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World Journal of Clinical Cases Dec 2022The purpose of this study was to report the rare case of a pregnant woman with congenital dysfibrinogenemia (CD) misdiagnosed as acute fatty liver. She was treated...
BACKGROUND
The purpose of this study was to report the rare case of a pregnant woman with congenital dysfibrinogenemia (CD) misdiagnosed as acute fatty liver. She was treated according to the principles of acute fatty liver but achieved good clinical results.
CASE SUMMARY
A 30-year-old woman presented with 39 (6/7) wk of menopause and 6 h of irregular abdominal pain and attended our hospital. Emergency surgery was performed due to fetal distress. Postoperative management followed the treatment principle of acute fatty liver. DNA sequencing was carried out on the pregnant woman and her pedigree. Coagulation values of the patient on admission were prothrombin time 33.7 s, activated partial thromboplastin time 60.4 s, thrombin time 45.2 s, and fibrinogen 0.60 g/L. DNA sequencing results showed that the woman carried a pathogenic heterozygous variation of the fibrinogen alpha chain gene (FGA), which is closely related to hereditary fibrinogen abnormality, and the mutation site was located in . After a follow-up period of 12 mo, the mother and her newborn had a good prognosis without bleeding or thrombosis.
CONCLUSION
Pregnant women with CD may have atypical symptoms, which can easily lead to misdiagnosis. In addition, treatment can be attempted according to the principles of acute fatty liver management. This rare pregnant patient with CD was caused by a novel FGA () gene mutation.
PubMed: 36569010
DOI: 10.12998/wjcc.v10.i35.12996 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jun 2022To analyze the phenotype and genotype of two Chinese family with inherited dysfibrinogenemia and the molecular pathogenic mechanism.
OBJECTIVE
To analyze the phenotype and genotype of two Chinese family with inherited dysfibrinogenemia and the molecular pathogenic mechanism.
METHODS
In the probands and their family members, coagulation routine, fibrinogen activity (Fg: A) and fibrinogen antigen (Fg: Ag) were detected. To find the mutation and exclude single nucleotide polymorphisms, all the exons and exons-intron boundaries of fibrinogen genes (FGA, FGB and FGG) were amplified by Ploymerase Chain Reaction (PCR), then sequenced. Bioinformatics prediction softwares were used to predict and score the change of function caused by the variant. PyMol were used to analyze the structure of protein caused by the variant. Clustal X software was used to analyze the conservation of the mutant amino acids.
RESULTS
The thrombin time (TT) of the two was slightly prolonged and could not be corrected by protamine sulfate, and the fibrinogen activity was significantly reduced (1.25 g/L and 1.17 g/L), but the fibrinogen antigen content was normal, respectively (3.50 g /L and 3.81 g/L). Genetic analysis showed that both probands were heterozygous missense variants (FGB exon 7 c.1115T>A (p.Val372Glu)), both of which originated from the paternal line. The prediction results of the four bioinformatics softwares indicate that this variant could be disease causing. Clustal X software showed that Val372 is highly conserved among homologous species. Based on the guidelines of the American College of Medical Genetics and Genomics, c.1115T>A was predicted to be likely pathgenic (PM2+PP1+PP2+PP3+PP4). PyMol showed that the secondary structure and three-dimensional structure of fibrinogen protein were changed by p.Val372Glu variant.
CONCLUSION
Inherited dysfibrinogenemia of the probands maybe caused by variant of FGB c.1115 T>A (p.Val372Glu), and the variant was firstly reported.
Topics: Afibrinogenemia; Fibrinogen; Humans; Mutation; Pedigree; Phenotype
PubMed: 35773760
DOI: No ID Found -
Journal of Thrombosis and Haemostasis :... May 2024Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular... (Review)
Review
Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal/fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.
Topics: Humans; Pregnancy; Female; Afibrinogenemia; Pregnancy Complications, Hematologic; Fibrinogen; Factor XIII; Delivery, Obstetric; Consensus
PubMed: 38266678
DOI: 10.1016/j.jtha.2024.01.008 -
Scientific Reports Jan 2022Plasma fibrinogen is commonly examined by Clauss fibrinogen assay, which cannot distinguish between quantitative and qualitative fibrinogen anomalies. However, our...
