A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder

Makoto Osada, Keiko Maruyama, Koichi Kokame, Ryunosuke Denda, Kohei Yamazaki, Hisako Kunieda, Maki Hirao, Seiji Madoiwa, Nobuo Okumura, Mitsuru Murata, Yasuo Ikeda, Kentaro Watanabe, Yuiko Tsukada, Takahide Kikuchi

研究成果: Article査読

抄録

We report a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage. Blood analysis revealed a decreased fibrinogen level with markedly elevated fibrinogen/fibrin degradation products and D-dimer levels. Despite hemostatic surgery and administration of several medications, such as nafamostat mesylate, tranexamic acid, and unfractionated heparin, the coagulation abnormalities were not corrected, and the patient experienced repeated hemorrhagic events. We found that administration of recombinant human thrombomodulin (rhTM) remarkably improved the patient’s pathophysiology. Screening and sequencing of the TM gene (THBD) revealed a previously unreported homozygous variation: c.793T.A (p.Cys265Ser). Notably, the Cys265 residue forms 1 of 3 disulfide bonds in the epidermal growth factor (EGF)–like domain 1 of TM. Transient expression experiments 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 because of EGF-like domain 1 misfolding. The reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular-coagulation–like symptoms observed in the patient. In summary, we identified a novel TM variant, c.793T.A (p.Cys265Ser). Patients homozygous for this variant may present with severe bleeding events; rhTM should be considered a possible treatment option for these patients.

本文言語English
ページ(範囲)3830-3838
ページ数9
ジャーナルBlood Advances
5
19
DOI
出版ステータスPublished - 2021 10月 12

ASJC Scopus subject areas

  • 血液学

フィンガープリント

「A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル