Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

Kate Burley, Claire S. Whyte, Sarah K. Westbury, Mary Walker, Kathleen E Stirrups, Ernest Turro, Oliver Chapman, Christopher Reilly-Stitt, Nicola J. Mutch, Andrew D. Mumford

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)1879-1883
Number of pages5
Issue number14
Early online date19 Jul 2016
Publication statusPublished - 6 Oct 2016

Bibliographical note

The NIHR BioResource-Rare Diseases and the ThromboGenomics
sequencing projects are supported by the National Institute for Health Research (NIHR; KB is an NIHR academic clinical fellow. SKW is supported by a Medical Research Council (MRC) Clinical Training Fellowship (MR/K023489/1). KS and ET are supported by the NIHR BioResource Rare Diseases. CSW and NJM are supported by the British Heart Foundation (FS/11/2/28579). ADM is supported by the NIHR Bristol Cardiovascular Biomedical Research Unit. Deposited in EuropePMC. PMCID:PMC5054699


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