C1 Esterase Inhibitor Deficiency Research Articles

Increased Activity of Coagulation Factor XII (Hageman Factor) Causes Hereditary Angioedema Type III

Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema. Three forms of HAE have been described. The classic forms, HAE types I and II, occur as a consequence of mutations in the C1-inhibitor gene. In contrast to HAE types I and II, HAE type III has been observed exclusively in women, where it appears to be correlated with conditions of high estrogen levels--for example, pregnancy or the use of oral contraceptives. A recent report proposed two missense mutations (c.1032C-->A and c.1032C-->G) in F12, the gene encoding human coagulation factor XII (FXII, or Hageman factor) as a possible cause of HAE type III. Here, we report the occurrence of the c.1032C-->A (p.Thr328Lys) mutation in an HAE type III-affected family of French origin. Investigation of the F12 gene in a large German family did not reveal a coding mutation. Haplotype analysis with use of microsatellite markers is compatible with locus heterogeneity in HAE type III. To shed more light on the pathogenic relevance of the HAE type III-associated p.Thr328Lys mutation, we compared FXII activity and plasma levels in patients carrying the mutation with that of healthy control individuals. Our data strongly suggest that p.Thr328Lys is a gain-of-function mutation that markedly increases FXII amidolytic activity but that does not alter FXII plasma levels. We conclude that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema. Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected with HAE type III. The results of our study represent an important step toward an understanding of the molecular processes involved in HAE type III and provide diagnostic and possibly new therapeutic opportunities.

Acquired C1 esterase inhibitor deficiency: an atypical first presentation intra‐operatively

We report a case of airway difficulties encountered as a result of blistering, oedema and bleeding from the oropharyngeal mucosa of an 85-year-old female undergoing an elective excision of a submandibular neck lump. This led to a delay in extubation by several hours. The patient was subsequently found to have an acquired form of C1 esterase inhibitor deficiency considered to be consequent of haematological malignancy.

Pregnancy and C1 esterase inhibitor deficiency: a successful outcome

Hereditary angioedema is a potentially life-threatening condition which can complicate pregnancy. A 34-year-old patient with known C1 esterase inhibitor (C1INH) deficiency was managed successfully in our department and her management was a part of a shared care strategy with the medical and anesthetic departments. Peripartum management plans along with an anesthetic plan were drawn up and clearly displayed in her records. She was admitted three times with abdominal pain which were self-limiting before she was admitted at term. An aggressive management strategy with C1INH concentrate facilitated a normal vaginal delivery.

C1-Esterase Inhibitor Deficiency and Elective Caesarean Section

C1-Esterase Inhibitor Deficiency and Elective Caesarean Section

Two Virus Reduction Steps Are Inherent in the Manufacturing Process of Berinert P, a C1-Esterase-Inhibitor Concentrate.

The clinical picture of hereditary angio-edema (HAE) is characterized by acute attacks of circumscribed swellings of the skin and sub-mucosa which recur after symptomless intervals of days to years. Episodes of swelling may involve the upper respiratory tract, including the tongue, pharynx, and larynx. This contributes to the mortality of up to 30% (or more in some families) due to suffocation as complication of laryngeal edema. This increased vascular permeability and massive local uncontrolled edema is most probably caused by uncontrolled activation of the complement system and by increased formation of bradykinin and C2 kinin due to deficiency or complete absence of C1-esterase inhibitor (C1-INH). The first line therapy for treatment of an acute attack and for short-term prophylaxis is intravenous administration of a plasma-derived C1-INH concentrate (where licensed). Such a C1-INH product is Berinert® P, licensed in e.g., Germany, Switzerland, France, and Japan. As, in general, plasma-derived products may potentially transmit viruses, special care is taken to minimize this risk by careful selection of plasma collection centers and donors. Furthermore, each donation is tested thoroughly for the absence of hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency viruses (HIV), and high titers of parvovirus B19 (B19V) by serological and/or NAT/PCR methods. In addition, the plasma pool for fractionation is tested and only released for further processing if the pool is non-reactive (negative) for HBsAg and non-reactive for antibodies against HCV and HIV-1/-2 as well as non-reactive for genomic sequences of HAV, HBV, HCV, HIV-1, and high titers of B19V (not exceeding 105 IU/ml). Selecting and testing the starting material for absence of blood borne viruses is a very important prerequisite to the production of the C1-INH concentrate; however, the manufacturing process of this product with its inherent capacity to inactivate and/or remove potentially present viruses in the plasma pool for fractionation complements the effort for a final product with a high margin of safety with regard to viruses. Two manufacturing steps - pasteurization (heat treatment of stabilized aqueous solution at 60°C for 10 hours) and hydrophobic interaction chromatography (HIC) - were validated for their capacity to inactivate and/or remove viruses. In these laboratory studies, the relevant blood borne viruses or specific and non-specific model viruses were employed: HIV and HAV as viruses of risk, bovine viral diarrhea virus (BVDV) as model virus for HCV and related viruses as West Nile virus (WNV), and canine parvovirus (CPV) as model virus for parvovirus B19 (B19V) demonstrating a very effective reduction of the infectivity by both manufacturing steps independently. Based on these virus validation studies it is evident that two complementary virus reduction steps are inherent in the manufacturing process of Berinert® P.Mean overall virus reduction factors for Berinert® PVirusVirus Reduction by Two Manufacturing Steps [log10]HI ChromatographyPasteurizationOverall Virus ReductionHIV≥ 4.5≥ 6.6≥ 11.1BVDV≥ 5.1≥ 9.2≥ 14.3PRV≥ 6.76.6≥ 13.3HAV≥ 3.3≥6.4≥9.7CPV6.71.48.1Furthermore, investigational studies demonstrate (i) an effective inactivation of B19V by pasteurization resulting in a virus reduction factor of ≥ 4.3 log10 and (ii) the removal of two different prion preparations by a single manufacturing step (microsomes and purified PrPSc by 3.1 log10 and 3.2 log10, respectively). Therefore, a high safety margin for pathogens can be attributed to Berinert® P.

A Variant in XPNPEP2 Is Associated with Angioedema Induced by Angiotensin I–Converting Enzyme Inhibitors

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

Angioedema in a patient with C1 esterase inhibitor deficiency.

Angioedema is characterized by recurrent, circumscribed, solitary or multiple subcutaneous and mucosal swelling, involving the extremities, face, larynx, bowel wall. Angioedema is due to hereditary or acquired varieties of C1 esterase inhibitor (C1INH) deficiency.A case of atypical acquired angioedema in a 49-year old man, responding favourably to cinnarizine and alcohol abstinence, is presented in this article. Cinnarizine was prescribed due to presumed alcoholic liver disease. The clinical significant amelioration was not associated with concomitant good laboratory result, which is a relatively common occurrence.

C 1-esterase inhibitor deficiency and elective caesarean section

C1-esterase inhibitor deficiency is a rare disorder of the complement system characterised by episodes of cutaneous and mucosal oedema. Life-threatening airway oedema can follow airway instrumentation or minor trauma. We describe the successful management of a 37-year-old primiparous woman with inherited C1-esterase inhibitor deficiency who was admitted at 38 weeks' gestation for elective caesarean section. Whilst undergoing general anaesthesia 18 months previously she had experienced facial and pharyngeal oedema despite prophylaxis (one unit of fresh frozen plasma). On this occasion she underwent elective caesarean section following intrathecal anaesthesia with 0.5% hyperbaric bupivacaine 2 mL and diamorphine 300 microg. Cardiovascular stability was ensured using glycopyrolate and intravenous Hartmann's solution 2 L; a live female infant was delivered successfully. There were no peri- or postoperative complications. Regional anaesthesia is the safest method for providing surgical anaesthesia in the obstetric patient. We believe elective caesarean section under regional anaesthesia should be considered if there are predicted difficulties with vaginal delivery.

General and subarachnoid anaesthesia in a patient with acquired C1 esterase inhibitor deficiency

General and subarachnoid anaesthesia in a patient with acquired C1 esterase inhibitor deficiency

Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence?

Hereditary angioedema (HAE) is caused by a deficiency in C1 esterase-inhibitor (C1-INH) and is characterised by skin swelling, abdominal pain and episodes of upper respiratory tract obstruction. Oedema of the larynx can result in rapid asphyxiation and requires emergency treatment. Three treatment options for emergency treatment of HAE are reviewed: fresh frozen plasma, solvent/detergent-treated plasma and C1-INH concentrate. It is concluded that while all three treatment options are theoretically effective in the emergency treatment of HAE, C1-INH is the treatment of choice.

