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

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with 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 pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted β -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (β +75.5%, 95% CI 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 identified 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.

• Authors: Michael Newnham, Kieron South, Marta Bleda, William R Auger, Joan A Barberà, Harm Bogaard, Katherine Bunclark, John E Cannon, Marion Delcroix, Charaka Hadinnapola, Luke S Howard, David Jenkins, Eckhard Mayer, Choo Ng, Christopher J Rhodes, Nicholas Screaton, Karen Sheares, Michael A Simpson, Mark Southwood, Li Su, Dolores Taboada, Matthew Traylor, Richard C Trembath, Sofia S Villar, Martin R Wilkins, John Wharton, Stefan Gräf, Joanna Pepke-Zaba, Michael Laffan, David A Lane, Nicholas W Morrell, Mark Toshner
• Journal: The European respiratory journal (Eur Respir J) Vol. 53 Issue 3 (03 2019) ISSN: 1399-3003 [Electronic] England
• PMID: 30655285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2019.

Chemical References

• Biomarkers
• von Willebrand Factor
• ADAMTS13 Protein
• ADAMTS13 protein, human

Topics

• ADAMTS13 Protein (genetics)
• Adult
• Aged
• Aged, 80 and over
• Biomarkers
• Case-Control Studies
• Chronic Disease
• Endarterectomy
• Female
• Humans
• Hypertension, Pulmonary (genetics, physiopathology)
• Linear Models
• Male
• Middle Aged
• Multivariate Analysis
• Pulmonary Embolism (genetics, physiopathology)
• Thrombosis (genetics, physiopathology)
• von Willebrand Factor (analysis)