Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis

Abstract

Inhibition of the tissue factor-factor VIIa complex reduces coagulation and inflammation in animal models of endotoxemia and sepsis and in patients with severe sepsis. However, the mechanism by which tissue factor-dependent activation of the coagulation cascade enhances inflammation is not known. We tested the hypothesis that coagulation proteases enhance inflammation during endotoxemia by activating protease-activated receptors (PARs) within the vasculature. We found that genetically modified mice expressing low levels of tissue factor exhibited reduced interleukin-6 expression and increased survival in a mouse model of endotoxemia compared with control mice. In contrast, hirudin inhibition of thrombin or a deficiency in either PAR-1 or PAR-2 did not affect interleukin-6 expression or mortality. However, combining hirudin treatment to inhibit thrombin signaling through PAR-1 and PAR-4 with PAR-2 deficiency reduced lipopolysaccharide-induced interleukin-6 expression and increased survival. Taken together, our results suggest that activation of multiple PARs by coagulation proteases enhances inflammation during endotoxemia.

Lipopolysaccharide signaling in endothelial cells

“…26 During sepsis, the endothelium shifts from an anticoagulant surface to a procoagulant surface by reduced expression of anticoagulatory molecules such as thrombomodulin, thereby shifting the action of thrombin towards the cleavage of fibrinogen and the generation of fibrin clots. 27,28 Furthermore, LPS may directly induce the prothrombotic state by upregulating the endothelial expression of tissue factor through an NF-kB-dependent mechanism. 29 These changes contribute to the disseminated intravascular coagulation characteristic of sepsis.…”

Coagulation factor III (tissue factor) is required for vascularization in zebrafish embryos

“…Also known as coagulation factor III, TF is the cell surface receptor for factor VII (FVII), which is responsible for triggering blood coagulation (Nemerson, 1988;Carson and Brozna, 1993). Tissue factor is involved in thrombosis and inflammation associated with sepsis, atherosclerosis, tumor progression, and embryogenesis (Pawlinski and Mackman, 2004;Chen and Dorling, 2009).…”

A small interfering RNA targeting proteinase‐activated receptor‐2 is effective in suppression of tumor growth in a Panc1 xenograft model

“…In addition to their roles in clotting, factors VIIa and Xa and thrombin activate various vascular cells. 56 TF-factor VIIa and TFfactor VIIa-factor Xa complexes can activate PAR-2, and factor Xa alone can also activate PAR-2. 56 This close relation between PAR-2 and TF may affect tumor growth.…”