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Background Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1‐INH‐HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1‐INH (rhC1‐INH) for HAE attacks in children. Methods This open‐label, phase 2 study included children aged 2‐13 years with C1‐INH‐HAE. Eligible HAE attacks were treated intravenously with rhC1‐INH 50 IU/kg body weight (maximum, 4200 IU). The primary end‐point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end‐point was time to minimal symptoms (TTMS

Objective: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the SERPING1 gene. It can affect many regions in the body, but potentially life-threatening laryngeal oedemas are of concern. Methods: Twenty-three subjects from two families were recruited for clinical data evaluation and molecular analysis at General Hospital Šibenik, Croatia. Results: Decreased levels of C1 inhibitor were detected in 12 adult patients and three young asymptomatic persons. The same novel deletion of two nucleotides on exon 3 (c.74_75delAT) was identified in all of them. A history of laryngeal oedema was present in 10 patients (83%), and all patients reported laryngeal attacks at least once a year. The delay in diagnosis decreased noticeably from the first to the last generation. Conclusions: We identified a novel causative mutation in SERPING1 in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship. Key messages Hereditary angioedema due to C1 inhibitor deficiency is a rare autosomal dominant disease caused by mutations in the SERPING1 gene, and laryngeal oedema is of concern because it can cause death by asphyxiation. A novel causative mutation in SERPING1, a deletion of two nucleotides on exon 3 (c.74_75delAT), was identified in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship because it appears that the mutation type may affect disease severity.

Hereditary Angioedema is an autosomal dominant inherited disease leading to oedema attacks with variable severity and localization predominantly caused by C1-INH deficit. More than 400 mutations have been already identified, however no genetic analysis of a Brazilian cohort of HAE patients with C1-INH deficiency has been published. Our aim was to perform genetic analysis of C1-INH gene (SERPING1) in Brazilian HAE patients. We screened the whole SERPING1 coding region from 30 subjects out of 16 unrelated families with confirmed diagnosis of HAE due to C1-INH deficiency. Clinical diagnosis was based on symptoms and quantitative and/or functional analysis of C1-INH. We identified fifteen different mutations among which eight were not previously described according to databases. We found five small deletions (c.97_115del19; c.553delG; c.776_782del7; c.1075_1089del15 and c.1353_1354delGA), producing frameshifts leading to premature stop codons; seven missense mutations (c.498C>A; c.550G>C; c.752T>C; c.889G>A; c.1376C>A; c.1396C>T; c.1431C>A); one nonsense mutation (c.1480C>T), and two intronic alterations (c.51+1G>T; c.51+2T>C). Despite the small number of participants in this study, our results show mutations not previously identified in SERPING1 gene. This study represents the first Brazilian HAE cohort evaluated for mutations and it introduces the possibility to perform genetic analysis in case of need for differential diagnosis.

Background Angioedema diagnosis classically targets the complement system (via C1 inhibitor (C1Inh) function and antigenic C4 level) and contact phase activation (via amidase activity). Bradykinin is responsible for angioedema attacks and is produced from contact phase activation secondary to failed C1Inh control. Objective We aimed to compare the diagnostic performances of spontaneous amidase activity and antigenic C4 level in C1Inh hereditary angioedema (C1Inh-HAE) patients. Methods Samples from 185 C1Inh-HAE patients (81 men, 104 women; confirmed by SERPING1 gene mutations) and from 99 blood donors (50 men, 49 women) were tested for C1Inh function, antigenic C4 level and spontaneous amidase activity. Results In the C1Inh-HAE group, antigenic C4 level was decreased ( n = 135) and amidase activity was increased ( n = 181). Receiver operating characteristic analyses showed higher diagnostic performance values for the spontaneous amidase assay compared to those of antigenic C4. Conclusion The spontaneous amidase activity assay should replace antigenic C4 level testing and should be tested alongside the C1Inh function for both AE screening and follow up of HAE patients.

Objective C1 inhibitor (C1INH) regulates not only the complement system but also the plasma kallikrein-kinin, fibrinolytic, and coagulation systems. The biologic activities of C1INH can be divided into the regulation of vascular permeability and anti-inflammatory functions. The objective was to clarify the serial change of C1INH in patients with sepsis. Methods We serially examined C1INH activity values (reference range, 70%-130%) and quantitative values (reference range, 160-330 μ g/mL) in patients with sepsis admitted into the intensive care unit of the Trauma and Acute Critical Care Center at Osaka University Hospital (Osaka, Japan) during the period between December 2012 and February 2013. We also analyzed their clinical course. We defined "refractory shock" as septic shock requiring steroid administration to maintain hemodynamics. Results The serial change of C1INH was evaluated in 5 patients (4 survivors and 1 nonsurvivor). Two patients were diagnosed as having refractory shock. In the nonsurvivor after refractory shock, C1INH activity on admission was 97.2%, and the quantitative value was 133.1 μ g/mL. In the other patient with refractory shock, C1INH activity on admission was 94.4%, and the quantitative value was 126.7 μ g/mL. This patient's general condition had improved by day 6, with increases in C1INH activity (139.9%) and quantitative value (250.1 μ g/mL). In the 3 nonrefractory shock patients, C1INH activity on admission was 130.6%±8.7%, and the quantitative value was 215±26.5 μ g/mL. Conclusions Enhancement of C1INH activity was not observed in the refractory shock patients, and the C1INH quantitative values were low. Further evaluation of the serial change of C1INH and the validity of C1INH replacement therapy in patients with septic shock may lead to a new strategy for sepsis management.

Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) is an autosomal dominant disease caused by mutations in the SERPING1 gene. A Jordanian family, including 14 individuals with C1-INH-HAE clinical symptoms, was studied. In the propositus and his parents, SERPING1 had four mutations leading to amino acid substitutions. Two are known polymorphic variants (c.167T>C; p.Val34Ala and c.1438G>A; p.Val458Met), the others are newly described. One (c.203C>T; p.Thr46Ile) is located in the N-terminal domain of the C1-inhibitor protein and segregates with angioedema symptoms in the family. The other (c.800C>T; p.Ala245Val) belongs to the serpin domain, and derives from the unaffected father. DNA from additional 24 family members were screened for c.203C>T mutation in the target gene. All individuals heterozygous for the c.203C>T mutation had antigenic and functional plasma levels of C1-inhibitor below 50% of normal, confirming the diagnosis of type I C1-INH-HAE. Angioedema symptoms were present in 14 of 16 subjects carrier for the c.203T allele. Among these subjects, those carrying the c.800T variation had more severe and frequent symptoms than subjects without this mutation. This family-based study provides the first evidence that multiple amino acid substitutions in SERPING1 could influence C1-INH-HAE phenotype.

