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International Journal of Molecular... Dec 2021Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are... (Review)
Review
Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240-410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.
Topics: Blood Coagulation; Blood Coagulation Tests; Fibrinogen; Hemorrhage; Humans; Mutation; Thrombosis
PubMed: 35008554
DOI: 10.3390/ijms23010132 -
British Journal of Haematology Nov 2023Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and... (Review)
Review
Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and genotype remain poorly defined. This review examines the genetic landscape discovered to date for this rare condition. The question of a possible oligogenic model of inheritance influencing phenotypic heterogeneity is raised, with discussion of the benefits and challenges of sequencing technology used to enhance discovery in this space. Considerable work lies ahead in order to achieve diagnostic and prognostic precision and subsequently provide targeted management to this complex cohort of patients.
PubMed: 37583269
DOI: 10.1111/bjh.19039 -
Research and Practice in Thrombosis and... Jul 2023Variants of fibrinogen sequences that bind to thrombin's catalytic sites are mostly associated with bleeding phenotypes, while variants with fibrinogen...
BACKGROUND
Variants of fibrinogen sequences that bind to thrombin's catalytic sites are mostly associated with bleeding phenotypes, while variants with fibrinogen nonsubstrate-thrombin-binding sites are commonly believed to cause thrombosis. AαGlu39 and BβAla68 play important roles in fibrin(ogen)-thrombin-nonsubstrate binding. The BβAla68Thr variant has been described in several unrelated families with apparent thrombotic phenotypes.
OBJECTIVES
Homozygous AαGlu39Lys variant (fibrinogen BOE II) was identified in a boy with dysfibrinogenemia who had multiple cerebral hemorrhages. A series of analyses were performed to assess the variant's functions and elucidate underlying bleeding mechanisms.
METHODS
Abnormal fibrinogen was purified from plasma and subjected to Western blot, fibrinogen and fibrin monomer polymerization, clottability, fibrinopeptides release, activated factor (F)XIII (FXIIIa) cross-linking, fibrinolysis, and scanning electron microscopy analyses.
RESULTS
Fibrinogen BOE II weakened the binding capacity of thrombin to fibrinogen and delayed the formation of fibrin clots. The release of fibrinopeptides, polymerization of fibrinogen catalyzed by thrombin, and cross-linking of FXIIIa of fibrinogen BOE II were impaired. In contrast, batroxobin-catalyzed fibrinogen polymerization and desA/desAB fibrin monomer polymerization did not differ from those in normal controls. Fibrin clots formed by fibrinogen BOE II were composed of thicker fibrin fibers and showed a faster fibrinolysis rate.
CONCLUSION
Defective fibrin(ogen)-thrombin-nonsubstrate binding is not necessarily associated with thrombotic disorders. When the hypercoagulable state created by increased circulating free thrombin is insufficient to compensate for defective hemostasis caused by slowly formed but rapidly lysed clots, the primary concern of thrombin-binding deficiency dysfibrinogenemia appears to be hemorrhage rather than thrombosis.
PubMed: 37601017
DOI: 10.1016/j.rpth.2023.102145 -
The Veterinary Record Oct 2020Afibrinogenaemic haemorrhage was previously reported in a Maine Coon cat. Two littermates subsequently died from surgical non-haemostasis, suggesting a hereditable...
OBJECTIVE
Afibrinogenaemic haemorrhage was previously reported in a Maine Coon cat. Two littermates subsequently died from surgical non-haemostasis, suggesting a hereditable coagulopathy.
METHODS
We prospectively recruited cats which were: a) Maine Coons with pathological haemorrhage (group 1, n=8), b) healthy familial relatives of group 1 (group 2, n=13) and c) healthy Maine Coons unrelated to groups 1 and 2 (group 3, n=12). Coagulation tests: prothrombin time, activated partial thromboplastin time and thrombin clotting time (TCT) were performed on citrated plasma along with quantification of fibrinogen. Routine haematological examination was performed on EDTA-anticoagulated blood collected contemporaneously.
RESULTS
Thirty-three blood samples were analysed. Fibrinogen concentrations were significantly reduced in groups 1 (P<0.01) and 2 (P<0.01) compared with group 3. Similarly, TCT was found to be significantly extended in group 1 (P<0.01) and group 2 (P=0.02) with respect to group 3.
CONCLUSIONS
Dysfibrinogenaemia was identified in clinical cases and their healthy relatives, suggesting that this may represent a hereditary condition of Maine Coon cats. Clinicians should be aware of the increased potential for non-haemostasis in this cat breed and consider assessing clotting function before (elective) surgery.
Topics: Animals; Blood Coagulation Tests; Cat Diseases; Cats; Hemorrhage; Prospective Studies
PubMed: 32826346
DOI: 10.1136/vr.105503 -
Blood Advances Mar 2024Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD...
Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.
Topics: Humans; Female; Fibrinogen; Afibrinogenemia; Prospective Studies; Retrospective Studies; Hemorrhage; Hemostatics
PubMed: 38286442
DOI: 10.1182/bloodadvances.2023012186 -
Diagnostics (Basel, Switzerland) Nov 2021Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia... (Review)
Review
Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management.
Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.
PubMed: 34829490
DOI: 10.3390/diagnostics11112140 -
Journal of Thrombosis and Thrombolysis Feb 2020Congenital dysfibrinogenemia is characterized with undetectable or low fibrinogen level by Clauss assay complicated by bleeding and/or thrombosis. These may lead to a...
