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The present paper reports a case of C-1-esterase-inhibitor-deficiency in pregnancy. After preoperative i.v. application of 500 E-1-esterase the section caesarean was performed. Problems of this disease, relevant for obstetrics have been described. An interdisciplinary cooperation between obstetrics, anaesthetics and dermatologists is important.
Hereditary C1 esterase inhibitor deficiency is often associated with immunpathologic disorders. The authors present a case of the rare coincidence of hereditary angioedema (HAE) and Crohn's disease. The history of the patient is analysed along with the familial occurrence of the disease. Characteristic abdominal manifestations of C1 esterase inhibitor deficiency are compared to the clinical signs of Crohn's disease. Differential diagnostic pitfalls are described along with efficatious therapeutic options.
The mechanisms involved in the activation of the coagulation cascade in severe falciparum malaria were studied in 22 adult patients (19 male, three female) aged 18-45 (mean +/- SD 31 +/- 11) years. Of these, nine had multiple vital organ dysfunction, and bleeding occurred in four patients, two of whom died. During acute illness the reduction in plasma antithrombin III (AT III) concentrations and elevation in thrombin-AT III complexes were associated with significant reductions in factor XII and prekallikrein activities, and an increase in the C1 inhibitor antigen/activity ratio. Serial plasminogen activity remained within the normal range in all patients while protein C activity was significantly reduced. All patients had markedly elevated plasma polymorphonuclear leucocyte elastase (PMN-elastase) levels with mild depletion of alpha-2 macroglobulin but normal concentrations of alpha-1 antitrypsin. There was no correlation between PMN-elastase concentrations and any of the coagulation parameters or concentrations of proteinase inhibitors. These results suggest that the intrinsic pathway of the clotting cascade is activated in severe malaria. This may cause activation of the complement system and release of bradykinin and PMN-elastase and could contribute to the pathogenesis of severe malaria.
Several studies suggest that complement plays an important role in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of low density lipoprotein (LDL) to bind and activate C1, the complex that triggers the classical pathway of complement. For this purpose, LDL was both obtained commercially and purified according to an established procedure, and oxidized (oxLDL) and enzymatically modified (E-LDL) derivatives were generated from each preparation. Whereas the unmodified LDL and oxLDL samples did not activate C1 in the presence of excess C1 inhibitor, the E-LDL derivatives obtained by sequential treatment of LDL with a protease and then with cholesterol esterase triggered efficient C1 activation under these conditions, with activation levels approximately 60% upon incubation with 1 microM E-LDL for 90 min at 37 degrees C. In agreement with these findings, as shown by surface plasmon resonance spectroscopy (SPR), the C1q recognition subunit of C1 showed no interaction with unmodified LDL but bound to both E-LDL samples with high affinity (K(D)=58-75 nM). More unexpectedly, although they did not trigger direct C1 activation, both oxLDL samples were also efficiently recognized by C1q. Whereas the oxLDL derivative of commercial LDL activated C1 to a significant extent ( approximately 30%) in the presence of C-reactive protein (CRP), much lower activation levels (<10%) were obtained using the oxLDL derivative of purified LDL. As measured by SPR, CRP bound equally well to the oxLDL and E-LDL derivatives obtained from purified LDL. These data provide the first experimental evidence that E-LDL triggers efficient C1 activation under conditions close to the physiological situation, suggesting that activation of the classical complement pathway by this derivative may be a crucial factor in the pathogenesis of atherosclerosis. In contrast, it appears unlikely that oxLDL significantly activates C1 directly or in a CRP-dependent manner in vivo.
Hereditary deficiency of C1-esterase inhibitor (C1-INH) which clinically manifests as hereditary angioedema is a rare disorder. In previously not diagnosed cases, a fatality rate of up to 30 % has been reported. The diagnosis of C1-esterase inhibitor deficiency should not be missed in patients presenting with angioedema in the face, stem or extremities. We report the case of a 17-year-old girl with recurrent abdominal pain and swelling of the hands.