Hereditary angioedema (HAE) is rare, disabling and sometimes life-threatening. The aim of this study is to describe its prevalence, symptomatology and treatment in Sweden. A total of 146 patients were identified; 110 adults and 36 children with HAE type I (n = 136) or II (n = 10), giving a minimum HAE prevalence of 1.54/100,000. All patients received a written questionnaire followed by a structured telephone interview. This report focuses on the 102 adults who responded. Females reported 19 attacks in the previous year vs. 9 for males (p < 0.01), and females reported 10 days of sick leave vs. 4 days for males (p < 0.05). For all treated acute attacks, plasma-derived Cl-inhibitor concentrate (pdClINH) (used in 27% of patients) had a good effect. For maintenance treatment, 43% used attenuated androgens and 8% used pdClINH, which reduced their attack rate by more than 50%. In conclusion, the minimum HAE prevalence in Sweden was 1.54/100,000. HAE affected females more severely. Attenuated androgens and pdClINH had a good effect on preventing attacks. Funding Agencies|Futurum the Academy for Healthcare; Jonkoping County Council; Linkoping University; Karolinska Institutet

Background Complement activation contributes significantly to inflammation-related damage in the heart after acute myocardial infarction. Knowledge on factors that regulate postinfraction complement activation is incomplete however. In this study, we investigated whether endogenous C1-inhibitor, a well-known inhibitor of complement activation, is expressed in the heart after acute myocardial infarction. Materials and methods C1-inhibitor and complement activation products C3d and C4d were analyzed immunohistochemically in the hearts of patients who died at different time intervals after acute myocardial infarction ( n = 28) and of control patients ( n = 8). To determine putative local C1-inhibitor production, cardiac transcript levels of the C1-inhibitor-encoding gene serping1 were determined in rats after induction of acute myocardial infarction (microarray). Additionally, C1-inhibitor expression was analyzed (fluorescence microscopy) in human endothelial cells and rat cardiomyoblasts in vitro. Results C1-inhibitor was found predominantly in and on jeopardized cardiomyocytes in necrotic infarct cores between 12 h and 5 days old. C1-inhibitor protein expression coincided in time and colocalized with C3d and C4d. In the rat heart, serping1 transcript levels were increased from 2 h up until 7 days after acute myocardial infarction. Both endothelial cells and cardiomyoblasts showed increased intracellular expression of C1-inhibitor in response to ischemia in vitro ( n = 4). Conclusions These observations suggest that endogenous C1-inhibitor is likely involved in the regulation of complement activity in the myocardium following acute myocardial infarction. Observations in rat and in vitro suggest that C1-inhibitor is produced locally in the heart after acute myocardial infarction.

C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE.

The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) represent one of the oldest unsolved problems of the disease. Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12-46C/T in disease phenotype. We studied 258 C1-INH-HAE patients from 113 European families, and we explored possible associations of F12-46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within-subject correlation. F12-46C/T carriers exhibited a significantly delayed disease onset (P

Background: Angio-oedema (AO) can be attributable to bradykinin (BK) accumulation, as is the case for prototypical hereditary AO (HAO) due to C1 inhibitor (C1-INH) deficiency. However, our clinical experience in a reference centre has shown that some patients display a clinical history suggestive of HAO, but exhibit normal C1-INH function, have no mutation in the causative genes associated with HAO (SERPING1, F12), and report no intake of drugs known to promote AO. Objective: We sought to determine the frequency and distribution of different AO subtypes suspected to be BK-mediated AO (BK-AO) and defined by clinical, history and biological criteria (enzyme activities implicated in BK formation and catabolism). Methods: The files of all patients referred to our centre for suspected BK-AO were retrospectively analysed. Results: The distribution of patients (n = 162) was 16 and 4% with a hereditary deficiency of C1-INH or a gain of factor XII function, respectively, 29% with iatrogenic BK-AO, 21% with non-iatrogenic defective kininase activity and 30% with idiopathic increased kinin formation. Conclusion: BK-AO may be caused by multiple inherited or acquired factors triggering BK accumulation. Therefore, we propose a novel typology for BK-AO based on the imbalance of production/catabolism of BK.

Purpose We conducted a meta-analysis aiming to evaluate the relationship between a common polymorphism (rs2511989 G>A) in the SERPING1 gene and the risk of age-related macular degeneration (AMD). Methods The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1, 2013, without any language restrictions. A meta-analysis was conducted using STATA 12.0 software. We calculated a crude odds ratio (OR) with a 95% confidence interval (95% CI) to evaluate the relationships under five genetic models. Results Seven case-control studies with a total of 7,159 patients with AMD and 5,797 healthy subjects met the inclusion criteria. The results of our meta-analysis showed that the SERPING1 rs2511989 polymorphism might be correlated with an increased risk of AMD (G allele versus A allele: OR = 1.09, 95% CI = 1.03–1.15, p = 0.020; GG + GA versus AA: OR = 1.14, 95% CI = 1.03–1.26, p = 0.014; GG versus GA+AA: OR = 1.10, 95% CI = 1.02–1.19, p = 0.012; GG versus AA: OR = 1.20, 95% CI = 1.07–1.34, p = 0.002; respectively). Results of subgroup analysis by ethnicity revealed positive correlations between the SERPING1 rs2511989 polymorphism and risk of AMD among Caucasians under five genetic models (all p0.05). Conclusions The current meta-analysis shows that the SERPING1 rs2511989 polymorphism may have a positive effect on the risk of AMD, especially among Caucasians.

