Treatment of Hereditary Angioedema With Plasma‐Derived C1 Inhibitor: A Review

8. Hereditary angioedema

C1 esterase inhibitor deficiency, airway compromise, and anesthesia.

In the vast majority of patients with hereditary angioedema (HAE), angioedema attacks are due to the quantitative or functional deficiency of C1-esterase inhibitor (C1-INH), which leads to increased vascular permeability and unregulated release of bradykinin. Exogenous administration of C1-INH is a rational way to restore the concentration and functional activity of this protein, regulate the release of bradykinin, and attenuate or prevent subcutaneous and submucosal edema associated with HAE. Recent international guidelines for the management of HAE include C1-INH as an option for acute treatment of HAE. In addition, these guidelines recommend C1-INH as first-line treatment for long-term prophylaxis and as the therapy of choice for short-term/preprocedural prophylaxis. Several C1-INH products are available, with approved indications varying across regions. For the acute treatment of HAE, both plasma-derived and recombinant C1-INH formulations have been shown to be effective and well tolerated in adolescents and adults with HAE, with onset of relief within 30 min to a few hours. Plasma-derived C1-INH is approved for use in children, and recombinant C1-INH is being evaluated in this population. Intravenous (IV) and subcutaneous (SC) formulations of C1-INH have been approved for routine prophylaxis to prevent HAE attacks in adolescents and adults. Both formulations when administered twice weekly have been shown to reduce the frequency and severity of HAE attacks. The SC formulation of C1-INH obviates the need for repeated venous access and may facilitate self-administration of HAE prophylaxis at home, as recommended in HAE treatment guidelines. As with most rare diseases, the costs of HAE treatment are high; however, the development of additional acute and prophylactic medications for HAE may result in competitive pricing and help drive down the costs of HAE treatment.

US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency

This article was originally published online on 8 April 2015BackgroundThe aim of this study was to show the clinical characteristics and treatment of Hereditary Angioedema (HAE) in a tertiary center from Curitiba, south of Brazil.MethodsA cross-sectional study reviewing records of patients in the Hospital de Clínicas, Federal University of Paraná. We analised the clinical characteristics, laboratory tests and treatment of patients with HAE.ResultsForty two patients, male (45%), age mean 27.1±16.9 years. Symptoms started at median age 14 years (range 1 to 58ys.). Thirty seven (86%) had familial history of HAE. They had a median of 2 episodes/mo (range 0.2 to 30) lasting 3±1.7 days/episode. Edema of limbs, face, genital and laryngeal, abdominal pain, diarrhea and vomiting were seen in 73.8%, 52.4%, 23.8%, 17%, 81%, 24% and 38.1%, respectively. Twenty four (57%) had low C4 level, mean serum level of C4=12.7±10.6 mg/dL; 26 (62%) had low levels of C1 esterase inhibitor, 4 (9.5%) had low functional C1 esterase inhibitor and 12 (28.6%) had C1q deficiency and 3 (7.1%) had HAE type III confirmed. Fifteen (28.9%) were treated with Danazol 175±134 mg/day, 15 (28.9%) were using tranexamic acid as needed. No patient had Icatibant access.ConclusionsHAE is a difficult to control disease. Patients needs to have a facilitated access to newer therapies to control their symptoms and reduce the adverse events of Danazol. This article was originally published online on 8 April 2015 BackgroundThe aim of this study was to show the clinical characteristics and treatment of Hereditary Angioedema (HAE) in a tertiary center from Curitiba, south of Brazil. The aim of this study was to show the clinical characteristics and treatment of Hereditary Angioedema (HAE) in a tertiary center from Curitiba, south of Brazil. MethodsA cross-sectional study reviewing records of patients in the Hospital de Clínicas, Federal University of Paraná. We analised the clinical characteristics, laboratory tests and treatment of patients with HAE. A cross-sectional study reviewing records of patients in the Hospital de Clínicas, Federal University of Paraná. We analised the clinical characteristics, laboratory tests and treatment of patients with HAE. ResultsForty two patients, male (45%), age mean 27.1±16.9 years. Symptoms started at median age 14 years (range 1 to 58ys.). Thirty seven (86%) had familial history of HAE. They had a median of 2 episodes/mo (range 0.2 to 30) lasting 3±1.7 days/episode. Edema of limbs, face, genital and laryngeal, abdominal pain, diarrhea and vomiting were seen in 73.8%, 52.4%, 23.8%, 17%, 81%, 24% and 38.1%, respectively. Twenty four (57%) had low C4 level, mean serum level of C4=12.7±10.6 mg/dL; 26 (62%) had low levels of C1 esterase inhibitor, 4 (9.5%) had low functional C1 esterase inhibitor and 12 (28.6%) had C1q deficiency and 3 (7.1%) had HAE type III confirmed. Fifteen (28.9%) were treated with Danazol 175±134 mg/day, 15 (28.9%) were using tranexamic acid as needed. No patient had Icatibant access. Forty two patients, male (45%), age mean 27.1±16.9 years. Symptoms started at median age 14 years (range 1 to 58ys.). Thirty seven (86%) had familial history of HAE. They had a median of 2 episodes/mo (range 0.2 to 30) lasting 3±1.7 days/episode. Edema of limbs, face, genital and laryngeal, abdominal pain, diarrhea and vomiting were seen in 73.8%, 52.4%, 23.8%, 17%, 81%, 24% and 38.1%, respectively. Twenty four (57%) had low C4 level, mean serum level of C4=12.7±10.6 mg/dL; 26 (62%) had low levels of C1 esterase inhibitor, 4 (9.5%) had low functional C1 esterase inhibitor and 12 (28.6%) had C1q deficiency and 3 (7.1%) had HAE type III confirmed. Fifteen (28.9%) were treated with Danazol 175±134 mg/day, 15 (28.9%) were using tranexamic acid as needed. No patient had Icatibant access. ConclusionsHAE is a difficult to control disease. Patients needs to have a facilitated access to newer therapies to control their symptoms and reduce the adverse events of Danazol. HAE is a difficult to control disease. Patients needs to have a facilitated access to newer therapies to control their symptoms and reduce the adverse events of Danazol.

