A blood-clotting protein called tissue factor (TF) may be responsible for the increased risk of cardiovascular side-effects that has bedevilled COX-2 inhibitor analgesics such as Vioxx (rofecoxib), US researchers suggest.

Writing in the Journal of Experimental Medicine (JEM, published online August 27), researchers led by Timothy Hla from the Department of Cell Biology at the University of Connecticut Health Center in Farmington described how blocking the COX-2 enzyme – the mechanism by which the COX-2 inhibitors (coxibs) reduce pain – in mice also stimulates the production of TF, described as the primary initiator of blood coagulation. This blood-clotting effect may explain the coxibs’ association with heart attacks and strokes.

Hla and his colleagues demonstrated that the metabolism of endocannabinoids by the COX-2 enzyme in endothelial cells, coupled to the prostacyclin synthase (PGIS) enzyme, normally activates the nuclear receptor peroxisomal proliferator-activated receptor (PPAR), which regulates the expression of tissue factor.

In mice, however, administering coxibs suppresses PPAR activity and induces TF expression in the vascular endothelium (the cells that line blood vessels), as well as raising the level of circulating TF activity, the researchers reported. Conversely, PPAR agonists suppress coxib-induced TF expression and reduce circulating TF activity in vivo, they added.

According to Hla et al, these experiments are evidence that “COX-2-dependent attenuation of TF expression is abrogated by coxibs, which may explain the prothrombotic side-effects for this class of drugs”. Moreover, they suggested, PPAR agonists “may be used therapeutically to suppress coxib-induced cardiovascular side-effects.”

Last year researchers from Imperial College London and Queen Mary’s School of Medicine and Dentistry in the UK published a study suggesting that COX-2 inhibitors may increase the risk of cardiovascular side-effects by inhibiting the COX-1 enzyme in endothelial cells that makes prostacyclin.

As prostacyclin thins the blood, suppressing it would increase the chance of blood clotting, with potential longer-term consequences such as heart attacks or strokes.