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Hematology (Amsterdam, Netherlands) Dec 2021: Congenital dysfibrinogenemia (CD) is a coagulation disorder caused by mutations in the fibrinogen genes, which result in abnormal fibrinogen function. However, the...
BACKGROUND
: Congenital dysfibrinogenemia (CD) is a coagulation disorder caused by mutations in the fibrinogen genes, which result in abnormal fibrinogen function. However, the precise pathogenesis underlying it remains unclear.
METHODS
: In this study, we identified a novel heterozygous mutation in an asymptomatic patient with CD caused by γ Ala327Val mutation. Aimed to investigate the pathogenesis, functional studies of fibrinogen isolated from the proband and her family members were performed, such as coagulation function, fibrinogen aggregation test, and fibrin clot lysis test. Coagulation was monitored using a thromboelastometer, and the fibrin clot network structure was observed by scanning electron microscopy. The effect of the mutation on fibrinogen structure and function was predicted by molecular modeling.
RESULTS
: The fibrinogen activity concentration in patients with CD was significantly lower than that in healthy individuals, indicating that fibrinogen activity was low. Proband's fibrinogen activity concentration was 0.75 g/L(Clauss method) and antigen concentration (immune turbidimetry method) was 1.59 g/L(normal reference range for both parameters: 2.0-4.0 g/L). Thromboelastography showed that the K value of patients with CD was higher than that of healthy individuals and Angle values were decreased, indicating that mutation impaired fibrinogen function. Compared to fibrinogen from healthy individuals, fiber network structure of the proband was loose, pore size was increased, and fiber branch nodes were increased.
CONCLUSIONS
: Ala327Val heterozygous missense mutation leads to changes in the structure of fibrinogen D region and impairs the aggregation function of fibrinogen. This mutation is reported here for the first time.
Topics: Afibrinogenemia; Blood Coagulation; Female; Fibrinogens, Abnormal; Heterozygote; Humans; Middle Aged; Mutation, Missense; Point Mutation
PubMed: 33663356
DOI: 10.1080/16078454.2021.1893977 -
Hamostaseologie Dec 2023Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis.
OBJECTIVE
Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis.
METHODS
The one-stage clotting method was used to test the fibrinogen activity (FIB:C), whereas immunoturbidimetry was performed to quantify the fibrinogen antigen (FIB:Ag). Furthermore, DNA sequence analysis was conducted to confirm the site of mutation. Conservation analysis and protein model analysis were performed using online bioinformatics software.
RESULTS
The FIB:C and FIB:Ag of the proband were 1.28 and 2.20 g/L, respectively. Gene analysis revealed a heterozygous c.293C > A (p.BβAla68Asp) mutation in . Bioinformatics and modeling analysis suggested that the missense mutation could potentially have a deleterious effect on fibrinogen.
CONCLUSION
The BβAla68Asp mutation in exon 2 of may account for the reduced FIB:C levels observed in the pedigree. To our knowledge, this point mutation is the first report in the world.
Topics: Humans; Fibrinogen; Afibrinogenemia; Genotype; Mutation, Missense; Mutation; Hemostatics; Pedigree
PubMed: 37516116
DOI: 10.1055/a-2116-8957 -
Frontiers in Medicine 2020A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months,...
A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months, the patient developed a severe bleeding disorder. The bleeding was due to fibrin polymerization defect that upon sequencing was shown to be dysfibrinogenemia Krakow III. Elimination of the mTor inhibitor ameliorated the clinical bleeding state.
PubMed: 33330551
DOI: 10.3389/fmed.2020.591546 -
Ugeskrift For Laeger Jan 2024Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia.... (Review)
Review
Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia. Phenotypic manifestations are variable, patients may be asymptomatic or suffer from bleeding or thrombosis. Most of congenital fibrinogen disorders are coincidentally discovered. Fibrinogen concentrate is used to treat bleeding, whereas low-molecular weight heparin is most often administered for the treatment of thrombotic complications. The aim of this review is to provide an update of the knowledge of congenital fibrinogen disorders for Danish physicians.
Topics: Humans; Fibrinogen; Afibrinogenemia; Hemorrhage; Hemostasis; Hemostatics; Thrombosis
PubMed: 38235772
DOI: 10.61409/V04230274 -
Ryoikibetsu Shokogun Shirizu 1998
Review
Topics: Afibrinogenemia; Blood Coagulation Tests; Diagnosis, Differential; Fibrin; Fibrinogen; Humans
PubMed: 9833540
DOI: No ID Found -
Annals of Clinical Biochemistry Jun 2024The presence of latent fibrin clots is a recognised pre-analytical factor that causes inaccurate immunoassay results. This report details a case of a patient with...
