Heterogeneity in the suppression of platelet cyclooxygenase-1 activity by aspirin in coronary heart disease.
OBJECTIVE
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 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 micromol/L) for 1 hour or lipopolysaccharide (0.1 microg/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.
Sciulli
Maria G
MG
Department of Medicine and Center of Excellence on Aging, G. d'Annunzio University, School of Medicine Gabriele d'Annunzio University Foundation, Chieti, Italy.
Renda
Giulia
G
Capone
Marta L
ML
Tacconelli
Stefania
S
Ricciotti
Emanuela
E
Manarini
Stefano
S
Evangelista
Virgilio
V
Rebuzzi
Antonio
A
Patrignani
Paola
P
D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology*; D000001:Calcimycin / Q000494:pharmacology; D003327:Coronary Disease / Q000097:blood* / Q000201:enzymology*; D051545:Cyclooxygenase 1 / Q000097:blood*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007189:Indans / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000201:enzymology; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D007189:Indans; C093700:L 745337; D008070:Lipopolysaccharides; D016718:Arachidonic Acid; D000001:Calcimycin; D013929:Thromboxane B2; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin