Objective-The interindividual variation in platelet ␣ 2  1 exceeds a 2-fold variance in platelet ␣ IIb  3 level. Our objective was to parse the contribution of mean platelet volume (MPV) and integrin gene alleles to this variation in large cohorts of patients with acute coronary syndrome (ACS) and normal subjects. Methods and Results-Platelet ␣ IIb  3 and ␣ 2  1 levels were measured by flow cytometry in whole blood from 320 ACS patients and 128 normal subjects and compared with MPV, platelet count, ITGA2 rs28095, and ITGB3 rs5918 alleles. In all subjects, a strong direct correlation was found between MPV and ␣ IIb  3 level (PϽ0.001). Neither MPV nor ␣ IIb  3 level correlated with ITGB3 rs5918 alleles. In the case of ␣ 2  1 level, MPV contributed modestly, whereas ITGA2 rs28095 exerted a greater effect. An inverse correlation was found between MPV and the rs28095 minor allele. Conclusion-MPV is the major effector of platelet ␣ IIb  3 level, whereas the ITGA2 rs28095 alleles influence ␣ 2  1 level more than MPV does. The rs28095 minor allele, associated with lower MPV, likely exerts this effect via the influence of ␣ 2  1 on megakaryocyte maturation. Because of the hyperactivity of larger platelets, MPV is an accurate metric of risk for adverse outcome in ACS. Key Words: arterial thrombosis Ⅲ platelets Ⅲ thrombosis Ⅲ integrins Ⅲ mean platelet volume D ifferences in the level of integrins expressed on the surface membranes of platelets can have a significant effect on platelet reactivity and adverse outcomes in a variety of thrombotic and hematologic dyscrasias. Quantitative differences have been recorded in the plasma membrane levels of 2 relevant integrins, ␣ 2  1 (a receptor for collagen) and ␣ IIb  3 (a receptor for fibrinogen and von Willebrand factor). Quantitative measurements of platelet surface membrane ␣ IIb  3 among normal subjects, using direct binding of radiolabeled monoclonal antibodies or flow cytometry, have demonstrated a 2-to 3-fold difference, ranging from 25 000 to 75 000 molecules per platelet. 1-5 An allelic variation involving either the ␣ IIb or  3 gene (ITGA2B and ITGB3, respectively) that can account for this difference has not yet been identified. In the case of ␣ 2  1 , the range observed among normal subjects is greater, reported to be as high as 10-fold, and is strongly associated with allelic variants of the ␣ 2 gene ITGA2. 6 -8 The total number of integrin molecules and other receptors on platelets is influenced to a large extent by the total surface area of plasma membrane and consequently the mean platelet volume (MPV), which itself has a very strong genetic component. 7,9 Giles et al 10 noted a 7% increase in MPV in patients with acute myocardial infarction (nϭ14) and a 20% increase in platelet ␣ IIb  3 relative to control subjects (nϭ14). In addition, Yakushkin et al 11 recently provided the first association between MPV and ␣ IIb  3 levels in acute coronary syndrome (ACS) patients (nϭ65).The objective of this study was to parse the relative contribution of MP...
