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Antiplatelet therapy for the management of patients with cardiovascular risks often includes a combination therapy of aspirin and clopidogrel, acting through inhibition of thromboxane generation and blockade of Gi-coupled P2Y12 receptor, respectively. We hypothesized that ADP acting through P2Y12 regulates physiological thromboxane levels. The serum thromboxane levels in mice ( n = 3) dosed with clopidogrel and prasugrel were decreased by 83.1 ± 5.3% and 94.26 ± 1.75% respectively compared to untreated mice. Pre-treatment of human blood ( n = 3) ex vivo with active metabolites of clopidogrel or prasugrel led to a reduction in thromboxane levels to 16.3 ± 3.2% and 4.9 ± 0.8% respectively, compared to untreated human serum. We also evaluated serum thromboxane levels in P2Y receptor null mice ( n = 4). Whereas serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, those in the P2Y12 null mice were inhibited by 83.15 ± 3.8%. Finally, in a pilot study, serum thromboxane levels were reduced by 76.05 ± 8.41% in healthy human volunteers ( n = 6) upon dosing with clopidogrel, compared to the levels before dosing. In conclusion, P2Y12 antagonism alone can decrease physiological thromboxane levels. Thus, this study could pave way the for newer/modified treatment regimens for the management of patients with thrombotic complications who are allergic or non-responsive to aspirin. [ABSTRACT FROM AUTHOR]