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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Newnham reports other from MSD, from GSK, outside the submitted work.
Conflict of interest: Dr. SOUTH has nothing to disclose.
Conflict of interest: Dr. Bleda has nothing to disclose.
Conflict of interest: Dr. Auger reports grants from Bayer, non-financial support from Bayer, outside the submitted work.
Conflict of interest: Dr. Barberà has nothing to disclose.
Conflict of interest: Dr. Bunclark has nothing to disclose.
Conflict of interest: Dr. Cannon reports other from Actelion, other from GSK, other from MSD, outside the submitted work.
Conflict of interest: Dr. Delcroix has nothing to disclose.
Conflict of interest: Dr. Hadinnapola has nothing to disclose.
Conflict of interest: Dr. Howard reports grants from Bayer PLC, during the conduct of the study.
Conflict of interest: Dr. Jenkins reports grants and personal fees from Bayer, personal fees from Actelion, outside the submitted work.
Conflict of interest: Dr. Mayer reports personal fees from Actelion, personal fees from Bayer, personal fees from MSD, personal fees from Pfizer, outside the submitted work.
Conflict of interest: Dr. Ng has nothing to disclose.
Conflict of interest: Dr. Rhodes has nothing to disclose.
Conflict of interest: Dr. Screaton has nothing to disclose.
Conflict of interest: Dr. Sheares reports other from Actelion, Bayer, MSD and GSK, and has been on an advisory board for Actelion, outside the submitted work.
Conflict of interest: Prof. Simpson has a contract of service with Genomics plc, outside the submitted work; .
Conflict of interest: Dr. Southwood has nothing to disclose.
Conflict of interest: Dr. Su has nothing to disclose.
Conflict of interest: Dr. Traylor has nothing to disclose.
Conflict of interest: Dr. Trembath has nothing to disclose.
Conflict of interest: Dr. Villar has nothing to disclose.
Conflict of interest: Dr. Wilkins has nothing to disclose.
Conflict of interest: Dr. Wharton reports personal fees from Actelion Pharmaceuticals Ltd., outside the submitted work.
Conflict of interest: Dr. Gräf has nothing to disclose.
Conflict of interest: JPZ or her institution have received research/educational grants; JPZ has been serving at advisory boards for Actelion, Bayer, Merck, GSK
Conflict of interest: Dr. Laffan reports grants from British Heart Foundation, during the conduct of the study; personal fees from Shire , outside the submitted work.
Conflict of interest: Dr. Lane has nothing to disclose.
Conflict of interest: Dr. Morrell has nothing to disclose.
Conflict of interest: Dr. Toshner reports grants, personal fees, non-financial support and other from Actelion, grants, non-financial support and other from Bayer, grants, personal fees, non-financial support and other from Merck, non-financial support and other from GSK, during the conduct of the study. Dr. Toshner reports grants and personal fees from Bayer, personal fees from GSK, grants and personal fees from Merck, grants and personal fees from Actelion, grants from Roche, during the conduct of the study.
Conflict of interest: Dr. Bogaard has nothing to disclose.
Conflict of interest: Dr. Taboada reports personal fees from Actelion, Bayer, GlaxoSmithKline, Lilly, MDS, Pfizer, outside the submitted work.
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