Effect of intradermal tumor necrosis factor-alpha-induced inflammation on coagulation factors in dermal vessel endothelium - An in vivo study of human skin biopsies

Inflammatory mediators were shown to exert procoagulant effects on cultured human endothelial cells (EC). In the present study the effect of intraderm al application of tumor necrosis factor-alpha (TNF-alpha) on the expression of factors involved in regulation of coagulation at the EC surface, i.e. t issue factor (TF), thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) was studied in humans in vivo. The endothelial expression of these f actors was evaluated immunohistochemically in biopsies taken after intrader mal application of 5000 U TNF-alpha in 8 healthy volunteers. After 6 and 22 h biopsies were taken from the injection sites. At TNF-alpha injected site s typical inflammatory changes, e. g. EC upregulation of adhesion molecules and accumulation of leukocytes were detected. In parallel we could documen t EC expression of TF. downregulation of TM and depletion of tissue factor pathway inhibitor (TFPI) in inflamed areas. Early depletion of endothelial I kappaB alpha at the site of inflammation after application of TNF-alpha p oints to an activation of the NF-kappaB pathway. Our data suggest that, as shown in in vitro experiments, TNF-alpha activates the NF-kappaB pathway an d induces specific procoagulant changes of EC due to expression of TF, down regulation of TM and depletion of TFPI in vivo in humans. This procoagulant shift in the haemostatic balance on the cell surface. caused by TNF-alpha -induced inflammation. is likely to contribute to thrombosis associated wit h tissue inflammation in humans.