Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias

Abstract

Hereditary dysfibrinogenaemia is characterized by the presence of functionally abnormal plasma fibrinogen. Dysfibrinogenaemia is a heterogeneous disorder associated with different mutations throughout the three genes that code for the fibrinogen sub-units, affecting many different aspects of fibrinogen/fibrin activity. Dysfibrinogenaemia may be discovered during the investigation of individuals who present with bleeding or thombosis, or may be found in individuals during routine coagulation screening. More specialized coagulation tests may confirm the diagnosis of dysfibrinogenaemia but do not reliably distinguish between the different fibrinogen variants and are not usually useful in predicting bleeding or thrombotic risk. Advances in molecular diagnostics have facilitated the investigation of the molecular causes of fibrinogen disorders. Several 'hot spot' areas have been identified where mutations causing a high proportion of cases of dysfibrinogenaemia are found (AalphaArg16 and gammaArg275). Molecular diagnostics have also shown that many fibrinogen variants share the same causative mutation. There is a discrepancy between the quality of the molecular and functional data available for each mutation and the clinical information on individuals and their family members. However, there are accumulating data that the 'hot spot' mutations accounting for 60-80% of cases of dysfibringenaemia are not associated with a significant bleeding or thrombosis in the absence of other risk factors. Rapid screening for these mutations may provide reassurance for patients in the presurgical setting.

Why dysfibrinogenaemias still matter

“…Hereditary dysfibrinogenaemias are caused by a variety of mutations in the three fibrinogen genes that code for its polypeptide chains and may be uncovered in patients who present with thrombosis or bleeding or may be discovered by routine coagulation testing (5, 6). Mutations can result in quantitative defects, such as afibrinogenaemia or hypofibrinogenaemia or qualitative defects resulting in functional deficiencies in the protein’s activities or a combination of both.…”

“…Studies of afibrinogenaemias have given us data about the synthesis, assembly, and secretion of fibrinogen (7–9), while investigation of qualitative dysfibrinogenaemias has provided a great deal of information on fibrin polymerisation, fibrinolysis, platelet aggregation, and other functions (2, 10, 11). Dysfibrinogenaemias can also give us clues about relationships between molecular structure/function and clinical consequences (5, 6). …”

Fibrinogen Columbus II: A novel c.1075G>T mutation in the FGG gene causing hypodysfibrinogenemia and thrombosis in an adolescent male

“…Hypodysfibrinogenemia is a rare disorder characterized by a reduced fibrinogen antigen level, associated with a disproportionately low functional activity . A systematic review of literature by Casini et al identified 51 index cases of hypodysfibrinogenemia with 32 causative mutations, clustered in the COOH‐terminal of the γ or the Aɑ chains .…”

“…Fibrinogen, a 340 kDa glycoprotein, consists of three homologous polypeptide chains (Aɑ, Bß, and γ), encoded by FGA , FGB , and FGG genes, respectively, which are clustered on the long arm of chromosome 4 . Congenital fibrinogen disorders may be classified into quantitative deficiency (afibrinogenemia and hypofibrinogenemia) or qualitative defect (dysfibrinogenemia or hypodysfibrinogenemia) in the synthesized protein . Phenotypic manifestations include arterial and venous thrombotic events in addition to bleeding.…”

Evaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding

“…The presence of a bleeding or thrombotic phenotype is dependent on the underlying mutation. 88 One case report of ICH and cephalhematomas in a child with suspected dysfibrinogenemia has been published. The case in that report was unique in that the patient had a long history of bleeding and almost undetectable fibrinogen levels.…”