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

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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

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    Burley, K., Whyte, C. S., Westbury, S. K., Walker, M., Stirrups, K. E., Turro, E., Chapman, O., Reilly-Stitt, C., Mutch, N. J., & Mumford, A. D. (2016). Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood, 128(14), 1879-1883.