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Philippe De Moerloose - One of the best experts on this subject based on the ideXlab platform.
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congenital afibrinogenemia identification and characterization of two novel homozygous fibrinogen aα and bβ chain mutations in two tunisian families
Thrombosis Research, 2016Co-Authors: Yessine Amri, Nour El Houda Toumi, Sondess Hadj Fredj, Philippe De MoerlooseAbstract:Abstract Introduction Inherited abnormalities of fibrinogen (FG) are rare coagulation disorders divided into two types: quantitative abnormalities (afibrinogenemia and hypofibrinogenemia) or qualitative abnormalities (Dysfibrinogenemia and hypo-Dysfibrinogenemia) of circulating fibrinogen. In particular, congenital afibrinogenemia is inherited as an autosomal recessive mode and is usually determined by homozygous or compound heterozygous mutations affecting any of the three fibrinogen genes (FGA, FGB and FGG), resulting in the complete absence or extremely reduced amount of fibrinogen. The aim of the present study was to characterize the fibrinogen abnormalities in two Tunisian families. Methods Coagulation studies were performed on the patients and family members. All the exons and the flanking intron regions of fibrinogen genes were screened by direct sequencing. Results Probands had concomitant bleeding complications with infinitely prolonged standard coagulation assays. Mutational screening of the fibrinogen gene cluster of each proband, disclosed two previously undescribed homozygous point mutations. The first mutation was a major truncation (AαArg252Stop) leads to a severe premature termination codon in the exon 5 of the FGA gene. This mutation defines in vivo the importance of the αC flexible segment in the secretion of a stable fibrinogen molecule. The second afibrinogenemic mutation (BβGly295Ala) occurs in the exon 7 of the FGB gene. This missense mutation would probably lead to significant conformational change not allowing the expression of the fibrinogen protein. Conclusion Current molecular characterization of these two fibrinogen abnormalities confirms the importance of the first portion of αC-region (αC-connector) as well as the Bβ globular domain in the secretion processes.
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fibrinogen geneva ii a new congenitally abnormal fibrinogen alpha chain gly17asp with a review of similar mutations resulting in abnormal knob a
Blood Coagulation & Fibrinolysis, 2014Co-Authors: Alessandro Casini, Marguerite Neermanarbez, Emmanuel De Maistre, Virginie Casinistuppi, Pierre Fontana, Philippe De MoerlooseAbstract:Congenital Dysfibrinogenemias are characterized by biosynthesis of a structurally abnormal fibrinogen molecule that exhibits reduced functional levels compared with the level of fibrinogen antigen. To date a large number of mutations have been identified in patients with Dysfibrinogenemia. Mutations occurring at the thrombin cleavage site (Arg16-Gly17 in the mature alpha-chain) at the amino-terminal end of the fibrinogen alpha chain are a common cause of the disease. These mutations causing abnormal fibrin polymerization are associated with different phenotypes. Here, we report the identification of a novel heterozygous missense mutation of Glycine 17 (Gly17Asp) in a female patient with mild bleeding manifestations, and compare it with other previously reported mutations also resulting in abnormal knob A.
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congenital fibrinogen disorders an update
Seminars in Thrombosis and Hemostasis, 2013Co-Authors: Philippe De Moerloose, Alessandro Casini, Marguerite NeermanarbezAbstract:Hereditary fibrinogen abnormalities comprise two classes of plasma fibrinogen defects: Type I, afibrinogenemia or hypofibrinogenemia, which has absent or low plasma fibrinogen antigen levels (quantitative fibrinogen deficiencies), and Type II, Dysfibrinogenemia or hypoDysfibrinogenemia, which shows normal or reduced antigen levels associated with disproportionately low functional activity (qualitative fibrinogen deficiencies). In afibrinogenemia and hypofibrinogenemia, most mutations of the FGA, FGB, or FGG fibrinogen encoding genes are null mutations. In some cases, missense or late truncating nonsense mutations allow synthesis of the corresponding fibrinogen chain but intracellular fibrinogen assembly and/or secretion are impaired. Afibrinogenemia is associated with mild-to-severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Thromboembolism may occur either spontaneously or in association with fibrinogen substitution therapy. Women with afibrinogenemia suffer from recurrent pregnancy loss but this can also occur in women with hypofibrinogenemia. Dysfibrinogenemia, caused mainly by missense mutations, is commonly associated with bleeding, thrombophilia, or both; however, most individuals are asymptomatic. HypoDysfibrinogenemia is a subcategory of this disorder. Even in specialized laboratories, the precise diagnosis of some fibrinogen disorders may be difficult. Determination of the molecular defects is important because it gives the possibility to confirm the diagnosis, to elaborate a diagnostic strategy, to distinguish in some cases that the patient is at risk of thrombosis rather than bleeding, and to enable prenatal diagnosis. However, genotype–phenotype correlations are not easy to establish. Replacement therapy is effective in treating bleeding episodes, but because the pharmacokinetics of fibrinogen after replacement therapy is highly variable among patients, it is important to adjust the treatment individually.
