PAR4 Mediates an Elevated Risk for Thrombosis in Blacks Relative to Whites (425.1)

Abstract

Coronary heart disease (CHD) is the leading cause of mortality in the US amongst all races. CHD disproportionality burdens blacks relative to whites and even after adjusting for other demographic parameters, blacks have a two‐fold increase in incidence of CHD and a decrease in long‐term survival. Occlusive thrombus formation is the underlying cause of mortality associated with CHD. Due to the importance of platelets in CHD and formation of occlusive thrombi, the response of platelets from blacks and whites to thrombin and its protease‐activated receptors (PAR1 and PAR4) was characterized. Platelets isolated from blacks and whites differentially responded to PAR4 but not PAR1. Specifically, platelets from blacks were hyperaggregable to low and intermediate doses of PAR4‐activating peptide (PAR4‐AP) compared to platelets from whites. The mechanism responsible for the racial difference in PAR4 mediated platelet reactivity however is still unknown. We hypothesize that changes in expression or activity of proteins known to participate in the PAR4 pathway are responsible for the racial difference in platelet PAR4 reactivity. To test this hypothesis, the PAR4 pathway in platelets from blacks and whites was characterized. No measurable difference was observed in the surface expression of PAR4 on platelets from blacks or whites however following stimulation with low dose PAR4‐AP (50uM), platelets from blacks had an increase in PAR4 signaling components compared to whites including intracellular Ca2+ release, RAP1 activation, and integrin αIIbβ3 activation. This data suggest that the kinetics of platelet activation through PAR4‐AP is hyper‐responsive in blacks compared to whites due to a shift in threshold downstream of the receptor. As PAR1 antagonists are currently in clinical trials and PAR4 antagonists are in pre‐clinical development, this work has important clinical implication as to which patients may benefit the most from selective PAR inhibition and is the first to suggest a racial component in the prevention of occlusive thrombus formation and stroke.Grant Funding Source: RO1 MD007880