title: Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins in platelets.
abstract: The polymorphism responsible for the Pl(A2) alloantigen on the beta(3)-component of beta(3)-containing integrins is reported to be a risk factor for coronary thrombosis. This study examined the effect of Pl(A2) on the function of beta(3)-integrins using platelets from subjects homozygous and heterozygous for Pl(A1) and Pl(A2). There was overlap in the distribution of the dissociation constant (K(d)) and maximum fibrinogen binding (B(max)) values for fibrinogen binding to alpha(IIb)beta(3) on platelets from Pl(A1) and Pl(A2) homozygotes and Pl(A1)/Pl(A2) heterozygotes. However, whereas there was no statistical difference in these values for the Pl(A1) homozygotes and Pl(A2) heterozygotes, the K(d) for the Pl(A2) homozygotes was significantly lower than that for the Pl(A1)/Pl(A2) heterozygotes, but was not statistically different from that for the Pl(A1) homozygotes. No differences were detected in ADP sensitivity between platelets from Pl(A1) homozygotes and Pl(A1)/Pl(A2) heterozygotes, in the IC(50) for RGDS inhibition of fibrinogen binding to alpha(IIb)beta(3), in the alpha(v)beta(3)-mediated adhesion of platelets to osteopontin and vitronectin, and in the phorbol ester-stimulated adhesion to fibrinogen of B lymphocytes expressing alpha(IIb)beta(3) containing either the Pl(A1) or the Pl(A2) polymorphism. Finally, no differential effects of Pl(A2) on turbidometric platelet aggregation, platelet secretion, or platelet thrombus formation were found as measured in the PFA-100. Because no differences were detected in the ability of beta(3)-integrins to interact with ligands based on the presence or absence of the Pl(A2) polymorphism, the results suggest that factors unrelated to beta(3)-integrin function may account for the reported association of the Pl(A2) allele with coronary thrombosis.
authors.affiliation: Hematology-Oncology Division, the Center for Experimental Therapeutics, and the General Clinical Research Center of the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. bennetts@mail.med.upenn.edu
authors.forename: J S
authors.initials: JS
authors.lastname: Bennett
authors.forename: F
authors.initials: F
authors.lastname: Catella-Lawson
authors.forename: A R
authors.initials: AR
authors.lastname: Rut
authors.forename: G
authors.initials: G
authors.lastname: Vilaire
authors.forename: W
authors.initials: W
authors.lastname: Qi
authors.forename: S C
authors.initials: SC
authors.lastname: Kapoor
authors.forename: S
authors.initials: S
authors.lastname: Murphy
authors.forename: G A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology*; D016824:Antigens, Human Platelet / Q000235:genetics* / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D003328:Coronary Thrombosis / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D039661:Integrin beta3; D008297:Male; D008875:Middle Aged; D053495:Osteopontin; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D011110:Polymorphism, Genetic; D012795:Sialoglycoproteins / Q000378:metabolism; D014162:Transfection; D019096:Vitronectin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016824:Antigens, Human Platelet; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D019096:Vitronectin; D053495:Osteopontin; D000244:Adenosine Diphosphate; D005340:Fibrinogen