Platelets are key mediators of atherothrombosis,yet,limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study,we investigate the association of platelet hyperreactivity and cardiovascular events,and introduce a tool,the Platelet Reactivity ExpreSsion Score (PRESS),which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD),those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity,adjusted HR 2.76,95% CI 1.5–5.1,p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81,95% CI 0.68 –0.94,n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77,95% CI 0.75 –0.79,n = 35). Following multivariable adjustment,PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90,CI 1.07–3.36; p = 0.027,n = 129,NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction. Platelet hyperreactivity is associated with cardiovascular events in patients with PAD. Here the authors derive and validate a circulating platelet genetic signature to discriminate platelet hyperreactivity and cardiovascular risk.
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