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

Abstract

We encountered a 45-year-old Japanese man who suffered from pulmonary thromboembolism and huge right ventricular thrombus after inferior vena cava (IVC) filter implantation without apparent thrombus in either the deep veins or inside the IVC filter. The biochemical data showed a discrepancy in the level of fibrinogen between the immunological and thrombin time methods, suggesting hypodysfibrinogenemia. The sequencing of the fibrinogen γ-chain gene (FGG) revealed a novel heterozygous missense mutation in exon 8 - a TGT to TCT transversion in codon 326 - resulting in an amino acid substitution of serine for cysteine (γCys326Ser). The characterization of the protein did not show known mechanisms for thrombosis in dysfibrinogenemia, such as dimer or albumin-binding complex formation. In summary, the current case with a life-threatening thrombotic event was found to have a novel heterozygous missense mutation resulting in γCys326Ser, which was suggested as a predisposing factor of the thrombosis. Known mechanisms responsible for thrombosis in the current case were not demonstrated, suggesting other mechanisms including superimposing inherited and/or acquired risk factors. When a patient presents with unusual thrombosis such as breakthrough pulmonary embolism and huge thrombus in the right ventricle, as in the current case, the laboratory process for heritable thrombophilia should be considered.

Fibrin clot properties to assess the bleeding phenotype in unrelated patients with hypodysfibrinogenemia due to novel fibrinogen mutations

“…Patients with hypodysfibrinogenemia are more prone to develop adverse outcomes than patients with dysfibrinogenemia [36,37]. The bleeding phenotype is usually severe, although dependent on the antigenic fibrinogen levels [38].…”

Novel variant fibrinogen γp.C352R produced hypodysfibrinogenemia leading to a bleeding episode and failure of infertility treatment

“…These data indicated that substitutions of γp.C352 led to a drastic change in the tertiary structure of the γ-module caused by the destruction of an intra-peptide disulfide bridge, resulting in reduced secretion of variant fibrinogen and impaired function of polymerization. Finally, five out of seven families possessing substitutions of γp.C352, namely, Cordoba [24], Tokai [25],…”