Heart attacks and strokes result from clots formed in the blood vessels of the heart or brain, respectively. The laboratory of Paul Bray, MD, demonstrated that platelets from Black individuals were more reactive than those from White individuals, suggesting a genetic basis for some of the racial discrepancy observed in vascular diseases associated with clotting. Having observed these differences, his team went on to identify the genetic variant responsible for this hyper-reactivity, common in people of African, but not European, ancestry. By analyzing DNA from roughly 13,000 patients with heart attacks and strokes, they showed the hyper-reactive gene variant was associated with increased risks for stroke and reduced bleeding. Anti-platelet drugs are the first-line pharmacotherapy for these vascular diseases. However, additional work by Bray’s group showed that the commonly used drug, the P2Y12 inhibitor clopidogrel, did not inhibit platelet hyper-reactivity among individuals with the genetic variant (primarily Blacks), whereas another P2Y12 inhibitor, ticagrelor, effectively inhibited platelet reactivity in both Blacks and Whites. These discoveries have laid the groundwork for individualized anti-platelet therapies in disorders with racial predilections.
Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Edelstein LC, Simon LM, Montoya RT, Holinstat M, Chen ES, Bergeron A, Kong X, Nagalla S, Mohandas N, Cohen DE, Dong J-f, Shaw C, Bray PF. Nat Med. 2013 December;19(12):1609.
Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Edelstein LC, Simon LM, Lindsay CR, Kong X, Montoya RT, Tourdot BE, Chen ES, Ma L, Coughlin S, Nieman M, Holinstat M, Shaw CA, Bray PF. Blood. 2014 November 27;124(23):3450.
Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis. Tourdot BE, Conaway S, Niisuke K, Edelstein LC, Bray PF, Holinstat M. Arterioscler Thromb Vasc Biol. 2014 December;34(12):2644.
Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial. Tricoci P, Neely M, Whitley M, Edelstein LC, Simon LM, Shaw C, Fortina P, Moliterno DJ, Armstrong PW, Aylward P, White H, Van de Werf F, Jennings LK, Wallentin L, Held C, Harrington RA, Mahaffey KW, Bray PF. Blood Cells, Molec and Dis. 2018 September;72:37.
The protease-activated receptor 4 Ala120Thr variant alters platelet responsiveness to low-dose thrombin and protease-activated receptor 4 desensitization, and is blocked by non-competitive P2Y12 inhibition. Whitley MJ, Henke DM, Ghazi A, Nieman M, Stoller M, Simon LM, Chen E, Vesci J, Holinstat M, McKenzie SE, Shaw CA, Edelstein LC, Bray PF. J Thromb Haemost. 2018 December;16(12):2501.
Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics. Tourdot BE, Stoveken H, Trumbo D, Yeung J, Kanthi Y, Edelstein LC, Bray PF, Tall G, Holinstat M. Arterioscler Thromb Vasc Biol. 2018 July;38(7):1632.
A function-blocking PAR4 antibody is markedly antithrombotic in the face of a hyperreactive PAR4 variant. French SL, Thalmann C, Bray PF, Macdonald LE, J Murphy AJ, Sleeman MW, Hamilton JR. Blood Adv. 2018 June 12;2(11):1283.