Defective platelet response to arachidonic acid and thromboxane A(2) in subjects with Pl(A2) polymorphism of beta(3) subunit (glycoprotein IIIa).
The membrane complex alpha(IIb)beta(3) is the major receptor for fibrinogen and is involved in platelet adhesion and aggregation. Evidence has been presented that the Pl(A2) allele of the beta(3) Pl(A1/A2) gene polymorphism might be an independent risk factor for coronary thrombosis, but the matter is still controversial. We investigated the relationship between this polymorphism and possible alterations of platelet functions in vitro. The platelet adhesion to fibrinogen-coated microplate wells and the aggregation induced by several different agonists were tested in 63 healthy volunteers, among them, 49 subjects with Pl(A1/A1) polymorphism, 12 subjects with Pl(A1/A2) polymorphism and two subjects with (PlA2/A2) polymorphism. Subjects with PlA1/A2 polymorphism or with Pl(A2/A2) polymorphism showed significantly lower platelet responses as compared with Pl(A1/A1) subjects when either arachidonic acid or the thromboxane A(2) analogue, U46619, were used as agonists. In resting condition and after thrombin or ADP stimulation, platelet function was normal in all the subjects. An increased sensitivity to the anti-aggregatory effect of acetylsalicylic acid was observed in platelets from subjects with the Pl(A2) allele. Finally, using a flow-cytometric evaluation and determining the beta-thromboglobulin plasma levels, we did not find any evidence of a Pl(A2) platelet hyper-reactivity ex vivo. Our findings are not consistent with the hypothesis that the purported increase of cardiovascular risk in these subjects may be as a result of platelet hyperactivation. On the contrary, the Pl(A2) allele is associated with a platelet functional deficiency, specifically linked to the activation of the fibrinogen receptor by thromboxane A(2).
Andrioli
G
G
Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy.
Minuz
P
P
Solero
P
P
Pincelli
S
S
Ortolani
R
R
Lussignoli
S
S
Bellavite
P
P
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D016718:Arachidonic Acid / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D003327:Coronary Disease / Q000097:blood / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000235:genetics; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D018709:Statistics, Nonparametric; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000819:agonists* / Q000378:metabolism; D001620:beta-Thromboglobulin / Q000032:analysis
D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001620:beta-Thromboglobulin; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D001241:Aspirin