Introduction Hereditary angioedema (HAE 1 ) is a disease associated with deficiency of C1-inhibitor. Deficiency is inherited in an autoso- mal dominant manner and is due to decreased expression (Type 1 HAE) or expression of dysfunctional protein (Type 2 HAE). In both cases the affected individuals are heterozygotes. An important feature of both forms of hereditary angioedema is that functional levels of C1-inhibitor are usually only 30% of nor- mal. The reason for this value not being the expected 50% is not entirely clear but is assumed to be due to an increased level of C1-inhibitor consumption, or due to a translational defect, pos- sibly due to trans-inhibition by the mutant mRNA or protein, or other unknown mechanisms (1-4). In addition to inherited C1- inhibitor deficiency, an acquired form exists. In most cases acquired angioedema is caused by auto-antibodies against C1- inhibitor, produced by a malignant B-cell clone, or generated as a consequence of an autoimmune process. The auto-antibodies © 2004 Schattauer GmbH, Stuttgart Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor Sriram Ravindran 1 ,Thomas E. Grys 2 , Rodney A.Welch 2 , Marc Schapira 3 , Philip A. Patston 1,4 1 Department of Oral Medicine and Diagnostic Sciences, and 4 Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA 2 Department of Medical Microbiology and Immunology, University of Wisconsin, Madison,Wisconsin, USA 3 Department of Hematology, CHUV, University of Lausanne, Switzerland Thromb Haemost 2004; 92: 1277–83 1 μM was needed to inhibit 3 nM kallikrein.We propose that this apparent protection from inhibition was mediated by kal- likrein binding to the cells via the heavy chain in a high molec- ular weight kininogen and zinc independent manner.Protection of kallikrein from inhibition was not observed when C1-inhibi- tor truncated in the amino-terminal domain by the StcE metal- loproteinase 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 acti- vation seen in angioedema. Keywords Coagulation inhibitors, proteases/inhibitors, endothelial cells, contact phase Summary Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with C1- inhibitor 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 max- imum levels to prevent unwanted prekallikrein activation. Studies with purified proteins do not adequately explain this observation. Therefore to investigate why reduction of C1- inhibitor to levels seen in angioedema patients results in exces- sive 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 Blood Coagulation, Fibrinolysis and Cellular Haemostasis 1277 Correspondence to: Philip Patston Department of Oral Medicine and Diagnostic Sciences College of Dentistry, University of Illinois at Chicago Chicago, Illinois 60612, USA Tel.: +1 312 996 8554, Fax: +1 312 355 2688 E-mail: patston@uic.edu Received January 7, 2004 Accepted after resubmission September 26, 2004 Financial 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.). Prepublished online November 8, 2004 DOI: 10.1160/TH04-01-0008