Platelet GP IIIa Pl A Polymorphisms Display Different Sensitivities to Agonists

• DOI: 10.1161/01.cir.101.9.1013
• Publication Date: 2012-06-12T00:42:29Z
• Authors: Alan D. Michelson; Mark I. Furman; Pascal Goldschmid...; Mary Ann Mascelli; Craig Hendrix; Lindsay Coleman; Jeanette Hamlington; Marc R. Barnard; Thomas Kickler; Douglas J. Christie; Sourav Kundu; Paul F. Bray
• Keywords: Abciximab; P-selectin

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 Pl(A2) polymorphism of GP IIIa syndromes raise question as to whether this variation may contribute hyperreactivity.In study, we characterized functional parameters in healthy donors Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) Pro (Pl(A2)) substitution at position 33 subunit IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal (20 Pl(A1,A1), 20 Pl(A1,A2), 16 Pl(A2,A2)). Compared Pl(A1,A1) platelets, Pl(A2)-positive showed gene dosage effect for significantly greater surface-expressed P-selectin, IIb/IIIa-bound fibrinogen, activated response low-dose ADP. Surface expression was similar resting all 3 genotypes on Pl(A2,A2) after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 Pl(A1,A2)). Pl(A1,A2) were more sensitive inhibition aggregation by pharmacologically relevant concentrations aspirin abciximab.Pl(A2)-positive displayed lower threshold activation, heterozygous alleles increased sensitivity 2 antiplatelet drugs. These vitro studies relevance vivo thrombotic conditions.