Hereditary angioedema is an inherited disease that causes periodic swelling attacks, which can be life threatening and have a major effect on a patient's life. Studies have shown that home therapy for angioedema reduces disease severity, leads to faster relief of symptoms, and improves quality of life. Most studies have been conducted in adults. We report a 13-year-old boy who quickly learned self-administration, which resulted in reduced frequency and severity of attacks. The aim of this report is to emphasize that children should be considered for self-administration training and that the process does not have to be long or complicated.

Summary Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P = 0·049) and during the next 24 h CRP rose significantly (P = 0·002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P = 0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset.

Objective To provide an update on the molecular mechanisms of hereditary angioedema (HAE). Data Sources MEDLINE and PubMed databases were searched to identify pertinent articles using the following key terms: hereditary angioedema , angioedema , C1 inhibitor , bradykinin , contact system , factor XII , mechanism , pathophysiology , severity , permeability , and estrogen . Study Selections Articles were selected based on their relevance to the subject matter. Results Although the biochemical basis of "classic" HAE is known to result from C1 esterase inhibitor (C1INH) deficiency, a new form, HAE with normal C1INH, has been identified. HAE types I and II are caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1INH. In HAE with normal C1INH, mutations in the F12 gene have been identified in a subset of individuals, but the genetic defect remains unknown in most patients. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system that increases vascular permeability. HAE disease severity is highly variable and may be influenced by polymorphisms in other genes and other factors, such as hormones, trauma, stress, and infection. Conclusion Hereditary angioedema is a heterogeneous disorder with a complex pathophysiology. Implicated genes include SERPING1 and FXII in patients with HAE from C1INH deficiency and HAE with normal C1INH levels, respectively. Disease severity is highly variable.

To the Editor, Hereditary angioedema due to C1-inhibitor deficiency (C1INH-HAE) is a rare disease inherited in an autosomal dominant manner, with reduced levels (type I) or impaired function (type II) of C1-inhibitor (C1-INH) [1]. C1-INH regulates the coagulation pathway, fibrinolytic system, complement cascade and kallikrein-kinin system. Uncontrolled activation of these pathways produces increased bradykinin levels which leads to enhanced vascular permeability and edema formation. The most common presentation involves edema of the intestinal wall causing abdominal colicky pain that may mimic an acute abdomen, and edema of the subcutaneous tissue affecting extremities, face or the genital area. Although less frequent, angioedema can also affect the larynx and cause death because of asphyxiation. An early diagnosis is therefore of vital importance. C1-INH-HAE diagnosis is usually performed by determination of antigenic concentration and functional activity of C1-INH (C1-INH, f-C1-INH) in sera/plasma. CINH gene study is also available for diagnosis, although in a few cases the mutation is not found. Most authors advise against testing complement in patients before the age of 1 year [2] because C1-INH levels had been shown to be lower than in adults [3]. However, most complement components increase during the first days, rapidly surpassing adult values [4]. To date, there are no available data comparing C1-INHHAE diagnosis carried out by means of genetic testing versus complement components determination in a pediatric population. Our aim was to assess the accuracy of complement testing in the diagnosis of type I C1-INH-HAEmade by means of genetic testing in a pediatric population. We studied twenty-nine children from twenty-one unrelated families suspected of having C1-INH-HAE due to personal and/or family history. Informed consent was obtained from parents. The Local Ethics Committee approved the study (PI-1377). Suspicion of HAE was based on personal history and/or family history of episodes of angioedema not responding to antihistamines, corticosteroids and epinephrine and/or abdominal episodes of colicky pain that did not subside with conventional therapies, as well as episodes of laryngeal oedema where other causes had been excluded. The last criterion for suspecting HAE was to have a relative who had been diagnosed with Type I C1-INH-HAE. Blood venous samples were collected. Citrated-, EDTAcoated plasma tubes and serum tubes were obtained from patients upon informed consent and approval from the local Ethics committee. C1-INH and C4 levels were quantified on serum samples by nephelometry (Siemens, Marburg, Germany) and C1-INH functionality was assayed in citrated plasma samples with the commercial kit Berichrom (Siemens) following manufacturer ’s instructions. Additionally, DNA samples were obtained from peripheral blood mononuclear cells with the Gentra Puregene BloodCore (Gentra Systems, Minneapolis, MN). Genetic analysis of suspected de novo mutations was carried out by * Maria Pedrosa m.pedrosa.d@gmail.com

Background Angiotensin-converting enzyme (ACE) inhibitor–induced angioedema is a rare, albeit serious emergency that can result in airway compromise and potentially death if not treated promptly. Currently, there are no agents approved by the Food and Drug Administration to target ACE inhibitor angioedema and to prevent intubation. C1 inhibitors are approved for hereditary angioedema but may show promise in alleviating inflammation associated with ACE inhibitor angioedema. Case Report A 41-year-old man presented to the emergency department with swelling of his lips a few days after starting lisinopril for hypertension. Despite receiving diphenhydramine, ranitidine, and methylprednisolone, the swelling progressed to the patient's tongue. A C1 inhibitor was ordered in an effort to prevent intubation. Before the arrival of the medication, the patient was intubated emergently for airway protection. After receipt of the C1 inhibitor, the swelling dramatically improved, and the patient was successfully extubated after less than 18 hours from presentation. Why Should an Emergency Physician Be Aware of This? This case illustrates a potential role for C1 inhibitors in the emergency setting for treating drug-induced angioedema, which may prevent or minimize mechanical ventilation time.

Summary Hereditary angioedema (HAE) is an autosomal dominant disease due to mutations in the C1 inhibitor gene (C1NH) that affects protein synthesis (HAE type I) or function (HAE type II). In 45 subjects affected by HAE diagnosed through clinical features and C1 inhibitor deficiency from the south of Italy (38 with type I and 7 with type II HAE), the whole C1NH coding region was screened for mutations by direct DNA sequencing. A severity score based on clinical manifestation, age at disease onset, and need for long-term prophylaxis was used to investigate possible genotype-phenotype correlations. A series of 22 different mutations was identified: nine missense (40.9%), five nonsense (22.7%), six frameshift (27.3), one small deletion (4.5%), and one splicing defect (4.5%). Nine C1NH mutations have not been previously described. No correlation was found between C1 inhibitor function level and severity score or age at first attack. Moreover, there was no correlation between different types of mutations and clinical phenotype. The number of different mutations identified highlights the heterogeneity of C1 inhibitor deficiency and supports the hypothesis that HAE clinical phenotype is not strictly related to the type of mutation but rather depends on unknown factors.

