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PubMed2001

In vitro interaction of C1-inhibitor with thrombin.

Previous observations of increased generation of thrombin during acute attacks of angioedema in plasma of patients with C1-inhibitor (C1-INH) deficiency prompted us to evaluate the interaction of C1-INH with thrombin in both purified systems and human plasma. For this purpose, we used several methods: (1) sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting analysis; (2) enzyme-linked immunosorbent assays to measure complexes between C1-INH and thrombin and inactivated C1-INH; and (3) kinetic studies using a chromogenic assay. We found that the interaction of purified C1-INH with thrombin is associated with the formation of bimolecular complexes of molecular weight (Mr) 130 000 and 120 000 as well as with the appearance of a cleaved form of C1-INH of Mr 97 000. The kinetic studies of inhibition of thrombin by C1-INH showed an average second-order rate constant of 19/s per mol/l, which was significantly increased in the presence of heparin. The addition of thrombin to human plasma was not associated with detectable C1-INH-thrombin complex formation or with cleavage of C1-INH. In conclusion, our data demonstrate that C1-INH upon interaction with thrombin, in part, forms enzyme-inhibitor complexes and, in part, is cleaved. The low second-order rate constant and the lack of a significant interaction in plasma suggest that the inhibition of thrombin by C1-INH has a minor role in circulating blood; however, its role might be important at the endothelial surface, where high concentrations of glycosaminoglycans occur.

Complement C1 Inactivator Proteins↗
PubMed2005

Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema.

BACKGROUND: Abdominal edema attacks in patients with hereditary angioedema are often extremely painful, associated with vomiting and diarrhea, and have a high potential for causing recurrent disability of the patient. STUDY DESIGN AND METHODS: Intraindividual comparison of retrospective data in 75 hereditary angioedema patients comprising 4,834 abdominal attacks treated with C1 inhibitor concentrate versus 17,444 untreated abdominal attacks. RESULTS: The mean duration of abdominal attacks was 92.0 hours (SD, 40.8 hr) when untreated compared to 39.9 hours (SD, 30.0 hr) when treated. Patients reported a mean maximal pain score of 8.6 (SD, 1.7; range, 1-10) for untreated attacks compared to 4.5 (SD, 2.9) when treated. Vomiting occurred in 83.3 percent of untreated attacks and in 6.0 percent of treated attacks, respectively. Diarrhea was reported in 41.8 percent of untreated attacks and in 11.0 percent of treated attacks, whereas cardiovascular collapse due to hypovolemia was observed in 3.5 percent of untreated attacks versus 0.1 percent in treated attacks. Mean time to relief of symptoms was 53.5 minutes when treated early compared to 114 minutes when treatment was delayed. No drug-related adverse or serious adverse events were observed as far as the injections were performed correctly. CONCLUSION: C1 inhibitor concentrate is highly effective and safe in treating abdominal attacks in patients suffering from hereditary angioedema.

Abdominal Pain↗
PubMed1981

New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin.

p-Guanidinobenzoate derivates were prepared and their inhibitory effects on trypsin, plasmin, pancreatic kallikrein, plasma kallikrein, thrombin, C1r and C1 esterase were examined. Among the various inhibitors tested, 6'-amidino-2-naphthyl-4-guanidinobenzoate dihydrochloride, 4-(beta-amidinoethenyl)phenyl-4-guanidinobenzoate dimethanesulfonate and 4-amidino-2-benzoylphenyl-4-guanidinobenzoate dimethanesulfonate were the most effective inhibitors of trypsin, plasmin, pancreatic kallikrein. plasma kallikrein and thrombin and they strongly inhibited the esterolytic activities of C1r and C1 esterase, and then strongly inhibited complement-mediated hemolysis.

Benzamidines↗
PubMed1997

[Ascites and suspected acute abdomen in hereditary angioedema due to C1 inhibitor deficiency].

HISTORY AND CLINICAL FINDINGS: A 35-year-old man, for 8 years known to have hereditary angio-oedema with recurrent cutaneous swellings and occasional attacks of gastrointestinal pain, developed very painful, colic-like upper abdominal symptoms and frequent vomiting. INVESTIGATIONS: Routine laboratory tests were normal, except for leucocytosis of 18,200 WBC/microliter. The plasma concentrations of C1-esterase inhibitor (5.6 mg/dl) and of complement factor C4 (10.0 mg/dl) were reduced. Computed tomography revealed about 500 ml free fluid, a perihepatic effusion and definite oedematous thickening of the ileal wall. TREATMENT AND COURSE: During conservative treatment with infusions and no food by mouth the symptoms regressed. Abdominal ultrasonography was normal (no free intraabdominal fluid). Since discharge (now more than 15 months ago) the patient has been on danazole medication (200 mg/d). CONCLUSION: Recurrent gastrointestinal colics are typical of for hereditary angio-oedema and can imitate an acute abdomen. Concurrent ascites has only recently been described. Appropriate instruction of the patient and his/her medical practitioner is important to avoid unnecessary laparotomy.

Abdomen, Acute↗
PubMed2006

Viral safety of C1-inhibitor NF.

We studied the efficacy of virus reduction by three process steps (polyethylene glycol 4000 (PEG) precipitation, pasteurization, and 15nm virus filtration) in the manufacturing of C1-inhibitor NF. The potential prion removing capacity in this process was estimated based on data from the literature. Virus studies were performed using hepatitis A virus (HAV) and human immunodeficiency virus (HIV) as relevant viruses and bovine viral diarrhea virus (BVDV), canine parvovirus (CPV) and pseudorabies virus (PRV) as model viruses, respectively. In the PEG precipitation step, an average reduction in infectious titer of 4.5log(10) was obtained for all five viruses tested. Pasteurization resulted in reduction of infectious virus of >6log(10) for BVDV, HIV, and PRV; for HAV the reduction factor was limited to 2.8log(10) and for CPV it was zero. Virus filtration (15nm) reduced the infectious titer of all viruses by more than 4.5log(10). The overall virus reducing capacity was >16log(10) for the LE viruses. For the NLE viruses CPV and HAV, the overall virus reducing capacities were >8.7 and >10.5log(10), respectively. Based on literature and theoretical assumptions, the prion reducing capacity of the C1-inhibitor NF process was estimated to be >9log(10).

Animals↗
PubMed1975

Protease inhibitors in plasma of patients with chronic urticaria.

The hypothesis that deficiencies of plasma protease inhibitors might play a role in the pathogenesis of chronic urticaria was evaluated. Plasma levels were measured in patients with urticaria and a matched control group for alpha1-antitrypsin, alpha2-macroglobulin, total trypsin-inhibiting capacity, kallikrein-inhibiting capacity, and the complement factors C1 esterase inhibitor, C3, and C4. A total of 92 patients with chronic urticaria or more than three months' duration was studied. Patients with acquired cold urticaria had significantly decreased levels of alpha1-antitrypsin and total antitrypsin activity. In patients with acquired angioneurotic edema, alpha1-antitrypsin levels and antichymotrypsin activities were lowered, with less significant decreases in anti-trypsin and antikallikrein activities. Levels of C1 esterase inhibitor , C3, and C4 were normal in all groups. There was no correlation between the increased sensitivity to intracutaneously administered kallikrein injection and deficiencies of of protease inhibitors.

Adolescent↗
PubMed1978

Possible mechanisms of the first step of the classical complement activation pathway: binding and activation of C1.

Different immunoglobulin preparations of human monoclonal IgM, normal human and rat IgG, as well as purified rabbit antibodies were treated by various methods, fragmentation, aggregation and complexing with antigen. The ability of the treated and untreated preparations to fix isolated human C1, to activate the classical complement pathway (to consume C4 in normal human serum) were compared. It was found that the different methods affected the conformation of the immunoglobulin molecules in different ways and induced changes to a greater or lesser extent in the two capacities of the preparations tested. In the case of the monoclonal IgM preparation a strong C1-fixation was observed without measurable complement activation. Other preparations, interfacially aggregated human IgG, BSA-anti-BSA and OA-anti-OA immune complexes had a very weak C1-fixing but a marked complement activating capacity. Some preparations, e.g. heat-aggregated IgG, both fixed and activated C1 effectively, aggregates with a complement-activating capacity without C1-fixing effect were separated by gel-filtration. It was demonstrated further, that at a given time only a part of the activated C1 molecules could be found fixed to the immunoglobulins, the other part was released into the fluid phase after activation. On the basis of the results of this and previous studies a hypothesis is proposed suggesting three possible results of the interaction between C1 and the different preparations: (1) firm fixation and activation; (2) binding not followed by activation and (3) a transient binding leading to activation. The possible application of this hypothesis for the interpretation of the results of the different methods for detecting immune complexes is discussed.

Angioedema↗
PubMed1986

Molecular cloning of human C1 inhibitor: sequence homologies with alpha 1-antitrypsin and other members of the serpins superfamily.

Genetic and acquired diseases in man show that the proteolytic activity of the complement component C1 is crucially regulated by C1 inhibitor (C1-INH), a plasma protein whose suspected relatedness to other serine proteinase inhibitors (serpins) contrasts with its atypically large size and high degree of glycosylation. Indeed we have found that the C1-INH polypeptide precursor synthesized in a cell-free system is a 64-kDa protein, hence it exceeds the length of the precursor forms of typical serpins. Seeking more conclusive sequence information and a probe for the structural locus, we isolated C1-INH cDNA clones from a library representing size-enriched human liver mRNA. Nucleotide sequence analysis of a clone covering the carboxyterminal half of C1-INH conclusively documents the relatedness of this protein with the serpins, and reveals 27% amino acid identity with alpha 1-antitrypsin.

Cloning, Molecular↗
PubMed2002

C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction.

OBJECTIVE: To investigate the efficacy and the safety of the parenteral administration of C1-inhibitor to patients with severe sepsis or septic shock. DESIGN: Double blind, randomized, and placebo-controlled trial. SETTING: Surgical and medical intensive care units of a tertiary care university hospital. PATIENTS: Forty consecutive patients (20 C1-inhibitor/20 placebo) who entered the intensive care unit with severe sepsis or septic shock. INTERVENTION: C1-inhibitor intravenously in a 1-hr infusion, starting with 6000 IU, followed by 3000 IU, 2000 IU, and 1000 IU at 12-hr intervals, compared with placebo. MEASUREMENTS AND MAIN RESULTS: C1-inhibitor administration significantly increased plasma C1-inhibitor antigen and activity levels during days 1-4 (p <.007). Patients in the C1-inhibitor group had significantly lower serum creatinine concentrations on day 3 (p =.048) and 4 (p =.01) than placebo patients. Multiple organ dysfunction assessed by logistic organ dysfunction and sepsis-related organ failure assessment scores was less pronounced in patients treated with C1-inhibitor. Mortality rate was similar in both groups. There were no C1-inhibitor-related side effects. CONCLUSIONS: C1-inhibitor administration attenuated renal impairment in patients with severe sepsis or septic shock.

Adult↗
PubMed1980

[The effect of burns on the complement system].

Serum levels of total complement CH 50 and the complement components C1, C1 inactivator, C2, C4, C3c, and C3 activator were measured in 20 patients with burn injuries. The findings were assessed for any possible correlations between the results of serological investigations, severity of burns and clinical aspects of the patients.

Adolescent↗
PubMed2004

A novel RNA splice site mutation in the C1 inhibitor gene of a patient with type I hereditary angioedema.

We describe a patient with type I hereditary angioedema presenting recurrent episodes of skin swelling and abdominal pain. Laboratory examination showed reduced levels of CH50 and C4 with a normal C3 level. The C1 inhibitor was decreased to 7.0 mg/dl (normal, 10-25 mg/dl) with a remarkably reduced activity (<25%; normal, 80-125%). DNA analysis of the C1 inhibitor gene revealed a novel point mutation at the 3' acceptor mRNA splice site of the intron 5 (G-->A at nucleotide 8722). This mutation may abolish the correct splicing of the intron 5 and create unstable mRNA.

Angioedema↗
PubMed2004

Worsening fluid retention in a patient with hereditary angioedema and end-stage renal disease.

A 60-year-old woman who was diagnosed with hereditary angioedema (HAE) developed nephrotic syndrome, with end-stage renal disease (ESRD) occurring about 2.5 years later. During her slide toward ESRD, she experienced three severe episodes of angioedema that each resulted in significant fluid retention. Though the therapeutic administration of C1-inhibitor concentrate was effective in controlling her angioedema, seemed ineffective in preventing her from developing ESRD requiring hemodialysis treatment. We theorized that the patient's low colloid osmolality and glomerular perfusion were important facilitators of her attacks of angioedema.

Angioedema↗
PubMed2004

Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung.

PURPOSE: Gene expression profiling has been shown to be a valuable tool for prognostication and identification of cancer-associated genes in human malignancies. We aimed to identify potential prognostic marker(s) in non-small cell lung cancers using global gene expression profiles. EXPERIMENTAL DESIGN: Twenty-one previously untreated patients with non-small cell lung cancer were analyzed using the Affymetrix GeneChip high-density oligonucleotide array and comparative genomic hybridization. Identified candidate genes were validated in an independent cohort of 45 patients using quantitative real-time reverse transcription-PCR and Western blot analyses. Follow-up data for these patients was collected and used to assess outcome correlations. RESULTS: Hierarchical clustering analysis yielded three distinct subgroups based on gene expression profiling. Cluster I consisted of 4 patients with adenocarcinoma and 1 with squamous cell carcinoma (squamous cell carcinoma); clusters II and III consisted of 6 and 10 patients with squamous cell carcinoma, respectively. Outcome analysis was performed on the cluster groups containing solely squamous cell carcinoma, revealing significant differences in disease-specific survival rates. Moreover, patients having a combination of advanced Tumor-Node-Metastasis stage and assigned to the poor prognosis cluster group (cluster II) had significantly poorer outcomes. Comparative genomic hybridization analysis showed recurrent chromosomal losses at 1p, 3p, 17, 19, and 22 and gains/amplifications at 3q, 5p, and 8q, which did not vary significantly between the cluster groups. We internally and externally validated a subset of 11 cluster II (poor prognosis)-specific genes having corresponding chromosomal aberrations identified by comparative genomic hybridization as prognostic markers in an independent cohort of patients with lung squamous cell carcinoma identifying CSNK2A1 and C1-Inh as independent predictors of outcome. CONCLUSION: CSNK2A1 and C1-Inh are independent predictors of survival in lung squamous cell carcinoma patients and may be useful as prognostic markers.

Aged↗
PubMed2003

The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant.

C1-inhibitor (C1-Inh) is a serine protease inhibitor (serpin) with a unique, non-conserved N-terminal domain of unknown function. Genetic deficiency of C1-Inh causes hereditary angioedema. A novel type of mutation (Delta 3) in exon 3 of the C1-Inh gene, resulting in deletion of Asp62-Thr116 in this unique domain, was encountered in a hereditary angioedema pedigree. Because the domain is supposedly not essential for inhibitory activity, the unexpected loss-of-function of this deletion mutant was further investigated. The Delta 3 mutant and three additional mutants starting at Pro76, Gly98, and Ser115, lacking increasing parts of the N-terminal domain, were produced recombinantly. C1-Inh76 and C1-Inh98 retained normal conformation and interaction kinetics with target proteases. In contrast, C1-Inh115 and Delta 3, which both lack the connection between the serpin and the non-serpin domain via two disulfide bridges, were completely non-functional because of a complex-like and multimeric conformation, as demonstrated by several criteria. The Delta 3 mutant also circulated in multimeric form in plasma from affected family members. The C1-Inh mutant reported here is unique in that deletion of an entire amino acid stretch from a domain not shared by other serpins leads to a loss-of-function. The deletion in the unique N-terminal domain results in a "multimerization phenotype" of C1-Inh, because of diminished stability of the central beta-sheet. This phenotype, as well as the location of the disulfide bridges between the serpin and the non-serpin domain of C1-Inh, suggests that the function of the N-terminal region may be similar to one of the effects of heparin in antithrombin III, maintenance of the metastable serpin conformation.

Amino Acid Sequence↗
PubMed2004

[A case of lung cancer with hereditary angioedema treated effectively by chemo-radiotherapy with C1 esterase inhibitor concentrate and danazol].

Lung cancer with hereditary angioedema was diagnosed in a 69-year-old man. Laboratory examinations revealed depletion of the fourth component of complement and C1 inhibitor activity. A bone metastasis was present. After the first chemotherapy, acute attacks of edema in the upper chest and the laryngeal mucosa occurred and dyspnea progressed, but these symptoms were immediately improved by administration of C1 inhibitor concentrate. Because of the danger of angioedema that might be expected following chemo-radiotherapy, he was treated with danazol. The patient then showed no sign of an edema attack during therapy for lung cancer.

Aged↗