Angioödeme bei familiärem Mangel von Komplement-Faktor-1-Esterase-Inhibitor und α1-Antitrypsin

A 15-year-old girl had suffered from episodic, sometimes threatening angioedema of the face, nasopharyngeal space and distal extremities beginning at age 13. A C1-esterase inhibitor (C1-INH) deficiency was revealed protein-chemically and functionally. There was also an alpha (1)-antitrypsin (AAT) deficiency with heterocygotic phenotype PiMZ. The combination of C1-INH and AAT deficiency was also found in the patient's mother and brother. Under 8-month therapy with 200 mg/d danazol per os (reduction of the dosis in the last month to 100 mg/d), there was no further edema, the C1-INH concentration normalized and there was also an increase in C1-INH function. During the observation period, use of the emergency set with C1-INH concentrate was not required. This is the first reported case of angioedema in combination of two hereditary enzyme defects C1-INH deficiency (autosomal-dominant genetics) and AAT deficiency (autosomal-recessive). In addition to a survey of current literature, the current state of diagnostics and therapy of the hereditary angioedema is presented.

Hereditary angioneurotic edema of the larynx

Hereditary angioneurotic edema (HAE) is an autosomal dominant disease resulting from a deficiency of functional C1-esterase inhibitor. If not recognized promptly and treated properly the disease can result in a fatal outcome as it causes laryngeal edema, which can lead to a life-threatening acute upper airway obstruction. We present the case of a 37-year-old female with HAE of the larynx, who was diagnosed early and treated properly, together with a review of the literature.

Inhibitor of Human Plasma Kallikrein DX-88 for the Treatment of Acute Attack in a Family with Hereditary Angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disorder that results in a deficiency of C1 esterase inhibitor (C1-INH), with a 1/10,000 to 1/50,000 prevalence worldwide (Nzeako 2001). Affected individuals manifest with recurrent attacks of intense, massive, localized non-pitting edema, without an allergic component, responding poorly to epinephrine and steroids. Prophylaxis include antifibrinolytic or androgens. A worrisome potentially fatal complication is laryngeal edema, which currently has no abortive therapy available.C1-INH is a serine protease inhibitor that also regulates kinin generation. Angioedema results from uncontrolled activation of the classical complement pathway generating vasoactive peptide or contact system activation release of bradykinin from high molecular weight kininogen. Knockout mouse data supports the role of bradykinin for the edema generation. However, other mediators may be involved. C1-INH gene disruption in mice showed increased vascular permability, which was reversed by intravenous C1-INH, bradykinin, and plasma kallikrein inhibitor (Hun 2002). Therefore, DX-88 (Dyax Corporation), a recombinant polypeptide inhibitor of plasma kallikrein, was used as an abortive agent for the treatment of acute attacks in HAE. We describe our institution's experience in treating an HAE family, affected father with his two affected daughters, with DX-88 in a jointly conducted adult and pediatric hematology clinical trial. EDEMA I is an ascending four dose placebo controlled study to assess the efficacy and tolerability of DX-88 for acute attacks of HAE. Patients presented for treatment within 4 hours of a moderately severe acute attack and were observed for 8 hours. All three presented with abdominal attacks. The first daughter, on Oxandrin prophylaxis, presented with cramping, gnawing abdominal pain, associated nausea and rash. Subjective resolution of nausea, cramping and rash occured within 1 hour of treatment. The abdominal distention had partial resolution with continuing response up to 8 hours.The second daughter had more severe recurrent symptoms associated with her menses. She used imported C1-INH concentrate for acute attacks. She presented with mid to upper abdominal cramping and nausea. She had no resolution of symptoms with treatment. Her abdominal attack of 10/10 pain increased with nausea. She subsequent developed erythema marginatum.. The study was stopped 4 hours post dose. She was admitted for narcotic pain medication for symptomatic relief. The father, on Oxandrin prophylaxis, presented with abdominal attack, left hand and scrotal edema, and extensive erythema marginatum; reticular rash over the neck, back, arms, and shoulder. The attacks improved within 1 hour of treatment with significant resolution within 2 hours. The rash and abdominal symptoms resolved completely. The left hand and scrotal edema had partial resolution typical of his disease course, with continuing response up to 8 hours.HAE families have debilitating acute attacks despite prophylaxis. Replacement therapy with C1-INH concentrate is not commercially available in the United States. We treated an HAE family with DX-88 for acute attacks. Two had responses and the non responder was a potential placebo. The treatment was well tolerated. Longer follow up for safety and efficacy with ideal drug dosing are needed. Trial results are currently being analyzed. DX-88 is a promising, non plasma based, treatment for acute attacks of patients with HAE.

Correction of recurrent angioedema related to C1 esterase inhibitor deficiency as a secondary event following nonmyeloablative allogeneic stem cell transplantation in a patient with myelofibrosis

Correction of recurrent angioedema related to C1 esterase inhibitor deficiency as a secondary event following nonmyeloablative allogeneic stem cell transplantation in a patient with myelofibrosis

Angioedema hereditário: considerações sobre terapia

Hereditary Angioedema was first described by William Osler in 1888 and it is caused by a hereditary or acquired deficiency of C1 esterase inhibitor (C1-INH). Treatment is indicated for acute attacks or prophylaxis of angioedema which occur in the subcutaneous tissue respiratory or gastrointestinal tracts. Treatment includes attenuated androgens, inhibitors of kininogen or plasminogen, like tranexamic acid or e-aminocaproic acid and the administration of C1-INH concentrate. We describe the peculiarities of the treatment chosen for 10 patients (4 families) with HAE and their evolution. Ten patients (1-38 years old) with HAE were diagnosed by clinical history and laboratory evaluation. The following tests were performed for the complement system: C1-INH, C4 and C3 levels and hemolytic assay (CH50 and APH50) for the classic and alternative pathways. Treatment was initiated considering severity of symptoms, age, gender and therapeutic response of the patient. Clinical evaluation showed: 4/10 patients with recurrent subcutaneous edema; 3/10 with previous laryngeal edema and 3/10 with sporadic symptoms. Different severity of symptoms was verified in the same family. The laboratory evaluation detected: low C1-INH levels (10/10); low serum C4 level (8/10); undetectable CH50 (3/10) and low CH50 levels (6/10); low APH50 levels (2/10). Six out of ten patients did not receive any specific treatment and 2 of them had high risk of asphyxia. One adolescent had been controlled with e-aminocaproic acid, one child had been changed from danazol to tranexamic acid, a 30 year old female patient had received oxandrolone and a 38 year old man had been treated with danazol. Although HAE is caused by the same defect and affects members of the same family, various approaches have been taken to treat these patients. We observed different alternatives of prophylactic therapy for HAE, of which some did not require drug therapy.

Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond

Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Metabolic alteration of the N-glycan structure of a protein from patients with a heterozygous protein deficiency

Glycosylation, an important post-translation modification, could alter biological activity or influence the clearance rates of glycoproteins. We report here the first example of a heterozygous protein deficiency leading to metabolic alteration of N-glycan structures in residual secreted protein. Analysis of C1 esterase inhibitor (C1INH) glycans from normal individuals and patients with hereditary deficiency of C1INH demonstrated identical O-glycan structures but the N-glycans of patients with a heterozygous genetic deficiency were small, highly charged and lacked sialidase releasable N-acetylneuraminic acid. Structural studies indicate that the charge character of these aberrant N-glycan structures may result from the presence of mannose-6-phosphate residues. These residues might facilitate secretion of C1INH through an alternate lysosomal pathway, possibly serving as a compensatory mechanism to enhance plasma levels of C1INH in these deficient patients.

Acute Upper Airway Angioedema Secondary to Acquired C1 Esterase Inhibitor Deficiency

Survey of Anesthesiology: April 2004 - Volume 48 - Issue 2 - p 93-94 doi: 10.1097/01.sa.0000119073.92230.3c

Management of hereditary angioedema: a Canadian approach

C1 esterase inhibitor (C1-INH) deficiency is a rare disorder that lacks consensus for diagnosis therapy and management. Recognizing that Canada is behind the European approach to this disorder, we have formed the Canadian Hereditary Angioedema Society (CHAES)/Société d’angioédème héréditaire du Canada (SAHC) to foster knowledge of this disorder in Canada and to advance care of patients with this disorder in Canada. We here present a review of treatment of this disorder in Canada including prevention of angioedema events and use of replacement therapy and present an algorithm for diagnosis therapy and management of C1-INH deficiency in Canada for discussion at our International Conference on Hereditary Angioedema to be held in Toronto, Canada, October 24th to 26th, 2003.

DX-88 and HAE: a developmental perspective

An example of an approach to the developmental philosophy of novel recombinant products is explored by using the exemplar of Hereditary Angioedema (HAE). Plasma kallikrein is believed to be an important mediator of angioedema in patients with genetic deficiency of C1 esterase inhibitor (HAE patients). DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein which in early clinical studies demonstrates a useful efficacy/safety ratio in the treatment of acute attacks of HAE.