New Fibrinogen Substitution (gSer313Arg) with Hypodysfibrinogenemia and the Use of Thromboelastography in Diagnosis of Hypo/Dysfibrinogenemia.

Fibrinogen, also known as factor I, is an integral component of both the coagulation and fibrinolytic pathways. The functions of this 340 kDa glycoprotein include fibrin clot formation, non-substrate thrombin binding and platelet aggregation. It is encoded by 3 genes, FGA, FGB and FGG, clustered on chromosome 4q. Disorders of fibrinogen are extremely rare, and may be qualitative or quantitative, resulting from defects in synthesis, processing, polymerization, crosslinking or clot lysis. Clinical manifestations vary from life threatening bleeding disorders to thromboembolism. We report here the identification of a novel g313Ser®Arg substitution in the gD domain that affects both expression level and fibrinogen function in a 3 year old African American child and her mother with a history of epistaxis and menorrhagia respectively.

Plasma samples showed low Clauss fibrinogen concentrations (0.5 and 0.4 g/L) and extended thrombin clotting times (40 and 39 s) for both the proband and her mother (normal 1.5-4.0 g/L and 18-26 s respectively). Estimation of physical fibrinogen concentrations by HPLC quantitation of fibrinopeptides gave values of 1.2 and 1.5 g/L respectively (normal 1.5-4.0 g/L). While these latter values clearly indicate hypofibrinogenemia, the discrepancy between the activity based and physical concentrations suggest a concomitant functional defect. Thromboelastography (TEG) performed on the child showed a low angle and reduced maximum amplitude indicating a platelet or fibrinogen dysfunction or deficiency. A TEG® platelet mapping‘ study confirmed a significant impairment of fibrinogen function. Examination of purified fibrinogen by SDS-PAGE showed a normal pattern of Aa, Bb and g chains, with an additional minor band in the g region showing increased mobility. Electrospray ionisation mass spectrometry of separated chains again confirmed an abnormality in the g chain with measured masses of 48,399 and 48,400 Da from two separate measurements compared to control values of 48,394 Da (SEM 0.6, n=3). DNA sequencing of FGG revealed a novel heterozygous mutation of AGT to CGT at codon 339 (c.1015A>C). The g313Ser®Arg substitution has not been previously reported and we have named the new variant fibrinogen Detroit II.

The majority of variant chains are not secreted resulting in hypofibrinogenemia. However, a minor population of dysfunctional variant g chains (∼15 % of total g chains) was expressed in plasma fibrinogen causing hypodysfibrinogenemia. TEG was a useful assay for the diagnosis of the hypo/dysfibrinogenemia and should be considered in the evaluation of patients with bleeding symptoms.

No relevant conflicts of interest to declare.