Published Online
on June 19, 2006

A more recent version of this article appeared on June 27, 2006

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Submitted on October 20, 2005
Revised on April 14, 2006
Accepted on April 24, 2006

Residual Arachidonic Acid-Induced Platelet Activation via an Adenosine Diphosphate-Dependent but Cyclooxygenase-1- and Cyclooxygenase-2-Independent Pathway. A 700-Patient Study of Aspirin Resistance

Andrew L. Frelinger III PhD, Mark I. Furman MD^*, Matthew D. Linden PhD, Youfu Li MD, Marsha L. Fox RN, MS, Marc R. Barnard MS, and Alan D. Michelson MD

From the Center for Platelet Function Studies, Department of Pediatrics (A.L.F., M.D.L., M.L.F., M.R.B., A.D.M.), Division of Cardiovascular Medicine, Department of Medicine (M.I.F., Y.L.), University of Massachusetts Medical School and the Cardiac Catheterization Laboratories (M.I.F.), UMass Memorial Health Care, Worcester, Mass.

^* To whom correspondence should be addressed. E-mail: mark.furman{at}umassmed.edu.

Background--Thrombotic events still occur in aspirin-treated patients with coronary artery disease.

Methods and Results--To better understand aspirin "resistance," serum thromboxane B₂ (TXB₂) and flow cytometric measures of arachidonic acid-induced platelet activation (before and after the ex vivo addition of aspirin and indomethacin) were analyzed in 700 consecutive aspirin-treated patients undergoing cardiac catheterization. In 680 of 682 evaluable patients, serum TXB₂ concentrations were reduced compared with nonaspirinated healthy donors. Twelve patients had serum TXB₂ that was lower than nonaspirinated healthy donors but >10 ng/mL. Arachidonic acid stimulated greater platelet activation in patients with high serum TXB₂ (>10 ng/mL) than in patients with low serum TXB₂. Addition of ex vivo aspirin reduced arachidonic acid-induced platelet activation to similar levels regardless of serum TXB₂ concentrations, which suggests that patients with high residual serum TXB₂ concentrations were either noncompliant or underdosed with aspirin. Among the remaining 98% of patients, ex vivo administration of either aspirin or indomethacin failed to prevent platelet activation across all degrees of arachidonic acid-induced platelet activation and aspirin doses. Although the patients were not randomized with respect to clopidogrel treatment, multivariate analysis showed that arachidonic acid-induced platelet activation was less in patients receiving clopidogrel.

Conclusions--There is a residual arachidonic acid-induced platelet activation in aspirin-treated patients that (1) is caused by underdosing and/or noncompliance in only 2% of patients and (2) in the remaining patients, occurs via a cyclooxygenase-1 and cyclooxygenase-2 independent pathway, in direct proportion to the degree of baseline platelet activation, and is mediated in part by adenosine diphosphate-induced platelet activation.

Key words: platelets • aspirin • thrombosis • aspirin resistance • drug resistance • coronary disease

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