Nobuo Okumura - One of the best experts on this subject based on the ideXlab platform.
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heterozygous variant fibrinogen γa289v kanazawa iii was confirmed as hypoDysfibrinogenemia by plasma and recombinant fibrinogens
International Journal of Laboratory Hematology, 2020Co-Authors: Takahiro Kaido, Masahiro Yoda, Tomu Kamijo, Chiaki Taira, Yumiko Higuchi, Nobuo OkumuraAbstract:INTRODUCTION Congenital fibrinogen disorders are classified as afibrinogenemia, hypofibrinogenemia, Dysfibrinogenemia, and hypoDysfibrinogenemia. However, difficulties are associated with discriminating between Dysfibrinogenemia, hypofibrinogenemia, and hypoDysfibrinogenemia using routine analyses. We previously reported a heterozygous variant fibrinogen (γA289V; Kanazawa III) as hypoDysfibrinogenemia; however, the same variant had previously been described as hypofibrinogenemia. To clarify the production of γA289V fibrinogen, we expressed recombinant γA289V (r-γA289V) fibrinogen and compared it with wild-type (WT) and adjacent recombinant variant fibrinogens. METHODS Target mutations were introduced into a fibrinogen γ-chain expression vector by site-directed mutagenesis, and the vector was then transfected into Chinese hamster ovary cells to produce recombinant fibrinogen. Fibrinogen was purified from the plasma of the proposita, and culture media and fibrinogen functions were analyzed using fibrin polymerization, plasmin protection, and FXIIIa-catalyzed fibrinogen cross-linking. RESULTS The fibrinogen concentration ratio of the culture media to cell lysates was markedly lower for r-γA289V fibrinogen than for WT. Because the secretion of recombinant γF290L (r-γF290L) fibrinogen was similar to WT, we compared r-γF290L fibrinogen functions with WT. The fibrin polymerization of Kanazawa III plasma (K-III) fibrinogen was significantly weaker than normal plasma fibrinogen. Moreover, K-III fibrinogen showed a markedly reduced "D:D" interaction. However, all functions of r-γF290L fibrinogen were similar to WT. An in silico analysis confirmed the above results. CONCLUSION The present results demonstrated that γA289 is crucial for the γ-module structure, and the γA289V substitution markedly reduced fibrinogen secretion. Moreover, K-III fibrinogen showed markedly reduced fibrin polymerization and "D:D" interactions. γA289V fibrinogen was confirmed as hypoDysfibrinogenemia.
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congenital Dysfibrinogenemia in a japanese family with fibrinogen naples bβala68thr manifesting as superior sagittal sinus thrombosis
Blood Coagulation & Fibrinolysis, 2017Co-Authors: Satoru Yoshida, Tetsuya Kibe, Risa Matsubara, Shinichiro Koizumi, Kenji Nara, Koji Amano, Nobuo OkumuraAbstract:: Congenital Dysfibrinogenemia refers to the presence of a dysfunctional fibrinogen molecule, typically because of mutations in the fibrinogen gene. About 20% of fibrinogen gene mutations are responsible for thrombosis. Here, we described the case of a 17-year-old Japanese boy, who had a sudden stroke because of superior sagittal sinus thrombosis associated with Dysfibrinogenemia. Genetic testing confirmed the presence of homozygous fibrinogen Naples (BβAla68Thr) mutation, which was previously reported as a causative mutation for thrombotic Dysfibrinogenemia only in an Italian family. In this Japanese family, the patient's 12-year-old asymptomatic sister was also homozygous for this mutation. She, like her brother, was started on warfarin therapy. This report highlights the occurrence of fibrinogen Naples that has caused severe thrombotic complications in a young member of a Japanese family.