C1-inhibitor (C1Inh), antithrombin III (ATIII), alpha 1-antitrypsin (a1AT), and alpha 2-antiplasmin (a2AP) are known inhibitors of factor XIa (FXIa). However, their precise contribution to FXIa inactivation in vivo is not known. We investigated FXIa inactivation in chimpanzees and assessed the contribution of these inhibitors to FXIa inactivation in patients with presumed FXI activation. Chimpanzees were infused with FXIa and the various FXIa-FXIa inhibitor complexes formed were measured. Most of FXIa was complexed to C1Inh (68%), followed by a2AP (13%), a1AT (10%), and ATIII (9%). Analysis of the plasma elimination kinetics revealed a half-life time of clearance (t1/2) for the FXIa-FXIa inhibitor complexes of 95 to 104 min, except for FXIa-a1AT, which had a t1/2 of 349 min. Due to this long t1/2, FXIa-a1AT complexes were predicted to show the highest levels in plasma samples from patients with activation of FXI. This was indeed shown in patients with disseminated intravascular coagulation, recent myocardial infarction or unstable angina pectoris. We conclude from this study that in vivo C1Inh is the predominant inhibitor of FXIa, but that FXIa-a1AT complexes due to their relatively long t 1/2 may be the best parameter to assess FXI activation in clinical samples.
A case of hereditary angioedema secondary to C1 esterase inhibitor deficiency associated with lupus-like nephritis is reported. The patient was initially treated with both corticosteroids and danazol and subsequently had Guillain-Barré syndrome together with appearance of circulating immune complexes and an increase in total complement and C1q, C3, C4, B, and C1 esterase inhibitor levels. Guillain-Barré syndrome might be secondary to danazol therapy since this drug could increase both circulating immune complex production and complement synthesis, thereby providing additional substrate for the underlying immune complex disease. Normalization of complement might therefore be hazardous in lupus with underlying complement deficiency states.
We investigated the influence of dextran sulfate, heparin, heparan sulfate, and dermatan sulfate on the inhibition of FXIa (where FXIa is activated factor XI, for example), FXIIa, and kallikrein by C1 inhibitor, alpha1-antitrypsin, alpha2-antiplasmin, and antithrombin III. The second-order rate constants for the inhibition of FXIa by C1 inhibitor, alpha1-antitrypsin, alpha2-antiplasmin, and antithrombin III, in the absence of glycosaminoglycans, were 1.8, 0.1, 0.43, and 0.32 x 10(3) M-1 s-1, respectively. The rate constants of the inactivation of FXIa by C1 inhibitor and by antithrombin III increased up to 117-fold in the presence of glycosaminoglycans. These data predicted that considering the plasma concentration of the inhibitors, C1 inhibitor would be the main inhibitor of FXIa in plasma in the presence of glycosaminoglycans. Results of experiments in which the formation of complexes between serine protease inhibitors and FXIa was studied in plasma agreed with this prediction. Glycosaminoglycans did not enhance the inhibition of alpha-FXIIa, beta-FXIIa, or kallikrein by C1 inhibitor. Thus, physiological glycosaminoglycans selectively enhance inhibition of FXIa without affecting the activity of FXIIa and kallikrein, suggesting that glycosaminoglycans may modulate the biological effects of contact activation, by inhibiting intrinsic coagulation without affecting the fibrinolytic potential of FXIIa/kallikrein.
We report a 59-year-old woman who had progressive symptoms of angioedema for 3 years, culminating in an attack of laryngeal stridor. C1 esterase inhibitor deficiency was confirmed and treatment with tranexamic acid produced considerable clinical benefit and improvement in complement levels. Two years later she developed clinical evidence of lymphocytic lymphoma. Splenectomy resulted in rapid correction of complement abnormalities. The patient received 6 months of chemotherapy after surgery and remained asymptomatic with normal complement levels 4 years later.
