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C1-inhibitor (C1-INH) is an important regulator of the complement, coagulation, fibrinolytic and contact systems. The quantity of protease/C1-INH complexes in the blood is proportional to the level of the in vivo activation of these four cascade-like plasma enzyme systems. Parallel determination of C1-INH-containing activation complexes could be important to understand the regulatory role of C1-INH in diseases such as hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE). We developed in-house ELISAs to measure the concentration of complexes of C1-INH formed with active proteases: C1r, C1s, MASP-1, MASP-2, plasma kallikrein, factor XIIa, factor XIa, and thrombin, as well as to determine total and functionally active C1-INH. We measured the concentration of the complexes in EDTA plasma from 6 healthy controls, from 5 with type I and 5 with type II C1-INH-HAE patients during symptom-free periods and from five patients during HAE attacks. We also assessed the concentration of these complexes in blood samples taken from one C1-INH-HAE patient during the kinetic follow-up of a HAE attack. The overall pattern of complexed C1-INH was similar in controls and C1-INH-HAE patients. C1-INH formed the highest concentration complexes with C1r and C1s. We observed higher plasma kallikrein/C1-INH complex concentration in both type I and type II C1-INH-HAE, and higher concentration of MASP-1/C1-INH, and MASP-2/C1-INH complexes in type II C1-INH-HAE patients compared to healthy controls and type I patients. Interestingly, none of the C1-INH complex concentrations changed significantly during HAE attacks. During the kinetic follow-up of an HAE attack, the concentration of plasma kallikrein/C1-INH complex was elevated at the onset of the attack. In parallel, C1r, FXIIa and FXIa complexes of C1-INH also tended to be elevated, and the changes in the concentrations of the complexes followed rather rapid kinetics. Our results suggest that the complement classical pathway plays a critical role in the metabolism of C1-INH, however, in C1-INH-HAE, contact system activation is the most significant in this respect. Due to the fast changes in the concentration of complexes, high resolution kinetic follow-up studies are needed to clarify the precise molecular background of C1-INH-HAE pathogenesis. [ABSTRACT FROM AUTHOR]

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Hereditary angioedema (HAE) is a rare, but potentially life-threatening disorder, characterized by acute, recurring, and self-limiting edematous episodes of the face, extremities, trunk, genitals, upper airways, or the gastrointestinal tract. HAE may be caused by the deficiency of C1-inhibitor (C1-INH-HAE) but another type of the disease, hereditary angioedema with normal C1-INH function (nC1-INH-HAE) was also described. The patient population is quite heterogeneous as regards the location, frequency, and severity of edematous attacks, presenting large intra- and inter-individual variation. Here, we review the role of the complement system in the pathomechanism of HAE and also present an overview on the complement parameters having an importance in the diagnosis or in predicting the severity of HAE. [ABSTRACT FROM AUTHOR]

Background The clinical expressions of hereditary angioedema with C1-inhibitor deficiency (C1- INH- HAE) and its related burden may negatively affect patient quality of life. This study aimed to assess health-related quality of life ( HRQoL) in children with C1- INH- HAE. Methods Children (N = 98: 34 C1- INH- HAE patients, 64 healthy controls) aged 3-18 years were recruited in Israel and Hungary. All individuals completed a demographic questionnaire, a disease activity and site questionnaire, and the Pediatric Quality of Life Inventory (Peds QL™) 4.0 Generic Core Scales (child self-report and maternal proxy report) to assess HRQoL. Results Among C1- INH- HAE patients, nine (26.5%) had 1-5 attacks/year, six (17.6%) had 6-18 attacks/year, eight (23.5%) had 25-60 attacks/year, and 11 (32.4%) were asymptomatic over the previous year. Children with C1- INH- HAE attacks demonstrated lower HRQoL than healthy control children across the total score, school, and psychosocial dimensions of the Peds QL™. The number of C1- INH- HAE attacks negatively correlated with the total HRQoL score (r = −0.48, p = 0.008), school-related HRQoL (r = −0.39, p = 0.02), and psychosocial HRQoL (r = −0.43, p = 0.01). Patients with multisite laryngeal, abdominal, and peripheral C1- INH- HAE attacks had a lower HRQoL compared with those who experienced solely peripheral attacks across the total score (p = 0.04), physical (p = 0.04), and school (p = 0.02) domains. There was no significant difference between asymptomatic C1- INH- HAE patients and healthy controls. Conclusions Children with symptomatic C1- INH- HAE demonstrate impaired HRQoL compared with healthy controls. HRQoL was affected by the frequency and site of C1- INH- HAE attacks and mostly in the school and physical domains. [ABSTRACT FROM AUTHOR]

