The use of tobacco products is directly linked to the increased risk of developing several life threatening complications, like myocardial infarction (MI) and ischemic stroke (IS). MI and IS are both caused by spontaneous clot formation within the blood vessels, leading to the occlusion of arteries supplying nutrient rich blood to either cardiac muscle or cerebral tissue. An important molecule used for platelet-platelet signaling during clot formation is 5-hydroxytryptamine (5-HT). Previous studies have shown that sympathetic nervous system (SNS) stimulation, induced by nicotine, results in elevated concentrations of 5-HT within the blood, but the link between this increase and the increased risk for MI and IS has yet to be made. Therefore, we hypothesize that elevated concentrations of 5-HT stimulated by nicotine, induce a hyperactive platelet phenotype in smokers resulting in the increased risk for MI and IS. To test this hypothesis, we incubated isolated platelets from nonsmoker's in a high concentration cocktail of 5-HT and other known platelet signaling molecules released after SNS stimulation, to see if these elevated concentrations were inducing the hyperactive platelet activity observed in smokers. Incubation of nonsmoker's platelets in the cocktail resulted in more platelets aggregating together after stimulation with collagen than platelets from nonsmokers without addition of the cocktail. Next we looked to block individual receptors on the platelets known to be used for platelet-platelet signaling during clot formation. After blocking these receptors, we were able to reduce the effect of the cocktail on nonsmoker's platelets. Complete negation of the cocktails effect on the magnitude of the aggregation cascade on nonsmoker's platelets was only achieved when all three receptors were blocked at the same time indicating that the receptors are working independently of each other. Interestingly a time dependent relationship between the cocktail and triple block was observed indicating that platelets exposed to the cocktail first aggregate at a higher magnitude even in the presence of the triple block than when the platelets were exposed to the triple block first. These finding have implication in potential therapies or screenings for high risk MI or IS patients as reduction of reactivity of platelets to clotting factors within the blood vessels could reduce the chance of both MI and IS from occurring.