Abstract 59: Disparity in Protection from Thrombotic Risk Depends on Platelet Thrombin Receptor PAR4
Aberrant platelet activation contributes to the mortality associated with coronary heart disease (CHD). Our lab group has recently shown that platelets from black donors were hyper-responsive to activation of the thrombin receptor Protease-Activated Receptor-4 (PAR4) compared to platelets from white donors. The racial difference observed through PAR4 persists in platelets treated ex vivo with dual antiplatelet inhibitors (COX-1 inhibitor Aspirin and P2Y12 receptor inhibitor Clopidogrel), a standard of care for many CHD patients. The racial difference in PAR4 signaling is largely attributable to one PAR4 variant more frequently expressed in blacks than whites, PAR4 T120A. Independent of race, T120 is associated with greater PAR4-mediated platelet reactivity compared to the A120 variant. The role PAR4 variation plays in regulating thrombin-mediated platelet activation in CHD has not been elucidated to date. We hypothesize that patients homozygous for the T120 will have an increase in PAR4-mediated platelet reactivity compared to patients homozygous for A120. To investigate this hypothesis, we studied PAR4 signaling in platelets obtained from healthy donors and patients with CHD on dual antiplatelet therapy. Healthy donors taking either a COX-1 or P2Y12 inhibitor who are homozygous for threonine at amino acid 120, have an increase in platelet reactivity as measured by aggregation, αIIbβ3 activation and granule secretion compared to individuals who are homozygous for alanine at amino acid 120. Interestingly, subjects heterozygous at 120 exhibit platelet reactivity which is in between what is observed for people homozygous for alanine or threonine at this amino acid. This study reinforces the personalized medicine approach to therapeutic intervention and challenges the one size fits all approach which often leaves at risk populations without adequate protection from thrombotic events and stroke.
Author Disclosures: B. Tourdot: None. M. Holinstat: Research Grant; Significant; R01 MD007880.
- © 2015 by American Heart Association, Inc.