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Journal of Thrombosis and Haemostasis :... May 2017Essentials Hypodysfibrinogenemia is rarely reported among the congenital fibrinogen disorders. This first systematic literature review led to identification of 51... (Review)
Review
UNLABELLED
Essentials Hypodysfibrinogenemia is rarely reported among the congenital fibrinogen disorders. This first systematic literature review led to identification of 51 hypodysfibrinogenemic cases. Diagnosis based only on functional/antigenic fibrinogen ratio may be insufficient. Family studies show an incomplete segregation of mutation with the clinical phenotypes.
SUMMARY
Background Hypodysfibrinogenemia is a rare disease characterized by decreased levels of a dysfunctional fibrinogen. It shares features with both hypo- and dysfibrinogenemia, although with specific molecular patterns and clinical phenotypes. Objectives To better define the genetics, the diagnosis and the clinical features of hypodysfibrinogenemia. Patients/Methods A systematic literature search led to 167 records. After removal of duplicates, abstract screening and full-text reviewing, 56 molecular and/or clinical studies were analyzed, including a novel FGB missense mutation in a woman with a mild bleeding phenotype. Results A total of 32 single causative mutations were reported, mainly in the COOH-terminal region of the γ or Aα chains at heterozygous or homozygous state. Seven additional hypodysfibrinogenemias were due to compound heterozygosity. The hypofibrinogenemic phenotypes were a result of an impaired assembly or secretion or an increased clearance of the fibrinogen variant, whereas the dysfibrinogenemic phenotype was mainly a result of a defective fibrin polymerization and an abnormal calcium or tPA binding. Among 51 identified index cases, a functional/antigenic fibrinogen ratio < 0.7 had a sensitivity of 86% for the diagnosis of hypodysfibrinogenemia. Eleven patients (22%) were asymptomatic at time of diagnosis, 23 (45%) had a mild bleeding phenotype with mainly obstetrical or gynecologic-related hemorrhage and 22 (43%) had experienced at least one thrombotic event, including 23 venous and eight arterial thromboses. Conclusions This first systematic review on hypodysfibrinogenemia shows the heterogeneity of causative mutations and that misdiagnosis could occur in relation to the functional and antigenic fibrinogen levels. Family studies reveal an incomplete segregation of the mutation with the clinical phenotype.
Topics: Adult; Afibrinogenemia; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Female; Fibrinogen; Genetic Markers; Genetic Predisposition to Disease; Heterozygote; Humans; Mutation, Missense; Phenotype
PubMed: 28211264
DOI: 10.1111/jth.13655 -
Blood Coagulation & Fibrinolysis : An... Mar 2024Rotational thromboelastometry (ROTEM) is a global hemostasis assay. The diagnosis added value of ROTEM in congenital dysfibrinogenemia remains to be established. The aim...
Rotational thromboelastometry (ROTEM) is a global hemostasis assay. The diagnosis added value of ROTEM in congenital dysfibrinogenemia remains to be established. The aim of this study was to analyze clot formation by ROTEM in a cohort of dysfibrinogenemic patients and to establish correlations with genotype, clinical features, and coagulation parameters. The study included genetically confirmed congenital dysfibrinogenemia cases (n = 63) and healthy controls ( n = 50). EXTEM, INTEM, FIBTEM tests were used to measure ROTEM parameters, that is, clotting time (CT), clot formation time (CFT), maximal clot firmness (MCF) and amplitude 10 min after CT (A10). The ISTH bleeding assessment tool was used to determine bleeding episodes. CT (INTEM) was statistically significantly shorter in congenital dysfibrinogenemia patients compared to controls while CFT (EXTEM) was prolonged. Patients's MCF in EXTEM, INTEM, and FIBTEM were similar to controls while A10 (FIBTEM) was statistically significantly lower. Fibrinogen activity was positively correlated with fibrinogen antigen, A10 and MCF in all three assays. Bleeding phenotypes were observed in 23 (36.5%) patients. Only CFT in EXTEM and CT in INTEM were statistically different in patients with bleeding phenotype versus controls. Carriers of the FGA mutation p.Arg35His had a CT (EXTEM) slightly prolonged and a reduced A10 (FIBTEM) compared to controls. Some ROTEM parameters were able to distinguish congenital dysfibrinogenemia patients from controls, and patients with a bleeding phenotype. Prolonged CFT in EXTEM were associated with congenital dysfibrinogenemia and bleeding phenotype. Bleeding episodes in most patients were generally mild and prevalence of thrombosis was very low.