Rituximab-induced Elimination of Acquired Angioedema Due to C1-Inhibitor Deficiency

A case of normal C1 esterase inhibitor hereditary angioedema successfully treated with berotralstat

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

C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded beta-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack.

Successful Management of Hereditary Angioedema (HAE) and Thrombophilia during Pregnancy: A Case Study

Paternal mosaicism and hereditary angioedema in a Taiwanese family

Hereditary angioedema (HAE) is a rare disease caused by deficiency of C1 esterase inhibitor (C1-INH). It is an autosomal dominant disease caused by a variety of mutations in the C1-INH gene. C1-INH is an important regulator of several pathways. One pathway it affects is the kallikrein–kinin pathway, which results in the generation of bradykinin. Bradykinin is an important mediator of edema. Diagnosis is based on low levels of C1-INH. HAE with normal C1-INH is also recognized in the literature and the pathophysiology is due to another aspect of the pathway being affected leading to increased bradykinin level. Bradykinin results in intermittent swelling of the cutaneous and mucosal surfaces. The swelling usually evolves over several hours and lasts a few days. Location of the swelling can involve any part of the body including fatal laryngeal edema. Newer treatments exist to treat acute attacks and reduce the frequency of future attacks. Earlier diagnosis and treatment of hereditary angioedema can prevent HAE-associated mortality. Statement of novelty: New treatments are used to treat these attacks. These treatments are aimed at patients having a more normal life with hereditary angioedema.

Hereditary angioedema (HAE) is a clinical disorder characterized by a deficiency of C1 esterase inhibitor (C1-INH). HAE has traditionally been divided into two subtypes. Unique among the inherited deficiencies of the complement system, HAE Types I and II are inherited as an autosomal dominant disorder. The generation of an HAE attack is caused by the depletion and/or consumption of C1-inhibitor manifested as subcutaneous or submucosal edema of the upper airway, face, extremities, or gastrointestinal tract. Attacks can be severe and potentially life-threatening, particularly with laryngeal involvement. Despite the availability of C1-INH for the treatment of HAE since the 1980s in Europe and other countries, HAE treatment in the United States was limited to androgen therapy. The human plasma-derived C1 esterase inhibitor (Cinryze™), distributed by Lev Pharmaceuticals, was approved in October 2008 for the prevention of HAE attacks based on the results of a phase III clinical trial. This review aims to describe the history of C1-INH replacement in HAE as well as the pharmacology, efficacy and safety of C1-INH, concentrating on Cinryze as the first approved chronic replacement treatment for the prophylaxis of HAE attacks.

Hereditary angioedema: An orphan but an original disease?

Background: Hereditary angioedema (HAE), caused by absolute or functional deficiency of C1-esterase inhibitor (C1-INH), is characterized by recurrent, disfiguring, and potentially life-threatening attacks of subcutaneous and submucosal edema. The mean age of first attack is 10 years and earlier onset may be predictive of a more severe disease course. HAE treatment guidelines recommend on-demand (acute) therapy as standard of care for all HAE patients and prophylaxis for those with frequent and/or more disabling attacks, as well as those with inadequate response to on-demand therapy. This phase 3 trial compared twice-weekly prophylaxis …