Idiopathic angioedema with F12 mutation: is it a new entity?

Gelincik, Aslı; Demir, Semra; Olgaç, Müge; Karaman, Volkan; Toksoy, Güven; Çolakoğlu, Bahattin; Büyüköztürk, Suna; Uyguner, Zehra Oya

doi:10.1016/j.anai.2014.11.018

Cited by 11 publications

(9 citation statements)

References 11 publications

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“…We have coined this mutation Del&Ins, for short. Finally, a substitution mutation (A324P) and a six-amino acid duplication event (FXII-Dup) in broadly the same area of the FXII molecule were reported in associated with FXII-HAE [74,75]. The overarching hypothesis is that all pathogenic forms of FXII increase the sensitivity to natural triggers for bradykinin production.…”

Section: Fxii-haementioning

confidence: 98%

Hereditary angioedema: the plasma contact system out of control

Maat

Hofman

Maas

2018

Journal of Thrombosis and Haemostasis

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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.

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Section: Fxii-haementioning

confidence: 98%

Hereditary angioedema: the plasma contact system out of control

Maat

Hofman

Maas

2018

Journal of Thrombosis and Haemostasis

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“…As a result, the protein migrates at a height that is indistinguishable from normal FXII ( 33 ). Similarly, the molecular weight of mutation A324P is virtually identical to normal FXII and no changes in glycosylation are expected ( 37 ), leaving the molecular weight of mutant FXII nearly identical to normal FXII.…”

Section: Factor XIImentioning

confidence: 99%

The Search for Biomarkers in Hereditary Angioedema

Kaplan

Maas

2017

Front. Med.

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The unpredictable nature of attacks of tissue swelling in hereditary angioedema requires the identification of reliable biomarkers to monitor disease activity as well as response to therapy. At present, one can assess a C4 level (by ELISA) to assist in diagnosis but neither C4 nor C1 inhibitor levels reflect clinical course or prognosis. We will here review a collection of plasma proteins involved in blood coagulation, fibrinolysis, and innate immunity (Figure 1). A main focus is those proteins that are key to the formation of bradykinin (BK); namely, factor XII, plasma prekallikrein/kallikrein, high-molecular weight kininogen, and BK itself since overproduction of BK is key to the disease. Considerations include new approaches to measurement of active enzymes, ELISA methods that may supersede SDS gel analysis of bond cleavages, and examples of changes outside the BK cascade that may reflect when, where, and how an attack of swelling is initiated. We will discuss their usefulness as biomarker candidates, with pros and cons, and compare the analytical methods that are being developed to measure their levels or activity.

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“…The available genetic evidence of HAE-related mutations clearly points towards a central role of the plasma contact system in this disease. Most HAE patients have SERPING1 gene mutations (encoding for C1-inhibitor ( C1-INH ) production) [ 14 , 15 ] while a small minority have mutations in the F12 gene, with normal C1-INH activity [ 16 – 20 ].…”

Section: Bradykinin-mediated Angioedemamentioning

confidence: 99%

“…Genome-wide screening of a subset of HAE patients with normal C1-INH level and function (formerly called type III HAE) resulted in the discovery of disease-related mutations in the F12 gene (named FXII-HAE). Since then, several mutations in HAE patients have been described, (mostly) located in the proline -rich region of FXII (according to mature amino acid sequence: Thr309Arg, Thr309Lys, Ala324Pro, 72-bp deletion at c971_1018þ24 and an 18-bp duplication c894_911, and c1681-1G/A in intron 13) [ 16 – 20 , 59 ]. Additionally, isolated cases of normal C1-INH with FXII mutation have been successfully treated with the bradykinin-receptor antagonist—icatibant.…”

Section: Blood Coagulationmentioning

confidence: 99%

Bradykinin: Inflammatory Product of the Coagulation System

Hofman

Maat

Hack

et al. 2016

Clinic Rev Allerg Immunol

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Episodic and recurrent local cutaneous or mucosal swelling are key features of angioedema. The vasoactive agents histamine and bradykinin are highly implicated as mediators of these swelling attacks. It is challenging to assess the contribution of bradykinin to the clinical expression of angioedema, as accurate biomarkers for the generation of this vasoactive peptide are still lacking. In this review, we will describe the mechanisms that are responsible for bradykinin production in hereditary angioedema (HAE) and the central role that the coagulation factor XII (FXII) plays in it. Evidently, several plasma parameters of coagulation change during attacks of HAE and may prove valuable biomarkers for disease activity. We propose that these changes are secondary to vascular leakage, rather than a direct consequence of FXII activation. Furthermore, biomarkers for fibrinolytic system activation (i.e. plasminogen activation) also change during attacks of HAE. These changes may reflect triggering of the bradykinin-forming mechanisms by plasmin. Finally, multiple lines of evidence suggest that neutrophil activation and mast-cell activation are functionally linked to bradykinin production. We put forward the paradigm that FXII functions as a ‘sensor molecule’ to detect conditions that require bradykinin release via crosstalk with cell-derived enzymes. Understanding the mechanisms that drive bradykinin generation may help to identify angioedema patients that have bradykinin-mediated disease and could benefit from a targeted treatment.

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Idiopathic angioedema with F12 mutation: is it a new entity?

Cited by 11 publications

References 11 publications

Hereditary angioedema: the plasma contact system out of control

Hereditary angioedema: the plasma contact system out of control

The Search for Biomarkers in Hereditary Angioedema

Bradykinin: Inflammatory Product of the Coagulation System

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