Semin Thromb Hemost 2006; 32: 049-060
DOI: 10.1055/s-2006-939554
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Inflammation and the Activated Protein C Anticoagulant Pathway

Charles T. Esmon1
  • 1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation; Departments of Pathology, and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center; and Howard Hughes Medical Institute, Oklahoma City, Oklahoma
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Publication History

Publication Date:
02 May 2006 (online)

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ABSTRACT

After a coagulation stimulus, the blood clotting cascade amplifies largely unchecked until very high levels of thrombin are generated. Natural anticoagulant mechanisms (for example, the protein C anticoagulant pathway) are amplified to prevent excessive thrombin generation. Thrombin binds to thrombomodulin (TM) and this complex and then activates protein C ~1000 times faster than free thrombin. Protein C activation is enhanced ~20-fold further by the endothelial cell protein C receptor (EPCR). Activated protein C proteolytically inactivates factor Va (FVa) and FVIIIa, thereby blocking the amplification of the coagulation system, a process that is accelerated by protein S. TM not only accelerates protein C activation, but also decreases endothelial cell activation by blocking high-mobility group protein-B1 inflammatory functions and suppressing both nuclear factor-kappa B nuclear translocation and the mitogen-activated protein kinase pathways. The thrombin-TM complex also activates thrombin-activatable fibrinolysis inhibitor, a procarboxypeptidase that renders fibrin resistant to clot lysis and neutralizes vasoactive molecules such as complement C5a. Activated protein C has a variety of antiinflammatory activities. It suppresses inflammatory cytokine elevation in animal models of severe sepsis, inhibits leukocyte adhesion, decreases leukocyte chemotaxis, reduces endothelial cell apoptosis, helps maintain endothelial cell barrier function through activation of the sphingosine-1 phosphate receptor, and minimizes the decrease in blood pressure associated with severe sepsis. Most of these functions are dependent on binding to EPCR. Overall this pathway is critical to both regulation of the blood coagulation process, and control of the innate inflammatory response and some of its associated downstream pathologies.

REFERENCES

Charles T EsmonPh.D. 

Oklahoma Medical Research Foundation

Cardiovascular Biology Research Program, 825 NE 13th Street, Oklahoma City, OK 73104

Email: Charles-Esmon@omrf.ouhsc.edu