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Polish Archives of Internal Medicine Dec 2019Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual...
Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare coagulation factor deficiencies. Most of congenital fibrinogen disorders are suspected in individuals with bleeding tendency or coincidentally discovered, for instance prior to surgery. Fibrinogen disorders could be also found in patients with thrombotic events, impaired wound healing, and recurrent spontaneous abortions. Afibrinogenemia manifests as mild to severe bleeding, while hypofibrinogenemia is often asymptomatic. Dysfibrinogenemia, a qualitative fibrinogen disorder, is associated with bleeding, thrombosis, or with no symptoms. Recent recommendations issued by the International Society on Thrombosis and Haemostasis in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients with suspected congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, that is, reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic workup and clinical management of patients with afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia from a perspective of internists who may encounter patients with reduced fibrinogen concentration in everyday practice. Despite the fact that hematologists are in front line for the management of patients with bleeding tendency, internists should be aware of the clinical and laboratory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures.
Topics: Adult; Afibrinogenemia; Blood Coagulation Tests; Female; Fibrinogen; Genetic Predisposition to Disease; Genetic Testing; Hemorrhage; Humans; Male; Middle Aged; Poland; Thrombosis; Young Adult
PubMed: 31797863
DOI: 10.20452/pamw.15082 -
The Journal of Clinical Investigation Feb 1969A 17 yr old female with a congenital bleeding disorder was found to suffer from dysfibrinogenemia. Whole blood and plasma coagulation times were delayed and...
A 17 yr old female with a congenital bleeding disorder was found to suffer from dysfibrinogenemia. Whole blood and plasma coagulation times were delayed and thrombelastograms were grossly abnormal. Clottability of plasma fibrinogen by addition of thrombin was not demonstrated during the 30 min test period. Fibrinogen was revealed by turbidometric and immunologic techniques. Other coagulation factors were present in normal amounts and prothrombin activation was normal. Patient's plasma inhibited thrombin clotting times of normal plasma and purified normal fibrinogen. Fibrinolysis was not detected. The plasma fibrinogen migrated normally on paper and cellulose acetate electrophoresis, but on immunoelectrophoresis it displayed a faster mobility than normal fibrinogen. On immunodiffusion the antigenic determinants were similar to those of normal fibrinogen. The patient's fibrinogen-antifibrinogen precipitins required longer to appear and the resultant precipitin was broader and hazier than those elicited with normal fibrinogen. These findings suggest the presence of two discrete populations of fibrinogen molecules. Investigation of the family of the patient suggested that the defect has an autosomal dominant pattern of heredity. Immunologic comparisons of our patient's plasma and of her relatives with plasma of patients with "Fibrinogen Baltimore" and "Fibrinogen Cleveland" revealed certain differences in immunoelectrophoretic mobility as well as in immunodiffusion. In keeping with the nomenclatures of abnormal fibrinogens in the literature, we propose the term "Fibrinogen Detroit" for this fibrinogen.Physicochemical properties of "Fibrinogen Detroit" were investigated also and compared with those of normal fibrinogen. Purified normal fibrinogen (clottability 96.7%) and "Fibrinogen Detroit" revealed homogeneity when studied by ultracentrifugation and immunoelectrophoresis. Native and cleaved "Fibrinogen Detroit" had the same sedimentation constants and molecular weights as the normal. In fresh samples. 3 moles of free SH groups/mole of fibrinogen were titrated in both. Determination of the amino acid composition revealed a decreased content of lysine, glucosamine, and galactosamine in abnormal fibrinogen. Total carbohydrates, protein-bound hexoses, sialic acid, and hexosamine were decreased in the abnormal fibrinogen. In an investigation with Doctors Blombäck a specific molecular defect was revealed in the N-terminal disulfide knot of the alpha (A) chain in which the arginine at the 19th position was replaced by serine. It is believed that the substitution of a strongly basic amino acid with a neutral hydroxy acid may result in considerable conformational changes in the N-terminal disulfide knot of fibrinogen which might affect the "active site" for polymerization. The lower carbohydrate content observed in "Fibrinogen Detroit" may have been the result of a change in primary and tertiary structure of the protein.
