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The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies

Lookup NU author(s): Dr Vicky Brocklebank, Dr Edwin Wong, Professor Kevin MarchbankORCiD, Professor Tim Goodship, Professor David KavanaghORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


BACKGROUND: Differentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopaenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS-13 activity. The identification of alternative complement pathway abnormalities in atypical haemolytic uraemic syndrome, along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS.OBJECTIVES: We describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs.PATIENTS/METHODS: 14 consecutive aHUS patients were screened for mutations in C3, CD46, CFH, CFI and CFB, as well as factor H antibodies. All aHUS patients had ADAMTS-13 activity above 10%.RESULTS: 11/14 (79%) aHUS patients had platelet counts below 30 x 109 /l during the acute phase. Median presenting creatinine was 295 μmol/l whilst 5/14 (36%) presented with a serum creatinine level below 200 μmol/l. Alternative complement pathway mutations were detected in 9/14 (64%) patients, including CD46 mutations in 5/14 (36%). Patients were identified with novel mutations in CFB and C3 that have not been previously reported.CONCLUSIONS: We demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations may mimic TTP. ADAMTS-13 activity >10% in a patient with a TMA should necessitate genetic screening for complement abnormalities. This article is protected by copyright. All rights reserved.

Publication metadata

Author(s): Phillips EH, Westwood JP, Brocklebank V, Wong EKS, Tellez JO, Marchbank KJ, McGuckin S, Gale DP, Connolly J, Goodship THJ, Kavanagh D, Scully MA

Publication type: Article

Publication status: Published

Journal: Journal of Thrombosis and Haemostasis

Year: 2016

Volume: 14

Issue: 1

Pages: 175-185

Print publication date: 01/01/2016

Online publication date: 11/01/2016

Acceptance date: 25/10/2015

Date deposited: 15/11/2015

ISSN (print): 1538-7933

ISSN (electronic): 1538-7836

Publisher: Wiley-Blackwell


DOI: 10.1111/jth.13189

PubMed id: 26559391


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Funder referenceFunder name
305608European Union's Seventh Framework Programme (FP7)