¹Department of Medicine and Center of Excellence on Aging, "G. d'Annunzio" University, School of Medicine "Gabriele d'Annunzio" University Foundation, Chieti, Italy; Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy; and Institute of Cardiology, Catholic University, School of Medicine, Rome, Italy.

Correspondence: Paola Patrignani, PhD, Sezione di Farmacologia, Dipartimento di Medicina e Scienze dell'Invecchiamento, Università di Chieti "G. d'Annunzio," Via dei Vestini, 31, 66013 Chieti, Italy. E-mail: ppatrignani@unich.it

^*This study was supported by grants from the Italian Ministry of University and Research (MIUR and FIRB) to P.P.

Received 23 January 2006; Accepted 13 April 2006.

Abstract

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 mol/L) for 1 hour or lipopolysaccharide (0.1 g/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.