From the Journals

New gene variant found for hereditary bleeding disorder



Clinical symptoms in a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage, led to the discovery of a novel gene variant causing her bleeding disorder.

Blood analysis of the patients showed decreased fibrinogen level with “markedly elevated fibrinogen/fibrin degradation products and D-dimer levels.” Attempts to treat the patient with hemostatic surgery, administration of several medications, including nafamostat mesylate, tranexamic acid, and unfractionated heparin, produced no correction of her coagulation abnormalities, and the patient experienced repeated hemorrhagic events, according to researchers from the Tokyo Saiseikai Central Hospital, Japan, and colleagues.

However, the researchers found that treatment with recombinant human thrombomodulin (rhTM) remarkably improved the patient’s pathophysiology, according to the results of a case study reported in Blood Advances.

Genetic analysis

Upon screening and sequencing of the patient’s thrombomodulin gene, a previously unreported homozygous variation, c.793T>A (p.Cys265Ser) was discovered. Under normal circumstances, the Cys265 residue forms one of three disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of thrombomoduliin (TM), according to the researchers.

However, transient expression analysis of the patient’s mutation using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably due to EGF-like domain 1 misfolding, according to the researchers and the reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular coagulation-like symptoms observed in the patient, the speculated.

“The clinical symptoms of the patient in this study were characterized by recurrent hemorrhage, indicating that TM-C265S mainly causes hyperfibrinolysis rather than hypercoagulation. The C265S mutation may disrupt the timely and delicate balance between coagulation and fibrinolysis,” the researchers suggested.

The authors reported that they had no conflicts of interest.

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