The presence of latent fibrin clots is a recognised pre-analytical factor that causes inaccurate immunoassay results. This report details a case of a patient with Graves' disease and congenital dysfibrinogenemia (CD) that had serum thyroid function test results (TFTs) that were not in keeping with clinical signs or symptoms. Analysis of plasma samples taken from the patient was shown to provide more accurate results than those obtained using serum samples. Further cases of patients with CD, all sharing the same genetic mutation of fibrinogen, and discordant TFTs are described, where TFTs measurement in serum samples proved to be unreliable. Despite evidence of fibrin effecting immunoassays, this is the first report of its kind linking CD to erroneous immunoassay results. The mechanism is postulated to be related to atypical forms of fibrinogen resulting in latent fibrin in serum samples blocking the antigen binding site and leading to incorrect results. Congenital dysfibrinogenemia is asymptomatic in most patients and therefore abnormal, albeit inaccurate, TFTs may be the first finding. Recognition of CD as a cause of discordant results is important when interpreting TFTs to avoid unnecessary investigations and inappropriate clinical interventions to those with the disorder and potentially identify undiagnosed cases.
PubMed: 38844473
DOI: 10.1177/00045632241263494 -
Hamostaseologie Dec 2023
PubMed: 38096836
DOI: 10.1055/a-2218-6919 -
Annals of Translational Medicine Sep 2018Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin... (Review)
Review
Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin deficiency in the 1965, many other conditions have been described so far, which have then allowed to currently detect an inherited or acquired predisposition in approximately 60-70% of patients with thromboembolic disorders. These prothrombotic risk factors mainly include qualitative or quantitative defects of endogenous coagulation factor inhibitors, increased concentration or function of clotting proteins, defects in the fibrinolytic system, impaired platelet function, and hyperhomocysteinemia. In this review article, we aim to provide an overview on epidemiologic, clinic and laboratory aspects of both acquired and inherited rare thrombophilic risk factors, especially including dysfibrinogenemia, heparin cofactor II, thrombomodulin, lipoprotein(a), sticky platelet syndrome, plasminogen activator inhibitor-1 apolipoprotein E, tissue factor pathway inhibitor, paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopenia.
PubMed: 30306081
DOI: 10.21037/atm.2018.08.12 -
The Journal of Clinical Investigation Jul 1977To test the possibility that a functionally abnormal fibrinogen may exist in some patients with liver disease, we studied the plasma and purified fibrinogens of five...
To test the possibility that a functionally abnormal fibrinogen may exist in some patients with liver disease, we studied the plasma and purified fibrinogens of five patients whose plasma thrombin times were prolonged at least 40% over normal controls. In no patient was there evidence of disseminated intravascular coagulation and/or fibrinolysis. No abnormalities were detected by immunoelectrophoresis of plasmas or purified fibrinogens. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of reduced patient fibrinogens showed normal mobility and amount of Aalpha, Bbeta, and gamma chains. Alkaline polyacrylamide gel electrophoresis and gradient elution, DEAE-cellulose chromatography of admixtures of radio-iodinated patient (125)I-fibrinogen and normal (131)I-fibrinogen showed identical mobility in the gel and simultaneous elution from the column, respectively. Thrombin and Reptilase (Abbott Scientific Products Div., Abbott Laboratories, South Pasadena, Calif.) times of purified patient fibrinogens were prolonged, and calcium ions improved but did not completely correct these defects. Increasing amounts of thrombin progressively shortened the clotting times of patient fibrinogens but not to the level of normal. Addition of equal amounts of patient fibrinogen to normal fibrinogen resulted in a prolongation of the thrombin time of the normal protein. Thrombin-induced fibrinopeptide release was normal. Fibrin monomers prepared from patient plasmas and purified fibrinogens demonstrated impaired aggregation at low (0.12) and high (0.24) ionic strength. These studies demonstrate that some patients with liver disease and prolonged plasma thrombin times have a dysfibrinogenemia functionally characterized by an abnormality of fibrin monomer polymerization.
Topics: Alcoholism; Batroxobin; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Chemical and Drug Induced Liver Injury; Fibrin; Fibrinogen; Humans; Liver Cirrhosis; Liver Diseases; Prothrombin Time; Thrombin
PubMed: 874092
DOI: 10.1172/JCI108773 -
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