Mutations that modify the amino acid sequence of C1-INH (except Val458Met) are associated with HAE. More than 200 different mutations scattering the entire C1-INH gene have been reported. The main objective of this study was to report the mutational findings in a HAE cohort of 138 Portuguese patients followed in specialized consultation all over the country. DNA was extracted from peripheral blood with QiaSymphony BioRobot (QIAGEN Portugal). The sequence reactions were performed by using a DNA sequencing kit (Big Dye terminator cycle sequencing v1.1/v3.1 from Applied Biosystems) and sequencing products were immediately submitted to direct sequencing on an Applied Biosystem 3130 DNA Analyser. DNA sequences were analyzed at four different stages. Raw data and sequence alignments of all 8 exons and intron–exon boundaries were performed for each patient individually with SeqScape software and using SERPING1 gene NG_009625 of 24,300 bp (12-March-2011) as reference sequence. Sequence comparisons among patients and controls were performed with software CodonCode Aligner v.3.7 from CodonCode Corp and with Geneious 4.5 from Biomatters Lda. A total of 94 point mutations were observed among patients, and 67% of them were located on exon 8. In addition, we noticed one not described stop codon at position c.1459 C>T in three different patients. Translation termination was also found on exon 3 and 7, as a result of mutations at positions c.481A>7, c.1174C>T. In this population, the prevalence of the missense mutation p.Arg444Cys was 39 out of 42. Mutational analysis revealed 22 different pathogenic mutations, of which 64% were not described on HAE database. Although identification of disease causing mutations is not necessary to establish HAE diagnosis, studies on gene expression and characterization of rearrangements in SERPING1 gene are suggested in order to get new insights on function and genetic tests of C1 inhibitor.

Summary Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the C1 inhibitor gene SERPING1. Phenotype and clinical features of the disease are extremely heterogeneous, varying even within the same family. Compared to HAE cohorts in other countries, the genetic background of the Swiss HAE patients has not yet been elucidated. In the present study we investigated the mutational spectrum of the SERPING1 gene in 19 patients of nine unrelated Swiss families. The families comprise a total of 111 HAE-affected subjects which corresponds to approximately 70% of all HAE-affected patients living in Switzerland. Three of the identified mutations are newly described. Members of family A with a nucleotide duplication as genetic background seem to have a more intense disease manifestation with a higher attack frequency compared to the other families. Newly designed genetic screening tests allow a fast and cost-efficient testing for HAE in other family members.

Background: The prevalence of acquired angioedema (AAE) is hitherto unknown and, to date, less than 200 patients have been reported worldwide. AAE is associated with lymphoproliferative conditions and autoantibodies against C1 inhibitor (C1INH). Rituximab (RTX) is increasingly used in the treatment of AAE patients. Methods: A nationwide study of AAE patients was performed in Denmark. Clinical features, associated disorders, treatments and outcomes were registered. Results: Eight AAE patients were identified. The diagnostic delay was on average 1 year and 8 months. Patients were treated with C1INH concentrate or icatibant on demand. Six patients were diagnosed with a clonal B-cell disorder during follow-up, on average 2.5 years after the first swelling. Two patients had monoclonal B-cell lymphocytosis (MBL). Two patients received RTX. Conclusions: AAE is a rare condition occurring in less than 10% of patients with C1INH deficiency in Denmark. AAE is highly associated with haematologic disorders, and we recommend yearly follow-up visits with clinical examination and blood tests including flow cytometry to diagnose B-cell conditions at an early stage. We report 2 patients with AAE and associated MBL, which is a benign expansion of clonal B lymphocytes. MBL can be the precursor of chronic lymphocytic leukaemia or is associated with non-Hodgkin's lymphoma. If angioedema is poorly controlled with standard treatment regimens, we suggest treatment of the associated haematologic disorder. Based on a review of the literature and our own data, we recommend therapy with RTX, especially in patients with anti-C1INH autoantibodies.

Background Treatment of hereditary angioedema (HAE) in ‘older adults’ (those aged ≥65 years) has not been well studied. The international Berinert Patient Registry collected data on the use of intravenous plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH; Berinert®/CSL Behring) in patients of any age, including many older adults. Methods This observational registry, conducted from 2010 to 2014 at 30 US and seven European sites, gathered prospective (post-enrollment) and retrospective (pre-enrollment) usage and adverse event (AE) data on subjects treated with pnfC1-INH. Results The registry documented 1701 pnfC1-INH infusions in 27 older adults. A total of 1511 HAE attacks treated with pnfC1-INH administration were reported among 25 of the 27 (92.6 %) older adults. Among the older adults, mean (standard deviation [SD]) (8.8 [4.1] IU/kg) and median (6.4 IU/kg) pnfC1-INH doses were lower than those reported for 252 ‘younger adults’ (those aged

Because of the growing impact of late onset cognitive loss, considerable effort has been directed toward the development of improved diagnostic techniques for Alzheimer’s disease (AD) that may pave the way for earlier (and more effective) therapeutic efforts. Serum-based biomarkers are the least expensive and invasive modality for screening and routine monitoring. We systematically reviewed the literature to assemble a list of serum biomarkers relevant to AD. In parallel, we conducted a proteomic LC-MS/MS analysis of serum collected from neurologically normal subjects and subjects with mild cognitive impairment (MCI) and early AD (n = 6 in all). Complement C3 and alpha-2-macroglobulin were identified from both the literature review and our proteomic screen for further validation. For these two candidates, ELISA was performed on serum collected from a small independent cohort of subjects for longitudinal analysis. Serum was serially collected from neurologically normal subjects (n = 5) and subjects with MCI who were subsequently followed for a period of two years (n = 5) and regrouped into stable MCI and progressive MCI or AD (n = 6). The ability of each marker to predict which subjects with MCI would progress to dementia and which would remain cognitively stable was assessed. Patients with probable cerebral amyloid angiopathy were also identified (n = 3). This preliminary analysis tested the most-promising serum protein biomarkers for AD and we concluded that none are yet ready for use in the clinical diagnosis and management of dementia. However, a more thorough assessment in longitudinal studies with higher statistical power is warranted.

