Why dysfibrinogenaemias still matter

Weisel, John W.

doi:10.1160/th09-07-0432

Cited by 9 publications

(10 citation statements)

References 15 publications

(17 reference statements)

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“…The decreased fibrinogen clotting activity-antigen ratio is typical for dysfibrinogenemia, but the phenotypic characteristics in dysfibrinogenemia can differ widely and go right up to normal activityantigen ratios, like reported in fibrinogen Denver (28). Furthermore, proper diagnosis for every patient with suspected dysfibrinogenemia should incorporate gene sequence analysis, as the findings reported herein support the understanding of structure-function relations and provide predictive value for individual patients (29).…”

Section: Discussionsupporting

confidence: 61%

Novel point mutation in fibrinogen (Innsbruck; BβArg44Gly)

Würtinger

Griesmacher²,

Ivaškevičius³

et al. 2015

Hamostaseologie

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SummaryThis is a report of a novel fibrinogen point mutation (fibrinogen Innsbruck), a C/G point mutation at position 220 of exon two of the fibrinogen B|-chain leading to B|3Arg44Gly. The heterozygous mutation was found in a 16-year-old adolescent, hospitalized for the management of juvenile depression, who suffered from multiple epistaxis episodes during his stay at the university hospital in Innsbruck, Austria. Fibrinogen (based on the Clauss method) and fibrinogen antigen levels were highly discrepant (86 vs. 223 mg/dl) with thrombin time and reptilase time being in the respective upper reference ranges. Densitometric analysis of electrophoretic band pattern showed a reduction of a-polymers, indicating an impaired fibrin polymerization. This is in agreement with structural analysis, which showed a disturbance of the flexibility and structure of the region surrounding the fibrinoeptide B cleavage site. Fibrinogen Nijmegen, a mutation at the same position, is causative for thrombosis, whereas fibrinogen Innsbruck appears to lead to a bleeding tendency, illustrating that even mutations at the same position can cause contrary symptoms.

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Section: Discussionsupporting

confidence: 61%

Novel point mutation in fibrinogen (Innsbruck; BβArg44Gly)

Würtinger

Griesmacher²,

Ivaškevičius³

et al. 2015

Hamostaseologie

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“…Mutant fibrinogen molecules in heterozygous propositi can circulate as homodimers (that is, both identical chains are mutated) or heterodimers (that is, only one chain is mutated). The proportions of these will affect fibrinogen function, and the reliable effects of the causative mutations can be confused by accompanying altered concentrations of fibrinogen in the blood . As the diagnosis can be made at a young age, some patients will not have had the time to develop thrombotic or bleeding symptoms at the time of published reports, and will thus be considered to be asymptomatic.…”

Section: Clinical Features Of Dysfibrinogenemiamentioning

confidence: 99%

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Casini

Neerman-Arbez

Ariëns

et al. 2015

Journal of Thrombosis and Haemostasis

125

135

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Summary Congenital dysfibrinogenemia is a qualitative congenital fibrinogen disorder characterized by normal antigen levels of a dysfunctional fibrinogen. The diagnosis is usually based on discrepancies between fibrinogen activity and antigen levels, but could require more specialized techniques for the assessment of fibrinogen function, owing to some limitations in routine assays. Molecular abnormalities, which are frequently heterozygous missense mutations localized in exon 2 of FGA and exon 8 of FGG, lead to defects in one or more phases of fibrinogen to fibrin conversion, fibrin network formation, and other important functions of fibrinogen. The clinical phenotype is highly heterogeneous, from no manifestations to bleeding and/or thrombotic events. Asymptomatic propositi and relatives with the predisposing genotype are at risk of developing adverse outcomes during the natural course of the disease. Correlations between genotype and phenotype have not yet been clearly established, with the exception of some abnormal fibrinogens that severely increase the risk of thrombosis. Functional analysis of polymerization and fibrinolysis, structural studies of the fibrin network and the viscoelastic properties of fibrin clot could help to predict the phenotype of congenital dysfibrinogenemia, but have not yet been evaluated in detail. The management is essentially based on personal and family history; however, even individuals who are still asymptomatic and without a family history should be carefully assessed and monitored. Particular situations, such as pregnancy, delivery, and surgery, require a multidisciplinary approach.

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“…In addition, functional analyses, such as turbidimetry assaying fibrin polymerization and lysis and evaluation of the fibrin clot structure (viscoelastic properties, permeability, fiber density, and architecture), could be performed in research laboratories to better try to assess the patient phenotype. 39,93…”

Section: Management Of Dysfibrinogenemia and Hypodysfibrinogenemiamentioning

confidence: 99%

Clinical Features and Management of Congenital Fibrinogen Deficiencies

Casini

Moerloose

Neerman-Arbez

2016

Semin Thromb Hemost

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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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Why dysfibrinogenaemias still matter

Cited by 9 publications

References 15 publications

Novel point mutation in fibrinogen (Innsbruck; BβArg44Gly)

Novel point mutation in fibrinogen (Innsbruck; BβArg44Gly)

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Clinical Features and Management of Congenital Fibrinogen Deficiencies

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