Platelet glycoprotein IIIa PlA polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study

Abstract

Background - Recent data suggest that the PlA2 allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the PlA2 allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that PlA2-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with PlA genotype in modulating platelet aggregability. Methods and Results - Glycoprotein IIIa PlA genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the PlA1/A1 genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the PlA2-positive genotype (P>0.90). Conclusion - Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding PlA genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.