Abstract Number: PB0393
Meeting: ISTH 2020 Congress
Background: A 19-year-old Vietnamese female presented with left ovarian hemorrhage. On admission, her blood investigation revealed thrombocytopenia and decreased fibrinogen with markedly elevated FDP and D-dimer levels, which suggested she was on disseminated intravascular coagulation (DIC). Despite hemostasis surgery or administration of nafamostat mesilate and tranexamic acid, her blood abnormalities were not improved and she repeated critical hemorrhagic events. We found that recombinant thrombomodulin (rTM) had a remarkable effect on her bleeding disorder, although her plasma levels of soluble TM fragments were always high even before rTM administration.
Aims: To understand abnormalities of her hemostasis and to solve the reason why rTM works.
Methods: A congenital or hereditary disease was suspected because she had also experienced several hemorrhagic events in her childhood. We screened mutation of the thrombomodulin (THBD) gene in her family members, because administration of rTM was effective on coagulation disorders.
Results: We found an unreported THBD mutation, c.793T>A (p.Cys265Ser), homozygously in the patient and heterozygously in her parents. Cys265 is one of the cysteine residues forming three disulfide bonds in the EGF-like domain 1 of thrombomodulin. Transient expression experiments using COS-1 cells demonstrated the significantly reduced expression of TM-Cys265Ser on the plasma membrane as compared with wild-type TM. The TM-Cys265Ser variant was degraded by endoplasmic reticulum associated-degradation (ERAD), probably because of its misfolding in the EGF-like domain 1. The reduced expression of TM on the endothelial cell surface may cause the pathogenesis of DIC-like symptoms of the patient.
Conclusions: We have identified a novel TM mutation c.793T>A (p.Cys265Ser). The patient who has the homozygous mutation may present severe bleeding events, and rTM administration seems to work well for this disorder.
To cite this abstract in AMA style:Osada M, Maruyama K, Kokame K, Denda R, Yamazaki K, Kunieda H, Hirao M, Madoiwa S, Okumura N, Murata M, Ikeda Y, Tsukada Y, Kikuchi T. A Hereditary Bleeding Disorder Caused by a Novel Homozygous Mutation of Thrombomodulin Gene [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-hereditary-bleeding-disorder-caused-by-a-novel-homozygous-mutation-of-thrombomodulin-gene/. Accessed March 3, 2021.
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