Plasma fibrinogen is commonly examined by Clauss fibrinogen assay, which cannot distinguish between quantitative and qualitative fibrinogen anomalies. However, our previously reported Clauss fibrinogen assay utilizing clot waveform analysis (Clauss-CWA) provides additional information that contributes to the classification of fibrinogen anomalies. In this study, we adopted the Clauss-CWA method for an autoanalyzer to automatically measure the antigenic estimate (eAg) of fibrinogen in addition to the functional amount (Ac), and to thus provide the Ac/eAg ratio as a qualitative indicator. Performance was validated by receiver operating characteristics (ROC) and precision recall (PR) curve analyses using a patient cohort, consisting of a training cohort (n = 519) and a validation cohort (n = 523), both of which contained cases of congenital (hypo)dysfibrinogenemia as qualitative defects. We obtained an optimal cutoff of 0.65 for Ac/eAg by ROC curve analysis of the training cohort, offering superior sensitivity (> 0.9661) and specificity (1.000). This cutoff was validated in the validation cohort, providing positive predictive value > 0.933 and negative predictive value > 0.998. PR curve analysis also showed that Clauss-CWA provided excellent performance for detecting qualitative fibrinogen anomalies. The Clauss-CWA method may represent a useful approach for detecting qualitative fibrinogen abnormalities in routine laboratory testing.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Clinical Laboratory Techniques; Female; Fibrinogen; Humans; Infant; Infant, Newborn; Male; Middle Aged; Plasma; ROC Curve; Young Adult
PubMed: 35064141
DOI: 10.1038/s41598-021-04464-5 -
Hereditas Feb 2024Congenital fibrinogen disorders are a group of coagulation deficiencies caused by fibrinogen defects and are divided into four types, including afibrinogenemia,...
Congenital fibrinogen disorders are a group of coagulation deficiencies caused by fibrinogen defects and are divided into four types, including afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. In this study, we collected a family with hypofibrinogenemia, and genetics analysis identify a novel pathogenic variants (c.668G > C, p.Arg223Thr) in the FGG gene. And electron microscope observation revealed significant changes in the ultrastructure of fibrin of the proband. Our research expands the phenotypic and genetic spectrum associated with the FGG gene, which would facilitate in genetic counselling and prenatal genetic diagnosis.
Topics: Humans; Afibrinogenemia; Asian People; China; Fibrinogen; Mutation
PubMed: 38374144
DOI: 10.1186/s41065-024-00313-3 -
Haemophilia : the Official Journal of... Nov 2021Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities...
INTRODUCTION
Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities of fibrinogen. Although the diagnosis of CFDs is based on antigenic and functional level of fibrinogen, few genotypes are clearly correlated with phenotype.
METHODS
In this study, we investigated all of the referred patients diagnosed as CFDs in Taiwan's population between 1995 and 2020. Clinical features, laboratory data and genetic defects were analysed. Functional fibrinogen level was determined by the Clauss method. Antigenic fibrinogen was measured by an enzyme-linked immunosorbent assay. Fibrinogen genes were assessed for mutations by polymerase chain reaction and sequencing.
RESULTS
A total of 18 patients from six unrelated families with CFDs were identified. One patient from a consanguineous family was diagnosed as afibrinogenemia type 1A with a novel homozygous frameshift mutation in FGB exon 4. The other five (83.3 %) index patients were all diagnosed as dysfibrinogenemia type 3A caused by two novel and one known mutation. Six (33.3 %) patients from three families had a novel mutation in FGB exon 8. The clinical features and laboratory data were highly variable among these patients with the same mutation.
CONCLUSIONS
Three novel mutations of CFDs causing afibrinogenemia and dysfibrinogenemia were identified. The point mutation in FGB exon 8 is also a common mutation in Taiwan's population. Considerable phenotypic variability among the patients with an identical mutation was observed.
Topics: Afibrinogenemia; Fibrinogen; Homozygote; Humans; Mutation; Taiwan
PubMed: 34460979
DOI: 10.1111/hae.14399 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Jul 2021To investigate the clinical type and gene mutations, clinical manifestations, laboratory tests, diagnosis, and fibrinogen replacement therapy of congenital fibrinogen...
To investigate the clinical type and gene mutations, clinical manifestations, laboratory tests, diagnosis, and fibrinogen replacement therapy of congenital fibrinogen disorders. Clinical data of 146 patients with congenital fibrinogen disorders diagnosed from April 2000 to November 2020 were retrospectively analyzed. Among the 146 patients, 61 (41.8%) men and 85 (58.2%) women had a median age of 33.5 years at the time of consultation. 34 patients (34.7%) were found to suffer from the disease due to bleeding symptoms, 33 patients (33.7%) due to preoperative examination. 55 patients (56.1%) had at least one bleeding symptom, and 42 patients (42.9%) had no bleeding symptoms. There is a negative correlation between fibrinogen activity concentration and bleeding ISTH-BAT score (rs=-0.412, =0.001) . A total of 34 gene mutations were detected in 56 patients, of which 84.1% were missense mutations, and 16 new mutations were found. FGA Exon2 and FGG Exon8 mutations accounted for 71.4% of all mutation sites. Patients with afibrinogenemia were younger, with a median age of 2 (1-12) years, an ISTH-BAT score of 4, and patients with dysfibrinogenemia had significantly longer thrombin time (TT) , with a median of 28.5 (19.2-36.6) s. The 1 hour in vivo recovery (IVR) after fibrinogen infusion was (127.19±44.03) %, and the 24 hour IVR was (101.78±43.98) %. In addition to the obvious increase in the concentration of fibrinogen activity, the TT and the prothrombin time (PT) both decreased significantly, and the TT decreased more significantly, with an average decrease of 15.2% compared to the baseline after 24 hours of infusion. Most patients with congenital fibrinogen disorders have mild or no bleeding symptoms. Patients with afibrinogenemia have more severe symptoms. There is a negative correlation between the fibrinogen and the degree of bleeding. Genetic testing is helpful for the diagnosis of disease classification. FIB∶C/FIB∶Ag<0.7 can be used as a basis for clinical diagnosis. The TT can be used as the basis for the diagnosis of dysfibrinogenemia and the effectiveness of fibrinogen infusion.