Topics: Adolescent; Blood Coagulation Disorders; Blood Coagulation Tests; Child, Preschool; Chromatography, Ion Exchange; Female; Fibrinogen; Humans; Immunodiffusion; Immunoelectrophoresis; In Vitro Techniques; Male; Pedigree; Spectrophotometry; Thrombelastography; Ultracentrifugation
PubMed: 4974308
DOI: 10.1172/JCI105980 -
Haemostasis 2001Snake venom toxins are invaluable for the assay of coagulation factors and for the study of haemostasis generally. Thrombin-like enzymes (SVTLE) are used for fibrinogen... (Review)
Review
Snake venom toxins are invaluable for the assay of coagulation factors and for the study of haemostasis generally. Thrombin-like enzymes (SVTLE) are used for fibrinogen and fibrinogen breakdown product assays as well as detecting dysfibrinogenaemias. Since SVTLE are not inhibited by heparin, they can be used for assaying antithrombin III in samples containing heparin. Snake venom prothrombin activators are utilised in prothrombin assays, whilst Russell's viper venom (RVV) can be used to assay clotting factors V, VII, X and lupus anticoagulants (LA). Activators from the taipan, Australian brown snake and saw-scaled viper have also been used to assay LA. Protein C (PC) and activated PC (APC) resistance can be measured by means of RVV, Protac (from Southern copperhead snake venom) and STA-Staclot (from Crotalus viridis helleri) whilst von Willebrand factor can be studied with Botrocetin (Bothrops jararaca). Finally, snake venom C-type lectins and metalloproteinase disintegrins are being used to study platelet glycoprotein receptors and show great potential for use in the routine coagulation laboratory.
Topics: Animals; Anticoagulants; Blood Coagulation Tests; Coagulants; Hemostasis; Humans; Snake Venoms
PubMed: 11910187
DOI: 10.1159/000048065 -
Research and Practice in Thrombosis and... Dec 2021Afibrinogenemia and congenital dysfibrinogenemia (CD) are rare conditions with limited information available for appropriate management. Previous case reports have...
Afibrinogenemia and congenital dysfibrinogenemia (CD) are rare conditions with limited information available for appropriate management. Previous case reports have demonstrated the safe and efficacious use of fibrinogen replacement therapy (FRT) as a therapeutic approach to prevent hemorrhage and fetal loss in pregnant women with CD. In this case report, we present a 28-year-old pregnant woman who sought testing for CD given her family history. She denied any current or previous bleeding symptoms. Laboratory testing confirmed the diagnosis of CD. She was treated with FRT and prophylactic anticoagulation starting in her third trimester. She had preterm labor that prompted an urgent cesarean section with FRT support. This case adds to the sparse literature about fibrinogen disorders in pregnancy, and highlights the benefits, safety, and tolerability of FRT and prophylactic anticoagulation in pregnant women with CD. Finally, it emphasizes the importance of a multidisciplinary team approach for an uneventful delivery.
PubMed: 34816075
DOI: 10.1002/rth2.12619 -
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 -
International Journal of Molecular... Feb 2021The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the...
The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among and mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure-function relationship of fibrin to support hemostasis.
Topics: Adult; Afibrinogenemia; Aged; Aged, 80 and over; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Fibrinogen; Genotype; Humans; Male; Middle Aged; Mutation; Phenotype; Prothrombin; Structure-Activity Relationship; Thrombelastography; Thrombin
PubMed: 33668986
DOI: 10.3390/ijms22052286 -
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 -
Journal of Clinical Laboratory Analysis Mar 2018Dysfibrinogenemia is a rare coagulation disorder caused by mutations in the fibrinogen gene that results in abnormal fibrinogen function. Dysfibrinogenemia has a wide...
