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Thromb Haemost 2004; 92(06): 1277-1283
DOI: 10.1160/TH04-01-0008
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor

Sriram Ravindran
1   Department of Oral Medicine and Diagnostic Sciences
,
Thomas E. Grys
2   Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA
,
Rodney A.Welch
2   Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA
,
Marc Schapira
3   Department of Hematology, CHUV, University of Lausanne, Switzerland
,
Philip A. Patston
1   Department of Oral Medicine and Diagnostic Sciences
4   Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
› Author AffiliationsFinancial support: This work was supported by National Institutes of Health Grants HL-49242 (to P.A.P.), AI-051735 and AI-20323 (to R.A.W.), and by Swiss National Science Foundation Grant 31-36080.9 (to M.S.).
Further Information

Publication History

Received 07 January 2004

Accepted after resubmission 26 September 2004

Publication Date:
02 December 2017 (online)

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Summary

Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with C1inhibitor deficiency. Heterozygous individuals with <50% levels of active C1-inhibitor are susceptible to angioedema attacks indicating a critical need for C1-inhibitor to be present at maximum levels to prevent unwanted prekallikrein activation. Studies with purified proteins do not adequately explain this observation. Therefore to investigate why reduction of C1inhibitor to levels seen in angioedema patients results in excessive kallikrein generation we examined the effect of endothelial cells on the inhibition of kallikrein by C1-inhibitor. Surprisingly, it was found that a C1-inhibitor concentration of greater than 1 µM was needed to inhibit 3 nM kallikrein. We propose that this apparent protection from inhibition was mediated by kallikrein binding to the cells via the heavy chain in a high molecular weight kininogen and zinc independent manner. Protection of kallikrein from inhibition was not observed when C1-inhibitor truncated in the amino-terminal domain by the StcE metalloproteinase was used, which suggests a novel function for this unique domain. The requirement for high concentrations of C1-inhibitor to fully inhibit kallikrein is consistent with the fact that reduced levels of C1-inhibitor result in the kallikrein activation seen in angioedema.

Keywords

Coagulation inhibitors - proteases/inhibitors - endothelial cells - contact phase
 

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