Abstract
Platelet reactivity (PR), a key pharmacodynamic (PD) component of the action of antiplatelet drugs in cardiovascular disease (CVD) patients, is highly variable. PR is associated with occurrence or recurrence of thrombotic and bleeding events, but this association is modulated by several factors. Conventional pharmacogenetics explains a minor part of this PR variability, and among determinants of PR, circulating microRNAs (miRNAs) have been the focus of attention during these last years as biomarkers to predict PR and clinical outcomes in CVD. This being said, the impact of miRNAs on platelet function and the mechanisms behind it are largely unknown. The level of a set of candidate miRNAs including miR-126-3p, miR-150-5p, miR-204-5p and miR-223-3p was quantified in plasma samples of stable CVD patients and correlated with PR as assessed by light-transmission aggregometry and in vivo thrombin generation markers. Finally, miRNA target networks were built based on genes involved in platelet function. We show that all candidate miRNAs were associated with platelet aggregation, while only miR-126-3p and miR-223-3p were positively correlated with in vivo thrombin generation markers. In silico analysis identified putative miRNA targets involved in platelet function regulation. Circulating miRNAs were associated with different aspects of platelet reactivity, including platelet aggregation and platelet-supported thrombin generation. This paves the way to a personalized antithrombotic treatment according to miRNA profile in CVD patients.
Highlights
Platelets are involved in several processes, such as hemostasis, inflammation, cell proliferation and immune system modulation [1]
Western blot analysis in plasma samples revealed the absence of glycoprotein ITGA2b and PTPRC, indicating that no residual platelets and leukocytes were detectable in the samples
Circulating miRNAs are predominantly derived from platelets and are often associCirculating miRNAs are predominantly derived from platelets and are often associated ated with platelet reactivity in a wide variety of clinical studies
Summary
Platelets are involved in several processes, such as hemostasis, inflammation, cell proliferation and immune system modulation [1]. The exposition of the sub-endothelium following vessel injury induces platelet activation and triggers thrombus formation. A similar process is observed at the site of atherosclerosis, where platelets play a pivotal role in triggering acute thrombotic events upon plaque disruptions or even endothelial erosions [2,3]. The role of platelets in thrombus formation is mediated via several processes, including aggregation and thrombin generation occurring at the surface of activated platelets following exposition of prothrombotic phospholipids [4,5]. Treated with antiplatelet drugs, is highly variable and has been associated with thrombotic or bleeding events. Traditional pharmacogenomics approaches have far provided limited data on the causes of this heritable PR variability. Other approaches are needed to better explore this yet unexplained heritable PR variability, including genetic processes and a more global PR phenotyping
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