Early Diagnosis and Management of Congenital Afibrinogenemia: A Case Report of Umbilical Stump Bleeding.

Afibrinogenemia is an extremely rare bleeding disorder characterized by the absence or severe deficiency of fibrinogen, a major protein involved in the regulation of blood clotting. This disorder can have both hemorrhagic and/or thrombotic manifestations. We present the case of a female neonate who was diagnosed with congenital afibrinogenemia within the first two weeks of life. The patient presented with persistent bleeding from the umbilical stump, prompting a thorough investigation and workup. Early diagnosis and management were essential to preventing life-threatening bleeding events.

A Quest to Find the Aetiology of Pulmonary Embolism Beyond the Common: A Case of Dyshypofibrinogenemia Presenting as Pulmonary Embolism.

Hypodysfibrinogenemia-related thromboembolic disorder is a rarely encountered clinical entity. We present such a case of a 34-year-old lady with no known co-morbidities presenting to the accident and emergency unit with left-sided pleuritic chest pain associated with non-productive cough and breathlessness. Laboratory tests revealed fibrinogen level of 0.42 g/l (1.5-4g/l) with prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT) along with elevated d-dimer, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin. CT pulmonary angiogram (CTPA) found bilateral pulmonary embolism with right heart strain. Functional/antigenic fibrinogen ratio was 0.38. Genetic testing eventually revealed a heterozygous missense mutation in exon 8-p.1055G>C; p.Cys352Ser in the sequencing of the fibrinogen gene FGG (gamma chain) confirming the diagnosis of dyshypofibrinogenemia. She was treated with anticoagulants with fibrinogen replacement therapy and later discharged on apixaban.

Clinical manifestations and genetic mutation analysis of 20 patients with congenital Fibrinogen disorders / 中国输血杂志

【Objective】 To retrospectively analyze the clinical manifestations, related laboratory examinations and gene mutation of 20 patients with congenital Fibrinogen disorders (CFD) admitted to our hospital from February 2017 to December 2021, so as to improve the understanding of CFD diagnosis. 【Methods】 Clinical characteristics and laboratory examination of 20 CFD patients were collected, and common secondary hypoFibrinemia factors were excluded. Gene sequencing was performed on all exons and flanks of FGA, FGB and FGG genes of 20 patients to find gene mutation sites. The peripheral blood genomic DNA was collected from the family members of two CFD patients, and the genes of the corresponding mutation sites of the proband were detected. 【Results】 The 20 CFD patients had no history of bleeding; 11 female patients had no history of spontaneous abortion; all 20 patients had reduced Fib and prolonged thrombin time (TT). There were 13 gene mutations of different types in 20 patients, among which 90% (18/20) were missense mutations, 5% (1/20) was deletion mutation, and 5% (1/20) was frameshift mutation. Seven patients (35%) had Arg35His mutation at site 104 of the FGA chain, among which 3 new gene mutations have not been reported in China. 【Conclusion】 Most CFD patients with mild or asymptomatic symptoms can be diagnosed by genetic testing and screening. FGA chain Arg35His is a mutation hotspot in this region, and all of them are Uyghur. Whether the mutation of this site is related to ethnicity needs to be confirmed by further studies.

Structural and Functional Characterization of Four Novel Fibrinogen Mutations in FGB Causing Congenital Fibrinogen Disorder.

Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and structural analysis of 4 novel variants located in the FGB gene coding for fibrinogen Bß chain-heterozygous missense BßY416C and BßA68S, homozygous nonsense BßY345*, and heterozygous nonsense BßW403* mutations. The cases were identified by coagulation screening tests and further investigated by various methods. Fibrin polymerization had abnormal development with decreased maximal absorbance in all patients. Plasmin-induced fibrin degradation revealed different lytic phases of BßY416C and BßW403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of BßA68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of BßY416C, BßA68S, and BßW403*, and in the fiber density of BßY416C and BßW403*. Finally, homology modeling of BßA68S showed that mutation caused negligible alternations in the protein structure. In conclusion, all mutations altered the correct fibrinogen function or structure that led to congenital fibrinogen disorders.

Automated screening procedure for the phenotypes of congenital fibrinogen disorders using novel parameters, |min1|c and Ac/|min1|c, obtained from clot waveform analysis using the Clauss method.

INTRODUCTION: Fibrinogen activity (Ac) is widely measured, but fibrinogen antigen (Ag) is measured only in specialized laboratories, so it is difficult to discriminate congenital fibrinogen disorders (CFDs) from acquired hypofibrinogenemia (aHypo). In this study, to screen for CFD phenotypes we adopted novel parameters, |min1|c and Ac/ |min1|c, and compared these with validated Ac, Ag, and Ac/Ag, and previously proposed Ac/dH and Ac/|min1|. MATERIALS AND METHODS: We calibrated |min1| using a CN-6000 instrument and investigated the correlation between Ag and |min1|c for aHypo (n = 131) and CFD [18 dysfibrinogenemia (Dys), two hypodysfibrinogenemia (Hypodys) and four hypofibrinpogenemia (Hypo)]. Furthermore, we proposed a schema for screening CFD phenotypes using |min1|c and Ac/|min1|c. RESULTS: The |min1|c correlated well with Ag in aHypo, and Ac/|min1|c was a better parameter for screening Dys and Hypodys than Ac/dH and Ac/|min1|. With the combination of |min1|c and Ac/|min1|c parameters, 15 Dys, 2 Hypodys and four Hypo were categorized in agreement with the phenotype determined using Ag and Ac/Ag; conversely three Dys were classified as one Hypodys (AαR16C) and two Hypo (BßG15C). CONCLUSION: We demonstrated that |min1|c and Ac/|min1|c are valuable parameters for screening CFD patients and phenotypes in laboratories that do not measure Ag or perform genetic analysis.

Congenital fibrinogen disorder caused by digenic mutations of the FGA and FGB genes.

Objectives: Congenital fibrinogen disorders (CFDs) are caused by monoallelic or biallelic mutations in FGA, FGB, and FGG genes. Quantitative CFDs include afibrinogenemia and hypofibrinogenemia, while qualitative CFDs consist of dysfibrinogenemia and hypodysfibrinogenemia. Hypofibrinogenemia and dysfibrinogenemia are autosomal dominant disorders while afibrinogenemia is a recessive one. We aimed to perform genetic diagnosis of a Chinese patient with CFD.Methods: DNA was extracted from peripheral blood mononuclear cells (PBMCs) and targeted next generation sequencing (NGS) was applied using amplicon-based panel (www.ampliseq.com) targeting all exons and splice sites of FGA, FGB, and FGG genes. Identified mutations were confirmed by Sanger sequencing.Results: We have identified a novel heterozygous FGB c.560_561delTG (p.Val187GlufsTer2) frameshift deletion and a novel heterozygous FGA c.190T > G (p.Cys64Gly) missense mutations in a Chinese patient with CFD.Conclusion: This is the first report of digenic variants causing CFD, and these findings may improve understanding of the genetic architecture of CFD.