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PubMed1987

[Hereditary angioneurotic edema. Treatment of a pseudosurgical digestive attack with C1 inhibitor concentrate].

Although anabolic androgens can be used to prevent acute attacks of hereditary angioneurotic oedema, these are still observed. When they are severe, and even more so when they involve the larynx or the abdominal viscera, an emergency treatment is necessary, ideally with the purified C1-inhibitor (C1-INH) administered by intravenous infusion. In a case with pseudo-surgical abdominal symptoms, this treatment was followed by an unusually dramatic regression of all symptoms. Serial laboratory examinations showed an increase in C1-INH and C2 plasma levels and in the number of basophils within less than 30 minutes; the increase in C4 levels occurred later. Thus, C1-INH is very effective in the treatment of acute hereditary angioneurotic oedema, but the product is not widely available; it should be reserved to severe forms affecting the larynx and the viscera.

Abdomen, Acute↗
PubMed1993

Blood activation during neonatal extracorporeal life support.

Cardiopulmonary bypass for heart operations is associated with a whole body inflammatory reaction. The main factors involved in this reaction are the contact system and the complement system. The activation of the contact system is considered mainly responsible for impaired hemostasis because it affects platelet function. The activation of the complement system is considered the main cause for organ dysfunction, particularly of the lung, due to activation of leukocytes. This study in 10 neonates was undertaken to evaluate if there are effects of activation of the contact and the complement systems in neonatal extracorporeal life support comparable to those during cardiopulmonary bypass for cardiac operations. Two periods of blood activation during extracorporeal life support could be distinguished. The initial blood-material interaction at the onset of extracorporeal life support resulted in activation of both the contact and the complement systems. The contact activation was apparent by elevated factor XIIa-C1 esterase inhibitor complexes, decreased kallikrein inhibitory capacity, thrombin-antithrombin III formation, and moderate generation of fibrin(ogen) degradation products. The complement activation was characterized by elevated C3a, decreased leukocyte count, elastase release, and tumor necrosis factor-alpha production. This initial activation pattern subsided by 24 hours. A second activation period was observed 72 hours after the onset of extracorporeal life support, which was characterized only by increased clotting and fibrinolytic activity while no activation of the complement system was observed. We conclude that the initial activation pattern in extracorporeal life support is similar to that observed during cardiopulmonary bypass for cardiac operations. The contact activation that affects platelets might explain the continuous platelet consumption observed during extracorporeal life support. In this period, as in cardiopulmonary bypass, aprotinin given in the pump prime might be effective to prevent platelet consumption and impairment of hemostasis also in extracorporeal life support. The complement activation and leukocyte inflammatory reaction during the initial period are able to cause a capillary leak syndrome and might therefore explain the frequently observed temporary compromised lung function in extracorporeal life support. This reaction, as in cardiopulmonary bypass, might be reduced by the use of specific drugs or heparin coating also in extracorporeal life support. The cause of the second period of activation during extracorporeal life support requires further studies before adequate measures can be recommended.

Acute-Phase Proteins↗
PubMed1983

Human plasma kallikrein releases neutrophil elastase during blood coagulation.

Elastase is released from human neutrophils during the early events of blood coagulation. Human plasma kallikrein has been shown to stimulate neutrophil chemotaxis, aggregation, and oxygen consumption. Therefore, the ability of kallikrein to release neutrophil elastase was investigated. Neutrophils were isolated by dextran sedimentation, and elastase release was measured by both an enzyme-linked immunosorbent assay, and an enzymatic assay using t-butoxy-carbonyl-Ala-Ala-Pro-Val-amino methyl coumarin as the substrate. Kallikrein, 0.1-1.0 U/ml, (0.045-0.45 microM), was incubated with neutrophils that were preincubated with cytochalasin B (5 micrograms/ml). The release of elastase was found to be proportional to the kallikrein concentration. Kallikrein released a maximum of 34% of the total elastase content, as measured by solubilizing the neutrophils in the nonionic detergent Triton X-100. A series of experiments was carried out to determine if kallikrein was a major enzyme involved in neutrophil elastase release during blood coagulation. When 10 million neutrophils were incubated in 1 ml of normal plasma in the presence of 30 mM CaCl2 for 90 min, 2.75 micrograms of elastase was released. In contrast, neutrophils incubated in prekallikrein-deficient or Factor XII-deficient plasma released less than half of the elastase, as compared with normal plasma. The addition of purified prekallikrein to prekallikrein-deficient plasma restored neutrophil elastase release to normal levels. Moreover, release of elastase was enhanced in plasma deficient in C1-inhibitor, the major plasma inhibitor of kallikrein. This release was not dependent upon further steps in the coagulation pathway, or on C5a, since levels of elastase, released in Factor XI- or C5-deficient plasma, were similar to that in normal plasma, and an antibody to C5 failed to inhibit elastase release. These data suggest that kallikrein may be a major enzyme responsible for the release of elastase during blood coagulation.

Blood Coagulation↗
PubMed1985

Increased plasma concentrations of C9, C1-inhibitor and alpha 1-protease inhibitor associated with cigarette smoking.

The association between various parameters of acute and chronic smoking status and plasma levels of three proteins, C9, C1-inhibitor (C1-INH) and alpha 1-protease inhibitor (alpha 1-PI) were determined for 49 male cigarette smokers and 49 age-matched nonsmokers (mean age = 32.2 years). The mean number of cigarettes smoked was 28.7 per day while the cumulative consumption was only 18.1 pack-years. Plasma levels of all three proteins were significantly higher in the smokers than nonsmokers. Plasma C9 and alpha 1-PI concentrations correlated with cumulative cigarette consumption and plasma nicotine concentrations. While C1-INH concentration did not correlate with either cumulative cigarette consumption or plasma nicotine concentration, it correlated significantly with serum thiocyanate concentration. No consistent correlation was found between plasma concentration of these proteins and parameters of pulmonary function.

Adult↗
PubMed2006

Features of a newly cloned pig C1 esterase inhibitor.

The pig cDNA encoding C1 esterase inhibitor (C1-INH) was isolated and the homology of the sequence was compared with that from other animals. The structure of pig C1-INH contains a two disulfide bridge pattern identical to the human C1-INH. In the amino acid sequence of the first Cys-91 to the C-terminal end, the pigC1-INH has a 76.2% homology with the human protein, and the sequence of the reactive site is close to the human. A surface-bound form of pig and human C1-INH, pC1-INH-PI and hC1-INH, respectively, were next constructed. Stable Chinese hamster ovarian tumor (CHO) cell lines and pig endothelial cell (PEC) lines expressing these C1-INH-PI were prepared by transfection. The basic function and the species specificity of pCI-INH were then investigated using these transfectants. pC1-INH and hC1-INH have almost the same suppressive effect on pig, human, dog and rabbit sera in complement-dependent cell lysis, indicating little species specificity.

Amino Acid Sequence↗
PubMed2005

Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease caused by C1 inhibitor mutations. Although more than 100 mutations have been described, epidemiologic data are lacking; therefore, we developed a Spanish HAE patient registry. OBJECTIVE: To study the prevalence of HAE and the current state of diagnosis and treatment of this disease in Spain. METHODS: Epidemiologic data were obtained by direct contact with physicians who treat patients with HAE and with patients themselves. Diagnosis was evaluated by measuring C1 inhibitor levels and function, and most families also underwent genetic studies. RESULTS: We registered 444 patients (minimal prevalence, 1.09 per 100,000 inhabitants), many of whom are asymptomatic (never having symptoms) (n = 61, 13.7%). Most symptomatic patients (62.9%) receive long-term prophylaxis with attenuated androgens (80.9%) and antifibrinolytic agents (22.8%), alone or in combination, but no patients are receiving long-term prophylaxis with C1 inhibitor. There is a long delay in diagnosis (mean, 13.1 years). Nine patients underwent a tracheotomy as a consequence of a laryngeal attack, and 30 families recalled a total of 38 relatives who died of HAE, which underlines the severity of the illness. CONCLUSIONS: The detected minimal prevalence of HAE in Spain is 1.09 per 100,000 inhabitants. Because this is a rare disease and some patients may be misdiagnosed, this prevalence could be higher.

