Cyclooxygenase-2 inhibitors enhance shear stress-induced platelet aggregation.
OBJECTIVE
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 F(1alpha) 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.
Borgdorff
Piet
P
Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
Tangelder
Geert Jan
GJ
Paulus
Walter J
WJ
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D000077144:Clopidogrel; D001026:Coronary Artery Bypass; D023921:Coronary Stenosis / Q000188:drug therapy / Q000503:physiopathology*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D007555:Isoxazoles / Q000009:adverse effects*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D012307:Risk Factors; D033081:Shear Strength; D013927:Thrombosis / Q000503:physiopathology / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; C409945:parecoxib; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin