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PubMedDate not supplied

Characterisation of nucleotide sequence variants and disease-specific mutations involving the 3' end of the C1-inhibitor gene in hereditary angio-oedema.

The sixth, seventh and eighth exons of both alleles of the C1-inhibitor gene were nucleotide sequenced in 52 individuals from 20 kindred with type I hereditary angio-oedema (HAE), 5 kindred with type II HAE and 10 control kindred. Four previously unreported nucleotide which had no disease specificity were identified in addition to a sequencing error in the eighth exon. In addition, a T-->C mutation at position 8770 (resulting in a Phe-->Leu substitution at position 291) was identified on the abnormal allele of the affected members of a family with type I HAE due to an exon 6 donor splice site mutation. The significance of this mutation is not known. Disease-specific mutations were identified in 100% of type II HAE kindred and in 20% of type I HAE kindred. The relevance of these findings to the evolving understanding of the molecular genetics of HAE is discussed.

Alleles↗
PubMed1996

C-1-inhibitor binding monoclonal immunoglobins in three patients with acquired angioneurotic edema.

The syndrome of acquired angioneurotic edema (AAE) is characterized by the adult onset of angioedema, the lack of evidence for inheritance of the disorder, and the frequent association of the C1-inhibitor (C1-INH) deficiency with lymphoproliferative or other malignant diseases. Recently, a new type of AAE (type II AAE) has been described. The two major biologic differences of this new syndrome compared with all other previously reported AAE cases (type I AAE) are the presence in patients' sera of both anti-C1-INH autoantibodies, often monoclonal, and a circulating low molecular weight (95 kd) C1-INH protein. From the clinical point of view, the absence of underlying lymphoproliferative disease is the hallmark of type II AAE compared with type I AAE. However, the distinction between type I and type II AAE may not be so clear-cut. We report three patients with monoclonal gammopathies and AAE for whom the initial diagnosis was type I AAE. The demonstration by ELISA of the C1-INH binding ability of their monoclonal immunoglobulins in addition to the presence of 95 kd C1-INH protein enables us to change the diagnosis to type II AAE. From the therapeutic point of view, it is crucial to detect the anti-C1-INH antibody and to analyze the C1-INH size to distinguish type I and type II AAE, especially if patients have a monoclonal gammopathy, to give the appropriate treatment (attenuated androgens vs immunosuppressive regimen, respectively) to prevent a fatal outcome.

Aged↗
PubMed1999

C1-esterase inhibitor in graft failure after lung transplantation.

Graft failure after lung transplantation may occur immediately after transplantation due to reperfusion injury or later due to rejection and infection. Although the pathological mechanisms are not completely known, the clinical findings are similar to the adult respiratory distress syndrome. In this condition, the blood coagulation contact system and the complement system are activated, leading to a capillary leak syndrome. Activation of the contact as well as the complement system is regulated by a common inhibitor, C1-esterase inhibitor (C1-INH). We report on two patients who received high doses of C1-INH for 2 days during graft failure either due to reperfusion injury immediately after transplantation or due to an acute rejection 2 months after double-lung transplantation. In both cases of graft failure, a capillary leak syndrome occurred with pleural effusions of 7 l to more than 10 l per day. In case 1 disturbance of gas exchange during severe reperfusion injury could not be treated effectively with other treatment modalities like nitric oxide ventilation or surfactant administration. With the use of C1-INH, pleural effusions reduced within 12 h, leading to normal graft function within 4 days. In the second recipient, acute rejection forced the use of extracorporeal membrane oxygenation (ECMO) within 24 h despite immunosuppressive therapy. After administration of C1-INH, pleural effusions reduced from 19 l per day to 300 ml within 3 days of treatment. ECMO was discontinued after C1-INH treatment and the patient extubated 2 weeks later. This experience indicates that C1-INH may play a role in the management of capillary leak syndrome after lung transplantation.

Capillary Leak Syndrome↗
PubMed1993

Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion.