An 11-year-old white female with focal glomerulonephritis was found to have an absence of functional C1 esterase inhibitor. C1 esterase inhibitor measured by immunochemical means, however, was only slightly reduced. After an initial time period marked by variable hypocomplementemia, presumably due to immune complex formation associated with the nephritis, immunochemical signs of active and severe hereditary angioneurotic edema (HANE) developed. These have been unremitting for 3 1/2 years. Clinical signs of HANE, however, have never developed. Thus, during this time, there have been no clinical abnormalities despite the fact that free C1 esterase activity has been persistently present in this patient's serum and serum levels of functional C1 esterase inhibitor, C2 and C4 have been continuously less than 2% of normal. It appears, therefore, that this patient has an unusual form of HANE mainifested solely by the complement alterations seen during symptomatic attacks but without clinical expression of that serologic activity.
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.
In situ and in vitro studies suggest that activation of locally produced complement factors may act as a mediator between amyloid deposits and neurodegenerative changes seen in Alzheimer's disease (AD). C1-esterase inhibitor (C1-Inh), which regulates activation of C1 of the complement classical pathway, can be detected immunohistochemically in its inactivated form in activated astrocytes and dystrophic neurites in AD plaque areas. In this study, designed to investigate the cellular source of C1-Inh, C1-Inh was found to be secreted in a functionally active form by astrocytes cultured from postmortem human brain specimens as well as by neuroblastoma cell lines. Recombinant human interferon-gamma (IFN-gamma), which stimulates C1-Inh synthesis in various cell types, several-fold stimulated C1-Inh protein secretion by cultured human astrocytes derived from different regions of the central nervous system and by one (SK-N-SH) of two neuroblastoma cell lines (SK-N-SH and IMR-32) included in this study. In contrast to IFN-gamma, other cytokines [interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] that can be found in brain areas affected by AD, did not stimulate C1-Inh secretion by astrocytes or neuroblastomas in vitro. This inability to secrete C1-Inh is probably due to unresponsiveness at the transcriptional level, since C1-Inh secretion paralleled the expression of the 2.1-kb C1-Inh mRNA. In situ hybridization with a C1-Inh RNA antisense probe labeled neurons rather than astrocytes, suggesting a role for neurons as producers of complement regulatory proteins in vivo. Since IFN-gamma is apparently lacking in the brain parenchyma, and amyloid plaque-associated cytokines (IL-1beta, IL-6, TNF-alpha) do not stimulate C1-Inh expression in vitro, the nature of the stimulus responsible for neuronal C1-Inh expression in AD brains remains to be investigated.
The specificity of serpin superfamily protease inhibitors such as alpha 1-antitrypsin or C1 inhibitor is determined by the amino acid residues of the inhibitor reactive center. To obtain an inhibitor that would be specific for the plasma kallikrein-kinin system enzymes, we have constructed an antitrypsin mutant having Arg at the reactive center P1 residue (position 358) and Ala at residue P2 (position 357). These modifications were made because C1 inhibitor, the major natural inhibitor of kallikrein and Factor XIIa, contains Arg at P1 and Ala at P2. In vitro, the novel inhibitor, alpha 1-antitrypsin Ala357 Arg358, was more efficient than C1 inhibitor for inhibiting kallikrein. Furthermore, Wistar rats pretreated with alpha 1-antitrypsin Ala357 Arg358 were partially protected from the circulatory collapse caused by the administration of beta-Factor XIIa.
Components of the plasma kallikrein-kinin system were determined in plasma samples from ten healthy subjects and eight patients with septic shock. Five of the patients died. Low levels of Hageman factor, prekallikrein, and high molecular weight kininogen, together with significantly reduced concentrations of alpha 2-macroglobulin, were observed during septic shock both in patients who died and in the survivors. The patients who died also revealed a pronounced reduction of functional kallikrein inhibition determined by a chromogenic peptide substrate assay. In the survivors, however, functional kallikrein inhibition was very well preserved during septic shock, being within the range of values found in normals. Also plasma prekallikrein and C1-esterase inhibitor levels were slightly higher in the survivors than in those who died. Our results confirm that the plasma kallikrein-kinin system becomes activated during septicemia and that consumption of components of this protease system occurs. Because both C1-esterase inhibitor concentrations and functional kallikrein inhibitory activities were higher in patients who survived septic shock than in the fatal cases, our results suggest that functional inhibition of plasma kallikrein appears to play a major role in the outcome of this condition.
