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(Circulation. 2001;104:140.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Platelet Glycoprotein IIIa Pl^A Polymorphism, Fibrinogen, and Platelet Aggregability

The Framingham Heart Study

DaLi Feng, MD; Klaus Lindpaintner, MD; Martin G. Larson, SD; Christopher J. O’Donnell, MD; Izabella Lipinska, PhD; Patrice A. Sutherland, BS; Murray Mittleman, MD; James E. Muller, MD; Ralph B. D’Agostino, PhD; Daniel Levy, MD; Geoffrey H. Tofler, MD

From the Institute for Prevention of Cardiovascular Disease, Beth Israel Deaconess Medical Center (D.F., I.L., M.M.), the Cardiovascular Division, Brigham and Women’s Hospital (K.L.), the Cardiology Division, Massachusetts General Hospital, Harvard Medical School (C.J.O., J.E.M.), and the Statistics and Consulting Unit, Department of Mathematics, Boston University (R.B.D.), Boston, Mass; the Framingham Heart Study, the National Institutes of Health National Heart, Lung, and Blood Institute (M.G.L., C.J.O., P.A.S., D.L.), Framingham, Mass; and the Royal North Shore Hospital (G.H.T.), Sydney, Australia.

Correspondence to DaLi Feng, MD, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55th Fruit Street, Bulfinch 106, Boston, MA 02114. E-mail dfeng2{at}caregroup.harvard.edu

Background—— Recent data suggest that the Pl^A2 allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl^A2 allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl^A2-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl^A genotype in modulating platelet aggregability.

Methods and Results—— Glycoprotein IIIa Pl^A 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 Pl^A1/A1 genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl^A2-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 Pl^A genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Key Words: platelets • genetics • glycoproteins • fibrinogen

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