Acquired C1 esterase inhibitor deficiency in two patients presenting with a lupus-like syndrome and anticardiolipin antibodies.
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Antibodies, Anticardiolipin↗
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Assessment of Hageman factor activation in human plasma: quantification of activated Hageman factor-C1 inactivator complexes by an enzyme-linked differential antibody immunosorbent assay.
An enzyme-linked immunosorbent assay has been developed for the quantitation of activated Hageman factor-C1 inactivator (HF-C1 INH) complexes. Addition of increasing quantities of either of the major forms of activated Hageman factor (HFa or HFf) to normal plasma or to Hageman factor-deficient plasma leads to a dose-dependent increase in activated HF-C1 INH complexes. As little as 0.5 micrograms/mL of activated HF added to plasma can be detected, corresponding to activation of approximately 2% of plasma HF. The sensitivity of the assay is increased at least tenfold when complexes are formed in HF-deficient plasma, indicating competition between unactivated HF and activated HF-C1 INH complexes for binding to the antibody. Specificity is demonstrated in that addition of activated HF to hereditary angioedema plasma yields less than 1% of the activated HF-C1 INH complex formation obtained with normal plasma. Kaolin activation of HF-deficient plasma yields no detectable complex formation. Kaolin activation of prekallikrein-deficient plasma demonstrates a time-dependent increase in formation of activated HF-C1 INH complex consistent with the ability of HF in this plasma to autoactivate as the time of incubation with the surface is increased. Kaolin treatment of high-molecular weight (HMW) kininogen-deficient plasma yields an even more profound abnormality in the rate of formation of activated HF-C1 INH complexes reflecting the complex role of HMW kininogen in the initiation of contact activation. Although addition of corn inhibitor to plasma prevents activated HF-C1 INH complex formation, it does not inhibit activated HF sufficiently fast to prevent prekallikrein activation.
Blood Coagulation↗
[Hereditary angioedema caused by a deficiency of C1 esterase inhibitor. A sporadic case of late appearance].
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Adult↗
Influence of aromatic compounds on the interaction of activated C4 with EAC1.
The influence of amino acids and their derivatives on the formation of SAC14 from SAC1 and C4 were investigated. Among the compounds tested, aromatic amino acids containing phenolic hydroxyl group or carbobenzoxyl group inhibited the formation of SAC14. When aromatic compounds other than amino acids were tested, the inhibitory capacities of these compounds were found to relate to the substituent group incorporated in the aromatic ring. Aromatic compounds with subsituent groups with negative Hammett's substituent constant showed stronger inhibition. Conversely, compounds with group with positive constant showed weaker inhibition. These results may suggest that the increased electron density in the aromatic ring is responsible for the inhibition. Regardless of inhibition of SAC14 formation, these inhibitors did not affect the enzymatic action of EAC1 or C1 on C4 but inhibited the binding of activated C4 to EAC1.
Agglutination Tests↗
Alpha 1-antitrypsin Pittsburgh (Met358-->Arg) inhibits the contact pathway of intrinsic coagulation and alters the release of human neutrophil elastase during simulated extracorporeal circulation.
Cardiopulmonary bypass prolongs bleeding time, increases postoperative blood loss, and triggers activation of plasma proteolytic enzyme systems and blood cells referred to as the "whole body inflammatory response". Contact of blood with synthetic surfaces leads to qualitative and quantitative alterations in platelets, neutrophils, contact and complement systems. Contact and complement pathway proteins both induce neutrophil activation. alpha 1-antitrypsin Pittsburgh (Met358-->Arg), a mutant of alpha 1-antitrypsin, is a potent inhibitor of plasma kallikrein and thrombin. We investigated whether this recombinant mutant protein inhibited platelet activation, as well as contact and/or complement-induced neutrophil activation during simulated extracorporeal circulation. Arg358 alpha 1-antitrypsin did not prevent the 34% drop in platelet count at 5 min of recirculation, did not block the 50% decrease in ADP-induced platelet aggregation at 120 min of recirculation, nor inhibit the release of 6.06 +/- 1.07 micrograms/ml beta-thromboglobulin at 120 min of recirculation suggesting that the inhibitor had little effect on platelet activation. However, Arg358 alpha 1-antitrypsin totally blocked kallikrein-C1-inhibitor complex formation but not C1-C1-inhibitor complex formation. Most importantly, Arg358 alpha 1-antitrypsin decreased the release of 1.11 +/- 0.16 micrograms/ml human neutrophil elastase by 43%. The attenuation of neutrophil activation in the absence of an effect on complement activation via the classical pathway, supports the concept that kallikrein is a major mediator of neutrophil degranulation during cardiopulmonary bypass.