Topics: Humans; Thrombelastography; Prospective Studies; Blood Coagulation Tests; Hemorrhage; Fibrinogen; Afibrinogenemia; Piperidones; Benzeneacetamides
PubMed: 38251440
DOI: 10.1097/MBC.0000000000001274 -
Balkan Medical Journal Jan 2021
Topics: Aged; Aneurysm, Infected; Cyclophosphamide; Female; Fever; Glomerulonephritis, IGA; Hematoma; Humans; Sepsis; Tomography, X-Ray Computed
PubMed: 32720494
DOI: 10.4274/balkanmedj.galenos.2020.2020.5.208 -
Medical Principles and Practice :... 2002Coronary heart disease (CHD) is a leading cause of morbidity and mortality in the developed and developing countries. Several underlying genetic and environmental... (Review)
Review
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in the developed and developing countries. Several underlying genetic and environmental factors have been implicated in its etiology. Some of the hematological risk factors implicated in the development of coronary heart disease include antithrombin III deficiency, protein C and protein S deficiency, factor V Leiden mutation, prothrombin gene (20210A) mutation hyperhomocystinaemia, elevated factor VIII levels, plasminogen activator inhibitor type 1 and dysfibrinogenaemia. In general, these factors result in thrombosis, thus having a negative effect on the heart and blood vessels. This paper presents an overview of some of the hematological risk factors involved in the development of CHD.
Topics: Antithrombins; Bacterial Infections; Coronary Disease; Factor V; Factor VIII; Fibrinogen; Homocysteine; Humans; Mutation; Plasminogen Activator Inhibitor 1; Protein C; Protein S; Prothrombin; Risk Factors
PubMed: 12444311
DOI: 10.1159/000066407 -
Blood Oct 1998
Review
Topics: Adult; Afibrinogenemia; Amino Acid Sequence; Binding Sites; Blood Coagulation; Crystallization; Female; Fibrinogen; Hemorrhagic Disorders; Humans; Infant; Male; Models, Molecular; Molecular Sequence Data; Mutation; Point Mutation; Protein Conformation; Structure-Activity Relationship; Thrombophilia
PubMed: 9746756
DOI: No ID Found -
Research and Practice in Thrombosis and... Oct 2018Fibrinogen is a complex molecule comprised of two sets of Aα, Bβ, and γ chains. Fibrinogen deficiencies can lead to the development of bleeding or thromboembolic...
INTRODUCTION
Fibrinogen is a complex molecule comprised of two sets of Aα, Bβ, and γ chains. Fibrinogen deficiencies can lead to the development of bleeding or thromboembolic events. The objective of this study was to perform DNA sequence analysis of patients with clinical fibrinogen abnormalities, and to perform genotype-phenotype correlations.
MATERIALS AND METHODS
DNA from 31 patients was sequenced to evaluate disease-causing mutations in the three fibrinogen genes: ,, and . Clinical data were extracted from medical records or from consultation with referring hematologists. Fibrinogen antigen and functional (Clauss method) assays, as well as reptilase time (RT) and thrombin time (TT) were obtained for each patient. Molecular modeling was used to simulate the functional impact of specific missense variants on the overall protein structure.
RESULTS
Seventeen mutations, including six novel mutations, were identified in the three fibrinogen genes. There was little correlation between genotype and phenotype. Molecular modeling predicted a substantial conformational change for a novel variant, p.Ala289Asp, leading to a more rigid molecule in a region critical for polymerization and alignment of the fibrin monomers. This mutation is associated with both bleeding and clotting in the two affected individuals.
CONCLUSIONS
Robust genotype-phenotype correlations are difficult to establish for fibrinogen disorders. Molecular modeling might represent a valuable tool for understanding the function of certain missense fibrinogen mutations but those should be followed by functional studies. It is likely that genetic and environmental modifiers account for the incomplete penetrance and variable expressivity that characterize fibrinogen disorders.
PubMed: 30349899
DOI: 10.1002/rth2.12127 -
Polski Przeglad Chirurgiczny Apr 2020<b>Introduction: </b>Gastrointestinal bleeding is a common disease that surgeons encounter in everyday clinical practice. It is most often easy to diagnose...
<b>Introduction: </b>Gastrointestinal bleeding is a common disease that surgeons encounter in everyday clinical practice. It is most often easy to diagnose and treat. However, rare causes of bleeding can lead to delayed diagnosis and ineffective treatment. Dysfibrinogenemia is a qualitative fibrinogen disorder in which functional fibrinogen level is reduced with normal antigenic level. <br><b> Case report:</b> Herein we present the case of a 59-year-old female with recurrent gastrointestinal bleeds, that turned out to be an unusual manifestation of congenital dysfibrinogenemia. Detailed imaging and endoscopic diagnostics revealed portal hypertension with a non-bleeding 1-cm gastrointestinal stromal tumor and multiple angiodysplastic lesions in close proximity.
Topics: Afibrinogenemia; Female; Fibrinogen; Gastrointestinal Hemorrhage; Humans
PubMed: 32945266
DOI: 10.5604/01.3001.0014.0948 -
International Journal of Molecular... Jan 2022Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and...
