{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:50:02Z","timestamp":1791402602683,"version":"4.3.3"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006020","name":"Center for Translational Molecular Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006020","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012028","name":"Trombosestichting Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012028","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Major bleeding occurs annually in 1%\u20133% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [<jats:italic>CYP2C9<\/jats:italic>] and 4F2 [<jats:italic>CYP4F2<\/jats:italic>], gamma\u2010glutamyl carboxylase [<jats:italic>GGCX<\/jats:italic>]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit\u20101 (<jats:italic>VKORC1<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A case\u2010cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613\u2009years of follow\u2010up and a random subcohort of 978 patients. We determined variants in <jats:italic>CYP2C9<\/jats:italic>, <jats:italic>CYP4F2<\/jats:italic>, <jats:italic>GGCX<\/jats:italic>, <jats:italic>VKORC1<\/jats:italic> and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. <jats:italic>CYP4F2<\/jats:italic>\u2010TT carriership was associated with a 1.6\u2010fold (95% CI 0.9\u20132.8) increased risk of major bleeding compared with CC\u2010alleles, albeit not statistically significant. For the <jats:italic>CYP2C9<\/jats:italic> and <jats:italic>GGCX<\/jats:italic> variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in <jats:italic>CYP2C9<\/jats:italic> (poor metabolizer), <jats:italic>CYP4F2<\/jats:italic>\u2010TT, and <jats:italic>VKORC1<\/jats:italic>\u2010AA was associated with a 4.0\u2010fold (95%CI 1.4\u201311.4) increased risk, while carriers of both <jats:italic>CYP4F2<\/jats:italic>\u2010TT and <jats:italic>VKORC1<\/jats:italic>\u2010AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5\u201329.8) compared with carriers of CC alleles in <jats:italic>CYP4F2<\/jats:italic> and GG in <jats:italic>VKORC1<\/jats:italic>. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>CYP4F2<\/jats:italic> polymorphism was associated with major bleeding, especially in combination with <jats:italic>VKORC1<\/jats:italic> genetic variants. These variants could be considered to further personalize anticoagulant treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.2923","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T05:35:16Z","timestamp":1714455316000},"page":"416-424","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The <scp>BLEEDS<\/scp> case\u2010cohort"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9502-2434","authenticated-orcid":false,"given":"Eleonora","family":"Camilleri","sequence":"first","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Ghobreyal","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-817X","authenticated-orcid":false,"given":"Mettine H. A.","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Thrombosis and Hemostasis Leiden University Medical Center  Leiden The Netherlands"},{"name":"Einthoven Laboratory for Vascular and Regenerative Medicine Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2207-1830","authenticated-orcid":false,"given":"Pieter H.","family":"Reitsma","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Thrombosis and Hemostasis Leiden University Medical Center  Leiden The Netherlands"},{"name":"Einthoven Laboratory for Vascular and Regenerative Medicine Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix J. 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