While smoking has been on the decline, e-cigarette usage has been on the rise; especially in vulnerable populations. Furthermore, even though the contribution of third-hand smoke (THS) and- more recently- e- cigarettes to the pathogenesis of thrombotic diseases was documented, the involvement of third-hand e- cigarettes (THEC) 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 THEC, in the context of thrombotic disease and platelet biology, and in a device-, e-liquid-, and sex- specific manner. These studies are of paramount significance given the “perceived safety” of e-cigarettes, and will be conducted using a novel/new THEC exposure model. The Aims of our proposal are: Aim 1. Investigate the impact of THEC exposure on platelet-dependent disease states. While there is compelling evidence that e-cigarettes do exert negative health effects, the impact of THEC on platelet-dependent diseases is still unknown. To address this issue, we will determine the consequences of THEC exposure on normal hemostasis and platelet counts. Subsequent studies will examine whether THEC participates in the development of thrombosis-based disease. Finally, we will determine the effects of THEC on plasma “markers” of thrombosis. Notably, our experiments will be designed in a manner that addresses the role of the device, and e-liquid in mediating the “platelet”-dependent negative effects of THEC. Furthermore, our preliminary data does show, for the first time, that THEC, THS and e-cigarettes increase the risk of thrombotic cardiovascular disease. Aim 2. Investigate the mechanism by which THEC exposure modulates platelet function. Even though our published data indicated that THS and e-cigarettes modulate platelet activation, whether THEC produces similar effects (i.e., the mechanism by which it modulates platelet function) remains to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the impact of THEC exposure on the various platelet functional responses (e.g., GPIIb-IIIa activation), thromboxane A2 levels, and on biochemical “markers” of platelet activation. It is noteworthy that our preliminary data shows that THEC does enhance platelet aggregation and secretion. Collectively, these experiments will make significant contributions to our understanding of the consequences of THEC/e-cigarettes on platelet activation and cardiovascular human health, and the mechanism by/through which it exerts these effects, in a device-, e-liquid-, and sex-specific manner.