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

Michael Newnham; Kieron South; Marta Bleda; William Auger; Joan  Barberà; Harm Bogaard; Katherine  Bunclark; John Cannon; Marion  Delcroix; Charaka Hadinnapola; Luke Howard; David Jenkins; Eckhard Mayer; Choo Ng; Christopher Rhodes; Nicholas Screaton; Karen Sheares; Michael Simpson; Mark Southwood; Li Su; Dolores Taboada; Matthew Traylor; Richard Trembath; Sofia Villar; Martin Wilkins; John Wharton; Stefan Gräf; Joanna Pepe-Zaba; Michael Laffan; David Lane; Nicholas Morrell; Mark Toshner

doi:10.1183/13993003.01805-2018

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

Michael Newnham, Kieron South, Marta Bleda, William Auger, Joan Barberà, Harm Bogaard, Katherine Bunclark, John Cannon, Marion Delcroix, Charaka Hadinnapola, Luke Howard, David Jenkins, Eckhard Mayer, Choo Ng, Christopher Rhodes, Nicholas Screaton, Karen Sheares, Michael Simpson, Mark Southwood, Li SuDolores Taboada, Matthew Traylor, Richard Trembath, Sofia Villar, Martin Wilkins, John Wharton, Stefan Gräf, Joanna Pepe-Zaba, Michael Laffan, David Lane, Nicholas Morrell, Mark Toshner

Applied Health Research

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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.

Original language	English
Article number	1801805
Journal	European Respiratory Journal
Volume	53
Issue number	3
DOIs	https://doi.org/10.1183/13993003.01805-2018
Publication status	Published - 28 Mar 2019

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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Newnham, M., South, K., Bleda, M., Auger, W., Barberà, J., Bogaard, H., Bunclark, K., Cannon, J., Delcroix, M., Hadinnapola, C., Howard, L., Jenkins, D., Mayer, E., Ng, C., Rhodes, C., Screaton, N., Sheares, K., Simpson, M., Southwood, M., ... Toshner, M. (2019). The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension. European Respiratory Journal, 53(3), Article 1801805. https://doi.org/10.1183/13993003.01805-2018

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title = "The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.",

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.",

author = "Michael Newnham and Kieron South and Marta Bleda and William Auger and Joan Barber{\`a} and Harm Bogaard and Katherine Bunclark and John Cannon and Marion Delcroix and Charaka Hadinnapola and Luke Howard and David Jenkins and Eckhard Mayer and Choo Ng and Christopher Rhodes and Nicholas Screaton and Karen Sheares and Michael Simpson and Mark Southwood and Li Su and Dolores Taboada and Matthew Traylor and Richard Trembath and Sofia Villar and Martin Wilkins and John Wharton and Stefan Gr{\"a}f and Joanna Pepe-Zaba and Michael Laffan and David Lane and Nicholas Morrell and Mark Toshner",

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Newnham, M, South, K, Bleda, M, Auger, W, Barberà, J, Bogaard, H, Bunclark, K, Cannon, J, Delcroix, M, Hadinnapola, C, Howard, L, Jenkins, D, Mayer, E, Ng, C, Rhodes, C, Screaton, N, Sheares, K, Simpson, M, Southwood, M, Su, L, Taboada, D, Traylor, M, Trembath, R, Villar, S, Wilkins, M, Wharton, J, Gräf, S, Pepe-Zaba, J, Laffan, M, Lane, D, Morrell, N & Toshner, M 2019, 'The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.', European Respiratory Journal, vol. 53, no. 3, 1801805. https://doi.org/10.1183/13993003.01805-2018

TY - JOUR

T1 - The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.

AU - Newnham, Michael

AU - South, Kieron

AU - Bleda, Marta

AU - Auger, William

AU - Barberà, Joan

AU - Bogaard, Harm

AU - Bunclark, Katherine

AU - Cannon, John

AU - Delcroix, Marion

AU - Hadinnapola, Charaka

AU - Howard, Luke

AU - Jenkins, David

AU - Mayer, Eckhard

AU - Ng, Choo

AU - Rhodes, Christopher

AU - Screaton, Nicholas

AU - Sheares, Karen

AU - Simpson, Michael

AU - Southwood, Mark

AU - Su, Li

AU - Taboada, Dolores

AU - Traylor, Matthew

AU - Trembath, Richard

AU - Villar, Sofia

AU - Wilkins, Martin

AU - Wharton, John

AU - Gräf, Stefan

AU - Pepe-Zaba, Joanna

AU - Laffan, Michael

AU - Lane, David

AU - Morrell, Nicholas

AU - Toshner, Mark

PY - 2019/3/28

Y1 - 2019/3/28

N2 - 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.

AB - 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.

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DO - 10.1183/13993003.01805-2018

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JF - European Respiratory Journal

IS - 3

M1 - 1801805

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

Abstract

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