Dual antiplatelet therapy is associated with high alpha-tubulin acetylation in platelets from coronary artery disease patients

Abstract

Platelet inhibition is the main treatment strategy to prevent atherothrombosis. Despite dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor, high platelet reactivity persists in some patients due to poor response to treatment and is associated with ischemic risk. It remains unknown if circulating platelets in high-risk patients have different morphological characteristics which could participate in their pro-thrombotic potential. We postulated that alpha-tubulin acetylation, a cytoskeletal modification known to regulate platelet shape change, could reflect circulating platelet reactivity and impact their morphology. We collected arterial blood samples from 187 patients admitted for coronary angiography. Platelet reactivity was assessed in whole blood using multiplate analysis. Platelets were then isolated to evaluate alpha-tubulin acetylation level by western blotting. 141 patients were taking aspirin among which 32 were treated with an additional P2Y12 inhibitor. DAPT didn’t achieve sufficient platelet inhibition in 8 out of 32 patients. Participants provided written informed consent and the study was approved by the institutional ethics committee. Platelet alpha-tubulin acetylation was significantly increased in DAPT-treated patients ( P < 0.001). A minority of non-treated patients (11.4%) exhibited high alpha-tubulin acetylation (third acetyl alpha-tubulin tertile) whereas a high level was observed in most patients on efficient DAPT (83.3%). Interestingly, the proportion of patients with high acetyl alpha-tubulin (37.5%) level was drastically decreased in clopidogrel low responders. Multivariate logistic regression further supported that efficient DAPT is independently associated with a 27-fold increase in the likelihood of being in the highest acetyl alpha-tubulin tertile ( P < 0.001). We revealed high platelet alpha-tubulin acetylation as a potential marker of efficient platelet inhibition by dual antiplatelet therapy. Since alpha-tubulin acetylation is a hallmark of stable microtubules, its increase could contribute to maintaining resting morphology of circulating platelets.