Acquired C1-inhibitor deficiency can occur secondary to excessive C1-inhibitor consumption (type I) and be associated with a lymphoid hemopathy, or linked to the presence of anti-C1-inhibitor autoantibodies (type II) in a context of an isolated monoclonal gammopathy, sometimes associated with lymphoproliferation. Efficacy of danazol, tranexamic acid and/or corticosteroids is inconstant. Rituximab efficacy against type II angioedema has been reported.Description of 7 rituximab-treated patients, 6 with type II acquired angioedema and 1 with type I.Clinical efficacy (only for type II) was complete for 3, partial for 2 and 2 were therapeutic failures. Only 2 patients had improved biological parameters, with normalization of their C1-inhibitor levels and diminished anti-C1-inhibitor autoantibodies, observed 1-9 months after the last infusion of the second rituximab cycle. An associated lymphoproliferation did not affect the response to treatment.Rituximab efficacy in the treatment of acquired angioedema is inconstant and might require repeated cycles.

The molecular bases and clinical features of hereditary angioedema (HAE) have not been systematically documented in Japan or in other Asian countries. Thus, the authors researched the genetic and clinical characteristics of Japanese patients with HAE.The authors analyzed the CIINH gene for mutations in 13 unrelated Japanese patients with HAE by means of the polymerase chain reaction and nucleotide sequencing. In addition, the authors searched the literature from January 1969 to October 2010 on Japanese patients with HAE.Seven of the mutations found were novel, including 4 missense mutations (8728TG, 8831CA, 16661TG and 16885CA), 2 frameshift mutations (2281_2350del70, 14158delT) and 1 large deletion (at least 1 kb-length deletion including exon 4), whereas 6 mutations had previously been reported in European populations.The genetic and clinical characteristics in Japanese patients with HAE may be similar to those in Western patients although our sample size is small and the authors identified 7 novel mutations.

This study assessed variation in plasma levels of the complement regulatorC1 inhibitor (C1inh) in patients with age related macular degeneration (AMD) and controls. Plasma from391 AMD cases and 370 controls was assayed by rate nephelometry to determine C1inh protein levels. Protein levels were analysed for relationships with age, gender, smoking, AMD disease status and genetic variation in the SERPING1 gene, which encodes C1inh, using a multivariate analysis. t-Tests show a significant difference in C1inh levels in AMD cases compared with controls (p = 2.340E-6), smokers compared to non-smokers (p = 1.022E-4) and females compared to males (p = 1.661E-7). Multivariate analysis shows that after accounting for gender and smoking AMD status remained significant. Age was included in the model but was not significant. Including genetic variation in the model shows that one significant SNP (rs2649663) 5′ of the SERPING1 gene is associated with C1inh levels though this SNP is not associated with AMD. This suggests that genetic variation in the promoter region of the SERPING1 gene may influence expression of the gene.

Hereditary angioedema (HAE) due to C1-inhibitor (C1-Inh) deficiency is an autosomal dominant disease caused by mutations in the SERPING1 locus. According to protein levels in plasma, two HAE phenotypes have been described: Type I, with low circulating protein levels in plasma, and Type II, where the protein is present but dysfunctional. Although more than 200 mutations have been described to date, studies on the molecular basis of this autosomic dominant trait are scarce. Previous studies demonstrated that C1-Inh mRNA expression was decreased in HAE patients. Herein, we have confirmed these findings in a large series of Spanish patients. Moreover, when our data were analyzed taking into account the type of mutation carried by the patient (i.e., missense, frameshift,…), significant differences were amongst the control, nonsense and splicing mutations groups (P0.05). By opposite, no differences in C1-Inh mRNA expression were found between the control and HAE Type II groups, nor between treated and untreated patients groups, although a significant difference was observed between controls and untreated HAE Type I patients. An alternative splicing event has been described in the SERPING1 locus resulting in two different transcripts: the full-length and a shorter variant with skipping of exon 3. In order to investigate a possible role for this splicing in HAE, we quantified both mRNA variants in a series of 28 patients. No statistical differences were found in the expression of both variants between controls and patients when compared. However, a separate analysis considering each type of mutation evidenced a significant decrease (P: 0.0156) in the expression of the exon 3 skipping variant in those HAE Type I patients carrying nonsense mutations. Besides, median of the full variant's copy number was statistically decreased on the splicing group when compared with either stop and/or missense groups. The results of these studies provide new data about C1 inhibitor expression in HAE patients and shed more light on the transcriptional regulation of the SERPING1 locus. Quantitative analysis of splicing variants could help to determine the eventual variations of these two transcripts and their possible role under inflammatory stimuli.

Cinryze™ is a pasteurized, nanofiltered plasma derived concentrate of C1-inhibitor (pdC1-INH) licensed for the prophylactic treatment of hereditary angioedema. In a double-blind placebo-controlled crossover trial to evaluate Cinryze as prophylaxis, the frequency of attacks was halved (6.26 per 12 weeks on Cinryze versus 12.73 per 12 weeks on placebo). Furthermore, attacks were generally milder and of shorter duration. For treatment of acute attacks in patients receiving Cinryze, 1000 units, within 4 h of the start of an attack, the estimated time to the onset of unequivocal relief was reduced to 2 h, compared with more than 4 h in those treated with placebo. Cinryze and other similar products are going to change the future management of hereditary angioedema and have potential in other areas of medicine.

Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases.One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up.Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema.Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet.

Background: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients. Methods: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE. Results: The majority of patients were female (60%), the mean age was 37.7 ± 14.1 years. The mean age at the time of first angioedema symptom was 12.5 ± 9.2 years. Mean time lag between first symptom and diagnosis was 26 ± 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described. Conclusion: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.

