Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Abstract

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.

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

“…Approximately 30% of patients with CAF or severe hypofibrinogenemia develop thrombosis, which may be due to embolism of an unstable thrombus 9, 10. Congenital dysfibrinogenemia (CD) is a qualitative defect classified by decreased functional activity despite normal antigen levels 11. CD mutations are often inherited in an autosomal dominant manner and are commonly found in exon 2 of FGA , which encodes the thrombin cleavage site for EA exposure enabling EA‐D interactions, or in exon 8 of FGG , which is involved in D:D end‐to‐end assembly of fibrin 12.…”

Fibrin clot structure in patients with congenital dysfibrinogenaemia

“…In the setting of congenital dysfibrinogenaemia, fibrinogen variants with a well-identified thrombotic phenotype have been associated with hypofibrinolysis [36]. Several mechanisms, often overlapping, account for the hypofibrinolysis in these mutations, including impaired binding of tPA and plasmin to the abnormal fibrinogen as well as abnormal fibrin clot structure with an increased stiffness [3]. In this study, the FGA Arg573Cysmutation showed an abnormal fibrin network with thin fibres and a very dense clot, resulting in greater resistance to fibrinolysis.…”

“…Congenital dysfibrinogenaemia is characterised by a discrepancy between the functional and the antigen levels of circulating fibrinogen, reflecting the altered functional properties of the molecule due to structural defects [2].More than 100 causative mutations have been identified in congenital dysfibrinogenaemia, mainly heterozygous missense mutations in the amino-terminal portion of the A chain or in the carboxyl terminal region of the chain [3]. Almost all these molecular anomalies lead to ineffective polymerisation of the fibrin clot and may affect several other functions of the fibrinogen/fibrin [4].…”

“…Almost all these molecular anomalies lead to ineffective polymerisation of the fibrin clot and may affect several other functions of the fibrinogen/fibrin [4]. The clinical phenotype of dysfibrinogenaemic patients is highly heterogeneous, from absence of symptoms to major bleeding or thrombotic events, including pulmonary hypertension and renal amyloidosis [3]. During the natural course of the disease, even asymptomatic patients at the time of the diagnosis are at risk of developing adverse outcomes [5].…”

Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus

“…Dysfibrinogenemia has been reported to be caused by mutations in the coding regions of the FGA , FGB , or FGG [1,2,3]. The incidence of dysfibrinogenemia is difficult to estimate because there are a number of asymptomatic cases [2,3], but over 300 molecular abnormalities have been reported in a fibrinogen variants database [4].…”