MECHANISMS OF ARTERIAL THROMBOSIS IN WOMEN
Differences between men and women exist in platelet function and preliminary data suggest that some of these differences result from a higher fibrinogen binding to platelets from women than men. These sex related features may account for different expressions of coronary heart diseases between women and men. The central hypothesis of this project is that sex hormones regulate megakaryocyte genes that shape the expression and activation of fibrinogen receptors , i.e., GPIIb IIIa, resulting in a greater fibrinogen binding in women. The first aim of this study is to assess the effects of shear forces on platelet adhesion to various ligands in the context of sex related differences and sex hormone levels. The second aim is to use an in vitro model of cultured human megakaryocytes to study the effect of sex hormones on fibrinogen binding parameters. The third aim is to identify megakaryocyte molecules that are differently expressed in platelets from women and men in response to sex hormones. This will be accomplished by isolating relevant megakaryocyte cDNAs, which are differentially expressed in platelets from women and men in response to sex hormones, by isolating full length cDNAs, and by demonstrating that they modulate fibrinogen binding to GPIIb IIIa. The results of this investigation will help to identify sex related differences in the expression of coronary heart diseases, the selection of targets for therapeutic intervention, and in understanding the physiology of the platelet fibrinogen receptor.