Imperial College London
Alternate

ProfessorMikeLaffan

Faculty of Medicine, Department of Immunology and Inflammation

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 2178m.laffan

 
 
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Assistant

 

Mrs Lisa Pape +44 (0)20 3313 1320

 
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Location

 

5S5bHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Morrow:2020:10.1016/j.thromres.2020.11.002,
author = {Morrow, GB and Beavis, J and Harper, S and Bignell, P and Laffan, MA and Curry, N},
doi = {10.1016/j.thromres.2020.11.002},
journal = {Thrombosis Research: vascular obstruction, hemorrhage and hemostasis},
pages = {100--108},
title = {Characterisation of a novel thrombomodulin c.1487delC,p.(Pro496Argfs*10) variant and evaluation of therapeutic strategies to manage the rare bleeding phenotype.},
url = {http://dx.doi.org/10.1016/j.thromres.2020.11.002},
volume = {197},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - INTRODUCTION: A novel variant in the thrombomodulin (TM) gene, c.1487delC,p.(Pro496Argfs10), referred to as Pro496Argfs10, was identified in a family with an unexplained bleeding disorder. The Pro496Argfs10 variant results in loss of the transmembrane and intracellular segments of TM and is associated with an increase in soluble TM (sTM) in the plasma. The aim of this study was to characterise the effect of elevated sTM on thrombin generation (TG) and fibrinolysis, and to evaluate therapeutic strategies to manage the patients. METHODS: Plasma samples were obtained from two patients carrying the variant. TG was triggered using 5 pM tissue factor and measured using the Calibrated Automated Thrombogram. A turbidity clot lysis assay was used to monitor fibrinolysis. TM antigen was quantified by ELISA. RESULTS: Patients with the Pro496Argfs10 variant had significantly elevated plasma sTM compared to controls (372.6 vs. 6.0 ng/ml). TG potential was significantly lower in patients but was restored by inhibition of activated protein C (APC) or addition of activated Factor VII (FVIIa) or platelet concentrates. In vitro experiments suggested that activated prothrombin complex concentrates (APCC) posed a risk of thrombosis. The time to 50% lysis was significantly prolonged in patients compared to controls, 69.7 vs. 42.3 min. Clot lysis time was shortened by inhibition of activated thrombin activatable fibrinolysis inhibitor (TAFIa). CONCLUSIONS: Our data demonstrate that increased sTM enhances APC generation and reduces TG. Simultaneously, the rate of fibrinolysis is delayed due to increased TAFI activation by sTM. Treatment with platelet or FVIIa concentrates may be beneficial to manage this rare bleeding disorder.
AU  - Morrow,GB
AU  - Beavis,J
AU  - Harper,S
AU  - Bignell,P
AU  - Laffan,MA
AU  - Curry,N
DO  - 10.1016/j.thromres.2020.11.002
EP  - 108
PY  - 2020///
SN  - 0049-3848
SP  - 100
TI  - Characterisation of a novel thrombomodulin c.1487delC,p.(Pro496Argfs10) variant and evaluation of therapeutic strategies to manage the rare bleeding phenotype.
T2  - Thrombosis Research: vascular obstruction, hemorrhage and hemostasis
UR  - http://dx.doi.org/10.1016/j.thromres.2020.11.002
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33190022
UR  - https://www.sciencedirect.com/science/article/pii/S004938482030596X?via%3Dihub
UR  - http://hdl.handle.net/10044/1/84922
VL  - 197
ER  -
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