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 gene coding for fibrinogen Bβ chain-heterozygous missense BβY416C and BβA68S, homozygous nonsense BβY345*, and heterozygous nonsense BβW403* 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 BβY416C and BβW403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of BβA68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of BβY416C, BβA68S, and BβW403*, and in the fiber density of BβY416C and BβW403*. Finally, homology modeling of BβA68S 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.
Topics: Adolescent; Afibrinogenemia; Aged; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Female; Fibrinogen; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant, Newborn; Male; Middle Aged; Models, Molecular; Mutation; Phenotype; Protein Conformation; Structure-Activity Relationship
PubMed: 35054908
DOI: 10.3390/ijms23020721 -
The Journal of Biological Chemistry Oct 2013Strongly activated "coated" platelets are characterized by increased phosphatidylserine (PS) surface expression, α-granule protein retention, and lack of active...
Strongly activated "coated" platelets are characterized by increased phosphatidylserine (PS) surface expression, α-granule protein retention, and lack of active integrin αIIbβ3. To study how they are incorporated into thrombi despite a lack of free activated integrin, we investigated the structure, function, and formation of the α-granule protein "coat." Confocal microscopy revealed that fibrin(ogen) and thrombospondin colocalized as "cap," a single patch on the PS-positive platelet surface. In aggregates, the cap was located at the point of attachment of the PS-positive platelets. Without fibrin(ogen) retention, their ability to be incorporated in aggregates was drastically reduced. The surface fibrin(ogen) was strongly decreased in the presence of a fibrin polymerization inhibitor GPRP and also in platelets from a patient with dysfibrinogenemia and a fibrinogen polymerization defect. In contrast, a fibrinogen-clotting protease ancistron increased the amount of fibrin(ogen) and thrombospondin on the surface of the PS-positive platelets stimulated with collagen-related peptide. Transglutaminases are also involved in fibrin(ogen) retention. However, platelets from patients with factor XIII deficiency had normal retention, and a pan-transglutaminase inhibitor T101 had only a modest inhibitory effect. Fibrin(ogen) retention was normal in Bernard-Soulier syndrome and kindlin-3 deficiency, but not in Glanzmann thrombasthenia lacking the platelet pool of fibrinogen and αIIbβ3. These data show that the fibrin(ogen)-covered cap, predominantly formed as a result of fibrin polymerization, is a critical mechanism that allows coated (or rather "capped") platelets to become incorporated into thrombi despite their lack of active integrins.
Topics: Blood Coagulation; Blood Platelets; Blotting, Western; Female; Fibrin; Fibrinogen; Flow Cytometry; Humans; Microscopy, Confocal; Oligopeptides; Phosphatidylserines; Platelet Aggregation; Polymerization; Thrombasthenia; Thrombosis; Thrombospondins; Transglutaminases
PubMed: 23995838
DOI: 10.1074/jbc.M113.474163 -
The Journal of Biological Chemistry Dec 2012Adsorption of fibrinogen on fibrin clots and other surfaces strongly reduces integrin-mediated adhesion of platelets and leukocytes with implications for the...
Adsorption of fibrinogen on fibrin clots and other surfaces strongly reduces integrin-mediated adhesion of platelets and leukocytes with implications for the surface-mediated control of thrombus growth and blood compatibility of biomaterials. The underlying mechanism of this process is surface-induced aggregation of fibrinogen, resulting in the assembly of a nanoscale multilayered matrix. The matrix is extensible, which makes it incapable of transducing strong mechanical forces via cellular integrins, resulting in insufficient intracellular signaling and weak cell adhesion. To determine the mechanism of the multilayer formation, the physical and adhesive properties of fibrinogen matrices prepared from human plasma fibrinogen (hFg), recombinant normal (rFg), and fibrinogen with the truncated αC regions (FgAα251) were compared. Using atomic force microscopy and force spectroscopy, we show that whereas hFg and rFg generated the matrices with a thickness of ∼8 nm consisting of 7-8 molecular layers, the deposition of FgAα251 was terminated at two layers, indicating that the αC regions are essential for the multilayer formation. The extensibility of the matrix prepared from FgAα251 was 2-fold lower than that formed from hFg and rFg. In agreement with previous findings that cell adhesion inversely correlates with the extensibility of the fibrinogen matrix, the less extensible FgAα251 matrix and matrices generated from human fibrinogen variants lacking the αC regions supported sustained adhesion of leukocytes and platelets. The persistent adhesiveness of matrices formed from fibrinogen derivatives without the αC regions may have implications for conditions in which elevated levels of these molecules are found, including vascular pathologies, diabetes, thrombolytic therapy, and dysfibrinogenemia.
Topics: Blood Platelets; Cell Adhesion; Fibrin; Fibrinogen; Humans; Leukocytes; Microscopy, Atomic Force; Platelet Adhesiveness; U937 Cells
PubMed: 23086938
DOI: 10.1074/jbc.M112.410696