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PubMed1984

Studies of complement autoactivatability in hereditary angioedema: direct relationship to functional C-1-INA and the effect of classical pathway activators.

It has been observed earlier that the hemolytic complement in diluted sera obtained from patients with hereditary angioedema (HAE) undergoes spontaneous decay when incubated at 37 degrees C. Employing individual serum from patients at different stages of this disease it was demonstrated that this spontaneous loss of hemolytic complement also occurs without dilution and is directly linked to the absence of functional C-1-INA. Incubation of HAE serum resulted in a loss of activity which appears to be dependent upon the concentration of functional C-1-INA. While C-1-INA levels less than 50 micrograms/ml lead to rapid depletion with time, reconstitution of deficient sera with highly purified C-1-INA or of undiluted NHS inhibited spontaneous activation. Furthermore, NHS was rendered susceptible to autoactivation when its C-1-INA was depleted by passage over an anti-C-1-INA Sepharose 4B affinity column in the presence of 10 mM EDTA, indicating that in the absence of functional C-1-INA, C1 undergoes an uninhibited spontaneous autoactivation which leads to the consumption of C4 and C2 but not C3. Consumption of C3 was observed, however, in HAE sera that contained a significant amount of immune complexes. Incubation of HAE sera with highly purified Hageman factor fragment (5 micrograms/ml), or aggregated IgG (2 mg/ml) was found to accelerate the rate of decay when compared to untreated samples while sera from patients under treatment with Danazol or Stanozolol failed to autoactive. These results suggest that, the absence of C-1-INA, may, by itself trigger the dissociation and autoactivation of C1 in the sera of such patients; however, the presence of other complement activators accelerates the reaction. This inherent property of HAE sera, i.e., spontaneous autoactivation at 37 degrees C, may be a useful screening test but direct determination of C-1-INA activity is required to establish the precise diagnosis.

Angioedema↗
PubMed1987

Quantitation of (C1INH)2 C1r-C1s complexes in glomerulonephritis as an indicator of C1 activation.

C1 activation was assessed in several forms of glomerulonephritis by radioimmunoassay quantitation of circulating (C1INH)2 C1r-C1s complexes (INC). Eight patients with active systemic lupus erythematosus (SLE) and nephritis had elevated serum INC (mean = 15.3 vs control = 5.8, P less than 0.01). Their INC levels were normal during remission. Serum INC had a weak inverse correlation with serum C1q greater than 3 mg/dl (r = 0.42, P = 0.02). In longitudinal studies, serum INC also had a weak inverse correlation with serum C3 and C4. Only 1 of 10 patients with type I and 1 of 15 with type III membrano-proliferative glomerulonephritis (MPGN) had elevated serum INC. No patient with type II MPGN had elevated levels. Two of 10 patients with poststreptococcal glomerulonephritis (P-SGN) had elevated serum INC, but all normalized with convalescence. Patients with IgA nephropathy had normal serum INC. The data demonstrate the importance of C1 activation in SLE and P-SGN. The mechanism of complement activation in types I and III MPGN remains unclear; the data suggest, but do not prove, that C1-independent complement activation may occur in these patients.

Antigen-Antibody Complex↗
PubMed1988

Complement activation occurs through both classical and alternative pathways prior to onset and resolution of adult respiratory distress syndrome.

We have previously reported that plasma concentrations of the terminal complement (C) complex (TCC), C5b-9, increased significantly 2 days prior to onset of adult respiratory distress syndrome (ARDS) and also 1 day preceding its resolution. To determine the pathway of complement activation that preceded development and resolution of this acute inflammatory lung injury in septic patients, we quantified the C1rC1s-C1 inhibitor complex and the C3bP complex, which are generated following activation of classical and alternative complement pathways, respectively. Two days prior to diagnosis of ARDS, the plasma C1rC1s-C1 inhibitor complex and C3bP complex levels increased 22 and 14%, respectively. Furthermore, significant correlations were identified between concentrations of the TCC and C1rC1s-C1 inhibitor complex (r = 0.73, P = 0.003) and also with the levels of the TCC and C3bP complex (r = 0.81, P = 0.002) before onset of ARDS. Equally of interest, the C1rC1s-C1 inhibitor complex and C3bP complex concentrations increased 68 and 35%, respectively, 1 day before resolution of ARDS. Similarly, significant elevations of TCC concentrations preceding resolution of ARDS correlated with C1rC1s-C1 inhibitor complex (r = 0.66, P = 0.02) and also with C3bP complex (r = 0.72, P = 0.002) levels. Our results indicate that both the classical and alternative complement pathways are activated prior to onset of ARDS and also before its resolution in septic patients.

Complement Activating Enzymes↗
PubMed1979

Complement and contrast material reactors.

Patients showing systemic reactions to intravascular contrast media and patients receiving contrast media without reaction have significantly different mean values (p is less than 0.05) for functionally determined serum C1-esterase inhibitor (C1 INH) and total hemolytic complement (CH50). The lower concentration of these components in reactors appears in baseline serum samples (as well as after injection), and suggests that many anaphylactoid reactions to contrast media are conditioned by earlier complement consumption, and result directly from contrast-induced activation of complement, and other activation system components in the presence of inhibitor depression.

Complement C1 Inactivator Proteins↗
PubMed1980

Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema.

Treatment with 17 alpha-methyltestosterone and with some synthetic androgens prevents attacks of hereditary angioedema (HAE). However, the potential hepatotoxicity of 17 alpha-alkylated androgens raises the problem of long-term prophylactic use of these agents. Therefore we compared the efficacy in preventing HAE attacks of 17 alpha-alkylated steroids (danazol and stanozolol) with non-17 alpha-alkylated derivatives (quinbolone, nandrolone decanoate and mesterolone). As the latter group proved ineffective, it seems that a drug's efficacy in preventing HAE attacks is connected to its 17 alpha-alkylation. Moreover, our long-term observations with the minimum effective dose of danazol seem to indicate the absence of important collateral effects.

