Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy
Author(s)
Type
Journal Article
Abstract
Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognised dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) gene THBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor-induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared to controls, but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with rFVIIa or aPCC did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognised fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of haemostasis.
Date Issued
2016-10-06
Date Acceptance
2016-07-06
Citation
Blood, 2016, 128 (14), pp.1879-1883
ISSN
0006-4971
Publisher
American Society of Hematology
Start Page
1879
End Page
1883
Journal / Book Title
Blood
Volume
128
Issue
14
Copyright Statement
© 2016 American Society of Hematology
Subjects
Immunology
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Publication Status
Published