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At least 1,153 records · Page 64Linked to original sources
PubMed1996

C1 inhibitor deficiency in a patient with rheumatoid arthritis--increased risk of adverse effects of penicillamine?

We report the coincidence of hereditary angioedema and rheumatoid arthritis in a male patient and in his father. During treatment with D-penicillamine the patient developed a transient lupus-like disorder with glomerulonephritis that resolved when D-penicillamine was discontinued. He later was diagnosed with malignant lymphoma. Impaired classical complement pathway function could have contributed to development of the drug reaction.

Angioedema↗
PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗
PubMed1999

Acquired angioedema with C1 inhibitor deficiency: is the distinction between type I and type II still relevant?

BACKGROUND: Acquired angioedemas are divided into type I associated with lymphoproliferation and type II caused by anti-C1-inhibitor antibodies. Recent reports have suggested that this distinction is not so clear-cut, mainly because of the presence of antibodies against the C1 inhibitor in some cases belonging to the type I group. We report herein 2 additional cases of acquired angioedema with anti-C1-inhibitor antibody. MATERIAL AND METHODS: One man and 1 woman had had acquired angioedema for several years. In the man, a monoclonal component had been detected several years before the present study. In the second patient, a monoclonal component was detected during the study. The following data were studied on successive blood samples collected during angioedema manifestations: complement component levels, functional activity of the classical pathway, functional and antigenic C1 inhibitor doses, ELISA test to detect autoantibodies to C1 inhibitor and Western blot analysis of the C1 inhibitor. RESULTS: In both patients, CH50 and C4 activities were decreased, and an autoantibody to C1 inhibitor was detected. In 1 case, the antibody appeared after the monoclonal component; in the second case, it appeared before and belonged to a different immunoglobulin class. CONCLUSION: Our data suggest that the distinction between type I and type II acquired angioedema is no longer valid because of overlapping in some cases.

Aged↗
PubMed2000

Activation of clotting factors XI and IX in patients with acute myocardial infarction.

In acute coronary events, plaque rupture and the subsequent formation of the catalytic tissue factor-factor VIIa complex is considered to initiate coagulation. It is unknown whether clotting factors XI and IX are activated in acute coronary events. Therefore, we prospectively investigated the activation of clotting factors XI and IX as well as activation of the contact system and the common pathway in 50 patients with acute myocardial infarction (AMI), in 50 patients with unstable angina pectoris (UAP), and in 50 patients with stable angina pectoris (SAP). Factor XIa-C1 inhibitor complexes, which reflect acute activation of factor XI, were detected in 24% of the patients with AMI, 8% of the patients with UAP, and 4% of the patients with SAP (P<0.05), whereas factor XIa-alpha(1)-antitrypsin complexes, which reflect chronic activation, were observed equally in all 3 study groups. Factor IX peptide levels were significantly higher in the patients with AMI and UAP compared with the patients with SAP (P<0.01). No differences regarding markers of the common pathway were demonstrated. Fibrinopeptide A levels were elevated in patients with AMI compared with patients with UAP and those with SAP (P<0.01). Factor XIIa- or kallikrein-C1 inhibitor complexes were not increased. In conclusion, this is the first demonstration of the activation of clotting factors XI and IX in patients with acute coronary syndromes. Because these clotting factors are considered to be important for continuous thrombin generation and clot stability, their activation might have clinical and therapeutic consequences.

Angina Pectoris↗
PubMed1993

[Congenital C1-esterase inhibitor deficiency. A study of 4 Algerian families].

We present the results of a preliminary study (the first of this kind in Algeria) in which 4 families presenting with congenital deficiency of the C1-esterase inhibitor (C1-INH) responsible for hereditary angioneurotic oedema were biologically explored. The complement fractions C1-INH, C4 and C3d were assayed in 38 subjects of the 4 families. Extending this biological evaluation to all members of theses families enabled us to identify all asymptomatic subjects (46 percent in our series). In 2 patients the congenital disease was associated with systemic lupus erythematosus. Some clinico-biological discordances are reported and discussed in the light of data from the literature.

Adolescent↗
PubMedDate not supplied

Purification and characterization of RHP (factor H) and study of its interactions with the first component of complement.

RHP has been purified from the plasma of both normal individuals and patients with rheumatoid arthritis (RA). RHP from both these sources was shown to be identical with Factor H by reaction with antisera and N-terminal amino acid sequence analysis. Factor H, from both normal and RA sera, inhibited the solubilization of immune precipitates but did not affect prevention of immune precipitation. Factor H was shown to inhibit the haemolytic activity of fluid-phase C1, but unlike C1-inhibitor, it had little effect on C1 bound to EA (EAC1). Factor H was shown to complex with intact C1, to isolated C1q and to the C1r:C1s tetramer. However, binding of factor H to C1 did not dissociate the C1 macromolecule. A C1-Factor H complex was detected in the serum and plasma from normal individuals and patients with systemic lupus erythematosus and RA. Serum levels of this complex were reduced, by EDTA-treatment of serum and by activation of complement by the classical pathway.