Arginine↗
Slp is an essential component of an EDTA-resistant activation pathway of mouse complement.
Slp (sex-limited protein) is a mouse serum protein encoded by a major histocompatibility complex class III gene. It is considered to be a product of a duplicated complement component C4 gene, but without functional activity. Originally it has been found expressed only in adult males with the S region of the H-2d or H-2s haplotype. In this report we present evidence that Slp is involved in a form of mouse complement activation that occurs after fractionation of serum by polyethylene glycol precipitation. This activation pathway is EDTA-resistant (i.e., independent of classical and alternative pathway activation), is regulated by C1 inhibitor, and leads to the generation of hemolytically active membrane attack complexes. A positive correlation between this EDTA-resistant mouse complement activity and reported Slp levels was found. Direct evidence for a functional role of Slp came from substitution experiments in which purified Slp induced hemolytic activity in polyethylene glycol-fractionated, Slp-deficient mouse serum. Selective depletion of other complement components suggested a role for C1s-, C2, and C5, but not C3, in the Slp-dependent complement activation. A model for this type of mouse complement activation is presented.
Aging↗
Hereditary angio-oedema: its pathogenesis and management.
Hereditary angio-oedema is a genetically-determined disease. Usually the disease is due to a deficiency of C1-inhibitor or less commonly to the production of a functionally inactive molecule. The pathogenesis and clinical features of the disease are reviewed, and discussed in relation to the homeostatic role of C1 inhibitor. Finally the therapeutic approach to the disease is described and the scientific bases for the newer therapeutic discussed.
Anabolic Agents↗
Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema.
The metabolism of normal C1 inhibitor and two dysfunctional C1 inhibitors (Ta and WeI) was studied in 10 normal subjects and 8 patients with hereditary angioneurotic edema (HANE), 4 with low antigen concentration (type 1) and 4 with dysfunctional protein (type 2). The fractional catabolic rate of the normal C1 inhibitor in normal subjects was 0.025 of the plasma pool/hour, whereas in HANE subjects it was significantly elevated at 0.035 of the plasma pool/hour. The synthesis of normal C1 inhibitor was decreased in patients with type 1 HANE (0.087 mg/ kg per h compared with 0.218 mg/kg per h). The fractional catabolic rate of dysfunctional protein WeI was similar to normal and showed a slightly accelerated catabolism in patients with HANE, whereas the dysfunctional protein Ta had a strikingly decreased fractional catabolic rate in normals and subjects with HANE. The present study is compatible with reduced C1 inhibitor synthesis in patients with type 1 HANE consistent with a single functional C1 inhibitor gene. The lower than anticipated levels of C1 inhibitor in HANE type 1 appears to result from (a) the single functional gene and (b) increased catabolism of the protein, perhaps related to activation of C1 or other proteases.
Adolescent↗
Changes of C1 esterase inhibitor, alpha2 globulin and sedimentation rate after severe brain injury.
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Alpha-Globulins↗
The relationship between the binding ability and the rate of activation of the complement component C1.
