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Article

Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation

by
Georgia Ragia
1,2,*,†,
Thomas Thomopoulos
3,
Myria Pallikarou
1,2,
Natalia Atzemian
1,2,
Anthi Maslarinou
1,2,
Georgios Chalikias
4,
Athanasios Trikas
5,
Dimitrios N. Tziakas
4 and
Vangelis G. Manolopoulos
1,2,6,*
1
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece
2
Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus, 68100 Alexandroupolis, Greece
3
Department of Cardiology, “Elpis” General Hospital of Athens, 11522 Athens, Greece
4
Cardiology Department, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece
5
Department of Cardiology, Evaggelismos Hospital, 10676 Athens, Greece
6
Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Dragana Campus, 68100 Alexandroupolis, Greece
*
Authors to whom correspondence should be addressed.
†
Current address: Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Genes 2025, 16(6), 698; https://doi.org/10.3390/genes16060698
Submission received: 1 May 2025 / Revised: 3 June 2025 / Accepted: 5 June 2025 / Published: 9 June 2025
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

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.
Keywords: miR-CRAFT study; direct oral anticoagulants; rivaroxaban; apixaban; dabigatran; ADAMTS7; methylation; epigenetics miR-CRAFT study; direct oral anticoagulants; rivaroxaban; apixaban; dabigatran; ADAMTS7; methylation; epigenetics

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MDPI and ACS Style

Ragia, G.; Thomopoulos, T.; Pallikarou, M.; Atzemian, N.; Maslarinou, A.; Chalikias, G.; Trikas, A.; Tziakas, D.N.; Manolopoulos, V.G. Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation. Genes 2025, 16, 698. https://doi.org/10.3390/genes16060698

AMA Style

Ragia G, Thomopoulos T, Pallikarou M, Atzemian N, Maslarinou A, Chalikias G, Trikas A, Tziakas DN, Manolopoulos VG. Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation. Genes. 2025; 16(6):698. https://doi.org/10.3390/genes16060698

Chicago/Turabian Style

Ragia, Georgia, Thomas Thomopoulos, Myria Pallikarou, Natalia Atzemian, Anthi Maslarinou, Georgios Chalikias, Athanasios Trikas, Dimitrios N. Tziakas, and Vangelis G. Manolopoulos. 2025. "Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation" Genes 16, no. 6: 698. https://doi.org/10.3390/genes16060698

APA Style

Ragia, G., Thomopoulos, T., Pallikarou, M., Atzemian, N., Maslarinou, A., Chalikias, G., Trikas, A., Tziakas, D. N., & Manolopoulos, V. G. (2025). Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation. Genes, 16(6), 698. https://doi.org/10.3390/genes16060698

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