Acquired Angioedema (AAE) is a rare condition classified into two subtypes: Type I, which is associated with lymphoproliferative disorders, and Type II, which is linked with autoantibodies against C1-esterase inhibitor (C1-INH). Unlike Type I AAE, Type II has no correlation with lymphoproliferative disorders. We report the evaluation of angioedema that was associated with an underlying lymphoproliferative disorder for the purpose of discussing the relationship between C1q and a diagnosis of AAE. A literature review was completed for the purpose of assessing the diagnostic value of C1q when used in the workup of AAE. A PubMed/Web of Science search (1976-2010) produced 78 references (yielding 167 individual cases of AAE) using terminology "AAE." The case described a patient with a depressed C1q (

Purpose Single nucleotide polymorphisms (SNPs) in the complement component 1 inhibitor (SERPING1) gene have been shown to be significantly associated with age-related macular degeneration (AMD) in Caucasian populations. A replication study of an association between these SNPs and AMD in a Chinese population is reported in this study. Methods Six SNPs, including rs2511990, rs1005510, rs11546660, rs2511989, rs2511988, and rs4926 in SERPING1 were genotyped in a Han Chinese subject group using the SNaPshot method of ABI. This subject group was composed of 194 patients with choroidal neovascularization (CNV or wet) AMD, 78 patients with soft drusen, and 285 matched controls. P values of the SNPs were calculated using an additive model. Haplotype frequencies between cases and controls were compared by χ2 analysis. The haplotype analysis was performed using Haploview 4.0. Results None of the six SNPs showed significant association with AMD. None of the major haplotypes were observed to be significantly associated with AMD or choroidal neovascularization AMD (CNV) after a stringent Bonferroni correction. Conclusions We demonstrate that SNPs in SERPING1 are not significantly associated with AMD in the mainland Han Chinese population.

Eur J Clin Invest 2010; 40 (1): 4–10 Abstract Background Recent studies indicate a role for complement in the pathogenesis of aortic valve disease. However, the role of naturally occurring anti-complement mediators in this context is unknown. In this study, we have analysed this in three different pathological conditions of the aortic valve: degeneration, atherosclerosis and bacterial endocarditis. Materials and methods Human aortic valves were obtained at autopsy (n = 30): 5 control valves, 10 aortic valves with atherosclerotic changes, 10 aortic valves with degenerative changes and 5 degenerative changed aortic valves with bacterial infection. These valves were analysed immunohistochemically for the presence of activated complement (C3d and C5b9) and the complement inhibitors C1-inh and clusterin. Areas of positivity were then quantified. Results C3d, C5b9 and the complement inhibitors C1-inh and clusterin depositions were mainly found in the endothelium and extracellular matrix in aortic valves. All these mediators were already present in control valves, but the area of positivity increased significantly in response to the different diseases, with the highest increase in response to bacterial endocarditis. Interestingly, in all three aortic diseases, the depositions of complement were significantly more widespread than that of their inhibitors. Conclusions Our study indicates that anti-complement mediators (C1-inh and clusterin) are deposited in diseased aortic valves together with activated complement, indicating an existing counter response against complement locally in the valve. However, deposition of activated complement is significantly more widespread than that of its inhibitors, which could explain ongoing inflammation in those diseased aortic valves.

This study constitutes the first molecular analysis of hereditary angioedema (HAE) in Greece, where 11 patients from three unrelated families with recurrent angioedema attacks and decreased C1 inhibitor antigenic levels were analyzed for SERPING1 mutations. Interestingly, one family displayed a novel SERPING1 alteration, characterized by the substitution of two consecutive nucleotides TC to AA, resulting in a termination codon (F225X). To the best of our knowledge, this is the first report of such a mutation in SERPING1, causing HAE. The second family displayed the nonsense mutation W482X, and the third the missense mutation M1V, already described in the literature. The type of mutation did not predict clearly the disease phenotype, since even members of the same family displayed a variety of the frequency and the severity of angioedema attacks. Our study identified a novel mutagenesis mechanism for HAE pathogenesis, providing additional evidence for the genetic heterogeneity of the disease.

Background: Cl-inhibitor (C1-INH) deficiency leads to recurrent attacks of mucocutaneous edema and may be inherited (hereditary angioedema [HAE]) or acquired (acquired angioedema [AAE]), which have the same clinical picture characterized by angioedema involving the skin, gastrointestinal tract, and larynx. Although cutaneous swelling is evident, abdominal angioedema is still a diagnostic challenge and attacks can mimic surgical emergencies. There is currently no laboratory marker for identifying angioedema attacks. Objective: As coagulation and fibrinolysis are activated during angioedema attacks, we assessed if plasma measurements of prothrombin fragment F1 + 2 (marker of thrombin generation) and D-dimer (marker of fibrin degradation) can be useful for the diagnosis of angioedema because of C1-INH deficiency, especially in case of hidden locations as abdominal attacks. Methods: In addition to complement, we measured plasma levels of F1 + 2 and D-dimer in 28 patients with C1-INH deficiency during acute attacks and remission, 35 patients without C1-INH deficiency during abdominal colics, and 20 healthy subjects. Results: Plasma F1 + 2 levels were higher in patients with C1-INH deficiency during remission than in healthy controls (P = 0.001), and further increased during cutaneous and abdominal attacks (P = 0.0001); patients without C1-INH deficiency had normal F1 + 2 levels during abdominal colics. Plasma D-dimer levels were higher in patients with C1-INH deficiency during remission than in controls (P = 0.012) and increased during angioedema attacks, reaching higher levels than in patients without C1-INH deficiency during colics (P = 0.002). Conclusions: During acute angioedema attacks, patients with C1-INH deficiency have high prothrombin fragment F1 + 2 and D-dimer levels, the measurement of which may have an important diagnostic value.

