A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction

BACKGROUND: A Sex-specific, personalized approach to anti-platelet therapy may be important in patients with myocardial infarction (MI). OBJECTIVES: Our goal was to determine whether platelets activate differently in healthy men and women compared to following MI. METHODS: Blood was obtained from healthy subjects or patients presenting acutely with STsegment Elevation Myocardial Infarction (STEMI) and non-ST Segment Elevation Myocardial Infarction (NSTEMI). Platelet function through surface receptor activation was examined in healthy subjects, in patients with MI, and in age- and strain-matched mice before and after MI. Multivariate regression analyses revealed clinical variables associated with platelet receptor sensitivity at the time of MI. RESULTS: Platelets from healthy women are dose-dependently more active compared to men, particularly through the platelet thromboxane signaling pathway (7.8-fold increase in women vs. 3.0-fold in men, P=0.02). At the time of MI, platelet activation through surface proteaseactivated receptor 1 (PAR1) was less in women than men (3.5-fold vs. 8.5-fold, respectively, P=0.0001). Multivariate regression analyses revealed male sex (P=0.04) and NSTEMI (P=0.003) as independent predictors of enhanced platelet PAR1 signaling at the time of MI. Similar to humans, healthy female mice showed preferential thrombin-mediated platelet activation compared to male mice (8.7-fold vs. 4.8-fold, respectively; P