Hereditary angioedema: the plasma contact system out of control.

The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.

Distinct conditions support a novel classification for bradykinin-mediated angio-oedema.

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.

Enzymatic assays for the diagnosis of bradykinin-dependent angioedema.

BACKGROUND: The kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the SERPING1 gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). Besides C1-Inhibitor function and concentration, no biological assay of kinin metabolism is actually available to help physicians for the diagnosis of angioedema (AE). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE. METHODS: The plasma amidase assays are performed using the Pro-Phe-Arg-p-nitroanilide peptide substrate to evaluate the spontaneous amidase activity and the proenzyme activation. We analyzed data of 872 patients presenting with BK-dependent AE or BK-unrelated diseases, compared to 303 controls. Anti-high MW kininogen (HK) immunoblot was achieved to confirm HK cleavage in exemplary samples. Reproducibility, repeatability, limit of blank, limit of detection, precision, linearity and receiver operating characteristics (ROC) were used to calculate the diagnostic performance of the assays. RESULTS: Spontaneous amidase activity was significantly increased in all BK-dependent AE, associated with the acute phase of disease in HAE-nC1INH, but preserved in BK-unrelated disorders. The increase of the amidase activity was associated to HK proteolysis, indicating its relevance to identify kininogenase activity. The oestrogens, known for precipitating AE episodes, were found as triggers of enzymatic activity. Calculations from ROC curves gave the optimum diagnostic cut-off for women (9.3 nmol⋅min(-1)⋅mL(-1), area under curve [AUC] 92.1%, sensitivity 80.0%, and specificity 90.1%) and for men (6.6 nmol·min(-1)⋅mL(-1), AUC 91.0%, sensitivity 87.0% and specificity 81.2%). CONCLUSION: The amidase assay represents a diagnostic tool to help physicians in the decision to distinguish between BK-related and -unrelated AE.

Human C1-esterase inhibitor concentrate (Berinert).

Human C1-esterase inhibitor concentrate (C1-INH concentrate) is derived from human plasma and is indicated for the treatment of acute episodes of hereditary angioedema. Intravenous C1-INH concentrate provided rapid symptom relief in patients with acute abdominal or facial episodes associated with type I or II hereditary angioedema, according to the results of the randomized, double-blind, multicenter, placebo-controlled IMPACT-1 trial. The median time to the onset of symptom relief was significantly shorter with C1-INH concentrate 20 U/kg than with placebo (0.5 vs 1.5 hours). A subsequent noncomparative extension trial (IMPACT-2) showed the ongoing efficacy of 'on-demand' treatment with C1-INH concentrate; overall, the onset of symptom relief occurred in a median 30 minutes. Several additional studies demonstrated the efficacy of intravenous C1-INH concentrate in patients with laryngeal edema, skin swellings, or abdominal episodes associated with type I or II hereditary angioedema. Self-administered home therapy with intravenous C1-INH concentrate significantly improved health-related quality of life in patients with hereditary angioedema. Dermatology Life Quality Index and Short Form 36-item Health Survey scores were significantly improved from baseline by self-administered home therapy with C1-INH concentrate. Intravenous C1-INH concentrate was well tolerated in patients with hereditary angioedema, with no confirmed cases of viral transmission.