherothrombosis was attributed primarily to platelets, recent advances indicate the critical role of fibrin clot and plasma coagulation factors. Mechanisms of atherothrombosis and hypercoagulability vary depending on plaque erosion or plaque rupture. In addition to contributing to thrombus formation, factor Xa and thrombin can affect endothelial dysfunction, oxidative stress, vascular smooth muscle cell function as well as immune cell activation and vascular inflammation. By these mechanisms, they promote atherosclerosis and contribute to plaque instability. In this review, we first discuss the postulated vasoprotective mechanisms of protease-activated receptor signalling induced by coagulation enzymes under physiological conditions. Next, we discuss preclinical studies linking coagulation with endothelial cell dysfunction, thromboinflammation, and atherogenesis. Understanding these mechanisms is pivotal for the introduction of novel strategies in cardiovascular prevention and therapy. We therefore translate these findings to clinical studies of direct oral anticoagulant drugs and discuss the potential relevance of dual pathway inhibition for atherothrombosis prevention and vascular protection.<\/jats:p>","DOI":"10.1093\/cvr\/cvaa263","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T19:14:13Z","timestamp":1599160453000},"page":"2030-2044","source":"Crossref","is-referenced-by-count":54,"title":["Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment"],"prefix":"10.1093","volume":"117","author":[{"given":"Hugo","family":"ten Cate","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Thrombosis Expertise Center, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, The Netherlands"},{"name":"Department of Biochemistry, Thrombosis Expertise Center, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz J","family":"Guzik","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular & Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, UK"},{"name":"Department of Medicine, Jagiellonian University, Collegium Medicum, Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4126-1285","authenticated-orcid":false,"given":"John","family":"Eikelboom","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, Hamilton General Hospital and McMaster University, Hamilton, L8L 2x2, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri M H","family":"Spronk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Thrombosis Expertise Center, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, The Netherlands"},{"name":"Department of Biochemistry, Thrombosis Expertise Center, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,15]]},"reference":[{"key":"2021072816515884000_cvaa263-B1","doi-asserted-by":"crossref","first-page":"e1332","DOI":"10.1016\/S2214-109X(19)30318-3","article-title":"World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions","volume":"7","year":"2019","journal-title":"Lancet Glob Health"},{"key":"2021072816515884000_cvaa263-B2","first-page":"582","article-title":"Coronary artery 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