The role of dissociation of primary antigen-antibody bonds in the solubilization of immune complexes (IC) has been investigated using photo-affinity crosslinked IC comprising NAP15-BSA and murine monoclonal anti-DNP antibodies. Non-covalently linked IC were solubilized rapidly when incubated with normal human serum (NHS), whereas covalently-linked IC were solubilized poorly or not at all. The rate and extent of complement activation produced by incubating covalently-linked and non-covalently linked IC with NHS was similar as assessed by the production of the C1s:C1-inhibitor, C3:properdin and C5b-9 complexes and the anaphylatoxins C4a and C3a. Thus, the inability of serum to solubilize photo-affinity crosslinked IC must be due to failure of dissociation of primary antigen-antibody bonds.
BACKGROUND: Whereas complement is a key mediator of hyperacute xenograft rejection, its role in acute vascular rejection (AVR) is a matter of controversy. AVR is associated with de novo synthesis of endothelial cell-derived inflammatory mediators, including the leukocyte-recruiting adhesion molecule E-selectin. Here we investigate the role and mechanism of complement in human serum-induced porcine endothelial cell activation. METHODS: An in vitro xenotransplantation method was designed using porcine aortic endothelial cells stimulated with human serum in microculture wells. E-selectin expression was measured by cell-enzyme immunoassay. Complement inhibitors acting at different levels in the cascade were investigated for their effect on E-selectin expression. RESULTS: E-selectin was strongly induced by normal human serum but not by heat-inactivated serum. Compstatin, a synthetic C3 inhibitor, markedly reduced human serum-induced E-selectin expression. Purified C1-inhibitor suppressed E-selectin induction completely, indicating activation through the classical or lectin pathway. Furthermore, a monoclonal antibody (mAb) that inhibits cleavage of C5 or another mAb that blocks the function of C7, completely inhibited the expression of serum-induced E-selectin, consistent with the terminal C5b-9 complement complex being the mediator of the endothelial cell activation. Inhibition of the alternative pathway using a novel antifactor D mAb did not reduce E-selectin expression. CONCLUSION: Human serum-induced expression of porcine E-selectin is totally complement dependent, induced by a C1-inhibitor regulated pathway and mediated through the terminal complement complex. The data may have implications for therapeutic strategies, particularly of C1-inhibitor and anti-C5 mAb, to protect against endothelial cell activation and subsequent AVR of porcine xenografts.
Normal human serum contains 18 +/-5 mg/100 ml of C1 esterase inhibitor (alpha-2 neuraminoglycoprotein) as estimated by immunochemical means. Of 118 patients with hereditary angioneurotic edema, the sera of 80, from 42 kindred, contained a mean concentration of 3.15 mg/100 ml or 17.5% of normal. The mean serum concentration in 35 patients in 7 other kindred was 20 mg/100 ml or 111% of normal, and 3 patients in another kindred contained over 80 mg/100 ml or greater than 400% of normal. The nonfunctional inhibitors in patients' sera of these eight kindred were identical with normal C1 esterase inhibitor by Ouchterlony analysis, but they were different from normal and from each other with respect to their electrophoretic mobility, their capacity to bind C1 esterase, and their ability to inhibit esterolysis of N-acetyl-tyrosine-ethylester.
The effects of intravascular radiographic contrast media on the complement system were investigated in 46 patients. An ionic (sodium-/meglumine amidotrizoate, n = 22) or a non-ionic (iohexol, n = 24) contrast agent was applied for an i.v. urography. The levels of the complement-compounds C1q, C3, C5 and of the C1 inhibitor were determined at the end of the infusion and 20 minutes later. In both groups we obtained a significant (p less than 0.01) decrease of C3 during infusion for 10 to 15%. 20 minutes later these values were almost normalized again. Infusion of iohexol additionally caused a marked consumption of C5 and C1q (reduction to 85%), while the ionic contrast agent had no significant effect on these components. Both contrast media caused a decrease of the C1-inhibitor levels. Our results demonstrate an activation of the complement system by i.v. application of radiographic contrast media. The decrease of the C1q-level due to infusion of iohexol indicates an additional involvement of the classical activation pathway of the complement cascade.