Aprotinin reduces blood loss after cardiac operations and decreases the bleeding time. The mechanism of action of aprotinin that produces these effects is not clear. During simulated extracorporeal circulation the contact and complement systems, platelets, and neutrophils are activated. We investigated the effect of aprotinin on kallikrein-C1-inhibitor complex and C1-C1-inhibitor complex formation, neutrophil degranulation, and platelet release and aggregation during simulated extracorporeal circulation. Fresh heparinized human blood was recirculated at 37 degrees C for 2 hours in a spiral coil membrane oxygenator-roller pump perfusion circuit. Changes in platelet count, leukocyte count, platelet response to adenosine diphosphate, and plasma levels of beta-thromboglobulin, kallikrein-C1-inhibitor complexes, C1-C1-inhibitor complexes, and neutrophil elastase were measured before and at 5, 30, 60, and 120 minutes of recirculation at 0, 0.015, 0.03, 0.06, and 0.12 mg/ml doses of aprotinin. Platelet counts decreased to 36% +/- 12% of control values at 5 minutes and increased to 56% +/- 13% at 120 minutes without aprotinin. Aprotinin did not affect platelet counts, but it did prevent the decrease in sensitivity of platelets to adenosine diphosphate and it attenuated beta-thromboglobulin release. In the absence of aprotinin, kallikrein-C1-inhibitor and C1-C1-inhibitor complexes increased progressively to 0.53 +/- 0.14 U/ml and 2.38 +/- 0.33 U/ml, respectively, at 120 minutes. Kallikrein-C1-inhibitor complexes were completely inhibited and C1-C1-inhibitor complexes were partially inhibited at aprotinin concentrations of 0.03 mg/ml or greater. Release of neutrophil elastase was partially but not completely inhibited at the highest dose of aprotinin and was 50% inhibited at a dose of 0.03 mg/ml. Because activation of the fibrinolytic system does not occur in this system, the changes were independent of the inhibition of plasmin. We conclude that aprotinin in high doses completely inhibited kallikrein-induced activation of neutrophils and partially inhibited complement-induced activation. Aprotinin did not directly affect platelet adhesion or aggregation, but it indirectly preserved platelet sensitivity to agonists and also attenuated release of alpha-granule contents. The data indicate that in the presence of aprotinin platelet function was partially preserved, kallikrein production was totally inhibited, complement activation was partially inhibited, and neutrophil release was partially inhibited, thus attenuating the "whole body inflammatory response" associated with cardiopulmonary bypass.

Aprotinin↗
PubMed1998

Chromogenic assays for equine coagulation factors VII, VIII:C, IX, and X, and C1-esterase inhibitor.

OBJECTIVES: To adapt manual human chromogenic assays for coagulation factors VII (F.VII), VIII:coagulant (F.VIII:C), IX (F.IX), and X (F.X), and C1-esterase inhibitor (C1-INH) for use with an automated analyzer, and to measure the activity of these proteins in horses. ANIMALS: 10 healthy horses were used to determine ranges for the assays. Pooled plasma for standards was collected from an additional 20 healthy horses. PROCEDURE: A computer-assisted analyzer was programmed from the manual method for commercially available human F.VII, F.VIII:C, F.IX, F.X, and C1-INH chromogenic assay kits. Standards were prepared from pooled citrated equine plasma for the F.VII, F.VIII:C, and F.X assays, and from commercial pooled citrated human plasma for F.IX and C1-INH assays. RESULTS: Mean +/- SD activities in citrated equine plasma from 10 horses were 226 +/- 19% for F.VII; 209 +/- 31% for F.VIII:C; 149 +/- 38% for F.IX; 88 +/- 12% for F.X; and 18.4 +/- 8.4% for C1-INH. Intra-assay coefficients of variation (CV) were 5.3% for F.VII; 2.1% for F.VIII:C; and 3.0% for C1-INH. Interassay CV were 5.7% for F.VII; 7.4% for F.VIII:C; 3.8% for F.IX; 14.4% for F.X; and 22.0% for C1-INH. CONCLUSIONS: Human chromogenic assay kits can be automated and used to measure F.VII, F.VIII:C, F.IX, F.X, and C1-INH activities in citrated equine plasma. CLINICAL RELEVANCE: Human chromogenic assays can be routinely used to measure F.VII, F.VIII:C, F.IX, F.X, and C1-INH in horses, and may be useful in evaluation of horses with disorders of hemostasis.

