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The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension

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Title: The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension
Authors: Newnham, M
South, K
Bleda, M
Auger, WR
Barberà, JA
Bogaard, H
Bunclark, K
Cannon, JE
Delcroix, M
Hadinnapola, C
Howard, LS
Jenkins, D
Mayer, E
Ng, C
Rhodes, CJ
Screaton, N
Sheares, K
Simpson, MA
Southwood, M
Su, L
Taboada, D
Traylor, M
Trembath, RC
Villar, SS
Wilkins, MR
Wharton, J
Gräf, S
Pepke-Zaba, J
Laffan, M
Lane, DA
Morrell, NW
Toshner, M
Item Type: Journal Article
Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism (PE) that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-VWF axis in CTEPH, including its relationship to disease severity, inflammation, ABO groups and ADAMTS13 genetic variants. ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED; n=35), resolved PE (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF-multimeric size. CTEPH patients had decreased ADAMTS13 (adjusted β (95% CI)=−23.4 (−30.9– −15.1)%, p<0.001) and increased VWF levels (β=+75.5 (44.8–113)%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identify a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels. The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.
Issue Date: 17-Jan-2019
Date of Acceptance: 19-Dec-2018
URI: http://hdl.handle.net/10044/1/66846
DOI: https://dx.doi.org/10.1183/13993003.01805-2018
ISSN: 0903-1936
Publisher: European Respiratory Society
Journal / Book Title: European Respiratory Journal
Copyright Statement: ©ERS 2019
Sponsor/Funder: British Heart Foundation
British Heart Foundation
British Heart Foundation
Funder's Grant Number: FS/03/074/15912
PG/14/87/3118
FS/15/59/31839
Keywords: 11 Medical And Health Sciences
Respiratory System
Publication Status: Published online
Embargo Date: 2020-07-17
Online Publication Date: 2019-01-17
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine



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