title: Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation.
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.
authors.affiliation: Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, University Lyon I, France;
authors.forename: Yesim
authors.initials: Y
authors.lastname: Dargaud
authors.affiliation: Laboratoire d'Anatomie Pathologique, Hôpital Edouard Herriot, Lyon, France;
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Simone J H
authors.initials: SJ
authors.lastname: Wielders
authors.affiliation: Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, University Lyon I, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Trzeciak
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.affiliation: Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, University Lyon I, France;
authors.forename: Claude
authors.initials: C
authors.lastname: Négrier
authors.affiliation: Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
authors.forename: H Coenraad
authors.initials: HC
authors.lastname: Hemker
authors.affiliation: Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: Lindhout
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Castoldi
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000502:physiology; D001778:Blood Coagulation Disorders / Q000235:genetics*; D015944:Factor VIIIa / Q000378:metabolism; D015943:Factor Va / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011486:Protein C / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics*
chemical_list: D011486:Protein C; C546931:THBD protein, human; D018180:Thrombomodulin; D015943:Factor Va; D015944:Factor VIIIa; D013917:Thrombin