Flaujeac Factor Deficiency

Last update 01 Nov 2024

Basic Info

Synonyms

FITZGERALD TRAIT, Fitzgerald Trait, Fitzgerald factor deficiency

+ [15]

Introduction

A rare autosomal recessive inherited disorder characterized by prolonged partial thromboplastin time and absence of bleeding diathesis.

100 Clinical Results associated with Flaujeac Factor Deficiency

100 Translational Medicine associated with Flaujeac Factor Deficiency

0 Patents (Medical) associated with Flaujeac Factor Deficiency

Literatures (Medical) associated with Flaujeac Factor Deficiency

10 Sep 2024·Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics

[Analysis of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein deficiency and High molecular weight kininogen deficiency].

Article

Author: Wang, Mingshan ; Chen, Yuan ; Xie, Zuoting ; Jin, Yanhui ; Chen, Bile ; Zheng, Zhou ; Chen, Huilin

OBJECTIVETo analyze the laboratory phenotype and genetic variants of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein (PK) and High molecular weight kininogen (HMWK) deficiency and explore their molecular pathogenesis.METHODSA PK deficiency pedigree (10 individuals from 4 generations) and a HMWK deficiency pedigree (6 individuals from 3 generations) which were admitted to the First Affiliated Hospital of Wenzhou Medical University on December 3, 2021 and June 16, 2022, respectively were selected as the study subjects. Clinical data of the two pedigrees were collected, and the related coagulation indexes of the probands and their family members were determined. Genomic DNA of the two pedigrees was extracted from peripheral blood samples. All of the exons and flanking sequences of the KLKB1 and KNG1 genes of the probands were analyzed by direct sequencing. And the corresponding sites were sequenced among other family members. Bioinformatic software was used to analyze the conservation of variation sites and the effect of variant on the protein function.RESULTSThe plasma PK activity of proband 1, a 29-year-old female, and her brother were extremely low (< 1.0%). Proband 2 was a 66-year-old male with extremely low plasma HMWK activity (< 1.0%). Genetic sequencing revealed that the proband 1 and her brother had both harbored a homozygous c.417_418insCATTCTTA (p.Arg140Hisfs*3) insertional variant in exon 5 of the KLKB1 gene. Proband 2 had harbored a homozygous c.460C>A (p.Pro154Thr) missense variant in exon 4 of the KNG1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were respectively rated as pathogenic (PVS1+PM2_Supporting+PM4) and likely pathogenic (PS4+PM2_Supporting+PP3+PP4).CONCLUSIONThe c.417_418insCATTCTTA (p.Arg140Hisfs*3) variant of the KLKB1 gene and the c.460C>A (p.Pro154Thr) variant of the KNG1 gene probably underlay the decreased PK and HMWK activities in the two pedigrees, respectively.

01 Feb 2023·Journal of Thrombosis and Haemostasis

Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency–causing KNG1 variants, and estimated prevalence

Review

Author: Alesci, Sonja ; Echenagucia, Marion ; Lackner, Karl J ; Barco, Stefano ; Trinchero, Alice ; Ambaglio, Chiara ; Adenaeuer, Anke ; Krutmann, Sarah ; Sollfrank, Stefanie ; Ruiz-Sáez, Arlette ; Tomao, Luigi ; Häuser, Friederike ; Rocco, Vincenzo ; Nazir, Hanan Fawzy ; Ezigbo, Eyiuche D ; Pancione, Ylenia ; Lämmle, Bernhard ; Rossmann, Heidi

BACKGROUNDSevere high-molecular-weight kininogen (HK) deficiency is a poorly studied autosomal recessive contact system defect caused by pathogenic, biallelic KNG1 variants.AIMWe performed the first comprehensive analysis of diagnostic, clinical, genetic, and epidemiological aspects of HK deficiency.METHODSWe collected clinical information and blood samples from a newly detected HK-deficient individual and from published cases identified by a systematic literature review. Activity and antigen levels of coagulation factors were determined. Genetic analyses of KNG1 and KLKB1 were performed by Sanger sequencing. The frequency of HK deficiency was estimated considering truncating KNG1 variants from GnomAD.RESULTSWe identified 48 cases of severe HK deficiency (41 families), of these 47 have been previously published (n = 19 from gray literature). We genotyped 3 cases and critically appraised 10 studies with genetic data. Ten HK deficiency-causing variants (one new) were identified. All of them were truncating mutations, whereas the only known HK amino acid substitution with a relevant phenotype instead causes hereditary angioedema. Conservative estimates suggest an overall prevalence of severe HK deficiency of approximately one case per 8 million population, slightly higher in Africans. Individuals with HK deficiency appeared asymptomatic and had decreased levels of prekallikrein and factor XI, which could lead to misdiagnosis.CONCLUSIONHK deficiency is a rare condition with only few known pathogenic variants. It has an apparently good prognosis but is prone to misdiagnosis. Our understanding of its clinical implications is still limited, and an international prekallikrein and HK deficiency registry is being established to fill this knowledge gap.

01 Apr 2021·Journal of Thrombosis and HaemostasisQ2 · MEDICINE

Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low‐density lipoprotein receptor‐deficient mice

Q2 · MEDICINE

Article

Author: Gailani, David ; Tavori, Hagai ; Revenko, Alexey S ; Tucker, Erik I ; Gruber, András ; Lorentz, Christina U ; Ngo, Anh T P ; Reitsma, Stéphanie E ; Hagen, Matthew W ; Cheng, Quifang ; Jordan, Kelley R ; Fazio, Sergio ; Mueller, Paul A ; Puy, Cristina ; Hinds, Monica T ; Monia, Brett P ; McCarty, Owen J T

BACKGROUNDHuman coagulation factor (F) XI deficiency, a defect of the contact activation system, protects against venous thrombosis, stroke, and heart attack, whereas FXII, plasma prekallikrein, or kininogen deficiencies are asymptomatic. FXI deficiency, inhibition of FXI production, activated FXI (FXIa) inhibitors, and antibodies to FXI that interfere with FXI/FXII interactions reduce experimental thrombosis and inflammation. FXI inhibitors are antithrombotic in patients, and FXI and FXII deficiencies are atheroprotective in apolipoprotein E-deficient mice.OBJECTIVESInvestigate the effects of pharmacological targeting of FXI in experimental models of atherogenesis and established atherosclerosis.METHODS AND RESULTSLow-density lipoprotein receptor-knockout (Ldlr^-/- ) mice were administered high-fat diet (HFD) for 8 weeks; concomitantly, FXI was targeted with anti-FXI antibody (14E11) or FXI antisense oligonucleotide (ASO). 14E11 and FXI-ASO reduced atherosclerotic lesion area in proximal aortas when compared with controls, and 14E11 also reduced aortic sinus lesions. In an established disease model, in which therapy was given after atherosclerosis had developed, Ldlr^-/- mice were fed HFD for 8 weeks and then administered 14E11 or FXI-ASO weekly until 16 weeks on HFD. In this established disease model, 14E11 and FXI-ASO reduced atherosclerotic lesion area in proximal aortas, but not in aortic sinus. In cultures of human endothelium, FXIa exposure disrupted VE-Cadherin expression and increased endothelial lipoprotein permeability. Strikingly, we found that 14E11 prevented the disruption of VE-Cadherin expression in aortic sinus lesions observed in the atherogenesis mouse model.CONCLUSIONPharmacological targeting of FXI reduced atherogenesis in Ldlr^-/- mice. Interference with the contact activation system may safely reduce development or progression of atherosclerosis.

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Flaujeac Factor Deficiency

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