C1 Esterase Inhibitor Concentrate Research Articles

Interventions for the long-term prevention of hereditary angioedema attacks.

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.

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

Introduction. Human C1-esterase inhibitor (C1INH) is a multifunctional plasma glycoprotein with a broad spectrum biological activities, best known for its role in regulation of the classical complement pathway, contact activation system and its essential roles in the coagulation and fibrinolytic cascades [1,2]. The main targets of C1INH are C1 esterase, Factors XIa and XIIa, kallikrein, thrombin and plasmin. Low levels of functional C1INH in plasma are considered to be the primary cause for hereditary angioedema (HAE) with symptoms of swelling in the face, throat, hands, feet and abdomen. HAE patients receive replacement therapy with plasma-derived C1INH products recently licensed in the US and EU for prophylactic and acute treatment of HAE [1]. Studies suggest that supra-physiological doses of C1INH can promote thrombotic events.. To date the use of C1INH at plasma concentrations exceeding normal have been proposed in a range of disease states including renal transplant, myocardial infarction and acute lung injury. However, the mechanism and concentration required to augment the risk of thromboembolic events remains unclear and therefore raises questions about the safety of high dose C1INH therapy. We evaluated all possible sites of the C1INH concentration-dependent interaction with the coagulation system and here we focus on a hypothesis that supra-physiological concentrations of C1INH alter the anticoagulant protein C system. To study the interactive role of C1INH and the protein C pathway we performed thrombin generation assays (TGA) on plasmas from both male and female healthy donors in the presence of supra-physiologic concentrations of C1INH and increasing concentrations of thrombomodulin (TM).Methods. Platelet poor plasma (PPP) was isolated by centrifugation from blood of 20 healthy donors and mixed with 16 IU/ml of C1INH or with the same volume of buffer. The used C1INH concentration was 16 times bigger than normal values. Concentrations of TM added to the plasma samples were equal to 3, 6, 9, 12 and 15 nM. 4.5 pm tissue factor-induced thrombin generation was performed by continuous measurement of thrombin proteolytic activity of thrombin-specific substrate Z-Gly-Gly-Arg-AMC added to PPP before induction of coagulation. Thrombin peak was calculated using Origin software. Wilcoxon and sign paired tests with P=0.05 were used to obtain statistics.Results and conclusions. C1INH significantly reduced thrombin peak up to 2 times in the absence and at the lowest concentrations of TM (3 and 6 nM). Addition of 9 nM TM caused disappearance of the difference between the samples with and without C1INH. Finally, in the presence of 12 and 15 nM of TM, C1INH significantly enhanced thrombin peak (Figure 1A, B). Figure 1B demonstrates that reducing C1INH concentration can bring the thrombin peak back to the values obtained without C1INH presence. These results indicate that presence of TM crucially change the action of C1INH on coagulation and explains how supra-physiological concentrations of coagulation inhibitor may cause thrombosis in certain clinical situations.Figure 1. A: Effect of elevation of C1INH concentration on thrombin peak. Statistics was obtained using Wilcoxon (*) and Sign (**) paired tests with P value equal to 0.05 from 20 healthy donors. B: Representative dependence of thrombin peak on TM concentration with and without the presence of 16 IU/ml C1INH. C: representative dependence of Thrombin peak on C1INH concentration in the presence of TM.

Lupus-associated Angioedema Successfully Treated with C1 Esterase Inhibitor Concentrate in an Adolescent Female: A Case Report

Lupus-associated Angioedema Successfully Treated with C1 Esterase Inhibitor Concentrate in an Adolescent Female: A Case Report

A robust multiplexed assay to quantify C1-inhibitor, C1q, and C4 proteins for in vitro diagnosis of hereditary angioedema from dried blood spot

Hereditary angioedema (HAE) is a rare genetic disease caused by deficiency or dysfunction of C1 esterase inhibitor (C1-INH). Plasma C1-INH activity and concentrations of C1-INH and complement components 1q and 4 (C1q, C4) are critical to the HAE diagnosis. We describe a novel multiplexed assay to simultaneously measure C1-INH, C1q, and C4 levels in dried blood spot (DBS) of HAE patients. The blood proteins were extracted from 3 mm punches of DBS samples and were subsequently digested by trypsin. The signature peptide derived from each protein was quantified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Analyte-depleted blood was generated as a surrogate matrix for the preparation of calibration curves to overcome the interference of endogenous proteins, and the assay reproducibility was further monitored by assessing the signal of plasma transferrin as a house-keeping protein. The assay was fully validated following regulatory guideline, with a quantification range of 12.5–800 μg/mL for C1-INH and C4 and 3.13–200 μg/mL for C1q. The precision and accuracy ranged from 3.3%–9.8% and -8.2%–12.6%, respectively. All the patient samples exhibited C1-INH levels lower than normal range except the Type II patient and the C4 and C1q concentrations were as expected. Results from the DBS-based LC–MS assay were highly correlated with the ELISA data measured in plasma of the same subjects. The method described here offers unique advantages such as less invasive sampling, minimal blood processing, and easy transportation and sample storage, allowing, for the first time, C1-INH, C4, and C1q levels to be simultaneously determined in a drop of dried blood.