Animals↗
PubMed2002

C1-inhibitor for prophylaxis of xenograft rejection after pig to cynomolgus monkey kidney transplantation.

BACKGROUND: Early rejection of discordant porcine xenografts in primate recipients is initiated by the intragraft binding of either preformed (hyperacute xenograft rejection) or induced (acute vascular rejection) antiporcine recipient antibodies with subsequent complement activation via the classical pathway. We have investigated the efficacy of the supplemental administration of C1-inhibitor (C1-INH), a specific inhibitor of the classical complement activation pathway, for prophylaxis of xenograft rejection in a pig to primate kidney xenotransplantation setting. METHODS: Based on the results of pharmacokinetic studies performed in two nontransplanted monkeys, supplemental C1-INH therapy was administered daily to three Cynomolgus monkeys receiving a life-supporting porcine kidney transplant together with cyclophosphamide-induction/cyclosporine A/mycophenolat-mofetil/steroid immunosuppressive therapy. RESULTS: In the three monkeys receiving porcine kidney xenografts and continuous C1-INH treatment none of the grafts underwent hyperacute rejection; all xenografts showed initial function. Recipient survival was 13, 15, and 5 days. No graft was lost due to acute vascular rejection. All animals died with a functioning graft (latest creatinine 96, 112, and 96 micromol/liter) due to bacterial septicemia. CONCLUSION: We conclude that, in our model, supplemental C1-INH therapy together with a standard immunosuppressive regimen can be helpful for prevention of xenograft rejection in a pig to primate kidney xenotransplantation setting. The optimal dose and duration of C1-INH treatment, however, has yet to be determined.

Acute Disease↗
PubMed1984

Studies of four Japanese families with hereditary angioneurotic edema: simultaneous activation of plasma protease systems and exogenous triggering stimuli.

Forty-five relatives of 4 families with hereditary angioneurotic edema (HANE) were studied. Twenty-five, including 11 asymptomatic kindreds with the disposition, showed typical changes in complement system compatible with HANE. Follow-up study of HANE patients showed that, even in remission period, complement, coagulation and fibrinolytic systems can be activated. During edema attacks, moderate haemoconcentration and neutrophilia were encountered and kallikrein-kinin system was found to be also activated. Replacement therapy with C 1-inhibitor preparation for an edema attack revealed that clinical improvement paralleled the increase in blood levels of high molecular weight kininogen. Thus, HANE attack is considered to be elicited in kindreds with the hereditary disposition by activation of plasma protease systems, particularly by that of kallikrein-kinin system. On the other hand, exogenous triggers that can initiate activation of the protease systems can be classified into 2, neuro-humoral (sympathetic nerve response) and physico-chemical, categories. Hence, the edema attack of kindreds with the hereditary disposition can at least be modified by the biosynthesis of plasma factors and the individual susceptibility to the liberated catecholamines. These two different reaction processes are considered to be linked by the release of plasminogen activator and/or Hageman factor activating enzyme.

Angioedema↗
PubMed1998

In vitro stimulation of C1s proteolytic activities by C1s-presenting autoantibodies from patients with systemic lupus erythematosus.

Anti-C1s autoantibodies (IgG forms), which recognize the conjunction of C1s heavy chain and light chain (C1s-presenting autoantibodies) from patients with systemic lupus erythematosus (SLE), have been found to stimulate C1s enzymatic activities. This is due to acceleration of the proteolytic hydrolysis of the synthetic substrate C1-1 by C1s, enhancement of the complex formation of C1s with its natural pseudosubstrate, C1 inhibitor (C1 inh), and promotion of proteolytic activation of its natural substrate, C4. Seven of fifteen samples from patients with SLE were found to contain such autoantibodies. The hydrolysis of the synthetic substrate C1-1 catalyzed by C1s in 25 to 27 min in the presence of anti-C1s autoantibodies was equivalent to the hydrolysis of C1-1 catalyzed by C1s alone or C1s with control IgG from healthy sera in 110 min, approximately fourfold faster than the reaction in the absence of anti-C1s autoantibodies. Densitometry scanning data showed that the formation of the C1s-C1 inh complex in the presence of anti-C1s autoantibodies was three to four times greater than that with control IgG. It was also noticed that the autoantibodies convert almost all of the latent forms of C1s to an active form that binds to C1 inh. Another group of Western blots showed that C1s cleaved C4 alpha-chain three times faster in the presence of autoantibodies than of control IgG. It is likely that the overconsumption of complement components is common in the pathogenesis of tissue damage occurring in SLE.

