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Publication - Dr Sarah Westbury

    Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

    Citation

    Burley, K, Whyte, CS, Westbury, SK, Walker, M, Stirrups, KE, Turro, E, BioResource, N, Chapman, OG, Reilly-Stitt, C, Mutch, NJ & Mumford, AD, 2016, ‘Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy’. Blood, vol 128., pp. 1879-1883

    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.

    Full details in the University publications repository