{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:13:29Z","timestamp":1787224409145,"version":"build-2736575974"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Dutch Thrombosis Society","award":["2014.02"],"award-info":[{"award-number":["2014.02"]}]},{"name":"Norwegian Research Council, Nattopharma ASA and the European Union\u2019s Horizon 2020 research and innovation"},{"name":"Marie Sklodowska-Curie","award":["72260"],"award-info":[{"award-number":["72260"]}]},{"name":"Marie Sklodowska-Curie","award":["813409"],"award-info":[{"award-number":["813409"]}]},{"name":"Alexander von Humbold Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Vascular calcification is a hallmark of atherosclerotic burden and can predict the cardiovascular outcome. Vitamin K antagonists (VKA) are widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis but are also associated with increase vascular calcification progression. We aim to unravel the paradox that VKA suppresses plasma coagulation but promotes vascular calcification and subsequent atherosclerosis-dependent coagulability of the vessel wall.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Apoe \u2212\/\u2212 mice were placed on western-type diet enriched with the VKA warfarin for 18 weeks to measure atherosclerotic plaque burden, calcification, and coagulation. Patients (n = 54) displaying paroxysmal atrial fibrillation with a low cardiovascular risk, who were treated with VKA were included to measure pre-thrombotic state. Finally, primary vascular smooth muscle cells (VSMC) derived from human tissue explants were used for in vitro experiments. In Apoe\u2212\/\u2212 mice, VKA increases both atherosclerotic plaque size and calcification. Higher plaque calcification was associated with increased plasma levels of thrombin-antithrombin and factor IXa-antithrombin complexes in mice and patients treated with VKA. Mechanistically, phenotypic switching of VSMC into synthetic VSMC promotes thrombin generation, which is enhanced in a tissue-factor (TF)-dependent manner by VSMC calcification. Moreover, calcified VSMC exposed to whole blood under flow significantly enhanced platelet deposition and TF-dependent fibrin formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Oral anticoagulation with VKA aggravates vascular calcification and atherosclerosis. VSMC phenotype differentiation impacts coagulation potential in a TF-dependent manner. VKA-induced vascular calcification increases hypercoagulability and could thereby potentially positively affect atherothrombosis.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ehjopen\/oeab017","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T17:16:13Z","timestamp":1628270173000},"source":"Crossref","is-referenced-by-count":8,"title":["Vitamin K antagonist use induces calcification and atherosclerotic plaque progression resulting in increased hypercoagulability"],"prefix":"10.1093","volume":"1","author":[{"given":"Rick H","family":"van Gorp","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre , Maastricht, The Netherlands"},{"name":"Nattopharma ASA , Olso, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance C F M J","family":"Baaten","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre , Maastricht, The Netherlands"},{"name":"Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen , Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9041-1812","authenticated-orcid":false,"given":"Anxhela","family":"Habibi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre , Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-2363","authenticated-orcid":false,"given":"Armand M G","family":"Jaminon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre , Maastricht, The 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