Arthritis, Rheumatoid↗
PubMed1989

Angioedema with acquired deficiency of the C1 inhibitor: a constellation of syndromes.

Patients with angioedema are often referred to an allergist to rule out an allergic cause. In most of these cases, no allergic cause is identified, and the cases are labeled "idiopathic." Occasionally, a deficiency of the inhibitor of the first component of complement (C1INH) is discovered, which may be either hereditary or acquired. In comparison with the hereditary variant, the acquired deficiency of C1INH is extremely rare, approximately 40 cases having been reported to date. Measurement of the C1q subunit is the key to the differential diagnosis between hereditary and acquired deficiencies of C1INH--it is normal in the former and decreased in the latter. The acquired deficiency of C1INH is usually found in association with benign or malignant B-cell lymphoproliferative disorders, and the angioedema responds to therapy with androgens. A subset of six patients with acquired C1INH deficiency has been reported recently; they had anti-C1INH autoantibodies, no evidence of an underlying disease, a benign course, and variable responses to therapy. Two new cases of angioedema in patients with acquired C1INH deficiency are described in this report. One patient had no evidence of an underlying disease 11 years after the onset of angioedema. The other case was associated with a B-cell lymphoproliferative disorder that became evident 9 months after C1INH deficiency was diagnosed, and androgen therapy stopped the attacks of angioedema. In this second case, the functional activity of C1INH mirrored the clinical response to therapy.

Adult↗
PubMed1989

Pathways of kinin formation and role in allergic diseases.

We have developed new assays for the assessment of the plasma kinin forming system which have increased sensitivity and specificity. We utilize double-antibody ELISA assays for quantitation of complexes of activated Hageman factor-C1 inhibitor, kallikrein-C1 inhibitor, and kallikrein-alpha 2-macroglobulin which reflect activation of each enzyme. The fraction of cleaved high-molecular-weight kininogen is determined by immunoblotting using a monoclonal antibody to the light chain, and bradykinin is determined by radioimmunoassay. Activation of the Hageman factor-dependent pathway of kinin formation can occur when plasma is in contact with initiating surfaces or when C1 inhibitor function is diminished. The latter mechanism can occur in hereditary angioedema, in which the protein is absent or dysfunctional, or when plasma is diluted so that the effect of inhibitors is diminished and Hageman factor autoactivation is facilitated. Thus apparent "spontaneous" generation of bradykinin is seen upon incubation of plasma of hereditary angioedema patients under conditions in which normal plasma is unaffected. Studies of late-phase reactions have used a cutaneous model in which induced blisters are unroofed and challenged with antigen or buffer control using chambers which can be changed hourly. A time course of mediator release is obtained by assay of the blister fluids. Whereas most histamine is released during the first half hour, significantly elevated levels of activated Hageman factor and kallikrein complexes with C1 inactivator are seen in antigen-challenged sites between 4 and 6 hr. The presence of such complexes correlated with the presence of late-phase reactions rather than the histamine values or the magnitude of the immediate reaction. Although late-phase reactions are characterized by cellular infiltration, release of a variety of inflammatory low-molecular-weight mediators, and deposition of fibrin, activation of the Hageman factor-dependent pathway of kinin formation is also likely to be contributory.

Angioedema↗
PubMed1996

[Study of the relationship between complement activation and vascular endothelial damage in pregnancy induced hypertension].

OBJECTIVE: To evaluate the relationship between complement activation and vascular endothelial damage in pregnancy induced hypertension (PIH). METHODS: We quantified C1q, B-factor (BF) and C1-inhibitor (C1-INH) in peripheral and retroplacental sera of 35 nulliparous PIH patients and 20 normotensive controls with double antibody sandwich ELISA. Circulating endothelial cell (CEC)of the two groups were isolated with the density gradient system of Percoll liquid and counted under microscope. The correlation between CEC and C1q was analysed. RESULTS: (1) C1q concentrations in peripheral and retroplacental sera were significantly decreased in PIH patients than that in normotensive controls, however, the concentrations of BF and C1-INH were significantly elevated in PIH patients. The changes in retroplacental serum were much more profound than those in peripheral serum. (2) The count of CEC was significantly increased in PIH patients than that in controls. (3) The count of CEC was negatively correlated to C1q concentration. CONCLUSIONS: Not only the classical complement activation pathway but also the alternative complement activation pathway and complement regulatory protein play important roles in the pathogenesis of PIH, and complement activation and vascular endothelial damage is correlated. Evaluation of C1q, BF, C1-INH and CEC may be of value in clinical monitoring and management of PIH.