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comparison of fibrinogen synthesis and secretion between novel variant fibrinogen nagakute gamma305thr ala and other variants located in gamma305 308 residues
The Japanese journal of clinical pathology, 2012Co-Authors: Tamaki Kobayashi, Fumiko Terasawa, Yuka Takezawa, Nobuo OkumuraAbstract:We found and identified a novel heterozygous Dysfibrinogenemia with gammaT305A (ACA --> GCA) mutation in a 6-month old boy. Since his plasma antigenic concentration of fibrinogen was 1.12g/l and less than the lower limit of the reference interval, we guessed that the production of a variant fibrinogen might be a partial defect. To clarify this speculation, we altered the gamma-chain expression vector, transfected it into Chinese Hamster Ovary(CHO) cells, and synthesized recombinant gammaT305A fibrinogen alongside three other variant fibrinogens, gammaS306P, gammaH307Y, and gammaN308K, and the wild type (gammaN) fibrinogen. Fibrinogen concentration ratio of culture media/cell lysates decreased in the order of gammaT305A-, gammaS306P-, gammaH307Y-CHO cells, all three being lower in comparison to the gammaN-CHO cells. Western blotting analyses indicated that all of variant gamma-chains were assembled into fibrinogen molecules in the cells. These data indicate the possibility that secretion of gamma T305A-fibrinogen is slightly impaired and variant fibrinogen is accumulated in the cell. Of interest, the secretion of gammaH307Y-fibrinogen was decreased the most, whereas that of the gammaN308K-CHO cells was not affected. The tertiary structure of the yC nodule indicated that gamma305T-gamma307H residues are located in the inside of the nodule. In contrast, that of gamma308N is located on surface of the nodule. In conclusion, our results showed the variant fibrinogen, gammaT305A, has characteristics not only of Dysfibrinogenemia, but also might be hypofibrinogenemia, namely, hypo/Dysfibrinogenemia. Furthermore, gamma306S-gamma307H residues of the gammaC nodule play crucial roles for protein synthesis and fibrin polymerization.
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fibrinogen matsumoto ii γ308asn lys aat aag mutation associated with bleeding tendency
British Journal of Haematology, 1996Co-Authors: Nobuo Okumura, Fumiko Terasawa, Ken-ichi Furihata, Ichiro Ueno, S. Ishikawa, Tsutomu KatsuyamaAbstract:: Fibrinogen Matsumoto II is a hereditary dysfibrinogenaemia identified in a woman with Basedow's disease and a bleeding tendency. Coagulation tests of the patient's plasma revealed a prolonged thrombin time and a decreased fibrinogen level determined by functional method. Release of fibrinopeptide A and B was normal, whereas fibrin monomer polymerization was delayed. Fibrinogen gamma-chain gene of the propositus was heterozygous for a missense mutation that resulted in Asn-->Lys substitution at codon 308. Though the same amino acid substitution was also attributed to fibrinogen Kyoto I and Bicetre II, fibrinogen Matsumoto II showed different clinical manifestations from them.
Neerman Arbez Marguerite - One of the best experts on this subject based on the ideXlab platform.
