A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor

Bork, Konrad; Wulff, K.; Meinke, Peter; Wagner, Nicola; Hardt, Jochen; Witzke, Günther

doi:10.1016/j.clim.2011.07.002

Cited by 121 publications

(86 citation statements)

References 19 publications

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“…Several mutations in the factor XII gene have been identified in patients with HAE type III and all of these mutations are in the same factor XII gene region. [18][19][20] This suggests an association between altered processing of the factor XII protein and the disorder. However, how a defective factor XII protein affects BK levels is not understood yet.…”

Section: Hereditary Angioedemamentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecularweight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. Learning Objectives• To understand that the contact system consists of 4 proteins: factor XI, factor XII, PK, and HK • To understand that deficiency of factor XII, PK, or HK is not associated with a bleeding tendency in humans • To understand that targeting the contact system is an effective method to prevent thrombosis in mice •

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Section: Hereditary Angioedemamentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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“…In the last few years, two additional mutations in the F12 gene also located in exon 9 have been reported in patients with HAE: a deletion of 72 base pairs (bp, i.e. c.971_1018 +24 del72) [11] and a duplication of 18 bp (p.Pro298_Pro303dup) [12]. Initially known as HAE type III, HAE with normal C1-INH is currently classified into two subgroups: HAE with normal C1-INH and factor XII mutation (FXII-HAE) and HAE with normal C1-INH of unknown origin (U-HAE) [2].…”

Section: Introductionmentioning

confidence: 99%

Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor

Moreno¹,

Valle

Levy

et al. 2015

Int Arch Allergy Immunol

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Background: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. Methods: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. Results: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. Conclusions: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.

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“…22 A mutation in Factor XII has been identified in some of these patients. 23 C1-INH is a serpin-class protein, which acts as a nonreversible…”

Section: Discussionmentioning

confidence: 99%

Use of Ecallantide in Pediatric Hereditary Angioedema

et al. 2013

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WHAT'S KNOWN ON THIS SUBJECT:Patients with hereditary angioedema (HAE) have recurrent episodes of painful swelling. Several new therapies to prevent and treat HAE attacks are approved by the Food and Drug Administration, but their safety and efficacy in children are largely unknown.WHAT THIS STUDY ADDS: Ecallantide appears effective for treatment of HAE attacks in pediatric patients age 10 to 17 years with an acceptable safety profile. It represents a potential treatment option for adolescents with HAE. abstract OBJECTIVE: Hereditary angioedema (HAE) due to C1-inhbitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients ,18 years of age.METHODS: Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined. RESULTS:Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (21.4 6 0.9 ecallantide versus 20.9 6 0.6 placebo) and TOS (73.9 6 35.50 ecallantide versus 45.0 6 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed.CONCLUSIONS: Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified. Pediatrics 2013;132:e490-e497 AUTHORS:

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A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor

Cited by 121 publications

References 19 publications

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor

Use of Ecallantide in Pediatric Hereditary Angioedema

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