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

Abstract

Word Count: abstract 244 (abstract), 3639 (main) ABSTRACT 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<0.001). In the immediate post-MI environment, male mice showed preferential thrombin-mediated platelet activation compared to female mice (12.4-fold vs. 5.5-fold, respectively; P<0.001).3 CONCLUSIONS: These results outline a previously unrecognized sex-dependent platelet phenotype where inhibition of thrombin signaling in the peri-MI environment-particularly in males-may be an important consideration. CONDENSED ABSTRACTPreclinical studies evaluating anti-platelet drugs are generally conducted in platelets isolated from healthy individuals. Growing evidence suggests changes in platelet signaling properties in certain disease conditions compared to healthy platelets may alter the response to anti-platelet medications. This investigation revealed that platelets from men and women who are healthy and following MI signal differently, particularly through thromboxane and PAR1 receptors. This effect was especially noted in patients with NSTEMI compared to STEMI. These observations raise the possibility of considering a sex-specific anti-platelet regimen for males and females in atheroembolic vascular diseases such as NSTEMI..

Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT)

“…72 Indeed, in mice infected with SARS-CoV, TxA2 production was markedly increased in younger mice compared to middle aged mice, 72 in line with the higher risk for thrombosis in adults aged <60 yr. 7,72 Intriguingly, platelets from female mice seem significantly more reactive than from male mice, 73 whereas TxA2 generation, TxA2-platelet interaction, and platelet activation also seem increased in women compared to men. 74,75 All such observations seem consistent with the apparent increased risk of thrombosis in women following the AstraZeneca and J&J vaccines. 72 However, it is important to note that based on the current evidence, specific risk…”