(Circulation. 2000;101:1013.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Platelet GP IIIa PlA Polymorphisms Display Different Sensitivities to Agonists
From the Departments of Medicine and Pathology (P.F.B, C.H., L.C., J.H., T.K.), Johns Hopkins University School of Medicine, Baltimore, Md; Departments of Pediatrics, Medicine, and Surgery (A.D.M., M.I.F, M.R.B.), University of Massachusetts, Worcester; Heart and Lung Institute, Department of Medicine (P.G.-C.), Ohio State University, Columbus; Department of Clinical Pharmacology (M.A.M.), Centocor Inc, Malvern, Pa; and Dade-Behring (D.J.C., S.K.), Miami, Fla.
Correspondence to Paul F. Bray, MD, Ross 1015, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. E-mail pfb{at}welchlink.welch.jhu.edu
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 PlA2 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
PlA (HPA-1) polymorphism, a Leu (PlA1) to
Pro (PlA2) substitution at position 33 of the GP IIIa
subunit of the platelet GP IIb/IIIa receptor (integrin
IIbß3). We studied 56 normal donors (20
PlA1,A1, 20 PlA1,A2, and 16
PlA2,A2). Compared with PlA1,A1 platelets,
PlA2-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 PlA2,A2 platelets after ADP stimulation
(P=0.003 versus PlA1,A1;
P=0.03 versus PlA1,A2). PlA1,A2
platelets were more sensitive to inhibition of aggregation by
pharmacologically relevant concentrations of aspirin and abciximab.
Conclusions—PlA2-positive platelets displayed a lower threshold for activation, and platelets heterozygous for PlA alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.
Key Words: platelets • coronary disease • polymorphisms • inhibitors
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