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Blood. 2015 Feb 26;125(9):1497-501. doi: 10.1182/blood-2014-10-604553. Epub 2015 Jan 6.

Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation.

Author information

1
Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, University Lyon I, France;
2
Laboratoire d'Anatomie Pathologique, Hôpital Edouard Herriot, Lyon, France;
3
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; and.
4
Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.

Abstract

We describe a family with an autosomal dominant disorder characterized by severe trauma- and surgery-related bleeding. The proband, who experienced life-threatening bleeding during a routine operation, had normal clotting times, but markedly reduced prothrombin consumption. Plasma levels of all coagulation factors and of the main coagulation inhibitors were normal. Thrombin generation at low triggers was severely impaired and mixing experiments suggested the presence of a coagulation inhibitor. Using whole exome sequencing, the underlying genetic defect was identified as the THBD c.1611C>A mutation (p.Cys537Stop), which predicts a truncated form of thrombomodulin that is shed from the vascular endothelium. The patient had decreased expression of endothelium-bound thrombomodulin, but extremely elevated levels of soluble thrombomodulin in plasma, impairing the propagation phase of coagulation via rapid activation of protein C and consequent inactivation of factors Va and VIIIa. The same thrombomodulin mutation has been recently described in an unrelated British family with strikingly similar features.

PMID:
25564403
PMCID:
PMC4342361
DOI:
10.1182/blood-2014-10-604553
[Indexed for MEDLINE]
Free PMC Article

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