Adult↗
PubMed2004

N-linked glycosylation is required for c1 inhibitor-mediated protection from endotoxin shock in mice.

C1 inhibitor (C1INH) prevents endotoxin shock in mice via a direct interaction with lipopolysaccharide (LPS). This interaction requires the heavily glycosylated amino-terminal domain of C1INH. C1INH in which N-linked carbohydrate was removed by using N-glycosidase F was markedly less effective in protecting mice from LPS-induced lethal septic shock. N-deglycosylated C1INH also failed to suppress fluorescein isothiocyanate (FITC)-LPS binding to and LPS-induced tumor necrosis factor alpha mRNA expression by the murine macrophage-like cell line, RAW 264.7, and cells in human whole blood. In an enzyme linked immunosorbent assay, the N-deglycosylated C1INH bound to LPS very poorly. In addition, C1INH was shown to bind to diphosphoryl lipid A (dLPA) but only weakly to monophosphoryl lipid A (mLPA). As with intact LPS, binding of N-deglycosylated C1INH to dLPA and mLPA was diminished in comparison with the native protein. Removal of O-linked carbohydrate had no effect on any of these activities. Neither detoxified LPS, dLPA, nor mLPA had any effect on the rate or extent of C1INH complex formation with C1s or on cleavage of the reactive center loop by trypsin. These data demonstrate that N-linked glycosylation of C1INH is essential to mediate its interaction with the LPA moiety of LPS and to protect mice from endotoxin shock.

Animals↗
PubMed1987

Proteolysis and deglycosylation of human C1 inhibitor. Effect on functional properties.

The effects of proteolysis and deglycosylation on C1 inhibitor (C1Inh) were tested with respect to both its ability to form complexes with C1s and its capacity to block C1 autoactivation. Limited proteolysis of C1Inh by Staphylococcus aureus V8 proteinase, proline-specific endopeptidase or elastase generated a major high-Mr (approximately 86,000) fragment. In contrast with the fragment produced by elastase, which was inactive, the fragments resulting from V8 proteinase and proline-specific endopeptidase treatment retained activity. Deglycosylation with N-glycanase or O-glycanase, or both, had no major effect on the functional activity of C1Inh.

Complement C1 Inactivator Proteins↗
PubMed2001

Hereditary angioedema: a broad review for clinicians.

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

Acute Disease↗
PubMed1993

Contact, coagulation and platelet interaction with heparin treated equipment during heart surgery.

Heparin coating of an extracorporeal device may reduce blood activation. To evaluate protein and platelet interaction with Duraflo II surface treatment of the cardiopulmonary bypass (CPB) circuit, thirty coronary artery bypass grafting patients were randomly divided into two groups (Duraflo II, n = 15 or Control, n = 15). Binding of antibodies against factor XII, antithrombin III (ATIII) and platelet receptor GpIb were significantly higher (p < 0.01) on the Duraflo II treated surface. Hageman Factor fragment (HFf or factor XIIf) activity observed in the fluid phase tended to be lower in the treated circuits, although complexes of factor XIIf-C1 inhibitor (C1INH) increased by the same extent in both groups. Thrombin was effectively bound on the Duraflo II surface while thrombin-antithrombin III formation was reduced during the first phase of CPB. As expected, this thrombin inhibiting capacity remained higher on the Duraflo II, although in the arterial line a reduction of 10% per hour was observed. This indicated loss of functional bound heparin of the Duraflo II surface. During the second phase of CPB, after release of the aortic crossclamp, factor XII and thrombin were strongly activated in both groups indicated by a sharp increase in concentrations of T/AT complex as well as FPA. Platelet numbers tended to increase more in the control group during CPB than in the Duraflo II group, likely by interaction of platelet GpIb receptors on the Duraflo II treated surface (p < 0.01). However, platelet activation assessed by beta-TG was similar in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Antibody Reactions↗
PubMed1988

[The course of acquired C 1 esterase inhibitor deficiency in lymphoproliferative syndrome].