Antigen-Antibody Complex↗
PubMed1984

The fibrinolytic system in man.

The existence of a system in the human body capable of inducing the dissolution of endogenous pathologically formed thrombi was appreciated in ancient times. Considered in detail in this article are the data that have elucidated the physiologic regulation of which plasmin formation is dependent on, the plasma concentration of plasminogen, availability of activators of plasminogen in the plasma and surrounding tissue environment, the concentration of naturally present inhibitors, and the existence of fibrin in the circulation. Important in this rapidly progressive scientific discipline is consideration of the factors which control the synthesis of the components of this proteolytic enzyme system. Recently abundant information has indicated that this plasminogen-plasmin proteolytic enzyme system can be utilized therapeutically. Knowledge of the mechanisms of this system has permitted identification of agents that can be exogenously administered to releave thrombotic obstruction to blood flow in the venous (pulmonary emboli, deep vein thrombosis) and arterial (peripheral and central vessels) circulatory systems. Particularly important is the demonstration that thrombolytic agents can directly attack and alleviate the immediate cause of acute myocardial infarction. As a result of the innovations in the present decade, it is evident that the plasminogen system can be advantageously employed to reverse the pathologic effects of all thrombotic diseases.

Antifibrinolytic Agents↗
PubMed1985

Simultaneous turnover of normal and dysfunctional C1 inhibitor as a probe of in vivo activation of C1 and contact activatable proteases.

Simultaneous turnover of normal and dysfunctional C1-inhibitor (C1-INH) was carried out in 10 normal subjects and 13 patients with rheumatoid arthritis as a measure of the in vivo activation of C1 and the contact activatable enzymes. In the first series of experiments, dysfunctional protein We was used in simultaneous turnover studies in five normal subjects and nine patients. The fractional catabolic rate of the dysfunctional C1-INH, We, (FCR(d)) was unchanged in both groups but the fractional catabolic rate of the normal C1-INH (FCR(n)) was faster in the patients compared to the controls, in particular patients with vasculitis. The enzyme-dependent catabolism defined as FCR(n-d) X concentration of C1-INH X plasma volume, was raised in the patient group, and correlated with disease activity score (r = 0.83, P less than 0.05). Neither FCR(n) nor FCR(d) was dependent on C1-INH concentration. The latter was higher in the patients (206 mg/l compared with 155 mg/l) indicating a very high synthetic rate in the patients (280.81 micrograms/kg/h compared with 179.77 micrograms/kg). In the second series of turnovers in six patients and five normal subjects, another dysfunctional C1-INH, at, was used. The FCR of C1-INH was slower than C1-INH (We) (1.88%/h compared with 2.7%/h). Enzyme-dependent catabolism of C1-INH in these patients were raised and also correlated with disease activity score (r = 0.82, P less than 0.05).

Adult↗
PubMed2002

[Evaluation of C3c, C4 and C1-esterase inhibitor (C1-INH) during unstable angina].

BACKGROUND: The complement system plays an important role in the physiopathology of acute myocardial infarction (AMI) taking part in myocardial damage and reperfusion injury. The aim of this study is to investigate the plasmatic levels of some complement components (C3c, C4 and C1-INH) during unstable angina (C1-INH) and their different concentrations in relation to the different myocardial areas affected by ischemia. METHODS: The plasmatic levels of C1-INH, C3c and c4 in 30 patients affected by unstable angina, and those of 22 clinically healthy subjects (control group) were evaluated (Nefelometer Behering). The patients were divided into four groups according to the different myocardial area affected by ischemia (anterior, antero-lateral, lateral or inferior ischemia), RESULTS: No statistically significant differences were found in plasmatic levels of C3c, C4 and C1-INH between the group of patients and the control group. There is a statistically significant difference between the C1-INH levels of the patients with inferior ischemia and the plasmatic concentrations of the whole patients' group (p<0,01), the control group (p<0,01) and the group of patients with lateral ischemia (p<0,02). CONCLUSIONS: There seems to be a different activation of the complement system during unstable angina, in relation to the different myocardial area affected by ischemia.

