Heterogeneity in the suppression of platelet cyclooxygenase-1 activity by aspirin in coronary heart disease*.

Background and Objectives: Complete and persistent suppression of platelet thromboxane (TX) A₂ biosynthesis by aspirin is mandatory to fulfill its cardioprotection. We explored the determinants of heterogeneity of TXB₂ generation in clotting whole blood, a capacity index of platelet cyclooxygenase (COX) activity, in patients with coronary heart disease (CHD) versus healthy subjects treated with low-dose aspirin on a long-term basis.Methods: We studied 30 patients with CHD (ie, chronic stable angina, unstable angina, and acute myocardial infarction) and 10 healthy subjects, who were treated with low-dose aspirin (100 mg daily) on a long-term basis, 12 hours after the administration of 160 mg aspirin to ensure saturation of platelet COX-1 activity. Serum TXB₂ levels were assessed. The contribution of blood COX-2 to TXA₂ biosynthesis was explored by evaluation of the effect of a selective COX-2 inhibitor (L-745,337) added to heparinized whole blood stimulated with Ca⁺⁺ ionophore A23187 (20 μmol/L) for 1 hour or lipopolysaccharide (0.1 μg/mL) for 4 hours.Results: In healthy subjects serum TXB₂ levels ranged from 0.6 to 7.9 ng/mL (median, 2.1 ng/mL; mean ± SD, 3.2 ± 2.6 ng/mL). In CHD patients we detected enhanced variability in serum TXB₂ generation (median, 3.1 ng/mL [range, 0.15-47 ng/mL]; mean, 8.5 ± 12.3 ng/mL), which in 8 patients (27%) exceeded the mean value + 2 SDs detected in healthy subjects (ie, 8.4 ng/mL), set as the limit value for an adequate inhibition of platelet COX-1 by aspirin. Elevated whole-blood TXB₂ generation was not dependent on leukocyte count, COX-2 activity, or cigarette smoking but was plausibly a result of defective suppression of platelet COX-1 activity.Conclusions: Heterogeneity in the suppression of platelet COX-1 activity by aspirin occurred in CHD patients. The measurement of the serum TXB₂ level seems to be an appropriate biomarker to identify patients who have an inadequate inhibition of platelet COX-1 activity by aspirin.Clinical Pharmacology & Therapeutics (2006) 80, 115–125; doi: 10.1016/j.clpt.2006.04.011 [ABSTRACT FROM AUTHOR]