Imperial College London
Alternate

ProfessorJimCrawley

Faculty of Medicine, Department of Immunology and Inflammation

Professor of Haemostasis
 
 
 
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Contact

 

+44 (0)20 3313 2297j.crawley Website

 
 
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Location

 

5S5aCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Thomas:2015:10.1016/j.ebiom.2015.06.007,
author = {Thomas, MR and de, Groot R and Scully, MA and Crawley, JT},
doi = {10.1016/j.ebiom.2015.06.007},
journal = {EBioMedicine},
pages = {942--952},
title = {Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura},
url = {http://dx.doi.org/10.1016/j.ebiom.2015.06.007},
volume = {2},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated. METHODS: We analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG. RESULTS: 89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increa
AU  - Thomas,MR
AU  - de,Groot R
AU  - Scully,MA
AU  - Crawley,JT
DO  - 10.1016/j.ebiom.2015.06.007
EP  - 952
PY  - 2015///
SN  - 2352-3964
SP  - 942
TI  - Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura
T2  - EBioMedicine
UR  - http://dx.doi.org/10.1016/j.ebiom.2015.06.007
UR  - http://hdl.handle.net/10044/1/30053
VL  - 2
ER  -
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