Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease

Abstract 

Background

Platelets, long believed to be incapable of de novo protein synthesis, may retain their ability to form the cyclooxygenase (COX) enzyme once it has been inactivated by aspirin. This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients. We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration.

Methods

Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1, 3, 8, and 24h after observed ingestion of 80-mg enteric-coated aspirin. Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane (Tx) B₂ levels, and functionally by light transmission aggregometry in response to arachidonic acid. COX-independent platelet activity was measured in response to adenosine diphosphate, epinephrine and collagen.

Results

Plasma TxB₂ levels showed profound inhibition of TxA₂ formation, which was stable throughout 24h, in all but 1 subject. This subject had optimal response to aspirin (inhibition of platelet TxA₂ production within 1h), but recovered the ability to synthesize TxA₂ within 24h of aspirin ingestion. Arachidonic acid-induced platelet aggregation closely mirrored TxB₂ formation in this patient, portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion. COX-independent platelet aggregation triggered TxA₂ production to a similar extent in all patients, likely through signal-dependent protein synthesis.

Conclusions

COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration. Further research should consider increasing aspirin dosing frequency to twice daily, to allow sustained inhibition in such subjects.

Keywords: Aspirin, Coronary artery disease, Cyclooxygenase, Platelet aggregation, Thromboxane