Platelet GP IIIa Pl A Polymorphisms Display Different Sensitivities to Agonists

Abstract

Background —Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl A2 polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity. Methods and Results —In this study, we characterized functional parameters in platelets from healthy donors with the Pl A (HPA-1) polymorphism, a Leu (Pl A1 ) to Pro (Pl A2 ) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin α IIb β 3 ). We studied 56 normal donors (20 Pl A1,A1 , 20 Pl A1,A2 , and 16 Pl A2,A2 ). Compared with Pl A1,A1 platelets, Pl A2 -positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa–bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl A2,A2 platelets after ADP stimulation ( P =0.003 versus Pl A1,A1 ; P =0.03 versus Pl A1,A2 ). Pl A1,A2 platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab. Conclusions —Pl A2 -positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl A alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.