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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Platelet Cyclooxygenase Inhibition by Low-Dose Aspirin Is Not Reflected Consistently by Platelet Function Assays

Implications for Aspirin "Resistance"

Francesca Santilli, MD^_*, Bianca Rocca, MD, PhD, Raimondo De Cristofaro, MD, Stefano Lattanzio, BSc^_*, Laura Pietrangelo, BSc^_*, Aida Habib, PhD, Caterina Pettinella, PhD^_*, Antonio Recchiuti, PhD^_*, Elisabetta Ferrante, BSc^_*, Giovanni Ciabattoni, MD^_*, Giovanni Davì, MD^_* and Carlo Patrono, MD^,_*

^_* Center of Excellence on Aging, "G. d'Annunzio" University Foundation, Chieti, Italy
Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
Department of Internal Medicine, Catholic University School of Medicine, Rome, Italy
American University of Beirut, Beirut, Lebanon

Manuscript received July 25, 2008; revised manuscript received October 8, 2008, accepted October 14, 2008.

^_* Reprint requests and correspondence: Prof. Carlo Patrono, Department of Pharmacology, Catholic University School of Medicine, Largo F. Vito 1 00168 Rome, Italy (Email: carlo.patrono{at}rm.unicatt.it).

Objective: This study was conducted to assess the thromboxane (TX) dependence of biochemical and functional indexes used to monitor the effect of low-dose aspirin.

Background: Functional assays of the antiplatelet effects of low-dose aspirin variably reflect the TX-dependent component of platelet aggregation. Previous studies of aspirin resistance were typically based on a single determination of platelet aggregation.

Methods: We assessed the TXB₂ dependence of biochemical and functional indexes, as well as their intersubject and intrasubject variability during administration of the drug and after its withdrawal in 48 healthy volunteers randomized to receive aspirin 100 mg daily for 1 to 8 weeks.

Results: Serum TXB₂ was uniformly suppressed by 99% of baseline. Urinary 11-dehydro-TXB₂, arachidonic acid-induced aggregation, and VerifyNow Aspirin (Accumetrics Inc., San Diego, California) showed stable, incomplete inhibition (65%, 80%, and 35%, respectively). Adenosine diphosphate- and collagen-induced aggregation was highly variable and poorly affected by aspirin, with an apparent time-dependent reversal. Inhibition of platelet cyclooxygenase activity was nonlinearly related to inhibition of platelet aggregation. Platelet function largely recovered by day 3 post-aspirin, independently of treatment duration. With any functional assay, occasionally "resistant" subjects were found to be "responders" on previous or subsequent determinations.

Conclusions: Platelet cyclooxygenase activity, as reflected by serum TXB₂ levels, is uniformly and persistently suppressed by low-dose aspirin in healthy subjects. However, the effect of aspirin is variably detected by functional assays, potentially leading to misclassification of "responder" as "resistant" phenotypes owing to poor reproducibility of functional measurements. The nonlinearity of the relationship between inhibition of TX production and inhibition of platelet function has important clinical implications.

Key Words: aspirin • platelets • prostaglandins • antiplatelet drugs • pharmacology

Abbreviations and Acronyms   AA = arachidonic acid   ADP = adenosine diphosphate   COX = cyclooxygenase   CV = coefficient of variation   NSAID = nonsteroidal anti-inflammatory drug   Tmax = maximal aggregation   TX = thromboxane

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