Effect of selective and non-selective cyclooxygenase inhibitors on survival, platelet function and vein wall inflammation in a rat model of deep vein thrombosis

ABSTRACT

Worldwide, the withdrawal of rofecoxib and valdecoxib from the United State, Australian and European markets with substantial decline in the number of prescriptions for celecoxib attract attention. Inhibition of vascular synthesis of prostacyclin [PGI[2]] leaving platelet thromboxane A[2][TXA[2] synthesis unopposed is thought to increase risk ofthrombotic events. To decrease this risk, adding low aspirin has been suggested. In the present study, we compared celecoxib alone and with low-dose aspirin to indomethacin and to low-dose aspirin regarding the effects on survival, platelet function and vein wall inflammation in a rat model of deep vein thrombosis [DVT] induced by 3 days inferior vena cava ligation.The results showed significant decline in rate of survival in the celecoxib group and enhanced thrombogenesis compared to aspirin and indomethacin. Co-administration of low dose aspirin significantly reduced wet thrombus weight compared to celecoxib monotherapy. Platelet function was assessed by bleeding time and two platelet proteins released into plasma from a granules during platelet activation namely platelet factor 4 [PF4] and micro 3-thromboglobulin [f]-TG]. In the celecoxib group, bleeding time was not altered while plasma PF4 and /beta-TG were high compared to sham group. The level of these platelet markers in celecoxib group was comparable to the DVT group denoting significant platelet activation. Conversely, indomethacin, aspirin alone or with celecoxib were associated with significant increase in bleeding time and significant low values of plasma PF4 and /3-TG compared to DVT group denoting significant inhibition of platelet activity. All COX inhibitor treatments were associated with significant anti-inflammatory effect demonstrated by the low values of vein wall content of tumor necrosis factor-a [TNF-alpha] and interleukin-1 beta [IL-1beta] compared to DVT group. However, attenuation in the rise of myeloperoxidase activity was significant only with indomethacin possibly due to its greater anti-inflammatory effect.The present study shows that celecoxib shares standard non-steroidal anti-inflammatory [NSAIDs] e.g. indomethacin and aspirin, significant anti-inflammatory effect but seems to lack significant inhibitory effect on platelets. This would raise concerns about increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased with underlying inflammatory disorders and platelet activation e.g. venous stasis