The strength of the bond between C1 and C1 binders (as measured by C1q binding) has been correlated with the ability of the binders to activate C1. The rate of activation of C1 has been studied by following the extent of hydrolysis of the C1r and C1s subcomponents, using a purified preparation of C1 labelled with 125I. The rate of activation of C1 was not correlated with the binding strength between C1q and the C1 binders. Immune complexes were found to activate C1 rapidly, whereas glutaraldehyde-aggregated IgG failed to activate faster than the spontaneous activation seen on incubation of C1 alone; the strength of the bond between C1q and the binders was similar in the two cases. It is suggested that an interaction other than the binding between C1q and C1 binders is necessary for activation of C1. C1 bound to immune complexes was not activated in the presence of C1 inhibitor, indicating that the inhibitor can prevent the hydrolysis of C1r under the test conditions.
Antigen-Antibody Complex↗
Idiopathic nonhistaminergic angioedema.
PURPOSE: We sought to describe the characteristics of a group of patients with idiopathic nonhistaminergic angioedema and their response to prophylactic treatment with tranexamic acid. METHODS: We identified 25 patients (15 men and 10 women; age at diagnosis 16 to 77 years) who had idiopathic nonurticarial angioedema that was not prevented by histamine-1 (H1) blockers. Known causes of angioedema were excluded by clinical history, physical examination, and diagnostic tests. RESULTS: The median age at the onset of symptoms was 35 years (range 8 to 66). The frequency of attacks was > 12 per year for 16 patients, six to 11 per year for 6 patients, and one to five per year for 3 patients. All patients had cutaneous attacks, 13 (52%) reported swellings of the pharynx or larynx, and 5 (20%) had symptoms consistent with bowel angioedema. Because of the similarities between these patients and patients who are deficient in C1 inhibitor, the 15 patients with severe and frequent attacks were started on prophylactic treatment with the antifibrinolytic agent tranexamic acid, 1 g three times a day orally for 3 months, tapered according to its effectiveness. The symptoms of 11 patients decreased to less than one attack per year, and the remaining 4 patients had partial remissions (less than 4 attacks per year). Fourteen patients are still being treated with tranexamic acid. CONCLUSION: Patients with idiopathic nonhistaminergic angioedema appear to have similar clinical features and response to treatment with tranexamic acid as those who are deficient in C1 inhibitor. This suggests that those two forms of angioedema might have, at least in part, a similar pathogenesis.
Adolescent↗
Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor.
Although considerable progress has been made during the past two decades in the use of androgens to prevent attacks of hereditary angioedema, replacement of the deficient C1-inhibitor protein would provide a useful menas of treatment once an attack has begun. We studied the clinical use of C1 inhibitor that was partly purified on a large scale from pooled plasma. The in vivo efficacy and safety of this protein concentrate were evaluated during 11 intravenous infusions in eight patients with hereditary angioedema. Three patients received the C1-inhibitor preparation during an asymptomatic period. Increases in serum C4 activity provided evidence of the biologic activity of the infused inhibitor. Intravenous administration of the concentrate during acute abdominal or laryngeal attacks of hereditary angioedema in five patients resulted in abatement of symptoms in addition to increased serum C4 activity. No untoward effects of the intravenous administration of the C1 inhibitor were observed in these eight patients. Thus, this C1-inhibitor preparation seems to offer the potential for safe, effective replacement therapy and may provide a means of controlling an attack of hereditary angioedema that is in progress.
Angioedema↗
Interactions of tissue-type plasminogen activator with plasma inhibitors and their pharmacologic implications.
To delineate interactions of infused tissue-type plasminogen activator (t-PA) with inhibitors in plasma and their impact on fibrinolytic activity, serial plasma samples from patients with acute myocardial infarction and from normal rabbits given infusions of t-PA were assayed for t-PA antigen, activity of "fast acting" plasminogen activator inhibitor (PAI-1), and the presence and nature of t-PA-inhibitor complexes. In patients, endogenous t-PA circulated predominantly as a 100 kilodalton (kDa) complex with PAI-1, as verified by immunoprecipitation. During infusions, t-PA circulated not only as free t-PA (55 kDa) but also in complexes with PAI-1 (100 kDa), alpha 2-antiplasmin (110 kDa), and C1-esterase inhibitor (170 kDa). After termination of infusions, levels of free t-PA declined, while inhibitor complexes remained prominent. Free PAI-1 activity, assayed spectrophotometrically, was markedly elevated in the 24 hr interval after infusion of t-PA in 47% of patients with infarction. The specific activity of t-PA during infusions was 0.4 IU/ng or greater. However, during the 3 hr interval after infusions in patients, specific activity declined in association with prominence of t-PA complexes, predominantly with PAI-1. Infusions of t-PA in normal rabbits did not result in reactive increases in PAI-1 activity or in the t-PA-PAI-1 complex. After infusions, t-PA was associated predominantly with alpha 2-antiplasmin and C1-esterase inhibitor rather than PAI-1. t-PA inhibitor complexes were seen despite immediate acidification of whole blood, indicating that they were present in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Acquired C 1-inhibitor deficiency with angioedema due to pleomorphic immunocytoma in a patient with three malignant tumors: long-term follow-up data and presentation of an additional case.
Two cases of lymphoma-associated acquired C 1-inhibitor deficiency are described. In both patients, C 1-inhibitor deficiency and related symptoms preceded the diagnosis of the underlying neoplasm by several months. C 1-inhibitor deficiency was most likely due to consumption following immunocomplex formation. In both patients, a close relationship between low levels of C 1-inhibitor and tumor relapse was observed during follow-up. These findings indicate that measurement of C 1-inhibitor and complement factor C4 can be used as markers of disease activity in affected patients.
Angioedema↗
C1-esterase inhibitor substitution in sepsis.
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Complement C1 Inactivator Proteins↗
Interaction of C1-inhibitor with the C1r and C1s subcomponents in human C1.
1. Insoluble IgG-ovalbumin aggregates were used to bind and activate C1 from human serum. The bound C1 provided a useful reagent for studying the interaction of C1 subcomponents with C1-inhibitor. 2. C1-inhibitor bound to both subcomponents (C1r and C1s in C1 and formed stable complexes of respective apparent molecular weights 197,000 and 185,000, as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The binding reaction proceeded more readily with C1s than with C1r and was correlated with the inhibition of C1s esterase activity. 3. At physiological ionic strength, binding of C1-inhibitor to subcomponents C1r and C1s caused release of these subcomponents from the C1-immune aggregates complex, indicating that C1-inhibitor binding decreased the inter-subcomponent binding forces in C1. At low ionic strength, however, this release did not occur.
Complement C1↗
Inhibitors of kallikrein in human plasma.
Human plasma was fractionated by ammonium sulfate precipitation, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration to determine which method would give the greatest number of clearly separable kallikrein inhibitory peaks. With G-200 gel filtration three peaks could be separated which were demonstrated to contain alpha(2)-macroglobulin, C1 inactivator, and alpha(1)-antitrypsin. No other kallikrein inhibitors could be identified. The fractions containing C1 inactivator and alpha(2)-macroglobulin appeared to be more effective against kallikrein than that containing alpha(1)-antitrypsin. A patient with hereditary angioneurotic edema was shown to have an abnormal C1 inactivator protein capable of interfering with kallikrein's biologic, but not its esterolytic activity. Heat-treated human plasma, a commonly used source of kininogen for experiments with kallikrein, was shown to have kallikrein inhibitory activity.
Alpha-Globulins↗
Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease.
BACKGROUND: Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease. METHODS: We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a and C1-Inhibitor (C1 inh.) were measured enzymatically. RESULTS: Patients with UAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r=0.27, p<0.02), C3a (r=0.32, p<0.001) and C1 INH.(r=0.41, p<0.003), but not with flow mediated dilatation (r=0.09, P=0.41). Hs-CRP and C1 INH.were found to be independent predictors of UAP in a backward stepwise logistic regression model. CONCLUSIONS: We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP.
Aged↗