Background: Plasma-derived C1-inhibitor (C1-INH) concentrates (pdC1-INH) have been used as safe and effective treatments for hereditary angioedema with C1-INH deficiency (C1-INH-HAE) for >30 years. Notwithstanding this, sporadic reports and a study into the high-dose therapy of neonates with C1-INH concentrate administered in an off-label indication raised concerns that this drug might increase the risk of thromboembolism. Objective: To investigate the incidence of thromboembolism and the background of the risk factors related to treatment with pdC1-INH. Methods: Our retrospective cohort study of 144 patients with C1-INH-HAE compared the incidence of thromboembolism and its risk factors in patients who received pdC1-INH with those who did not receive pdC1-INH as well as with those treated with danazol or with tranexamic acid. Results: During the observation period (29 years), 104 of the 144 subjects received pdC1-INH. The average dose per treatment was 573.59 IU. None of the patients used an indwelling central venous catheter. Multiple risk factors for thromboembolism were identified in 93 of the 104 patients treated with pdC1-INH. The incidence rate of thromboembolism was 0.0019/100 person-years in patients treated with pdC1-INH, whereas it was 0.0211/100 person-years in the not-treated group. Conclusion: Our cohort study did not find any evidence for an increased risk of thromboembolism during treatment with pdC1-INH, despite the presence of multiple predisposing factors. [ABSTRACT FROM AUTHOR]

Background: The activation of plasma enzyme systems contributes to hereditary angioedema attacks. We aimed to study the activation markers of the fibrinolytic, coagulation, and contact systems in a larger number of paired samples obtained from the same C1-INH-HAE patients in symptom-free periods and during attacks.Methods: Eleven parameters (Factors XI, XII, and C1-inhibitor activity; the concentrations of the D-dimer, prothrombin fragments 1 + 2, plasminogen, plasminogen activator inhibitor-1 [PAI-1], thrombin-anti-thrombin III [TAT] complex, fibrinogen) were measured along with prothrombin time and activated partial thromboplastin time (aPTT), using commercial kits. We compared these markers in samples obtained from the same 39 patients during attack-free periods and during 62 edematous episodes. Forty healthy subjects of matching sex and age served as controls.Results: Compared with the healthy controls, significantly higher FXI and FXII activity (p = 0.0007, p = 0.005), as well as D-dimer (p < 0.0001), prothrombin fragments 1 + 2 (p < 0.0001), and TAT (p = 0.0303) levels were ascertained in the patients during symptom-free periods. The evaluation of samples from symptom-free periods or obtained during attacks revealed the increase of FXII activity, as well as of the concentration of D-dimer, prothrombin fragments 1 + 2, and TAT during edematous episodes. PAI-1 level, prothrombin time, and aPTT decreased significantly during attacks, compared with symptom-free periods. D-dimer level was significantly higher during multiple- vs. single-site attacks.Conclusions: Comparing a large number of paired samples from symptom-free periods or from edematous episodes allowed accurate appraisal of the changes occurring during attacks. Moreover, our study pointed out that individual episodes may be characterized by different marker patterns. [ABSTRACT FROM AUTHOR]

Hereditary angioedema resulting from C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder, characterized by recurrent attacks of edema formation. The management of pregnant patients with C1-INH-HAE is often a challenge for the physician. There is limited experience with novel therapies. Plasma-derived nanofiltered C1-INH (pnfC1-INH) is the only recommended therapeutic option during pregnancy. In our 26-year-old female patient with type II C1-INH-HAE, pregnancy was confirmed in the sixth week of gestation. During this period, the patient received the bradykinin B2-receptor antagonist, icatibant, on five occasions, as acute treatment. She experienced 119 attacks, for which she received 108 vials of pnfC1-INH during her pregnancy. The patient gave birth to a healthy baby. No side effects were detected with either treatment. No reports have been published to date on multiple dosing with icatibant during the first trimester of pregnancy. This therapy proved effective and free of maternal or fetal adverse effects. [ABSTRACT FROM AUTHOR]

• Erythema marginatum (EM) is the only objective prodromal symptom. • We measured coagulation parameters in the presence of EM for the first time. • We found differences in aPTT, as well as in D-dimer and Factor XI levels. • Erythema marginatum may be regarded as the initial phase of a HAE attack. • This may provide the basis for individualized therapy as early as during EM. Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent episodes of subcutaneous/submucosal edema, which may be preceded by erythema marginatum (EM) as a prodromal symptom. Our aim was to analyze the changes occurring in the parameters of the coagulation system during the development of EM and HAE attacks. Eight C1-INH-HAE patients (1 male, 7 females, median age: 41.7 years) were studied. Blood samples were obtained from all patients (during symptom-free periods, EM, and HAE attacks), as well as from 20 sex- and age-matched healthy controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, Factor V, Factor VII, Factor X, Factor XI, and Factor XII levels were measured. D-dimer levels were significantly lower, whereas aPTT was significantly prolonged in healthy controls vs. the values measured during the symptom-free period (p = 0.0497; p = 0.0043), in the presence of EM (p = 0.002; p = 0.0002), or during HAE attacks (p < 0.0001; p = 0.0002). We observed the following differences between samples taken during HAE attacks vs. in symptom-free periods: D-dimer levels were significantly elevated (p = 0.0391), while aPTT was significantly shorter during HAE attacks (p = 0.0159). D-dimer levels were significantly higher during EM than in symptom-free periods (p = 0.0078). Comparing the samples drawn during EM or during HAE attacks, there were no significant differences in the study parameters. D-dimer levels were elevated during EM and this suggests that EM may be part of the HAE attack. Nevertheless, further research into the complement and kinin-kallikrein systems is needed in more patients for a better understanding of the pathomechanism of EM. [ABSTRACT FROM AUTHOR]