BACKGROUND/OBJECTIVES: Among other substrates, the a disintegrin and metalloproteinase with thrombospondin motifs 7 () 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 expression on coagulation cascade, tissue remodeling and wound healing. We analyzed the potential effect of direct oral anticoagulant (DOAC) treatment on promoter methylation and followed it over time to assess whether DOACs epigenetically modulate 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, = 70) and 28 days of treatment (t2, = 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. promoter DNA methylation was analyzed with MIP-qMSP-PCR. RESULTS: A total of 16 minor bleeding events occurred. The baseline percentage of methylation did not differ between AF patients and controls (15.8% vs. 16.1%, = 0.908). In the patient cohort, DOAC therapy marginally decreased methylation from t0 to t2 (15.2% vs. 14.0%, = 0.044). This demethylation from t0 to t2 was statistically significant only in patients experiencing bleeding (17.1%. vs. 13.4%, = 0.010 in bleedings, 14.5% vs. 14.2%, = 0.561 in non-bleedings). No other differences were observed. CONCLUSIONS: 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 -dependent pathways.