Aged↗
PubMed1993

Clinical problems in the C1-inhibitor deficient patient.

The clinical course of C1-INH deficiency is presently well established. There is an inherited form (Hereditary Angioedema) characterized by recurrence of cutaneous and mucous swellings appearing early in life and usually accompanied by substantial family history, and an acquired form (Acquired Angioedema) where identical symptoms start after the fourth decade of life without family history. The acquired form can be associated with other diseases, mainly B cell disorders, and/or with autoantibodies to C1-INH. The biochemical characteristic is the functional deficiency of C1-INH and of C4 and C2. Moreover a marked deficiency of C1 is present in most acquired forms, but never in the inherited ones. C1-INH deficiency can be corrected by attenuated androgens that increase C1-INH levels in a few days and are effective in the prophylaxis of attacks, or by substitutive therapy with C1-INH plasma concentrate that is the life-saving drug in laryngeal edema. Patients with the inherited form have a uniformly good response to both these treatments which are otherwise effective only in a minority of patients with the acquired deficiency. In these subjects C1-INH concentrate needs to be given in higher doses and prevention of attacks is obtained with antifibrinolytic agents (Tranexamic acid).

Adolescent↗
PubMed1986

Assay characteristics and fibrin affinity of plasminogen activators of the intrinsic fibrinolytic system.

Plasminogen activators (PA) in the euglobulin fraction of dextran sulfate activated plasma (DS-EF) were assayed on fibrin plates. Activity related to tissue plasminogen activator (t-PA) or urokinase (u-PA) was quantified by antiserum inhibition. The DS-EF contained 30% t-PA, 30% u-PA and 40-50% activity unrelated to t-PA or u-PA. The latter was completely inhibited by 1.7 mumol/1 C1-inhibitor (C1INH), the two former were less sensitive. Addition of flufenamate to the DS-EF (DS-EF/Fluf) from normal and two factor XII (F XII)-deficient plasmas increased their activities to the same high level. More than 50% of the activity was unrelated to t-PA or u-PA, 30-40% was u-PA and 5-10% t-PA related. After addition of fibrinogen to DS-EF/Fluf and clotting with thrombin, the remaining solution contained only about 30% of the total activity, including less than 10% u-PA. The epsilon-aminocaproic acid inhibition pattern obtained with the DS-EF was uniform, and thus different from the biphasic pattern obtained with the low fibrin affinity PA, two-chain urokinase. Thus, both the plasma u-PA and the major unidentified PA in plasma have affinity for fibrin.

Adult↗
PubMed1989

Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon.

The molecular genetic basis of C1 inhibitor (C1 INH) deficiency in a patient with type I hereditary angioneurotic edema was studied. This patient was found to have an abnormally short C1 INH mRNA together with a normal message. Restriction fragment length polymorphism of the C1 INH gene was detected by Southern blot analysis of the patient's DNA after digestion with Pst I or Sac I, and hybridization with a full-length C1 INH cDNA. Hybridization of the same blot with three different fragments of the full-length cDNA suggested that exon VII and portions of both flanking introns were deleted in the C1 INH gene. Northern blot analysis of RNA from cultured monocytes, using a probe corresponding to exon VII, also indicated that the abnormal C1 INH mRNA had a deletion of these nucleotides. To confirm the hypothesis that the short C1 INH mRNA contained a deletion, the involved segment of the patient's C1 INH mRNA was amplified using the polymerase chain reaction (PCR). PCR amplification yielded two C1 INH DNA fragments of different lengths (380 and 160 bp). Southern blot and sequence analysis of both DNA fragments clearly revealed that the smaller 160-bp DNA was derived from the abnormal message and had a deletion of nucleotides corresponding to exon VII.

Angioedema↗
PubMed1994

Hereditary angioneurotic oedema: characterization of plasma kinin and vascular permeability-enhancing activities.

