Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III
Sven Cichon,Ludovic Martin,Hans Christian Hennies,Felicitas Müller,Karen Van Driessche,A. Karpushova,Wim J. Stevens,Roberto Colombo,Thomas Renné,Christian Drouet,Konrad Bork,Markus M. Nöthen +11 more
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TLDR
It is concluded that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema.Abstract:
Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema. Three forms of HAE have been described. The classic forms, HAE types I and II, occur as a consequence of mutations in the C1-inhibitor gene. In contrast to HAE types I and II, HAE type III has been observed exclusively in women, where it appears to be correlated with conditions of high estrogen levels--for example, pregnancy or the use of oral contraceptives. A recent report proposed two missense mutations (c.1032C-->A and c.1032C-->G) in F12, the gene encoding human coagulation factor XII (FXII, or Hageman factor) as a possible cause of HAE type III. Here, we report the occurrence of the c.1032C-->A (p.Thr328Lys) mutation in an HAE type III-affected family of French origin. Investigation of the F12 gene in a large German family did not reveal a coding mutation. Haplotype analysis with use of microsatellite markers is compatible with locus heterogeneity in HAE type III. To shed more light on the pathogenic relevance of the HAE type III-associated p.Thr328Lys mutation, we compared FXII activity and plasma levels in patients carrying the mutation with that of healthy control individuals. Our data strongly suggest that p.Thr328Lys is a gain-of-function mutation that markedly increases FXII amidolytic activity but that does not alter FXII plasma levels. We conclude that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema. Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected with HAE type III. The results of our study represent an important step toward an understanding of the molecular processes involved in HAE type III and provide diagnostic and possibly new therapeutic opportunities.read more
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Clinical practice. Hereditary angioedema.
TL;DR: A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier.
Journal ArticleDOI
Complement and coagulation: strangers or partners in crime?
Maciej M. Markiewski,Bo Nilsson,Kristina Nilsson Ekdahl,Tom Eirik Mollnes,Tom Eirik Mollnes,John D. Lambris +5 more
TL;DR: The interactions of the complement system with hemostasis and their roles in various diseases are reviewed and the crosstalk between complement and coagulation is well illustrated.
Journal ArticleDOI
Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group
Marco Cicardi,Werner Aberer,Aleena Banerji,Murat Bas,Jonathan A. Bernstein,Konrad Bork,Teresa Caballero,Henriette Farkas,Anete Sevciovic Grumach,Allen P. Kaplan,Marc A. Riedl,Massimo Triggiani,Andrea Zanichelli,Bruce L. Zuraw +13 more
TL;DR: Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting.
Journal ArticleDOI
In vivo roles of factor XII.
TL;DR: The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology.
Journal ArticleDOI
The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities.
TL;DR: There is revived interest in the CAS and KKS due to better understanding of their activities and the new appreciation of these systems will lead to several new therapies for a variety of medical disorders.
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Defective thrombus formation in mice lacking coagulation factor XII
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