Indobufen prevents tissue factor expression in human monocytes through a thromboxane-dependent mechanism

Background. Indobufen is a reversible inhibitor of platelet cyclooxygenase (Cox) activity, thereby suppressing thromboxane (Tx) synthesis. It is effective in a broad spectrum of prothrombotic conditions ranging from graft occlusion after CABG surgery, to restenosis after carotid endarterectomy, to thromboembolic events in patients with heart disease, and to intermittent claudication. More recently the ability of indobufen to suppress the enhanced Tx biosynthesis in a subset of episodes of platelet activation during the acute phase of unstable angina has been highlighted. This effect, which is not shared by aspirin, has been attributed to the inhibition of the inducible Cox isoform (Cox-2), which is expressed by monocytes in response to a local inflammatory milieu. Aim. To assess whether indobufen affects tissue factor (TF), the main initiator of thrombogenesis in vivo, and to investigate the relationship between Cox-derived products and TF. Methods. Human monocytes were obtained from peripheral blood of healthy donors. TF was evaluated as procoagulant activity (PCA) in monocyte lysates. TF protein and mRNA levels were determined by Western blot and RT-PCR analysis, respectively. Thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) formation was measured in monocyte supernatant by immunoenzymatic technique. Cox-1 and Cox-2 protein level, tyrosine phosphorylation and mitogen activated protein kinase (MAP-kinase) activation were determined by Western blot analysis. Results. Indobufen prevents TF expression in human adherent monocytes exposed to LPS through alteration of TxB2/PGE2 ratio that occurs through reduction of Tx but not of PGE2 synthesis. Prevention of LPS-induced ERK1/2 phosphorylation is highlighted as the mechanism responsible for the anti-TF effect of indobufen. Conclusions: Indobufen down-regulates TF in monocytes. This novel activity, coupled with the antiplatelet effect, may add benefit for the use of indobufen in the management of atherothrombosis.