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Comparison of different activators of coagulation by turbidity analysis of hereditary Dysfibrinogenemia and controls
'Ovid Technologies (Wolters Kluwer Health)', 2021Co-Authors: Marchi Cappelletti Rita, Neerman Arbez Marguerite, De Moerloose Philippe, Gay Valérie, Mourey Guillaume, Fiore Mathieu, Mouton Christine, Gautier Philippe, Casini AlessandroAbstract:Turbidity analysis is widely used as a quantitative technique in hereditary Dysfibrinogenemia. We aimed to compare several coagulation triggers in hereditary Dysfibrinogenemia and control plasmas. We included 20 patients with hereditary Dysfibrinogenemia, 19 with hotspot mutations Aα Arg35His (n = 9), Aα Arg35Cys (n = 2), γ Arg301His (n = 6), γ Arg301Cys (n = 2), and one with Aα Phe27Tyr, and a commercial pooled normal plasma. Fibrin polymerization was activated by bovine or human thrombin or tissue factor (TF), in the presence or absence of tissue type plasminogen activator. The lag time (min), slope (mOD/s), maximum absorbance (MaxAbs, mOD), and area under the curve (AUCp, OD s) were calculated from the fibrin polymerization curves and the time for 50% clot degradation (T50, min), AUCf (OD s) and the overall fibrinolytic potential from fibrinolysis curves. The lag time was significantly shorter and AUC increased in Aα Arg35His patients with bovine thrombin as compared with human thrombin. The MaxAbs and AUCp were significantly higher in γArg301His patients with bovine thrombin compared with human thrombin. Fibrin polymerization parameters of patients' samples were closer to those of control when assessed with TF compared with both human and bovine thrombin. T50 and overall fibrinolytic potential were similar in all samples regardless of the coagulation trigger used, however, with TF the AUCf of Aα Arg35His and γ Arg301His groups were significantly decreased compared with control. Bovine and human thrombin cannot be used equally for studying fibrin polymerization in hotspot hereditary Dysfibrinogenemia or control plasmas
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Case report: unmasked inherited Dysfibrinogenemia after everolimus therapy
'Frontiers Media SA', 2020Co-Authors: Merkulova, Alona A, Neerman Arbez Marguerite, Mitchell, Steven C, Merkulov Sergei, Wolberg, Alisa S, Schmaier, Alvin HAbstract: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
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Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders
'Georg Thieme Verlag KG', 2016Co-Authors: Neerman Arbez Marguerite, De Moerloose Philippe, Casini AlessandroAbstract:Congenital fibrinogen disorders are classified into two types of plasma fibrinogen defects: type I (quantitative fibrinogen deficiencies), that is, hypofibrinogenemia or afibrinogenemia, in which there are low or absent plasma fibrinogen antigen levels, respectively, and type II (qualitative fibrinogen deficiencies), that is, Dysfibrinogenemia or hypoDysfibrinogenemia, in which there are normal or reduced antigen levels associated with disproportionately low functional activity. These disorders are caused by mutations in the three fibrinogen-encoding genes FGA, FGB, and FGG. Afibrinogenemia is associated with mild to severe bleeding, whereas hypofibrinogenemia is often asymptomatic. For these quantitative disorders, the majority of mutations prevent protein production. However, in some cases, missense or late-truncating nonsense mutations allow synthesis of the mutant fibrinogen chain, but intracellular fibrinogen assembly and/or secretion are impaired. Qualitative fibrinogen disorders are associated with bleeding, thrombosis, or both thrombosis and bleeding, but many Dysfibrinogenemias are asymptomatic. The majority of cases are caused by heterozygous missense mutations. Here, we review the laboratory and genetic diagnosis of fibrinogen gene anomalies with an updated discussion of causative mutations identified
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Clinical Features and Management of Congenital Fibrinogen Deficiencies
'Georg Thieme Verlag KG', 2016Co-Authors: Casini Alessandro, De Moerloose Philippe, Neerman Arbez MargueriteAbstract:Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (Dysfibrinogenemia) or both (hypoDysfibrinogenemia) of plasmatic fibrinogen. Afibrinogenemia is often diagnosed at birth following prolonged umbilical cord bleeding and is characterized by spontaneous bleeding in all tissues, while hypofibrinogenemic patients are more often asymptomatic. Spontaneous spleen ruptures, painful bone cysts, cardiovascular events, and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of Dysfibrinogenemia are very heterogeneous, from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis. Hypodysfibrinogenemic patients can suffer from both major bleeding and recurrent thrombosis. Pregnancy of women with congenital fibrinogen disorders is a high-risk situation. Owing to the absence of controlled randomized studies, clinical management is mainly based on expert consensus. For the treatment and/or the prevention of bleeding, plasma-derived fibrinogen concentrates are the optimal choice. Treatment of thrombosis may be challenging. More specifically, management strategies should be tailored to each patient, taking the personal and familial history of bleeding and thrombosis, the genotype, and the specific clinical situation into account
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Natural history of patients with congenital Dysfibrinogenemia
'American Society of Hematology', 2015Co-Authors: Casini Alessandro, Lebreton Aurélien, Neerman Arbez Marguerite, Gautier Philippe, Blondon Marc, Koegel Jeremie, Tintillier Véronique, De Maistre Emmanuel, Biron Christine, De Moerloose PhilippeAbstract:We conducted a multicentre study of 101 subjects with Congenital Dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and of thrombotic events was 2.5 and 18.7 per 1000 patient-years respectively, with estimated cumulative incidences at an age of 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and post-partum hemorrhage of 19.8% and 21.4%, respectively. The risk of post-partum hemorrhage was associated with a previously identified bleeding phenotype (OR 5.8; 95%CI 1.2-28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi versus relatives, sex, mutation hotspots, fibrinogen levels and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including post-partum hemorrhage, but also of thrombotic event
Casini Alessandro - One of the best experts on this subject based on the ideXlab platform.
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Comparison of different activators of coagulation by turbidity analysis of hereditary Dysfibrinogenemia and controls
'Ovid Technologies (Wolters Kluwer Health)', 2021Co-Authors: Marchi Cappelletti Rita, Neerman Arbez Marguerite, De Moerloose Philippe, Gay Valérie, Mourey Guillaume, Fiore Mathieu, Mouton Christine, Gautier Philippe, Casini AlessandroAbstract:Turbidity analysis is widely used as a quantitative technique in hereditary Dysfibrinogenemia. We aimed to compare several coagulation triggers in hereditary Dysfibrinogenemia and control plasmas. We included 20 patients with hereditary Dysfibrinogenemia, 19 with hotspot mutations Aα Arg35His (n = 9), Aα Arg35Cys (n = 2), γ Arg301His (n = 6), γ Arg301Cys (n = 2), and one with Aα Phe27Tyr, and a commercial pooled normal plasma. Fibrin polymerization was activated by bovine or human thrombin or tissue factor (TF), in the presence or absence of tissue type plasminogen activator. The lag time (min), slope (mOD/s), maximum absorbance (MaxAbs, mOD), and area under the curve (AUCp, OD s) were calculated from the fibrin polymerization curves and the time for 50% clot degradation (T50, min), AUCf (OD s) and the overall fibrinolytic potential from fibrinolysis curves. The lag time was significantly shorter and AUC increased in Aα Arg35His patients with bovine thrombin as compared with human thrombin. The MaxAbs and AUCp were significantly higher in γArg301His patients with bovine thrombin compared with human thrombin. Fibrin polymerization parameters of patients' samples were closer to those of control when assessed with TF compared with both human and bovine thrombin. T50 and overall fibrinolytic potential were similar in all samples regardless of the coagulation trigger used, however, with TF the AUCf of Aα Arg35His and γ Arg301His groups were significantly decreased compared with control. Bovine and human thrombin cannot be used equally for studying fibrin polymerization in hotspot hereditary Dysfibrinogenemia or control plasmas
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Congenital structural and functional fibrinogen disorders: a primer for internists
'Towarzystwo Internistow Polskich Polish Society of Internal Medicine', 2019Co-Authors: Undas Anetta, Casini AlessandroAbstract:Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of 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 disorders, is associated with bleeding, thrombosis, or both, as well as no symptoms. Recent recommendations issued by the ISTH in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients suspected of congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, i.e. reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic work-up 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
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Fibrinogen Mahdia: A congenitally abnormal fibrinogen characterized by defective fibrin polymerization
'Wiley', 2017Co-Authors: Amri Y, Casini Alessandro, De Moerloose Philippe, Jouini H, Becheur M, Dabboubi R, Mahjoub B, Messaoud T, Sfar M T, Toumi N E HAbstract:Congenital Dysfibrinogenemia is a rare qualitative fibrinogen deficiency. Molecular defects that result in Dysfibrinogenemia are usually caused by mutations which affect fibrinopeptide release, fibrin polymerization, fibrin cross-linking or fibrinolysis
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Diagnostic des anomalies congénitales du fibrinogène
'John Libbey Eurotext', 2016Co-Authors: Lebreton Aurélien, Casini AlessandroAbstract:Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of circulating fibrinogen and qualitative disorders characterized by a discrepancy between the activity and the antigenic levels of fibrinogen (Dysfibrinogenemia and hypoDysfibrinogenemia). The biological diagnosis is based on a standard haemostasis assessment. All the coagulation tests that depend on the formation of fibrin as the end point are affected; although in Dysfibrinogenemia the specificity and sensitivity of routine test depend on reagent and techniques. A genetic exploration permits to confirm the diagnosis and may enhance the prediction of the patient's phenotype. Homozygous or composite heterozygous null mutations are most often responsible for afibrinogenemia while hypofibrinogenemic patients are mainly heterozygous carrier of an afibrinogenemic allele. Heterozygous missense mutations are prevalent in Dysfibrinogenemia, with two hot spot localized in exon 2 of the FGA and in the exon 8 of the FGG. The correlation between phenotype and genotype has been identified in some fibrinogen variants, including six mutations clustered in exons 8 and 9 of the FGG leading to hypofibrinogenemia with hepatic inclusions of abnormal fibrinogen aggregates as well as a few mutations associated with an increase risk of thrombotic events. A familial screening and additional functional assays should be carried out when possible