Acquired deficiency in C1 esterase inhibitor (C1 INH) was first described by Caldwell in 1972. Since that date, about 30 cases have been reported, in most cases during proliferative lymphocyte B syndromes. The acquired C1 INH deficiency can provoke episodes of angioneurotic edema as in hereditary AE. The complement profile differs, notably by the usual sudden fall in C1. Documented data suggest consumption of complement and therefore of C1 INH. The present case is the first reported of an acquired C1 INH deficiency during a cold hemagglutinin disease. The activation of complement by the classical pathway appears provoked by tumoral cells rather than a humoral factor, as suggested by the efficacy of anti-tumoral therapy in contrast to plasmapheresis in the present case. A possible mechanism for the C1 INH deficiency is discussed.

Anemia, Hemolytic, Autoimmune↗
PubMed1980

Complement inhibitors and immunoconglutinins in ulcerative colitis and Crohn's disease.

The serum concentrations of the complement inactivators C1INH, C3bINA and beta 1H have been determined in patients with ulcerative colitis and Crohn's disease and their correlation with C3 and properdin factor B examined. The incidence of immunoconglutinins (1K) in these patients was investigated. Raised serum concentrations of C1INH and C3bINA have been found in patients with active disease, but no significant alteration was found in serum concentration of beta 1H. An increasing incidence of positive 1K titres was found with increased length of disease history. These results suggest continuing complement activation in these diseases.

Colitis, Ulcerative↗
PubMedDate not supplied

Prekallikrein activation in the adult respiratory distress syndrome.

Prekallikrein is the zymogen form of plasma kallikrein, a proteolytic enzyme of the contact system of blood coagulation, fibrinolysis and kinin formation. To assess whether prekallikrein was activated in the adult respiratory distress syndrome (ARDS), we examined plasma samples from 12 critically ill patients including five individuals with ARDS. Using the ratio between functional prekallikrein and prekallikrein-kallikrein antigen as an index for prekallikrein activation, we found that prekallikrein was extensively activated in patients with ARDS, while this was significantly less in the case of critically ill patients without ARDS. Following activation of prekallikrein in plasma, kallikrein reacts with its substrates and with protease inhibitors, among which the alpha 2-glycoprotein C1-inhibitor. Thus, we examined whether C1-inhibitor of critically ill individuals was modified in a way suggesting that it had reacted with kallikrein. Such a modification was found in the five patients with ARDS, while it was not detectable in the seven patients without ARDS. This observation further confirmed the activation of prekallikrein in patients with ARDS. We suggest that plasma kallikrein-mediated reactions, which include bradykinin release and neutrophil activation, may contribute to the pathogenesis of ARDS.

Adolescent↗
PubMed1982

A rapid method for functional determination of C1 esterase inhibitor in plasma.

A functional determination of C1 esterase inhibitor (C1 INH) can be easily performed with an amidolytic assay by monitoring the inactivation of plasma kallikrein. In patients with urticaria as well as in healthy donors kallikrein inactivation, determined as the ratio of kallikrein activity at t60/t15, was found to be 0.47 +/- 0.06; in patients with hereditary angioneurotic edema (HANE). However, it amounted to 0.80 +/- 0.06. There was a good correlation between the inactivation rate of kallikrein and the protein levels of C1 INH (r = -0.93, p less than 0.001). In patients with HANE, levels of plasma kallikrein were slightly decreased (mean = 0.37 +/- 0.11 U/ml, normal mean = 0.47 +/- 0.09 U/ml), but still sufficient for monitoring kallikrein inactivation. In the case of one patient with functionally inactive C1 INH protein, the inactivation of kallikrein was impaired as in the conventional form of the disease.