BACKGROUND
Dysfibrinogenemia is a rare coagulation disorder caused by mutations in the fibrinogen gene that results in abnormal fibrinogen function. Dysfibrinogenemia has a wide spectrum of clinical manifestations including asymptomatic(55%), hemorrhage (25%), and thrombosis (20%).
METHODS
We reported a 30-year-old woman with 35 weeks gestation. She was misdiagnosed with hypofibrinogenemia in a local hospital, and then she was treated with fibrinogen concentrate. However, she was diagnosed as dysfibrinogenemia in our hospital base on her low function fibrinogen level (0.55 g/L) and her normal immunologic fibrinogen level (3.80 g/L). This patient had neither bleeding symptom nor thromboembolic event. Her obstetrical history included one normal pregnancy in 2008 with uneventful full-term delivery.
RESULTS
Multidisciplinary experts suggested that there should be no specific intervention in this case because of the patient had no previous episodes of abnormal bleeding or thrombotic. She had an uneventful delivery with no abnormal bleeding symptom or thromboembolic.
CONCLUSION
Dysfibrinogenemia patients without personal or family history of bleeding and thromboembolic events, do not need specific therapeutic intervention.
Topics: Afibrinogenemia; Blood Coagulation Tests; DNA Mutational Analysis; Female; Fibrinogen; Humans; Pregnancy; Pregnancy Complications, Hematologic
PubMed: 28948631
DOI: 10.1002/jcla.22319 -
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 -
BMC Veterinary Research Jun 2017Among coagulation disorders, primary fibrinogen deficiency is very rare in dogs. It is divided into hypofibrinogenemia, afibrinogenemia and dysfibrinogenemia....
BACKGROUND
Among coagulation disorders, primary fibrinogen deficiency is very rare in dogs. It is divided into hypofibrinogenemia, afibrinogenemia and dysfibrinogenemia. Afibrinogenemia has been described in three dogs. There are, however, no published case reports of primary hypofibrinogenemia in dogs.
CASE PRESENTATION
A 1.5 year-old male German Pointer dog was evaluated for a locked-jaw syndrome associated with eye protrusion which appeared after a minor head trauma. Three months before the trauma, a persistent increase in coagulation times was detected by the referring veterinarian after a strong suspicion of snake envenomation. Apart for the primary complaint, physical examination was normal. A complete hemostatic profile revealed a moderately increased prothrombin time, activated partial thromboplastin times and a dramatically decreased fibrinogen concentration (0.34 g/L, reference interval [1.3-4.8 g/L]). Platelet count, plasma D-dimers and antithrombin, were all within the reference intervals and not consistent with a disseminated intravascular coagulation. Other possible causes of hypofibrinogenemia such as chronic hemorrhage and liver failure were excluded by laboratory work-up and imaging studies. Finally, antifibrinogen circulating anticoagulants were excluded using a dilution of citrated plasma from the pooled plasma of healthy dogs. These results supported a diagnosis of congenital fibrinogen deficiency and secondary retrobulbar hematoma and/or cellulitis. The dog's condition improved rapidly after symptomatic treatment with corticosteroids and antibiotics. At the 1 year follow-up, the dog was clinically normal but a persistent hypofibrinogenemia (≤ 0.8 g/L) remained.
CONCLUSIONS
Various clinical presentations may occur in canine primary hypofibrinogenemia which should be included in the list of coagulation disorders. Diagnosis should include fibrinogen determination by coagulometric and non-coagulometric methods to differentiate from dysfibrinogenemia. There is no specific treatment but care should be taken to prevent bleeding and trauma. Emergency management of bleeding episodes with cryoprecipitate is the treatment of choice.
Topics: Afibrinogenemia; Animals; Dog Diseases; Dogs; Eyelid Diseases; Male
PubMed: 28629414
DOI: 10.1186/s12917-017-1110-8