Topics: Adult; Afibrinogenemia; Child; Child, Preschool; Female; Fibrinogen; Hemostatics; Humans; Infant; Male; Mutation; Retrospective Studies
PubMed: 34455742
DOI: 10.3760/cma.j.issn.0253-2727.2021.07.005 -
Hamostaseologie Dec 2020This article aims to analyze the phenotype and genotype of an inherited dysfibrinogenemia pedigree associated with a heterozygous mutation in the gene, and to...
OBJECTIVE
This article aims to analyze the phenotype and genotype of an inherited dysfibrinogenemia pedigree associated with a heterozygous mutation in the gene, and to investigate the pathogenesis of this disease.
CLINICAL PRESENTATION
The proband of interest is a 29-year-old woman. She was in her 37 weeks of gestation. Routine coagulation tests showed low fibrinogen activity (0.91 g/L; normal range: 2.0-4.0 g/L) and normal fibrinogen antigen (FIB:Ag) level (2.09 g/L; normal range: 2.0-4.0 g/L).
TECHNIQUES
The prothrombin time, activated partial thromboplastin time, thrombin time, and activity of plasma fibrinogen (FIB:C) were detected by the one-stage clotting method. The FIB:Ag, D-dimer, and fibrinogen degradation products were tested by the immunoturbidimetry method. To identify the novel missense mutation, fibrinogen gene sequencing and molecular modeling were performed. We used ClustalX-2.1-win and online bioinformatic software to analyze the conservation and possible effect of the amino acid substitution on fibrinogen.
RESULTS
Phenotypic analysis revealed that the FIB:C of the proband was significantly reduced while the FIB:Ag was normal. Sequencing analysis detected a heterozygous C.2185G > A point mutation in the gene (AαGlu710Lys). Bioinformatic and modeling analyses indicated that the mutation probably caused harmful effects on fibrinogen.
CONCLUSION
The heterozygous mutation of Glu710Lys in the gene was identified that could cause the reduction of the FIB structure stability and result in the dysfibrinogenemia.
Topics: Afibrinogenemia; Female; Fibrinogen; Heterozygote; Humans; Male; Mutation
PubMed: 33374030
DOI: 10.1055/a-1261-3884 -
Clinica Chimica Acta; International... Oct 2021Fibrinogen activity (Ac) is widely measured, but fibrinogen antigen (Ag) is measured only in specialized laboratories, so it is difficult to discriminate congenital...
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 (BβG15C).
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.
Topics: Afibrinogenemia; Blood Coagulation Tests; Fibrinogen; Hemostatics; Humans; Phenotype
PubMed: 34273336
DOI: 10.1016/j.cca.2021.07.012 -
International Journal of Hematology Nov 2021We identified a novel heterozygous AαE11del variant in a patient with congenital dysfibrinogenemia. This mutation is located in fibrinopeptide A (FpA). We analyzed the...
INTRODUCTION
We identified a novel heterozygous AαE11del variant in a patient with congenital dysfibrinogenemia. This mutation is located in fibrinopeptide A (FpA). We analyzed the effect of AαE11del on the catalyzation of thrombin and batroxobin and simulated the stability of the complex structure between the FpA fragment (AαG6-V20) peptide and thrombin.
MATERIALS AND METHODS
We performed fibrin polymerization and examined the kinetics of FpA release catalyzed by thrombin and batroxobin using purified plasma fibrinogen. To clarify the association between the AαE11 residue and thrombin, we calculated binding free energy using molecular dynamics simulation trajectories.
RESULTS
Increasing the thrombin concentration improved release of FpA from the patient's fibrinogen to approximately 90%, compared to the previous 50% of that of normal fibrinogen. Fibrin polymerization of variant fibrinogen also improved. In addition, greater impairment of variant FpA release from the patient's fibrinogen was observed with thrombin than with batroxobin. Moreover, the calculated binding free energy showed that the FpA fragment-thrombin complex became unstable due to the missing AαE11 residue.
CONCLUSIONS
Our findings indicate that the AαE11 residue is involved in FpA release in thrombin catalyzation more than in batroxobin catalyzation, and that the AαE11 residue stabilizes FpA fragment-thrombin complex formation.
Topics: Afibrinogenemia; Batroxobin; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Fibrin; Fibrinopeptide A; Heterozygote; Humans; Kinetics; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Protein Multimerization; Sequence Deletion; Structure-Activity Relationship; Thrombin
PubMed: 34333754
DOI: 10.1007/s12185-021-03200-z