Congenital dysfibrinogenemia is characterized with undetectable or low fibrinogen level by Clauss assay complicated by bleeding and/or thrombosis. These may lead to a diagnostic problem to some clinicians unfamiliar with this disease. We reported a case of congenital dysfibrinogenemia manifested as hemorrhage, repeated thrombosis, low fibrinogen levels through Clauss assay and but normal levels of fibrinogen through PT-derived tests. In conclusion, to patients with thrombosis complicated by decreased fibrinogen level, clinicians and laboratory physicians should be alert to the possibility of congenital dysfibrinogenemia.
Topics: Adult; Afibrinogenemia; Blood Coagulation Tests; Fibrinogens, Abnormal; Humans; Male; Thrombosis
PubMed: 31542854
DOI: 10.1007/s11239-019-01958-y -
Clinical Laboratory Apr 2021Fibrinogen plays an important role in hemostasis. The normal concentration of fibrinogen in blood plasma is between 1.8 - 4.2 g/L. Decreased fibrinogen levels are...
BACKGROUND
Fibrinogen plays an important role in hemostasis. The normal concentration of fibrinogen in blood plasma is between 1.8 - 4.2 g/L. Decreased fibrinogen levels are observed in congenital afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, disseminated intravascular coagulation, fibrinolytic therapy, some more severe hepatic parenchymal disorders, and increased blood loss. Elevated fibrinogen levels occur in inflammatory diseases and neoplastic diseases, in pregnancy, and postoperative conditions. Functional fibrinogen measurement is also one of the basic coagulation screening tests. The fibrinogen antigen assay is used to distinguish between qualitative and quantitative fibrinogen disorders.
METHODS
The aim of the study was the use of fibrinogen determination methods in differential diagnosis of hypofibrinogenemia and dysfibrinogenemia, statistical evaluation and determine the relationship of fibrinogen Clauss assay, prothrombin time (PT) derived fibrinogen assay, and fibrinogen antigen in the group of 60 patients with congenital fibrinogen disorders (n = 40 dysfibrinogenemia; n = 20 hypofibrinogenemia).
RESULTS
The results measured by the PT-derived fibrinogen assay were approximately four times higher compared to the fibrinogen Clauss assay in the group of patients with dysfibrinogenemia. In patients with hypofibrinogenemia, there is a correlation (r = 0.9016) between the fibrinogen Clauss assay and PT-derived fibrinogen assay with a statistical significance of p < 0.0001. Using a linear or quadratic interpolation function, we were able to determine the fibrinogen Clauss assay and the fibrinogen antigen assay before analysis.
CONCLUSIONS
The higher level of the PT-derived fibrinogen assay compared to the fibrinogen Clauss assay in the group of patients with dysfibrinogenemia may pose a greater risk to asymptomatic patients who require diagnosis and treatment in case of bleeding. The fibrinogen value using the PT-derived fibrinogen assay could erroneously give a normal level. The use of the interpolation function is important to estimate the value of fibrinogen activity and antigen before the analysis itself by the Clauss assay or analysis by the fibrinogen antigen assay.
Topics: Afibrinogenemia; Blood Coagulation Tests; Diagnosis, Differential; Female; Fibrinogen; Humans; Pregnancy; Prothrombin Time
PubMed: 33865248
DOI: 10.7754/Clin.Lab.2020.200820 -
Seminars in Thrombosis and Hemostasis Nov 2022Fibrinogen is a complex protein that plays a key role in the blood clotting process. It is a hexamer composed of two copies of three distinct chains: Aα, Bβ, and γ...
Fibrinogen is a complex protein that plays a key role in the blood clotting process. It is a hexamer composed of two copies of three distinct chains: Aα, Bβ, and γ encoded by three genes, , and clustered on the long arm of chromosome 4. Congenital fibrinogen disorders (CFDs) are divided into qualitative deficiencies (dysfibrinogenemia, hypodysfibrinogenemia) in which the mutant fibrinogen molecule is present in the circulation and quantitative deficiencies (afibrinogenemia, hypofibrinogenemia) with no mutant molecule present in the bloodstream. Phenotypic manifestations are variable, patients may be asymptomatic, or suffer from bleeding or thrombosis. Causative mutations can occur in any of the three fibrinogen genes and can affect one or both alleles. Given the large number of studies reporting on novel causative mutations for CFDs since the review on the same topic published in 2016, we performed an extensive search of the literature and list here 120 additional mutations described in both quantitative and qualitative disorders. The visualization of causative single nucleotide variations placed on the coding sequences of , and eveals important structure function insight for several domains of the fibrinogen molecule.
Topics: Humans; Fibrinogen; Afibrinogenemia; Mutation; Hemorrhage; Exons; Hemostatics
PubMed: 35073585
DOI: 10.1055/s-0041-1742170 -
Hematology/oncology Clinics of North... Dec 2021In patients presenting with a suspect hereditary bleeding disorder a detailed bleeding history is first obtained. Testing proceeds in a tiered manner with platelet... (Review)
Review
In patients presenting with a suspect hereditary bleeding disorder a detailed bleeding history is first obtained. Testing proceeds in a tiered manner with platelet count, platelet morphology, platelet histogram, PFA-100, fibrinogen, prothrombin time, and activated partial thromboplastin time. More detailed testing includes von Willebrand factor, individual clotting factor assays, and platelet function testing. Next, testing for a dysfibrinogenemia, FXIII, or a fibrinolytic defect is considered. Hemostatic abnormality is not demonstrated in a fraction of patients. An approach to management in these patients, such as desmopressin or antifibrinolytic therapy, may be required and empiric use of blood component therapy is discouraged.
Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Hemostatic Disorders; Humans; Laboratories; Platelet Function Tests
PubMed: 34391602
DOI: 10.1016/j.hoc.2021.07.002