{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:32:47Z","timestamp":1790721167984,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Competitiveness, Entrepreneurship and Innovation","award":["MIS 5047189"],"award-info":[{"award-number":["MIS 5047189"]}]},{"name":"Competitiveness, Entrepreneurship and Innovation","award":["NSRF 2014\u20132020"],"award-info":[{"award-number":["NSRF 2014\u20132020"]}]},{"name":"Greece and the European Union (European Regional Development Fund)","award":["MIS 5047189"],"award-info":[{"award-number":["MIS 5047189"]}]},{"name":"Greece and the European Union (European Regional Development Fund)","award":["NSRF 2014\u20132020"],"award-info":[{"award-number":["NSRF 2014\u20132020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Among other substrates, the a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) protease degrades thrombospondin-5 (the cartilage oligomeric protein, COMP), thrombospondin-1 (TSP-1) and the tissue inhibitor of metalloproteinases-1 (TIMP-1) indicating a potential role of ADAMTS7 expression on coagulation cascade, tissue remodeling and wound healing. We analyzed the potential effect of direct oral anticoagulant (DOAC) treatment on ADAMTS7 promoter methylation and followed it over time to assess whether DOACs epigenetically modulate ADAMTS7 and induce pathways associated with coagulation or endothelium repair machinery. Methods: Eighty-four DOAC-treated atrial fibrillation (AF) patients followed-up from baseline (t0) to 7 days (t1, n = 70) and 28 days of treatment (t2, n = 62) and 19 non-AF controls were included in the study. Genomic DNA was extracted from blood at all timepoints and was bisulfite-converted prior to methylation analysis. ADAMTS7 promoter DNA methylation was analyzed with MIP-qMSP-PCR. Results: A total of 16 minor bleeding events occurred. The baseline percentage of ADAMTS7 methylation did not differ between AF patients and controls (15.8% vs. 16.1%, p = 0.908). In the patient cohort, DOAC therapy marginally decreased ADAMTS7 methylation from t0 to t2 (15.2% vs. 14.0%, p = 0.044). This ADAMTS7 demethylation from t0 to t2 was statistically significant only in patients experiencing bleeding (17.1%. vs. 13.4%, p = 0.010 in bleedings, 14.5% vs. 14.2%, p = 0.561 in non-bleedings). No other differences were observed. Conclusions: ADAMTS7 is demethylated during DOAC-related bleedings, a mechanism potentially leading to COMP degradation and thus thrombin-induced platelet aggregation, as well as the induction of endothelium repair through different ADAMTS7-dependent pathways.<\/jats:p>","DOI":"10.3390\/genes16060698","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T05:11:49Z","timestamp":1749532309000},"page":"698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2421-5677","authenticated-orcid":false,"given":"Georgia","family":"Ragia","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"},{"name":"Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Thomopoulos","sequence":"additional","affiliation":[{"name":"Department of Cardiology, \u201cElpis\u201d General Hospital of Athens, 11522 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0918-5773","authenticated-orcid":false,"given":"Myria","family":"Pallikarou","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"},{"name":"Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7793-7082","authenticated-orcid":false,"given":"Natalia","family":"Atzemian","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"},{"name":"Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthi","family":"Maslarinou","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"},{"name":"Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4331-730X","authenticated-orcid":false,"given":"Georgios","family":"Chalikias","sequence":"additional","affiliation":[{"name":"Cardiology Department, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Trikas","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Evaggelismos Hospital, 10676 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4982-9181","authenticated-orcid":false,"given":"Dimitrios N.","family":"Tziakas","sequence":"additional","affiliation":[{"name":"Cardiology Department, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-5469","authenticated-orcid":false,"given":"Vangelis G.","family":"Manolopoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece"},{"name":"Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus, 68100 Alexandroupolis, Greece"},{"name":"Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Dragana Campus, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1080\/17501911.2025.2489921","article-title":"Cardiometabolic disease management: Influences from epigenetics","volume":"17","author":"Atzemian","year":"2025","journal-title":"Epigenomics"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rose, K.W.J., Taye, N., Karoulias, S.Z., and Hubmacher, D. 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