P. Borgdorff and GJ Tangelder - Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

With interest we have read the paper by Armstrong et al. (1). Unfortunately, they do not discuss and compare their findings to a study on COX-2 (cyclooxygenase-2) inhibition and platelet aggregation in rats (2).

In this latter study also parecoxib was used to selectively inhibit COX-2, albeit at a much higher concentration (20 mg/kg versus 0.5 mg/kg i.v.). In these rats COX-2 inhibition significantly increased shear stress-induced platelet aggregation in blood flowing through an extracorporeal shunt from carotid to femoral artery (from 14.3 ± 3.2 x 103 to 26.9 ± 5.3 x 103 of platelet aggregates per milliliter blood during 10 minutes, n=6, p= 0.0003). This was likely caused by suppression of prostacyclin formation ( arterial levels of its stable metabolite 6-keto-PGF1a decreased from 100 ± 25 to 36 ± 11 pg/ml, n=15, p< 0.0001).

A possible explanation for the difference between the two studies, apart from a species difference, might be use of an inadequate parecoxib dose in mice. The latter was only 1.5 – 2 times that in humans (20 mg i.v.). It is generally known that the smaller the animal (i.e. the higher the metabolic rate), the higher the effective dose needed; indeed, Armstrong et al. mention in their Discussion that for aspirin they needed a 100 times higher dose in mice than that required in man.

Other, less likely, explanations might be the use of platelets from donor mice labeled in-vitro with Indium in the mice study, while in rats aggregation was studied of endogenous pristine platelets; or: platelets aggregated on the venous side in mice, whereas in the rat study they aggregated in arterial blood.

In rats, enhanced platelet aggregation was also found after pretreatment with NS-398 (selective COX-2 inhibition) as well as with high dose aspirin (aselective COX-2 inhibition), while low-dose aspirin reduced platelet aggregation. In addition, in humans COX-2 inhibition by a single tablet of 50 mg rofecoxib (selective inhibitor) or by a 500-1000 mg oral dose of aspirin (aselective inhibitor) increased ADP-induced platelet aggregation during and immediately after blood sampling (3). Both treatments decreased plasma levels of 6-keto-PGF1a by 25-30 %.

Therefore, in contrast to the conclusion of Armstrong et al., our studies do support the hypothesis that acute inhibition of COX-2 in the circulation might increase the risk for thrombosis (i.e platelet aggregation).

References.
1. Armstrong PC, Kirkby NS, Zain ZN, Emerson M, Mitchell JA, Warner TD. Thrombosis is reduced by inhibition of COX-1, but unaffected by inhibition of COX-2, in an acute model of platelet activation in the mouse. PLoS.One. 2011;6:e20062.
2. Borgdorff P, Tangelder GJ, Paulus WJ. Cyclooxygenase-2 inhibitors enhance shear stress-induced platelet aggregation. J Am.Coll.Cardiol. 2006;48:817-23.
3. Borgdorff, P., Handoko, M. L., Wong, Y. Y., and Tangelder, G. J. COX-2 Inhibition by Use of Rofecoxib or High Dose Aspirin Enhances ADP-Induced Platelet Aggregation in Fresh Blood. The Open Cardiovascular Medicine Journal 4, 198-205. 2010.