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PRECLINICAL STUDIES

Cyclooxygenase-2 Inhibitors Enhance Shear Stress-Induced Platelet Aggregation

Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

Manuscript received December 13, 2005; revised manuscript received March 17, 2006, accepted March 22, 2006.

^_* Reprint requests and correspondence: Prof. Dr. Walter J. Paulus, Laboratory for Physiology, VUMC, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands. (Email: wj.paulus{at}vumc.nl).

OBJECTIVES: We aimed to investigate the effect of parecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on in vivo shear stress-induced platelet aggregation in a rat model of arterial bypass with focal narrowing.

BACKGROUND: Long-term use of COX-2 inhibitors is associated with increased incidence of adverse cardiovascular events, especially in patients with a history of cardiovascular disease. These patients are at risk for thrombotic occlusion of arterial stenoses initiated by shear stress-induced platelet aggregation.

METHODS: To mimic the combination of a tight arterial stenosis and high shear stress in rats, an extracorporeal shunt from carotid to femoral artery was compressed by the rollers of a pump. Platelet aggregation was continuously measured by a photometric detector in the shunt.

RESULTS: Pretreatment with parecoxib (20 mg/kg) almost doubled shear stress-induced platelet aggregation (188% vs. 100% in control subjects, p = 0.0003). This was accompanied by a fall in plasma 6-keto-prostaglandin F₁ from 100 ± 25 pg/ml to 36 ± 11 pg/ml (p < 0.0001). Enhanced platelet aggregation was also observed with high-dose aspirin (150 mg/kg) (146%; p = 0.02) but not with low-dose aspirin (25 mg/kg), which reduced aggregation (68%; p = 0.01). The effect of parecoxib was neutralized by low-dose (1 mg/kg) clopidogrel (from 188% to 92%; p = 0.0001), but not by low-dose aspirin (from 188% to 177%; p = NS).

CONCLUSIONS: In the presence of an arterial stenosis, COX-2 inhibitors enhance shear stress-induced platelet aggregation. This enhancement was prevented by low-dose clopidogrel but not by low-dose aspirin. Clopidogrel might therefore allow COX-2 inhibitors to be used without raising risk of thrombotic occlusion.

Abbreviations and Acronyms   ADP = adenosine diphosphate   COX-2 = cyclooxygenase-2   GP = glycoprotein   nPA = amount of platelet aggregates per milliliter of shunted blood   P2Y12 = 5'-diphosphate receptors   PGF = prostaglandin F   PGI2 = prostacyclin   vWf = von Willebrand factor

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