The mediator(s) responsible for localized enhanced vascular permeability that characterizes an exacerbation of hereditary angioneurotic oedema (HAE) is thought to be a product of either contact or complement system activation. In contrast to normal individuals, plasma from these patients generates both kinin and vascular permeability-enhancing activity following incubation at 37 degrees C. Depletion of C1 inhibitor in both normal and C2-deficient plasma, but not in contact factor-deficient plasmas, resulted in generation of these activities. The kinin activity from incubated HAE plasma was susceptible to kininase inactivation and was blocked by a Bk2 receptor antagonist. Furthermore, this activity was isolated from HAE plasma; amino acid sequence analysis proved it to be bradykinin. Similarly, the vasopermeability-enhancing activity from ethanol-fractionated or boiled HAE plasma, collected during either attack or remission, co-eluted with bradykinin on reverse-phase high performance liquid chromatography (HPLC). These studies conclusively demonstrate that bradykinin is the major kinin and mediator of enhanced vascular permeability generated during incubation of HAE plasma. The role of other bioactive products, such as the C2 kinin, at local sites of oedema formation remains to be further defined.

Amino Acid Sequence↗
PubMed1987

Interactions of plasma kallikrein and C1-s with normal and dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema: analytic gel studies.

Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a "doublet" form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1-s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.

Angioedema↗
PubMed1992

Long-term follow-up of non-systemic lupus erythematosus glomerulonephritis in patients with hereditary angioedema: report of four cases.

Hereditary angioedema (HAE) is characterized by a deficiency in C1 inhibitor protein (C1 INH) and by clinical symptoms of episodic swelling of subcutaneous or mucosal tissue. It has rarely been reported in association with non-systemic lupus erythematosus (SLE) glomerulonephritis (GN). A recent report of two cases indicates the prognosis to be poor, with both patients progressing to chronic renal failure 8 and 20 years after diagnosis. This report describes the 5-year follow-up of a previously unreported case of an 8-year-old boy with HAE and non-SLE membranoproliferative glomerulonephritis (MPGN). The patient developed macroscopic hematuria, azotemia, and a vasculitic rash. Treatment included prednisone and cyclophosphamide, resulting in clinical improvement. The present report also summarizes the long-term follow-up of three previously reported cases of HAE and non-SLE GN, 25, 16, and 10 years after their initial presentation. Patients monitored for 25 and 16 years had MPGN and normal renal function and received no therapy. The third patient, monitored for 10 years, had segmental MPGN. This patient presented with urinary abnormalities and, after treatment with prednisone, had improvement in her hematuria. None of these four patients developed chronic renal failure. These observations indicate a variable outcome in patients with HAE and non-SLE GN.

Aged↗
PubMed1989

Acquired C1 inhibitor (C1-INH) deficiency type II. Replacement therapy with C1-INH and analysis of patients' C1-INH and anti-C1-INH autoantibodies.

The response of two patients with autoantibody-mediated C1-inhibitor (C1-INH) deficiency to replacement therapy with C1-INH was studied over a period of 3 d. In patient 1 an acute attack of angioedema was successfully managed by infusion of 1,000 U of C1-INH concentrate. C1-INH function returned to normal levels within 30 min, while CH50 and C4 peaked after 6-7 h and C1 hemolytic activity reached 50-60% of normal after 3 d. Immediately after the injection an increase in C1-INH-anti-C1-INH complexes was observed. Based on NH2-terminal sequence analysis of the patients' Mr 96,000 C1-INH, it is concluded that this fragment is generated after cleavage of C1-INH in its active site by one of its target proteases without generating a covalent C1-INH-enzyme complex. In a second patient with a four to five times higher anti-C1-INH antibody titer, the infusion of 500 ml of plasma or of 2,000 U of C1-INH concentrate influenced neither the severity of the patient's angioedema nor the tested parameters, except for an increase in the amount of C1-INH-anti-C1-INH complexes. Analysis of patients' anti-C1-INH antibodies revealed that the antibodies recognize different epitopes within the C1-INH. This suggests that patients with acquired angioedema type II are a heterogenous group with respect to the C1-INH autoantibodies.

Amino Acid Sequence↗