The magnitude of the circadian effect was always larger than that of any of the three separate stressors for all platelet surface markers of platelet activation. Given that shift workers are at increased risk for cardiovascular events this larger effect of the circadian system as compared to behavioral stressors on platelet activation may warrant future studies to determine whether antiplatelet therapy in shift workers can be further optimized by basing the timing of therapy on their internal circadian phase rather than on their behavioral sleep/wake cycle. The three measured surface markers of platelet activation peaked at an endogenous circadian phase corresponding to 8–9AM, consistent with our hypothesis of the presence of an endogenous circadian rhythm in platelet function peaking around the vulnerable time for major adverse cardiovascular events. This is of likely clinical importance as these factors represent measures of the final common pathway of platelet aggregation ; adhesion of activated platelets to monocytes and neutrophils ; and adhesion of activated platelets to subendothelial collagen in the blood vessel wall. Indeed, FDA-approved drugs that block GPIIb-IIIa are of benefit as CHIR-99021 antithrombotic therapy in acute coronary syndromes, and in animal models, antagonism of platelet surface P-selectin and platelet surface GPIb has antithrombotic benefit. The later circadian peaks in aggregability, platelet count and ATP release suggest that these may not be as relevant to the day/night pattern of increased risk for thromboembolistic events in the morning as the measures of platelet size and platelet surface activated antigens, which represent in vivo circulating activated platelets. Indeed, although mechanisms for intrinsic circadian oscillations in platelets are unknown, circadian rhythms that are independent of transcription-translation feedback loops have recently been demonstrated in human red blood cells that are also anucleate and involve redox cycles of peroxiredoxins. Humoral factors that express large-amplitude endogenous circadian rhythms and that could drive the endogenous circadian rhythm in platelet function include cortisol, epinephrine, norepinephrine, and melatonin that have a concurrent peak, rapid rise, or rapid fall at the time of the circadian peak in the platelet surface markers of platelet activation. Future studies are required to investigate the relative influence of these circadian hormones on platelet function and to determine whether or not other humoral factors show relevant endogenous circadian rhythms and phases, independent of the behavioral sleep/wake and fasting/feeding cycle. Differences in timing of the endogenous circadian peaks between the platelet surface markers and WBA may be explained in part by the different circadian timing between platelet count and platelet surface markers, because platelet surface markers are not influenced by changes in platelet count, while WBA is increased with increasing platelet count. Alternatively, there may be a ‘ceiling effect’ in the aggregometry assay since platelets that are already partially .