Imperial College London
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Emeritus Professor David Lane

Faculty of Medicine, Department of Immunology and Inflammation

Emeritus Professor of Haematology
 
 
 
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Contact

 

+44 (0)20 3313 2295d.lane

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{South:2018:10.1111/jth.14275,
author = {South, K and Denorme, F and Salles, I and De, Meyer S and Lane, D},
doi = {10.1111/jth.14275},
journal = {Journal of Thrombosis and Haemostasis},
pages = {2289--2299},
title = {Enhanced activity of ADAMTS13 variant (R568K/F592Y/R660K/Y661F/Y665F) against platelet agglutination in vitro and in a murine model of acute ischaemic stroke},
url = {http://dx.doi.org/10.1111/jth.14275},
volume = {16},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundADAMTS13 circulates in a closed conformation, only achieving full proteolytic activity against von Willebrand Factor (VWF) following a substrateinduced conformational change. A gain of function (GoF) ADAMTS13 variant (R568K/F592Y/R660K/Y661F/Y665F) is conformationally preactivated.ObjectivesTo establish how the hyperactivity of GoF ADAMTS13 is manifest in experimental models mimicking the occlusive arterial thrombi present in acute ischaemic stroke.MethodsThe ability of GoF ADAMTS13 to dissolve VWFplatelet agglutinates was examined using an assay of ristocetininduced platelet agglutination and in parallel flow models of arterial thrombosis. A murine model of focal ischaemia was used to assess the thrombolytic potential of GoF ADAMTS13.ResultsWT ADAMTS13 required conformational activation to attain full activity against VWFmediated platelet capture under flow. In this assay GoF ADAMTS13 had an EC50 value >5fold lower than wild type (WT) (0.73±0.21 nM and 3.81±0.97 nM, respectively). The proteolytic activity of GoF ADAMTS13 against preformed platelet agglutinates under flow was enhanced >4fold compared to WT (EC50 values of 2.5±1.1 nM and 10.2±5.6 nM, respectively). In a murine stroke model GoF ADAMTS13 restored cerebral blood flow at a lower dose than WT ADAMTS13 and partially retained the ability to recanalise vessels when administration was delayed by 1 hour.ConclusionThe limited proteolytic activity of WT ADAMTS13 in in vitro models of arterial thrombosis suggests an in vivo requirement for conformational activation. The enhanced activity of the GoF ADAMTS13 variant translates to a more pronounced protective effect in experimental stroke.
AU  - South,K
AU  - Denorme,F
AU  - Salles,I
AU  - De,Meyer S
AU  - Lane,D
DO  - 10.1111/jth.14275
EP  - 2299
PY  - 2018///
SN  - 1538-7836
SP  - 2289
TI  - Enhanced activity of ADAMTS13 variant (R568K/F592Y/R660K/Y661F/Y665F) against platelet agglutination in vitro and in a murine model of acute ischaemic stroke
T2  - Journal of Thrombosis and Haemostasis
UR  - http://dx.doi.org/10.1111/jth.14275
UR  - https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14275
UR  - http://hdl.handle.net/10044/1/63369
VL  - 16
ER  -
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