While smoking has been on the decline, e-cigarette usage has been on the rise, even during the COVID19 pandemic. Furthermore, even though the contribution of traditional smoking to the pathogenesis of thrombotic diseases is well documented, the involvement of e-cigarettes in such disease processes remains unknown. Consequently, the present application outlines studies that address fundamental, mechanistic, and clinically- relevant translational aspects of the adverse-health effects of e-cigarettes, an increasingly popular form of tobacco, in the context of platelet biology, thrombotic disease and sex, and in a device-, and e-liquid-specific manner. Studies are also proposed to investigate, in a similar fashion, the toxicants that underlie e-cigarette effects. These studies are of paramount significance given the “perceived safety” of e-cigarettes. The Aims of this proposal are: Aim 1. Investigate the impact of e-cigarette exposure on platelet-dependent disease states. While there is compelling evidence that e-cigarettes do exert negative health effects, their impact on platelet-dependent diseases is still unknown. To address these issues, the consequences of e-cigarette exposure on normal hemostasis be will determined, in a dose-, and time-dependent fashion. Subsequent studies will examine whether e-cigarettes participate in the development of thrombosis disease. Finally, experiments are designed in a manner that addresses the role of the device, and e-liquid in e-cigarette effects, with sex as a biological variable. Aim 2. Investigate the mechanism by which e-cigarettes modulate platelet function. Even though the preliminary data indicated that e-cigarettes modulate hemostasis, the mechanism, by which they modulate platelet function remains to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the impact of e-cigarette exposure on the various platelet functional responses, biochemical/plasma “markers” of thrombosis, the mechanistic resistance to PGI2, and whether the effects are receptor mediated. Finally, studies are proposed to determine if e-cigarettes modulate the platelet miRnome. Aim 3. Define e-cigarettes toxicants with potent impact on platelet-dependent disease and function. While e-cigarettes are known to be source of a large number of toxicants, such as cotinine and acrolein, nothing is known regarding their specific impact on platelet activation/disease. Therefore, the effect of the e-cigarette toxicants, alone or in combination, on platelet function and associated disease will be investigated. Collectively, these experiments will make significant contributions to the understanding of the consequences of e-cigarettes on platelet activation and cardiovascular human health, and the mechanism and toxicants by/through which they exert these effects, in a dose-, time-, device-, e-liquid- specific manner, in the context of sex.