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Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders
'Georg Thieme Verlag KG', 2016Co-Authors: Neerman Arbez Marguerite, De Moerloose Philippe, Casini AlessandroAbstract:Congenital fibrinogen disorders are classified into two types of plasma fibrinogen defects: type I (quantitative fibrinogen deficiencies), that is, hypofibrinogenemia or afibrinogenemia, in which there are low or absent plasma fibrinogen antigen levels, respectively, and type II (qualitative fibrinogen deficiencies), that is, Dysfibrinogenemia or hypoDysfibrinogenemia, in which there are normal or reduced antigen levels associated with disproportionately low functional activity. These disorders are caused by mutations in the three fibrinogen-encoding genes FGA, FGB, and FGG. Afibrinogenemia is associated with mild to severe bleeding, whereas hypofibrinogenemia is often asymptomatic. For these quantitative disorders, the majority of mutations prevent protein production. However, in some cases, missense or late-truncating nonsense mutations allow synthesis of the mutant fibrinogen chain, but intracellular fibrinogen assembly and/or secretion are impaired. Qualitative fibrinogen disorders are associated with bleeding, thrombosis, or both thrombosis and bleeding, but many Dysfibrinogenemias are asymptomatic. The majority of cases are caused by heterozygous missense mutations. Here, we review the laboratory and genetic diagnosis of fibrinogen gene anomalies with an updated discussion of causative mutations identified
Rosanna Asselta - One of the best experts on this subject based on the ideXlab platform.
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Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains
MDPI AG, 2017Co-Authors: Elvezia Maria Paraboschi, Stefano Duga, Rosanna AsseltaAbstract:Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aα, Bβ, or γ fibrinogen-chain genes (FGA, FGB, FGG) have been described as being responsible for fibrinogen deficiencies (hypofibrinogenemia, hypo-Dysfibrinogenemia, Dysfibrinogenemia) and for more rare conditions, such as fibrinogen storage disease and hereditary renal amyloidosis. Instead, biallelic mutations have been associated with afibrinogenemia/severe hypofibrinogenemia, i.e., the severest forms of fibrinogen deficiency, affecting approximately 1–2 cases per million people. However, the “true” prevalence for these conditions on a global scale is currently not available. Here, we defined the mutational burden of the FGA, FGB, and FGG genes, and estimated the prevalence of inherited fibrinogen disorders through a systematic analysis of exome/genome data from ~140,000 individuals belonging to the genome Aggregation Database. Our analysis showed that the world-wide prevalence for recessively-inherited fibrinogen deficiencies could be 10-fold higher than that reported so far (prevalence rates vary from 1 in 106 in East Asians to 24.5 in 106 in non-Finnish Europeans). The global prevalence for autosomal-dominant fibrinogen disorders was estimated to be ~11 in 1000 individuals, with heterozygous carriers present at a frequency varying from 3 every 1000 individuals in Finns, to 1–2 every 100 individuals among non-Finnish Europeans and Africans/African Americans. Our analysis also allowed for the identification of recurrent (i.e., FGG-p.Ala108Gly, FGG-Thr47Ile) or ethnic-specific mutations (e.g., FGB-p.Gly103Arg in Admixed Americans, FGG-p.Ser245Phe in Africans/African Americans)
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Molecular characterization of 7 patients affected by dys- or hypo-Dysfibrinogenemia: identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation
'Elsevier BV', 2015Co-Authors: Rosanna Asselta, F. Peyvandi, M. Robusto, M. Platé, C. Santoro, S. DugaAbstract:Fibrinogen is a hexameric glycoprotein consisting of two sets of three polypeptides (the A\u3b1, B\u3b2, and \u3b3 chains, encoded by the three genes FGA, FGB, and FGG). It is involved in the final phase of the coagulation process, being the precursor of the fibrin monomers necessary for the formation of the hemostatic plug. Rare inherited fibrinogen disorders can manifest as quantitative deficiencies, qualitative defects, or both. In particular, Dysfibrinogenemia and hypo-Dysfibrinogenemia are characterized by reduced functional activity associated with normal or reduced antigen levels, and are usually determined by heterozygous mutations affecting any of the three fibrinogen genes. In this study, we investigated the genetic basis of dys- and hypo-Dysfibrinogenemia in seven unrelated patients. Mutational screening disclosed six different variants, two of which novel (FGB-p.Asp185Asn and FGG-p.Asn230Lys). The molecular characterization of the FGG-p.Asn230Lys mutation, performed by transient expression experiments of the recombinant mutant protein, demonstrated that it induces an almost complete impairment in fibrinogen secretion, according to a molecular mechanism often associated with quantitative fibrinogen disorders. Conversely, the FGB-p.Asp185Asn variant was demonstrated to be a gain-of-glycosylation mutation leading to a hyperglycosylation of the B\u3b2 chain, not affecting fibrinogen assembly and secretion. To our knowledge, this is the second gain-of-glycosylation mutation involving the FGB gene
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the molecular basis of quantitative fibrinogen disorders
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Rosanna Asselta, Maria Luisa TenchiniAbstract:Summary. Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of immunoreactive protein; and type II deficiencies (Dysfibrinogenemia and hypoDysfibrinogenemia, i.e. qualitative defects), showing normal or altered antigen levels associated with reduced coagulant activity. While Dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits. Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe. This review focuses on the genetic bases of type I fibrinogen deficiencies, which are invariantly represented by mutations within the three fibrinogen genes (FGA, FGB, and FGG) coding for the three polypeptide chains Aα, Bβ, and γ. From the inspection of the mutational spectrum of these disorders, some conclusions can be drawn: (i) genetic defects are scattered throughout the three fibrinogen genes, with only few sites appearing to represent relative mutational hot spots; (ii) several different types of genetic lesions and pathogenic mechanisms have been described in affected individuals (including gross deletions, point mutations causing premature termination codons, missense mutations affecting fibrinogen assembly/secretion, and uniparental isodisomy associated with a large deletion); (iii) the possibility to express recombinant fibrinogen mutants in eukaryotic cells is rapidly shedding light into the molecular mechanisms responsible for physiologic and pathologic properties of the molecule; (iv) though mutation analysis of the fibrinogen cluster does not yield precise information for predicting genotype/phenotype correlations, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis.
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The molecular basis of quantitative fibrinogen disorders
'Wiley', 2006Co-Authors: Rosanna Asselta, S. Duga, Maria Luisa TenchiniAbstract:Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of immunoreactive protein; and type II deficiencies (Dysfibrinogenemia and hypoDysfibrinogenemia, i.e. qualitative defects), showing normal or altered antigen levels associated with reduced coagulant activity. While Dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits. Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe. This review focuses on the genetic bases of type I fibrinogen deficiencies, which are invariantly represented by mutations within the three fibrinogen genes (FGA, FGB, and FGG) coding for the three polypeptide chains Aalpha, Bbeta, and gamma. From the inspection of the mutational spectrum of these disorders, some conclusions can be drawn: (i) genetic defects are scattered throughout the three fibrinogen genes, with only few sites appearing to represent relative mutational hot spots; (ii) several different types of genetic lesions and pathogenic mechanisms have been described in affected individuals (including gross deletions, point mutations causing premature termination codons, missense mutations affecting fibrinogen assembly/secretion, and uniparental isodisomy associated with a large deletion); (iii) the possibility to express recombinant fibrinogen mutants in eukaryotic cells is rapidly shedding light into the molecular mechanisms responsible for physiologic and pathologic properties of the molecule; (iv) though mutation analysis of the fibrinogen cluster does not yield precise information for predicting genotype/phenotype correlations, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis