Thromboxane A₂ generation, in the absence of platelet COX-1 activity, in patients with and without atherothrombotic myocardial infarction

Background: Aspirin's therapeutic action is via inhibition of platelet cyclooxygenase 1 (COX-1) thromboxane A2 (TxA₂) production. The aim of this study was to evaluate TxA₂ production, in the absence of platelet COX-1 activity, in coronary atherosclerotic heart disease patients with and without atherothrombotic myocardial infarction (MI). Methods and Results: TxA₂ production, in the absence of platelet COX-1 activity, was evaluated in 44 patients taking aspirin on 3 commercially available assays that detect metabolites of TxA₂ in the urine. Two assays measure urine 11-dehydro-thromboxane B2 (TxB₂) alone and 1 measures urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor- TxB2. Platelet COX-1 inhibition was confirmed on <10% platelet aggregation in response to ≥1 mmol/L arachidonic acid. Median urine 11-dehydro-TxB₂ was no different in those with and without a diagnosis of atherothrombotic MI (325 vs. 311 pg/mg creatinine, P=0.59 via polyclonal ELISA) and (312 vs. 244 pg/mg creatinine, P=0.11 via LC-MS/MS). Median urine 11-dehydro-TxB₂ plus 11-dehydro-2,3-dinor-TxB₂, however, was higher in those with vs. those without a diagnosis of atherothrombotic MI (1,035 vs. 606 pg/mg creatinine, P=0.03 via monoclonal ELISA). Conclusions: Differences in TxA₂ production, in the absence of platelet COX-1 activity, between those with vs. without atherothrombotic MI were not observed when TxA₂ generation was assessed on 11-dehydro-TxB₂ production alone (polyclonal ELISA or LC-MS/MS), but differences were observed when TxA₂ generation was assessed using 11-dehydro-TxB₂ plus 11-dehydro-2,3-dinor-TxB₂ (monoclonal ELISA). These findings highlight important differences between different commercially available assays for TxA₂ generation and suggest that 11-dehydro-2,3-dinor-TxB₂ may be critical to the biology of atherothrombosis.