Biochemical and Functional Characterization of Plasma Derived Human Celestrase 1

C1 esterase inhibitor deficiency, airway compromise, and anesthesia.

Hereditary angioedema (HAE), a rare autosomal dominant genetic disorder, is caused by a deficiency in functional C1 esterase inhibitor (C1-INH). This potentially life-threatening condition manifests as recurrent attacks of subcutaneous and submucosal swelling of the skin, gastrointestinal tract and larynx. The management of HAE includes treatment of acute episodes, short-term prophylaxis in preparation for exposure to known triggers and long-term prophylaxis to decrease the incidence and severity of HAE attacks. Four products are approved in the USA for the treatment of acute attacks of HAE, including one human plasma-derived C1-INH therapy, a recombinant human C1-INH product (rhC1-INH), a plasma kallikrein inhibitor and a bradykinin B2 receptor antagonist. In addition, one human plasma-derived C1-INH therapy and danazol are approved for prophylaxis of HAE attacks. rhC1-INH, extracted from the milk of transgenic rabbits, is a glycoprotein of 478 amino acids with an identical amino acid sequence to the endogenous human C1-INH protein. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U). The safety and efficacy of rhC1-INH in the treatment of acute attacks in patients with HAE were demonstrated in three randomized, double-blind, placebo-controlled studies and two open-label extension studies. In a pilot prophylaxis study, weekly administration of rhC1-INH 50 U/kg for 8 weeks reduced the incidence of HAE attacks and was well tolerated. Administration of rhC1-INH has not been associated with the development of anti-drug antibodies or antibodies to anti-host-related impurities.

An assessment of C1 inhibitor (C1-INH) functional assay ordering patterns

Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.

Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE. To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE. We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021. We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks. We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome. We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE. The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs.

Thromboembolic events associated with human plasma-derived C1 esterase inhibitor (C1-INH) use in patients with hereditary angioedema (HAE) have been reported in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database. The purpose of this article is to review and assess the strength of available evidence regarding the thrombogenicity of human plasma-derived C1-INH. A PubMed search was conducted of English language articles from January 1990 to December 2013 reporting the thrombogenicity of C1-INH. Original research articles were selected if the following criteria were met: (1) C1-INH was the focus of the study and (2) the authors addressed the pro- or antithrombotic potential of C1-INH. Additional articles on the clinical use of C1-INH in disease states other than HAE were obtained using reference lists of selected articles. Pivotal studies and prescribing information for C1-INH products were also reviewed. Limited animal and clinical data suggest that C1-INH, particularly at high doses of up to 500 U/kg (compared with the U.S. FDA-approved 20-U/kg dose), may be prothrombotic. In contrast, C1-INH has been used in some patients with myocardial infarction, ischemic stroke, sepsis, and capillary leak syndrome at off-label supratherapeutic doses (up to 100 U/kg) without evidence of a thrombogenic effect. Based on our review, thromboembolic events reported with C1-INH use are rare and patients with HAE who experienced such events often have underlying thromboembolic risk factors.

Despite its relatively common occurrence and life-threatening potential, the management of angioedema in the emergency department (ED) is lacking in terms of a structured approach. It is paramount to distinguish the different etiologies of angioedema from one another and more specifically differentiate histaminergic-mediated angioedema from bradykinin-mediated angioedema, especially in lieu of the more novel treatments that have recently become available for bradykinin-mediated angioedema. With this background in mind, this consensus parameter for the evaluation and management of angioedema attempts to provide a working framework for emergency physicians (EPs) in approaching the patient with angioedema in terms of diagnosis and management in the ED. This consensus parameter was developed from a collaborative effort among a group of EPs and leading allergists with expertise in angioedema. After rigorous debate, review of the literature, and expert opinion, the following consensus guideline document was created. The document has been endorsed by the American College of Allergy, Asthma & Immunology (ACAAI) and the Society for Academic Emergency Medicine (SAEM).

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

Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH), and icatibant in the treatment of acute angioedema attacks in adults with HAE. A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH, and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE, and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate OR synonyms OR icatibant). Only randomized clinical studies were selected. Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH, and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo. Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

Supra-Physiological Concentrations of C1 Esterase Inhibitor Enhance Thrombin Generation in the Presence of Thrombomodulin

Human C1-esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein best known for its key role in regulation of the classical complement pathway, contact activation system and intrinsic pathway of coagulation. By sequence homology and mechanism of protease inhibition it belongs to the serine proteinase inhibitor (serpin) superfamily. However, in addition to its inhibitory capacities for several proteases, it also exhibits a broad spectrum of non-inhibitory biological activities. C1-INH plays a key role in the regulation of vascular permeability, best demonstrated in Hereditary Angioedema (HAE) which is triggered by the deficiency of functional C1-INH in plasma? Since 1963, when the link between HAE and C1-INH was first identified, considerable progress has been made in the investigation of C1-INH structure and biological activities, understanding its therapeutic potential, and in the research and development of C1-INH-based therapies for the treatment of HAE and several other clinical conditions. However, augmentation therapy with C1-INH concentrates for patients with HAE is currently the only approved therapeutic application of C1-INH. This manuscript provides an overview of the structure and functions of human C1-INH, its role in HAE, summarizes published data available for recently approved C1-INH therapeutic products, and considers possible use of C1-INH for other applications.

8. Hereditary angioedema

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by quantitative (type I) or functional (type II) deficiency in C1 esterase inhibitor (C1-INH). It may be caused by new mutations in up to 20% of patients. Prevalence of HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons, without known differences among ethnic groups. C1-INH protein is a serine protease inhibitor that is important in controlling vascular permeability by acting on the initial phase of the complement activation, blood clotting, and fibrinolysis. Deficiency in functional C1-INH protein permits release of bradykinin, a key mediator of vascular permeability. Symptoms typically begin since childhood, worsening at puberty, and persist throughout the life, with unpredictable clinical course. The patients with HAE suffer from recurrent, acute attacks of edema that can affect any body sites, causing potentially life-threatening disorders (laryngeal edema). Results of clinical studies show that minor traumas, stress and medical interventions may be frequent precipitants of swelling episodes, but many attacks occur without an apparent cause. Pregnancy-associated hormonal changes may affect the course of C1-INH angioedema attacks by worsening, improving, or having no impact at all, but a higher percentage of pregnant women experienced an increase in C1-INH-HAE attack rates. Therapeutic options for patients with HAE are limited during pregnancy. C1-INH concentrate is recommended as the first-line therapy for pregnant women with HAE for on-demand treatment, shortterm and long-term prophylaxis, due to its safety and efficiency. Other therapies, e.g., treatment with fresh frozen plasma, androgens, icatibant, antifibrinolytics, may show variable efficacy, or cause undesirable side effects. The case below illustrates the successful treatment of HAE in a pregnant woman with C1 esterase inhibitor (C1-INH) concentrate. This patient had a very mild course of HAE during her lifetime and didn’t get any treatment. During pregnancy, she experienced a significant increase in the frequency of attacks, and the decision was made to start replacement therapy with a plasma-derived, double virus-inactivated C1-INH concentrate as a long-term prophylaxis throughout the full term of her pregnancy, before, during and after the cesarean section delivery.