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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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.
Original languageEnglish
Pages (from-to)1879-1883
Number of pages5
JournalBlood
Volume128
Issue number14
Early online date19 Jul 2016
DOIs
Publication statusPublished - 6 Oct 2016

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Thrombomodulin
Fibrinolysis
Thrombin
Carboxypeptidase B2
Plasmas
Blood
Hemorrhage
Thromboplastin

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Burley, K., Whyte, C. S., Westbury, S. K., Walker, M., Stirrups, K. E., Turro, E., ... Mumford, A. D. (2016). Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood, 128(14), 1879-1883. https://doi.org/10.1182/blood-2016-05-716092

Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. / Burley, Kate; Whyte, Claire S.; Westbury, Sarah K.; Walker, Mary; Stirrups, Kathleen E; Turro, Ernest; Chapman, Oliver; Reilly-Stitt, Christopher ; Mutch, Nicola J.; Mumford, Andrew D.

In: Blood, Vol. 128, No. 14, 06.10.2016, p. 1879-1883.

Research output: Contribution to journalArticle

Burley, K, Whyte, CS, Westbury, SK, Walker, M, Stirrups, KE, Turro, E, Chapman, O, Reilly-Stitt, C, Mutch, NJ & Mumford, AD 2016, 'Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy', Blood, vol. 128, no. 14, pp. 1879-1883. https://doi.org/10.1182/blood-2016-05-716092
Burley K, Whyte CS, Westbury SK, Walker M, Stirrups KE, Turro E et al. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood. 2016 Oct 6;128(14):1879-1883. https://doi.org/10.1182/blood-2016-05-716092
Burley, Kate ; Whyte, Claire S. ; Westbury, Sarah K. ; Walker, Mary ; Stirrups, Kathleen E ; Turro, Ernest ; Chapman, Oliver ; Reilly-Stitt, Christopher ; Mutch, Nicola J. ; Mumford, Andrew D. / Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. In: Blood. 2016 ; Vol. 128, No. 14. pp. 1879-1883.
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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.",
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AU - Reilly-Stitt, Christopher

AU - Mutch, Nicola J.

AU - Mumford, Andrew D.

N1 - The NIHR BioResource-Rare Diseases and the ThromboGenomics sequencing projects are supported by the National Institute for Health Research (NIHR; http://www.nihr.ac.uk). 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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N2 - 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.

AB - 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.

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