Acquired Angioedema Induced by Risperidone

Introduction: Angioedema is a serious reaction characterized by edema of the deep dermal and subcutaneous tissues. Case Presentation: A 38-year-old woman was admitted to Ibn-e-Sina psychiatric hospital (Mashhad, Iran) in 2010, with amphetamine-induced mood disorder with onset during intoxication. She began taking sodium valproate, and later, risperidone treatment was started. On the 9th day of risperidone treatment, drug-induced angioedema occurred. Laboratory tests showed an elevated erythrocyte sedimentation rate and elevated C-reactive protein, with normal C3, C4, and C1 esterase inhibitor concentrations. Conclusions: The risperidone treatment was discontinued, and only hydroxyzine and a low dose of hydrocortisone were prescribed. The edema resolved completely within 4 days. © 2016, Mazandaran University of Medical Sciences.

Use of a C1 Esterase Inhibitor Concentrate in Elderly Patients with Hereditary Angioedema: Findings from the International Berinert® (C1-INH) Registry

Use of a C1 Esterase Inhibitor Concentrate in Elderly Patients with Hereditary Angioedema: Findings from the International Berinert® (C1-INH) Registry

Safety of a C1 Esterase Inhibitor Concentrate in Pregnant Women with Hereditary Angioedema: Findings from the International Berinert Patient Registry

Safety of a C1 Esterase Inhibitor Concentrate in Pregnant Women with Hereditary Angioedema: Findings from the International Berinert Patient Registry

Assessment of Inhibitory Antibody Formation in Subjects with Hereditary Angioedema Treated with Plasma-Derived C1-Esterase Inhibitor Concentrate (Berinert®)

Assessment of Inhibitory Antibody Formation in Subjects with Hereditary Angioedema Treated with Plasma-Derived C1-Esterase Inhibitor Concentrate (Berinert®)

Estrogen-sensitive hereditary angioedema type II: a case report and review

Hereditary angioedema (HAE) is a rare autosomal condition due to inherited deficiency of C1 esterase inhibitor (C1INH). Estrogen reduces the concentration of C1INH and trigger angioedema; however, the estrogen sensitivity pattern is variable in HAE. Proper diagnosis and management is essential as this condition sometimes becoming life-threatening due to potential airway obstruction. We reported a 27-year-old woman experienced recurrent episodes of lips and face swellings over the last 4 years. Patient has positive family history of similar recurrent angioedema in her brother and cousin. Laboratory findings revealed normal C3, C4, C1q, and C1INH quantity but low activity (36% decreased). Subsequent visits revealed the intake of oral contraceptive pills and improvement of symptoms after discontinuation. To our knowledge, this is the first case report of HAE type II with estrogen-sensitive pattern in a Saudi woman improved after cessation of oral contraceptive pills.

The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema.

Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature.

Efficacy and Safety of a C1 Esterase Inhibitor Concentrate for Long-Term Prophylaxis in Hereditary Angioedema: Findings from a Large International Registry

Efficacy and Safety of a C1 Esterase Inhibitor Concentrate for Long-Term Prophylaxis in Hereditary Angioedema: Findings from a Large International Registry

Clinical Usage of a C1 Esterase Inhibitor Concentrate for Hereditary Angioedema: Final Results from a Large International Registry

The plasma-derived, pasteurized, nanofiltered C1-Inhibitor concentrate (pnfC1-INH; Berinert®/CSL Behring) has been used for the management of hereditary angioedema (HAE) for over 35 years in Europe and since 2009 in the US. An international patient registry was created to gather more administration and safety data for Berinert.

Training hereditary angioedema patients to self-administer intravenous C1 esterase inhibitor concentrate.

Hereditary angioedema (HAE) is a rare disorder that causes periodic attacks of sometimes painful swelling that may affect any organ system. HAE results in significant morbidity and diminished quality of life and requires patients to seek urgent medical care. HAE can be treated with C1 esterase inhibitor concentrate (C1-INH), icatibant, and ecallantide. Recent consensus guidelines recommend that all HAE patients be considered for training in self-administration of therapy to treat acute attacks or to prevent attacks. Many patients have safely and successfully self-administered intravenous infusions of C1-INH, resulting in rapid treatment, shortened attacks, and improved quality of life. With proper patient selection and adequate guidance and follow-up, self-administered C1-INH therapy is a viable and favorable option to treat HAE, particularly in patients with a moderate to high frequency of attacks.

