Hereditary Angioedema with Normal C1 Inhibitor

Magerl, Markus; Germenis, Anastasios E.; Maas, Coen; Maurer, Marcus

doi:10.1016/j.iac.2017.04.004

Cited by 47 publications

(46 citation statements)

References 95 publications

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“…In addition, when functional C1‐INH levels were measured in nl‐C1‐INH‐HAE based on inhibition of factor XIIa or kallikrein, a range of 60%‐75% of normal was reported . Data from off‐label experience tend to confirm the role of bradykinin in nl‐C1‐INH‐HAE and data that we presented here move in the same direction . However, lack of uniform diagnostic criteria for patients’ recruitment and a significant interindividual variability in response to treatment leave without convincing treatment strategy to approach nl‐C1‐INH‐HAE even within an off‐label area.…”

Section: Discussionsupporting

confidence: 58%

Impaired control of the contact system in hereditary angioedema with normal C1‐inhibitor

Bova

Suffritti

Bafunno

et al. 2020

Allergy

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Background: Hereditary angioedema (HAE) comprises HAE with C1-inhibitor deficiency (C1-INH-HAE) and HAE with normal C1-INH activity (nl-C1-INH-HAE), due to mutations in factor XII (FXII-HAE), plasminogen (PLG-HAE), angiopoietin 1 (ANGPT1-HAE), kininogen 1 genes (KNG1-HAE), or angioedema of unknown origin (U-HAE). The Italian network for C1-INH-HAE (ITACA) created a registry including different forms of angioedema without wheals. Objective: We analyzed clinical and laboratory features of a cohort of Italian subjects with nl-C1-INH-HAE followed by ITACA to identify specific biomarkers. Methods: A total of 105 nl-C1-INH-HAE patients were studied. Plasma concentrations of cleaved high-molecular-weight kininogen (cHK), vascular endothelial growth factors (VEGFs), angiopoietins (Angs), and secreted phospholipase A 2 enzymes (sPLA 2 ) were evaluated. Results:We identified 43 FXII-HAE patients, 58 U-HAE, and 4 ANGPT1-HAE. We assessed a prevalence of 1:1.4 × 10 6 for FXII-HAE and 1:1.0 × 10 6 for U-HAE. cHK levels in U-HAE patients were similar to controls in plasma collected using protease inhibitors cocktail (PIC), but they significantly increased in the absence of PIC. In FXII-HAE patients, cHK levels, in the absence of PIC, were significantly higher than in controls. We found a significant increase of VEGF-A, VEGF-C, and Ang1 levels in U-HAE patients compared to controls. In FXII-HAE, only VEGF-C levels were increased. Ang2 concentrations and sPLA 2 activity were not modified. The levels of these mediators in ANGPT1-HAE patients were not altered. Conclusions:Our results suggest that pathogenesis of FXII-, ANGPT1-, and U-HAE moves through an unbalanced control of kallikrein activity, with bradykinin as most likely mediator. VEGFs and Ang1 participate in the pathophysiology of U-HAE increasing the basal vascular permeability. K E Y W O R D S angioedema, biomarkers, epidemiology, genetic | 1395 BOVA et Al.

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Section: Discussionsupporting

confidence: 58%

Impaired control of the contact system in hereditary angioedema with normal C1‐inhibitor

Bova

Suffritti

Bafunno

et al. 2020

Allergy

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“…These data support recent studies showing the key role of the N-terminal domain of FXII in the activation of this molecule [30]. However, we must remember that most PMM2-CDG patients have not been exposed to the triggering factors that cause angioedema in carriers of the p.Thr309Lys mutation (pregnancy, oral contraceptives…) [31], and on the other hand that marked edemas were already reported in CDG patients [32][33][34][35][36].…”

Section: Discussionsupporting

confidence: 88%

Factor XII in PMM2-CDG patients: role of N-glycosylation in the secretion and function of the first element of the contact pathway.

Gálvez

Morena‐Barrio

López‐Lera

et al. 2020

Preprint

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Background. Congenital disorders of glycosylation (CDG) are rare diseases with impaired glycosylation and multiorgan disfunction, including hemostatic and inflammatory disorders. Factor XII (FXII), the first element of the contact phase, has an emerging role in hemostasia and inflammation. FXII deficiency protects against thrombosis and the p.Thr309Lys variant is involved in hereditary angioedema through the hyperreactivity caused by the associated defective O-glycosylation. We studied FXII in CDG aiming to supply further information of the glycosylation of this molecule, and its functional and clinical effects. Plasma FXII from 46 PMM2-CDG patients was evaluated by coagulometric and by Western Blot in basal conditions, treated with N-glycosydase F or activated by silica or dextran sulfate. A recombinant FXII expression model was used to validate the secretion and glycosylation of wild-type and variants targeting the two described FXII N-glycosylation sites (p.Asn230Lys; p.Asn414Lys) as well as the p.Thr309Lys variant. Results. PMM2-CDG patients had normal FXII levels (117%) but high proportions of a form lacking N-glycosylation at Asn414. Recombinant FXII p.Asn230Lys, and p.Asn230Lys&p.Asn414Lys had impaired secretion and increased intracellular retention compared to wild-type, p.Thr309Lys and p.Asn414Lys variants. The hypoglycosylated form of PMM2-CDG activated similarly than FXII fully glycosylated. Accordingly, no PMM2-CDG had angioedema. FXII levels did not associate to vascular events, but hypoglycosylated FXII, like hypoglycosylated transferrin, antithrombin and FXI levels did it. Conclusions. N-glycosylation at Asn230 is essential for FXII secretion. PMM2-CDG have high levels of FXII lacking N-glycosylation at Asn414, but this glycoform displays similar activation than fully glycosylated, explaining the absence of angioedema in CDG.

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“…Angioedema attacks in patients with HAE nC1‐INH and in patients taking ACE inhibitors are thought to be bradykinin mediated …”

Section: Differential Diagnosismentioning

confidence: 99%

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Maurer

Magerl

Ansotegui

et al. 2018

Allergy

467

974

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Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up‐to‐date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1‐inhibitor (type 1) and HAE with dysfunctional C1‐inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE‐1/2 be defined and classified?, (2) How should HAE‐1/2 be diagnosed?, (3) Should HAE‐1/2 patients receive prophylactic and/or on‐demand treatment and what treatment options should be used?, (4) Should HAE‐1/2 management be different for special HAE‐1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE‐1/2 management incorporate self‐administration of therapies and patient support measures?

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Hereditary Angioedema with Normal C1 Inhibitor

Cited by 47 publications

References 95 publications

Impaired control of the contact system in hereditary angioedema with normal C1‐inhibitor

Impaired control of the contact system in hereditary angioedema with normal C1‐inhibitor

Factor XII in PMM2-CDG patients: role of N-glycosylation in the secretion and function of the first element of the contact pathway.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

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