Cell Count↗
PubMed1977

Identification of RNA as a complement inhibitory component in an extract of Ehrlich ascites tumor cells.

A factor capable of inhibiting complement was obtained from intact Ehrlich ascites tumor cells by mild extraction with phosphate-buffered saline (PBS). The inhibitor caused a decrease in extent of lysis of EAC14 with a concomitant extension of Tmax. EA, EAC1, EAC4 and EAC142 were all less susceptible to complement-mediated lysis after treatment with the tumor cell extract. Partial purification of a complement inhibitor was accomplished. The inhibitor was rich in RNA and its activity was totally destroyed by RNAase but not DNAase. RNA from mouse tissues, yeast, and Escherichia coli also inhibited complement hemolytic activity. The partially purified material only inhibited lysis of EAC1 and EAC14. Slow inhibition of fluid phase C1 was also demonstrated. In addition, RNA-rich partially purified tumor cell extract was capable of precipitating with purified human C1q.

Animals↗
PubMed1986

Study of the effect of high molecular weight kininogen upon the fluid-phase inactivation of kallikrein by C1 inhibitor.

Plasma kallikrein and factor XIa circulate bound to high molecular weight kininogen, and such binding has been reported to protect these enzymes from inactivation by their respective inhibitors. However, this observation is controversial, and the effect of high molecular weight kininogen upon the interaction between kallikrein and C1 inhibitor (C1-INH) has been questioned. We have re-evaluated this reaction and studied the rate of inhibition of kallikrein by C1-INH in the presence and absence of high molecular weight kininogen. The second-order rate constant of inhibition of kallikrein by C1-INH was unaffected by saturating concentrations of high molecular weight kininogen. Our results suggest that although high molecular weight kininogen clearly augments the rate of formation of kallikrein and other enzymes of the contact activation pathway, it has no effect on the rate of enzyme inhibition by C1-INH.

Complement C1 Inactivator Proteins↗
PubMed2000

[Hereditary angioneurotic edema in children].

Hereditary angioneurotic edema results from the deficiency of C1-esterase inhibitor. The clinical picture of this autosomal dominant disorder is characterized by recurrent attacks of edema formation in the subcutis and/or the submucosa. The clinical records of 21 children with established hereditary angioneurotic edema were reviewed. Follow-up care included laboratory check-ups and abdominal ultrasound. Clinical manifestations of the disease first occurred in 2.5 to 12 years of age. Mechanical trauma was the most common precipitating factor. Pedigree-analysis revealed 19 patients with afflicted relatives. Long-term prophylaxis was initiated with tranexamic acid and danazol in 10 cases; 2 children required short-term prophylaxis. Therapy improved serum complement parameters significantly and reduced the frequency and severity of clinical manifestations. Acute, life-threatening edematous attacks were treated by the administration of C1-inhibitor concentrate, which achieved the resolution of the edema within several hours. Abdominal ultrasonography performed during the attack invariably demonstrated transitory ascites that resolved spontaneously after treatment. Adequate prophylaxis and follow-up care can spare pediatric patients from edematous attacks. Undesirable adverse effects can be avoided and the patient's quality of life can be enhanced considerably by administering the lowest effective drug dose.

Adolescent↗
PubMedDate not supplied

[Hereditary angioedema due to C1-esterase inhibitor deficiency].

The paper presents a case of family oedema by shortage of C1-esterase inhibitor, characterized by appearance at an early age (8 months), participation in some attacks of nasal mucous membrane, with nasal obstruction and sinusal manifestations and also the abnormally long period, up to 9 days, of some localized oedemas. The crises were absent during pregnancy. The study of four generations of the family showed the predominantly hereditary character of the genetic transmission. Two cases in which the disease apparently "overleapt" a generation, as clinical manifestations, were presented.

Adult↗
PubMed1978

Determination of prekallikrein in human plasma: optimal conditions for activating prekallikrein.

A method for the assay of human plasma prekallikrein in which a chromogenic synthetic tripeptide, PPAN, is used as a substrate for kallikrein is described. The conversion of prekallikrein to kallikrein is achieved by cold activation (0 degrees C) with water-soluble dextran sulfate. Conditions for obtaining optimal amounts of free kallikrein with respect to concentration of dextran sulfate, activation time, inhibitors (C-1-inactivator), and requirement of factor XII have been determined. The activation procedure is compared to other known procedures. The assay system was worked out for pooled normal plasma and is applicable to any plasma sample not liable to unwanted preactivation or incomplete inactivation, as revealed by control experiments. A survey in 15 apparently health individuals showed a mean activity of 476 +/- 58 (S.D.) mU/ml with a range of 385 to 586 mU/ml.

