Cyclooxygenase-2 Inhibitors Enhance Shear Stress-Induced Platelet Aggregation
Piet Borgdorff, PhD,
Geert Jan Tangelder, MD, PhD and
Walter J. Paulus, MD, PhD*
Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
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Figure 1 (Left) Experimental set-up with roller pump and photometric device, which measures platelet aggregation in the extracorporeal shunt between carotid and femoral artery. (Right) Aggregate detection (upper recording) and its quantification (lower recording). Note absence of platelet aggregation during autoperfusion and aggregation after the pump is switched on.
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Figure 2 Enhancement of pump-induced platelet aggregation by parecoxib (A) and by high-dose aspirin (B), as well as attenuation of pump-induced platelet aggregation by low-dose aspirin (B).
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Figure 3 Parecoxib (20 mg/kg) reduces the plasma level of the prostacyclin (PGI2) metabolite 6-keto-prostaglandin F1 from 100 ± 25 pg/ml (n = 7) to 36 ± 11 pg/ml (n = 15). *p < 0.0001.
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Figure 4 Changes of vascular resistance in the extracorporeally perfused hind limb during a 10-min pump perfusion run. Under control conditions a triphasic response to pump perfusion is observed, consisting of a very short dilation, followed by 4 to 5 min of vasoconstriction and a longer-lasting vasodilation. Both parecoxib (parec) (A) and high-dose aspirin (B) significantly reinforced the vasoconstrictive response (p = 0.04 and p = 0.03, respectively). Pretreatment with a low dose of clopidogrel (clop) prevented the parecoxib-induced reinforcement of vasoconstriction (A). Low-dose aspirin failed to induce significant changes from control (B).
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Figure 5 Enhancement of pump-induced platelet aggregation by parecoxib (Parec) is not significantly altered by co-administration of low-dose aspirin (asp) (A) but is neutralized with a low dose (1 mg/kg) of clopidogrel (clop) (B); higher doses of clopidogrel progressively reduced (5 and 25 mg/kg) or completely prevented (50 mg/kg) platelet aggregation.
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Figure 6 Proposed role of cyclooxygenase (COX)-2 and COX-1 in shear stress-induced platelet aggregation. Platelet aggregability is under continuous control of COX-2–induced endothelial prostacyclin (PGI2) that decreases calcium (Ca2+) by increasing the levels of cyclic adenosine monophosphate (cAMP). Shear stress starts the sequence of events by "unrolling" the plasma von Willebrand factor (vWf) and possibly by platelet deformation. Binding of the vWf A1-domain to platelet glycoprotein (GP) Ib receptors triggers intracellular Ca2+ mobilization with subsequent release of adenosine diphosphate (ADP) from dense granules and vWf from the alpha-granules. Adenosine diphosphate stimulates 5'-diphosphate (P2Y12)-receptors on the same and other platelets to activate GP IIb/IIIa receptors that bind fibrinogen and vWf, thereby causing aggregation. Platelet COX-1–induced thromboxane (TXA2)-formation reinforces aggregation at low or moderate shear stress but not at high shear stress (dotted lines). Shear stress-induced platelet aggregation can be prevented by blockade ( ) of P2Y12-receptors with clopidogrel.
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