Purpose Common genetic variation in the complement component 1 inhibitor gene (SERPING1) was recently reported to increase the risk of developing age-related macular degeneration (AMD). This study was performed to replicate the association between SERPING1 and AMD. Methods Seven single nucleotide polymorphisms (SNPs) tagging common haplotypes across SERPING1 were genotyped on 786 (The Mayo Clinic) subjects and the association with AMD studied using single SNP and haplotype association analyses. The SNP in intron 6 (rs2511989) previously reported to increase the risk of AMD was studied in an additional 1,541 subjects from the Age-Related Eye Disease Study (AREDS). Association with specific subtypes of AMD and interaction with four other loci: complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2/LOC387715), High Temperature Requirement Factor A1 (HTRA1), complement factor B/complement component 2 (CFB/C2), and complement component 3 (C3) involved in AMD was explored. Results The seven tag-SNPs were not associated with AMD in the Mayo subjects (p=0.13–0.70) and rs2511989 was also not associated with AMD in the Mayo or AREDS subjects (p=0.44–0.45). Evaluation of haplotypes across SERPING1 did not reveal association with AMD (p=0.14–0.97). SNPs were not associated with AMD subtypes (early, geographic atrophy, or exudation). No interaction with other AMD risk variants was observed. Conclusions We were unable to replicate the reported association between SERPING1 and AMD in two independent groups of subjects.

Summary Background Age-related macular degeneration is the most prevalent form of visual impairment and blindness in developed countries. Genetic studies have made advancements in establishing the molecular cause of this disease, identifying mutations in the complement factor H ( CFH ) gene and a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes. Variants in complement 3 ( C3 ) and an HLA locus containing both factor B and C2 genes have also been implicated. We aimed to identify further genetic risk factors for this disease. Methods We used a case–control study design in a UK sample of patients with age-related macular degeneration (n=479) and controls (n=479) and undertook a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs). Genes were selected as candidates on the basis of potential functional relevance to age-related macular degeneration. Significant initial findings were confirmed by replication in an independent US cohort of 248 unrelated patients with disease and 252 controls, and by high-density genotyping around association signals. Findings The SNP variant rs2511989, located within intron six of the SERPING1 gene, showed highly significant genotypic association with age-related macular degeneration (uncorrected p=4·0×10 −5 , corrected p=0·00372). We detected no evidence for association between disease and the other 31 candidate genes. The odds ratio for age-related macular degeneration in rs2511989 G/A heterozygotes compared with wild type G/G homozygotes was 0·63 (95% CI 0·47–0·84). A similar comparison of the A/A homozygotes with the wild type yielded an odds ratio of 0·44 (0·31–0·64). We replicated the observed genotypic association in a US cohort (p=0·008). Furthermore, a secondary high-density genotyping study across the SERPING1 gene region identified five additional SNP variants similarly associated with age-related macular degeneration (rs2244169, rs2511990, rs2509897, rs1005510, and rs2511988). Interpretation Genetic variation in SERPING1 significantly alters susceptibility to age-related macular degeneration. SERPING1 encodes the C1 inhibitor, which has a crucial role in inhibition of complement component 1 ( C1 ) and might implicate the classic pathway of complement activation in this disease. Funding Macula Vision Research Foundation, the Macular Disease Society, the Wellcome Trust, Brian Mercer Trust, the American Health Assistance Foundation, National Institutes of Health, the Howard Hughes Medical Institute.

Background: Melkersson-Rosenthal syndrome (MRS) is a rare disease whose full-blown form is characterized by orofacial swelling, facial palsy and lingua plicata. Objective: To investigate the complement system as well as its role in patients with MRS. Methods: Seven patients presenting at this hospital between November 2002 and May 2003 and meeting the diagnostic criteria according to Hornstein were evaluated retrospectively. The investigations included clinical signs, an analysis of the complement system including levels of CH50, C3, C4, C1 inhibitor (INH) functions and C1-INH antigen detection. Results: Two female patients showed isolated low levels of functional C1-INH as determined by duplicate tests. Both patients took estrogen-progestin contraceptives. Conclusion: Since deficiency in plasma protease C1-INH is known to lead to recurrent angioedema, we hypothesize that low levels of functional C1-INH may have contributed to the orofacial swelling in the 2 patients.

A man in his 60s was brought to the emergency department, with airway compromise and dysarthria due to a grossly enlarged tongue. As he was on a current course of antibiotics, he was treated for a likely antibiotic-associated allergic reaction. However, as he failed to improve with intramuscular and nebulised epinephrine, another cause of his symptoms was sought. Further discussion revealed a history of chronic lymphocytic leukaemia (CLL), which had recently relapsed. Investigations were ordered to confirm that the symptoms were due to acquired angioedema, and the patient was managed for this diagnosis based on the presence of an undetectable C4 level. This diagnosis was later confirmed when the results of specialist tests became available. The patient was treated for his relapsed CLL with good effect, and has had no further episodes of angioedema and an improvement in the level of his C1 esterase protein level and function.

We retrospectively studied the prevalence of C1 esterase inhibitor (C1 INH) deficiency in 131 patients with various lymphomas. We determined C1 INH activity, C1 INH antigen, and C4 concentration at diagnosis and after chemotherapy. In follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) consecutive patients were studied. In these entities, the prevalence of C1 INH deficiency was 10.2% in DLBCL, 4.1% in CLL, and 0% in FL and Hodgkin lymphoma. In indolent lymphomas, we identified only single cases of C1 INH deficiency, predominantly in splenic marginal zone lymphomas (SMZL) (four cases). Only three patients were symptomatic while the majority (11 cases) was asymptomatic. In DLBCL patients who were successfully treated with chemotherapy, complete normalization of C1 INH activity and C4 was observed. In contrast, C1 INH deficiency remained in SMZL patients after splenectomy. We conclude that C1 INH deficiency in lymphomas is frequently asymptomatic and responsive to immunochemotherapy.