Pasteurized and Nanofiltered, Plasma-Derived C1 Esterase Inhibitor Concentrate for the Treatment of Hereditary Angioedema

Hereditary angioedema (HAE) is a relatively rare autosomal dominant disorder that is typically characterized by recurrent episodes of edema in various body locations. It is most commonly caused by an inherited deficiency of functionally active C1 esterase inhibitor (C1-INH). Replacement therapy with a human plasma-derived C1-INH concentrate is recommended for the treatment and prophylaxis of acute attacks of HAE due to C1-INH deficiency (HAE-C1-INH). This article will discuss the current therapies available for the treatment of HAE-C1-INH, latest treatment guidelines, results of several studies demonstrating the efficacy and safety of the plasma-derived, pasteurized and nanofiltered C1-INH concentrate Berinert(®) (CSL Behring GmBH, Marburg, Germany), and future perspectives for the treatment and management of HAE-C1-INH.

The Effect of Weight on the Efficacy and Safety of C1 Esterase Inhibitor Concentrate for the Treatment of Acute Hereditary Angioedema

BackgroundDespite the worldwide obesity epidemic, there have been very few studies investigating the influence of body weight on treatment dosing and outcomes in patients with hereditary angioedema (HAE). ObjectiveThe purpose of this analysis was to determine whether the standard weight-based dosing recommendation of C1 esterase inhibitor (C1-INH) concentrate (20 IU/kg) is adequate in HAE patients with a high body mass index (BMI). MethodsData from patients treated for HAE attacks with 20 IU/kg of C1-INH concentrate were retrospectively analyzed from the open-label IMPACT2 study (International Multicenter Prospective Angioedema C1-INH Trial). Patients were categorized according to BMI as being normal body weight, overweight, or obese. Efficacy end points were time to onset of symptom relief and time to complete resolution of symptoms. The safety profile was evaluated according to adverse events occurring within 7 to 9 days of treatment. ResultsOf 57 patients, 24 (42%) were of normal body weight, 20 (35%) were overweight, and 13 (23%) were obese. Median (95% CI) time to onset of symptom relief was 0.37 hour (0.29–0.57) in normal-weight patients, 0.48 hour (0.39–0.53) in overweight patients, and 0.58 hour (0.41–0.94) in obese patients. Median time (95% CI) to complete resolution of symptoms was 15.2 hours (9.3–23.2) in normal-weight patients, 22.6 hours (11.3–44.6) in overweight patients, and 11.0 hours (5.6–23.6) in obese patients (differences not significant). There were no relevant differences in the incidence of adverse events in normal-weight patients (54%), overweight patients (30%), and obese patients (54%). ConclusionsTreatment of HAE attacks with weight-based doses of C1-INH concentrate provided reliable treatment response, regardless of body weight, in these patients with HAE.

Berinert® (C1-Esterase Inhibitor Concentrate) Treatment Is Not Related to Prothrombotic Risk Based On Preclinical Efficacy and Safety Investigations

Berinert® (C1-Esterase Inhibitor Concentrate) Treatment Is Not Related to Prothrombotic Risk Based On Preclinical Efficacy and Safety Investigations

PSY27 A Cost-Effectiveness Comparison of Icatibant and C1-Esterase Inhibitor Concentrate for the Symptomatic Treatment of Acute Attacks of Types I and II Hereditary Angioedema in the UK Setting

PSY27 A Cost-Effectiveness Comparison of Icatibant and C1-Esterase Inhibitor Concentrate for the Symptomatic Treatment of Acute Attacks of Types I and II Hereditary Angioedema in the UK Setting

Association of C1 Esterase-Inhibitor Functional Activity and Treatment Response With C1 Esterase-Inhibitor Concentrate (Berinert®) for Acute Attacks of Hereditary Angioedema

Diagnosis of hereditary angioedema (HAE) is based on functional C1 esterase-inhibitor (C1-INH) levels. We studied the association between C1-INH functional activity (C1-INHf) and efficacy endpoints in a post-hoc analysis of data obtained from the double-blind, placebo-controlled study I.M.P.A.C.T.1.

Absence of Inhibitory Anti-C1 Esterase-Inhibitor Antibody Formation in Subjects Treated With C1 Esterase-Inhibitor Concentrate (Berinert®) for Successive Hereditary Angioedema Attacks

Absence of Inhibitory Anti-C1 Esterase-Inhibitor Antibody Formation in Subjects Treated With C1 Esterase-Inhibitor Concentrate (Berinert®) for Successive Hereditary Angioedema Attacks

Effect of Time to Treatment on Treatment Response With C1 Esterase-Inhibitor Concentrate (Berinert®) for Acute Hereditary Angioedema Attacks

Treatment with C1 esterase-inhibitor (C1-INH) concentrate (Berinert®, CSL Behring, Marburg) is well established for hereditary angioedema (HAE) attacks; treatment as early as possible is recommended. To investigate the relationship between time to treatment and treatment response, we conducted a post-hoc analysis of data from the I.M.P.A.C.T studies.