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

doi:10.1182/blood-2016-05-716092

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

Applied Medicine

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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 language	English
Pages (from-to)	1879-1883
Number of pages	5
Journal	Blood
Volume	128
Issue number	14
Early online date	19 Jul 2016
DOIs	https://doi.org/10.1182/blood-2016-05-716092
Publication status	Published - 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; 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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10.1182/blood-2016-05-716092Licence: Unspecified

Accepted Manuscript
This research was originally published in Blood. Burley, K, Whyte, CS, Westbury, SK, Walker, M, Stirrups, KE, Turro, E, Chapman, O, Reilly-Stitt, C, Mutch, NJ & Mumford, AD., Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy' Blood, Vol: 128 pp-pp. 1879-1883 © the American Society of Hematology.
Accepted author manuscript, 1.42 MBLicence: Other

http://europepmc.org/abstract/MED/27436851Licence: Unspecified

Nicola Mutch
Person: Academic

Cite this

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title = "Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy",

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.",

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

note = "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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T1 - Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

AU - Burley, Kate

AU - Whyte, Claire S.

AU - Westbury, Sarah K.

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AU - Stirrups, Kathleen E

AU - Turro, Ernest

AU - Chapman, Oliver

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

PY - 2016/10/6

Y1 - 2016/10/6

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.

U2 - 10.1182/blood-2016-05-716092

DO - 10.1182/blood-2016-05-716092

M3 - Article

SN - 0006-4971

VL - 128

SP - 1879

EP - 1883

JO - Blood

JF - Blood

IS - 14

ER -

Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

Abstract

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Nicola Mutch

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