BACKGROUND: SerpinF2, SerpinG1, CystatinC and CD14 are involved in inflammatory processes and plasma extracellular vesicle (EV) -levels of these proteins have been reported to be associated with systemic vascular events. Evidence is accumulating that inflammatory processes may play a pivotal role both in systemic vascular events and in heart failure. Therefore, we studied the association between plasma extracellular vesicle SerpinF2-, SerpinG1-, CystatinC and CD14-levels and the occurrence of acute heart failure in patients. METHODS AND RESULT: Extracellular vesicle protein levels of SerpinG1, SerpinF2, CystatinC and CD14 were measured in an observational study of 404 subjects presenting with dysponea at the emergency department (4B-cohort). Plasma extracellular vesicles were precipitated in a total extracellular vesicles (TEX)-fraction and in separate LDL- and HDL-subfractions. Extracellular vesicle protein levels were measured with a quantitative immune assay in all 3 precipitates. Out of 404 subjects, 141 (35%) were diagnosed with acutely decompensated heart failure. After correction for confounders (including comorbidities and medications), levels of CD14 in the HDL-fraction (OR 1.53, p = 0.01), SerpinF2 in the TEX-and LDL-fraction (ORs respectively 0.71 and 0.65, p

Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs ofSERPING1andC5were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the sixC5SNPs, a marginal association was first detected between rs17611 and total DR patients (P=0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (Pcorr= 0.032, OR = 0.65 andPcorr= 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (Pcorr= 0.023). Regarding other variants inC5andSERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (allP>0.05). Our study revealed an association between DR andC5polymorphisms with clinical significance, whereasSERPING1is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.

Background The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. Methods We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. Results Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. Conclusions Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0611-x) contains supplementary material, which is available to authorized users.

Background Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of localized subcutaneous or submucosal edema. It is inherited in an autosomal dominant fashion and caused by a deficiency of C1 inhibitor (C1 INH). Most patients with HAE have an absolute deficiency of C1 INH (type I HAE), whereas the rest (approximately 15%) synthesize a dysfunctional C1 INH protein (type II HAE). Mosaicism is rare in HAE. Objective To describe the clinical manifestations, laboratory findings, and molecular genetic studies in a Taiwanese family with type I HAE with paternal mosaicism. Methods A family that included a 34-year-old man (index patient) and his 25-year-old brother who both had recurrent peripheral angioedema was evaluated. A younger sister had died of an unexplained cause at 18 years of age. We analyzed blood levels of C3, C4, and C1 INH and sequenced the SERPING1 ( C1NH ) gene that codes for C1 INH in 5 family members, including the parents and 3 brothers. Results The 4 men in the family had a novel mutation c.3_73del, p.N1fsX34 in exon 3 of the C1INH gene, resulting in C1 INH deficiency. Although the father carried this mutant gene, he had normal serum levels of C1 INH. Based on quantitative analysis of allele dosage by DNA fragment analysis (GeneScan), the father was determined to have genetic mosaicism. Conclusion Parental mosaicism is a possible explanation for normal C1 INH plasma concentrations in both parents despite clinically apparent HAE in the children.

[corrected] Hereditary angioedema (HAE) is a rare genetic disorder caused by a deficiency of the plasma protein C1 inhibitor (C1-INH). HAE is characterised by the onset of angioedema, which may develop in one or several organs, and may last from a few hours to several days. Oedema of the upper airway can be life-threatening. As a result of hormonal changes, some women experience more frequent angioedema attacks during pregnancy. During pregnancy, antifibrinolytic agents should only be used with caution, and attenuated androgens are contraindicated; therefore, replacement therapy with C1-INH concentrate represents one of few therapeutic options, but it is not widely documented.We report the first case study of the successful management with regular infusions of C1-INH concentrate, of two successive pregnancies in a patient with HAE. During the second half of the first pregnancy, C1-INH was administered on demand at home. For the second pregnancy, on demand treatment was intensified to prophylactic therapy, with once or twice weekly infusions from the middle of the second trimester in order to efficiently control the frequent attacks.This report illustrates that HAE can be successfully managed during pregnancy with C1-INH infusions at home. Since the number of crises may vary between pregnancies, the treatment regimen must be adapted to the patient's need.

IgA nephropathy (IgAN) is the most common form of chronic glomerulonephritis. Although glomerular deposition of complement components is well known, the evidence of serological complement activation in IgAN is inconclusive. We hypothesized that serum levels of complement components and regulatory proteins in patients with IgAN are correlated with its pathogenesis. In the present study we measured complement components in 50 patients with IgAN and 50 healthy volunteers. C5, C1 inhibitor, factor B, C4 binding protein, factor H, and factor I were measured with the use of single radial immunodiffusion. Mannose‐binding lectin (MBL) and properdin (P) were measured by enzyme‐linked immunosorbent assay (ELISA). The correlations among complements in the sera of patients with clinical gradings for IgAN (i.e., the good prognosis group, relatively good prognosis group, relatively poor prognosis group, and poor prognosis group) were evaluated. CH50, C4, factor B, P, factor I, and factor H were significantly higher in IgAN patients than in healthy controls. There were significant correlations between C5 and C4 binding protein, between C3 and C5, or between C4 and factor B in patients with IgAN. In the poor prognosis group, C4 binding protein was significantly higher than in the other groups of IgAN patients. hypercomplementemia occurs in IgAN and is associated with an increase in complement regulatory protein (CRP). C4 binding protein analyses can be used to predict disease prognosis. J. Clin. Lab. Anal. 21:77–84, 2007. © 2007 Wiley‐Liss, Inc.

Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions.165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3days post-percutaneous intervention (PCI) and, in one-third of the patients, 3months after PCI. In order to investigate the degree of Factor XII (FXII) activation, changes in FXIIa/AT and FXIIa/C1INH complex levels were quantified by ELISA.FXIIa/AT levels at admission (0.89±0.50; p0.01) were significantly higher than those in normal individuals (0.39±0.28), but the levels after 1-3days (0.33±0.33; p0.05) were essentially normalized. In contrast, the FXII/C1INH levels at admission (1.40±0.72; p0.001) and after 1-3days (0.83±0.59; p0.001) were both significantly higher than those in normal individuals (0.40±0.30). FXIIa/AT and FXIIa/C1INH complexes at admission (p0.001; p0.001) and after 1-3days (p0.02; p0.001) were significantly different from those at 3months. No significant differences were observed when the data were stratified for patency (open/closed culprit lesions).Both FXIIa/AT and FXIIa/C1INH complexes were significantly increased and reflected the activation of FXII in STEMI patients at admission. In particular, FXIIa/AT complex elevations support the hypothesis that clot propagation-mediated FXII activation had occurred, and this activation may be a target for anticoagulation in patients with cardiac infarction. Based on previous studies, the FXIIa/C1INH complex levels were primarily interpreted to reflex endothelial cell activation.