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Direct Oral Anticoagulant-Related Bleeding in Atrial Fibrillation Patients Leads to ADAMTS7 Promoter Demethylation
Georgia Ragia1,2, Thomas Thomopoulos3, Myria Pallikarou1,2
1Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece.
Insights
Direct oral anticoagulants (DOACs) may epigenetically modulate a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) expression. DOAC treatment demethylated ADAMTS7, particularly during bleeding events in atrial fibrillation patients.
Area of Science:
- Epigenetics and Molecular Biology
- Cardiovascular Medicine
- Pharmacology
Background:
- The a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) protease degrades key extracellular matrix proteins like COMP, TSP-1, and TIMP-1.
- ADAMTS7's role in coagulation, tissue remodeling, and wound healing suggests its expression is influenced by anticoagulant therapies.
- Direct oral anticoagulants (DOACs) are widely used for conditions like atrial fibrillation (AF).
Purpose of the Study:
- To investigate the effect of DOAC treatment on ADAMTS7 promoter methylation in AF patients.
- To determine if DOACs epigenetically modulate ADAMTS7 expression over time.
- To assess if DOACs induce pathways related to coagulation or endothelium repair through ADAMTS7.
Main Methods:
- Eighty-four AF patients and 19 controls were analyzed at baseline, 7 days, and 28 days of DOAC treatment.
- Genomic DNA was extracted, bisulfite-converted, and analyzed for ADAMTS7 promoter DNA methylation using MIP-qMSP-PCR.
- Bleeding events were recorded and correlated with methylation changes.
Main Results:
- Baseline ADAMTS7 methylation levels were similar between AF patients and controls.
- DOAC therapy led to a marginal decrease in ADAMTS7 methylation from baseline to 28 days (15.2% to 14.0%, p=0.044).
- This demethylation was statistically significant in patients experiencing bleeding events (17.1% to 13.4%, p=0.010) but not in non-bleeding patients.
Conclusions:
- ADAMTS7 undergoes demethylation during DOAC-related bleeding events.
- This epigenetic modulation may lead to COMP degradation, influencing thrombin-induced platelet aggregation.
- ADAMTS7 demethylation might also promote endothelium repair via specific pathways.
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.
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