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Heterogeneity in the suppression of platelet cyclooxygenase‐1 activity by aspirin in coronary heart disease
Author(s) -
Sciulli Maria G.,
Renda Giulia,
Capone Marta L.,
Tacconelli Stefania,
Ricciotti Emanuela,
Manarini Stefano,
Evangelista Virgilio,
Rebuzzi Antonio,
Patrignani Paola
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.04.011
Subject(s) - aspirin , medicine , platelet , myocardial infarction , cyclooxygenase , whole blood , thromboxane b2 , unstable angina , angina , cardiology , gastroenterology , pharmacology , chemistry , enzyme , biochemistry
Background and Objectives Complete and persistent suppression of platelet thromboxane (TX) A 2 biosynthesis by aspirin is mandatory to fulfill its cardioprotection. We explored the determinants of heterogeneity of TXB 2 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 TXB 2 levels were assessed. The contribution of blood COX‐2 to TXA 2 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 TXB 2 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 TXB 2 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 TXB 2 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 TXB 2 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