Adult↗
PubMed1986

The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency.

The correct diagnosis and characterization of C1-inhibitor deficiency depends on both clinical observations and laboratory evaluation of complement in plasma. Rocket immunoelectrophoresis for C4d is a sensitive assay for C4 activation in plasma. We have evaluated the value of this assay in identifying patients with C1-inhibitor deficiency. C4 activation was assessed in the plasmas of 15 patients with hereditary angioedema, five patients with variant form of hereditary angioedema, and four patients with acquired C1-inhibitor deficiency. Control groups consisted of 27 patients with chronic idiopathic urticaria and/or angioedema and seven normal volunteers. C4 activation was detected in all 52 plasma samples collected from the 24 patients with C1-inhibitor deficiency. The degree of C4 activation increased during attacks of angioedema and decreased (but remained elevated) during treatment with attenuated androgens. The concentrations of C4, C2, and C1 inhibitor were also measured; however, none of these measurements identified all of the patients with C1-inhibitor deficiency. Thus, we conclude that the measurement of C4 activation is one of the best tests available to evaluate a patient for C1-inhibitor deficiency, and a normal result will exclude the diagnosis of C1-inhibitor deficiency.

Androgens↗
PubMed1987

The late onset form of C1 esterase-inhibitor deficiency presenting as food allergy.

Two cases of late onset recurrent angioedema associated with deficiency of C1 esterase inhibitor are described. Both patients had life-threatening episodes of angioedema that they had related to the ingestion of certain foodstuffs. This was not confirmed by food challenges or by food allergy skin testing, although both patients had embarked on strict exclusion diets before the diagnosis of C1 esterase-inhibitor deficiency. Clinicians should be aware of the entity of late onset angioedema caused by C1 esterase deficiency mimicking food allergy and hence delaying the diagnosis of this potentially lethal condition.

Aged↗
PubMed1991

Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience.

Fifty-six patients affected with hereditary angioedema have been followed during long-term prophylaxis with attenuated androgens. The treatment was started in patients who had one or more severe attacks per month. In 24 patients, the therapy lasted for more than 5 years. The minimal effective dose usually did not exceed 2 mg/day of stanozolol or 200 mg/day of danazol. Only in two patients were these doses not sufficient to achieve the complete disappearance of symptoms. Irregular menstruation, but rarely amenorrhea, was the only significant side effect. One patient had to stop the therapy because of laboratory signs of hepatic cell necrosis. In one patient, danazol was administered during the last 8 weeks of pregnancy without side effects for the mother but with transient signs of virilization for the female baby. To find a biochemical marker for the minimal effective dose of androgen derivatives, we measured the plasma levels of C1 C1 INH complexes at different doses of stanozolol in four patients with hereditary angioedema. We found that these complexes, elevated before treatment, promptly reverted to normal values during androgen therapy and remained normal with any reduction of the dose of the drug as long as the patient remained symptom free. Therefore, the measurement of C1 C1 INH complexes appears to reflect the activity of the disease and not the amount of androgen that is administered.

Adolescent↗
PubMed1991

Acute consumption of C1 inhibitor in a patient with acquired C1-inhibitor deficiency syndrome.

Acquired C1-inhibitor (C1 INH) deficiency is usually found in association with an underlying disease that is believed to be responsible for increased C1 INH catabolism, ultimately leading to the development of C1 INH deficiency. We report a remarkable patient with acquired C1 INH deficiency in whom a unique progression of complement- and contact-system abnormalities has been observed. S. G. suffers from recurrent episodes of angioedema and hypotension. Results of repeated complement studies were initially normal, and the patient was diagnosed as having idiopathic anaphylaxis. Two years later, the patient was found to develop acute consumption of C1 INH with activation of the complement and contact systems during episodes of angioedema. The patient continued to have normal C1 INH levels and to have no evidence for complement- or contact-system activation between attacks of angioedema. One year later, her course evolved into a more typical course for acquired C1 INH deficiency consisting of continuously low functional C1 INH levels with evidence of activation of the complement and contact systems. S. G. provides a unique insight into the development of acquired C1 INH deficiency.

Acute Disease↗
PubMed1994

Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid.

C1-inhibitor deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema [AAE]). The two forms have the same clinical picture but differ in the response to treatment. Prophylaxis with antifibrinolytic agents produces better results in the acquired form than in the inherited form, in which androgen derivatives are more effective. It is hypothesized that activation of the contact and fibrinolytic systems is involved in the pathogenesis of attacks. We evaluated these two systems in plasma from eight patients with AAE and anti-C1-inhibitor autoantibodies (autoimmune AAE) by measuring the cleavage of high molecular weight kininogen and the complexes formed by plasmin and its inhibitor alpha 2-antiplasmin. We also measured complement parameters, autoantibody titer, and cleaved C1-inhibitor (relative molecular mass = 96,000), because autoantibodies to C1-inhibitor are known to facilitate its cleavage by proteases. Plasma was obtained from patients in remission, during prophylactic treatment with the antifibrinolytic agent tranexamic acid (2 to 4.5 gm/day) and also from two patients during acute attacks of edema. Levels of cleaved high molecular weight kininogen and antiplasmin-plasmin complexes in patients with AAE were both higher in basal conditions, during treatment, and during acute attacks than those in normal subjects (p < 0.001). The cleaved inactive form of C1-inhibitor was also present in all patients in all three conditions. Therapy with antifibrinolytic agents reduced the frequency and intensity of symptoms without significantly changing any of the biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