Extracts from malignant tissue reduce thrombomodulin expression on cultured human endothelial cells

Thrombomodulin is an endothelial cell protein pivotal in the activation of the zymogen protein C to the serine protease activated protein C. The studies reported in this manuscript demonstrate down-regulation of thrombomodulin on cultured human endothelial cells in the presence of tumour extracts obtained from two patients with cancer complicated by aggressived thrombosis. The effects were time and concentration dependentsd and appear to be specific, as other endothelial functions (von Willebrand factor production and procoagulant activity) proceeded unabated in the treated cells. The effect of tumour extracts on the neutrophil-endothelial cell interaction was also examined. The adherence of activated neutrophils to endothelial cellss incubated with the tumour extracts was augmented 10-fold compared to cells grown in medium alone. We concluded that reduction in thrombomodulin expression may represent an important pathogenetic mechanism of thrombosis in patients with malignancy. Additionally, tumour products may induce increased neutrophil adherence to the endothelium, thereby generating the clinical syndrome of thrombophlebitis.