Angioedema↗
PubMed1978

Remissions induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentrations of C1-inhibitor and the forth and second components of complement.

Serum concentrations of antigenic and functional C1-INH increased in patients in whom remissions from attacks of HANE were induced with danazol. The levels of C4 were directly related to serum concentrations of C1-INH antigens up to a concentration of about half the C1-INH found in normal plasma; at this point, the C4 concentrations were in the normal range and no longer correlated well with C1-INH concentration. Serum C2 levels correlated less well with C1-INH concentration. In normal serum there was a poor correlation between C1-INH, C4, and C2 levels, suggesting that C1-INH is normally present in excess of the amount needed for normal C4 levels. The increments in serum C1-INH were related to the dose of danazol.

Angioedema↗
PubMed2003

Sudden upper airway obstruction in patients with hereditary angioedema.

Hereditary angioedema (HAE) is clinically characterized by recurrent and self-limiting skin, intestinal, and life-threatening laryngeal edema. This study describes the age at which laryngeal edema first occurred, the time between onset and full development, and the effectiveness of therapy and prophylaxis in 123 HAE patients. 61 (49.7%) patients experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between age 11 and 45. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 354 laryngeal edemas cleared spontaneously without treatment and 208 laryngeal edemas were successfully treated with C1 inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. It is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.

Acute Disease↗
PubMed1980

Preparation of an R3 reagent (serum depleted of the third component of human complement (C3)) by immunoadsorption. Application to the hemolytic assay of human C3.

We have devised a simple one-step preparation of C3 depleted serum (R3). Fresh normal human serum, with complement activation inhibitors, was depleted of C3 by affinity chromatography on a Sepharose anti-C3c. To prevent non-specific interactions, a high ionic strength buffer containing saccharose was used. Immunochemical analysis and complement activity assays demonstrate that this C3 depleted serum is a suitable R3 reagent. This R3 reagent has been used successfully for titration of hemolytic activity of C3 in normal and abnormal sera. Two simple, specific and sensitive assays are described.

Animals↗
PubMed1998

Studies of adsorption, activation, and inhibition of factor XII on immobilized heparin.

The aim of the present investigation was to clarify whether immobilized heparin does, as previously suggested, prevent triggering of the plasma contact activation system. Purified FXII in the absence or presence of antithrombin and/or C1 esterase inhibitor as well as plasma was exposed for 1 to 600 seconds to a surface modified by end-point immobilization of heparin. With purified reagents, a process including surface adsorption and activation of FXII occurred within 1 second. In the presence of antithrombin, the resulting surface-bound alpha-FXIIa was inhibited within that time. Likewise, the adsorption of native FXII from plasma was a rapid process. However, the inhibition of surface-bound alpha-FXIIa was slightly slower than with purified components. Nevertheless, neither beta-FXIIa nor FXIa were found in the plasma phase. Exposure of a surface prepared from heparin molecules, lacking antithrombin binding properties, to plasma resulted in surface-bound alpha-FXIIa within 1 second. In the liquid phase, beta-FXIIa was detected after 2.5 seconds and, 12 seconds later, FXIIa and FXIa in complex with the C1 esterase inhibitor appeared. Addition of heparin to plasma prior to surface exposure did not prevent activation of surface-bound FXII, nor did it increase the beta-FXIIa inhibition rate and prevent FXI activation in plasma, although beta-FXIIa and FXIa-AT complex formation occurred. It is concluded that surface-immobilized heparin, unlike heparin in solution, effectively inhibits the initial contact activation enzymes by an antithrombin-mediated mechanism, thereby suppressing the triggering of the intrinsic plasma coagulation pathway.

Adsorption↗