Acetone↗
PubMed1995

Protection of retroviral vector particles in human blood through complement inhibition.

The rapid inactivation of murine-derived retroviral vectors in human or nonhuman primate sera is largely attributed to the activity of complement mediated through the classical pathway. In this study, we have further investigated the relationship between the human complement cascade and retrovirus inactivation. Preincubation in normal human serum effectively inactivated LXSN retroviral vector particles, whereas the vector maintained the ability to transduce cells following incubation in sera deficient in either the C1, C2, C3, C5, C6, C8, or C9 human complement proteins. Preincubation of serum with monoclonal antibodies (mAbs) that functionally block specific complement components, including C5, C6, C8, and C9, successfully protected the LXSN vector from complement-mediated inactivation. Treatment of serum with cobra venom factor, which consumes terminal complement, also effectively protected the vector from inactivation. LXSN vector survival in serum corresponded inversely to the level of complement activity following treatment of serum with anti-C5 mAb as assessed in an erythrocyte hemolytic assay. Additionally, pretreatment of human whole blood with anti-C5 mAb effectively inhibited inactivation of the LXSN vector. Taken together, these data demonstrate that formation of the membrane attack complex (MAC, C5b-9) is required for the inactivation of the murine-based LXSN retroviral vector in human blood and that this process can be abrogated with the use of soluble complement inhibitors.

3T3 Cells↗
PubMed1987

Effect of aprotinin and C1-esterase inhibitor on activation of the plasma kallikrein-kinin system in vivo.

Infusion of dextran sulfate in pigs rapidly activates the intrinsic cascade of the coagulation system including plasma prokallikrein and leads to release of kinin by limited proteolysis of kininogen. In this model, strong suppression of the DXS-induced activation of the plasma kallikrein-kinin system is seen at plasma aprotinin levels above 400 KIU/ml and C1INH levels above 4 U/ml.

Animals↗
PubMedDate not supplied

Epsilon-amino-caproic acid in the treatment of Osler's hereditary angioneurotic edema.

This clinical entity described for the first time by Osler in 1888 presented a great therapeutic problem during many decades because of its severity. Landerman and later on Donaldson and Evans established the pathogenic mechanisms of this disease finding a deficiency in the inhibitor of the first activated component of complement, an alpha 2 aminoglycoprotein, to be the mechanism responsible of the same. More concretely, alterations in the plasmin, kinin and kallikrein systems are those that will lead to a change in vascular permeability with resultant tissue alterations. Four cases of hereditary angioneurotic edema are studied in female patients aged between 15 and 50 years and with family history consistent with angioneurotic familiar edema in which there were six cases of death due to edema of the glottis. Once the diagnosis had been made the patients were subjected to treatment with EACA at doses of 2.5 gm every 6 hours. The determinations of complement were similar in the four cases, with marked decreases in C4 and C1 inhibitor with a decrease in total complement in three cases. Regarding secondary effects, vomiting was found only in one cases, which as the dose was reduced did not necessitate termination of treatment. In summary, considering the results obtained in the cases above, we believe that due to its good tolerance and moderate cost, epsilon-amino-caproic acid at the abovementioned dosage is an excellent pharmacological agent in the treatment of Osler's hereditary angioneurotic edema.

Adolescent↗
PubMed2006

Haploinsufficiency due to deletion within the 3'-UTR of C1-INH-gene associated with hereditary angioedema.

PURPOSE: Sequences within the non-coding 3'UTR (untranslated region) of genes were reported to be involved in the regulation of gene expression by modifying pathways of (co)transcription, post-transcriptional processing and RNA transport. However, direct biological evidence (i.e., knock-out models) is sparse. This report intends to correlate the first reported alteration within the 3'UTR of the C1 inhibitor (C1-INH) gene with clinical presentation of hereditary angioedema (HAE). METHODS AND RESULTS: Direct sequencing of genomic DNA revealed in all affected members of a family suffering from HAE a heterozygous 155 bp deletion 100 bp downstream of the physiological stop-codon in exon 8. A substantial reduction of both mRNA as well as C1-INH protein expression was revealed by RT-PCR and nephelometry, respectively. CONCLUSION: We suppose that the mutation within the 3'UTR interferes with integral pathways of gene expression leading to pathogenic haploinsufficiency in this family.

3' Untranslated Regions↗