Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists

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 l acking. Associations between the platelet PIA2 polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variatio n may contribute to platelet hyperreactivity. Methods and Results-In this study, we characterized functional parameters i n 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 alpha(IIb)beta(3)). We stud ied 56 normal donors (20 PIA1,A1, 20 Pl(A1,A2), and 16 Pl(A2A2)). Compared with pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage ef fect for significantly,greater surface-expressed P-selectin, GP IIb/IIIa-bo und fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surf ace expression of GP IIb/IIIa was similar in resting platelets of all 3 gen otypes but was significantly greater on Pl(A2,A2) platelets after ADP stimu lation (P=0.003 versus Pl(A1,A1); P=0.03 versus pl(A1,A2)). Pl(A1,A2) plate lets 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 activ ation, and platelets heterozygous for Pl(A) alleles showed increased sensit ivity to 2 antiplatelet drugs, These in vitro platelet studies may have rel evance for in vivo thrombotic conditions.