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

Crit Care Med. 2004 May;32(5 Suppl):S293-7. doi: 10.1097/01.ccm.0000128445.95144.b8.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Anticoagulants / therapeutic use
  • Blood Coagulation
  • Endopeptidases / physiology*
  • Endotoxemia / immunology*
  • Fibrin / physiology
  • Humans
  • Protein C / physiology
  • Receptors, Proteinase-Activated / physiology*
  • Sepsis / drug therapy
  • Sepsis / immunology*
  • Thrombin / physiology
  • Thromboplastin / physiology*


  • Anticoagulants
  • Protein C
  • Receptors, Proteinase-Activated
  • Fibrin
  • Thromboplastin
  • Endopeptidases
  • Thrombin