Increased von Willebrand Factor Processing in COPD, Reflecting Lung Epithelium Damage, Is Associated with Emphysema, Exacerbations and Elevated Mortality Risk
Received 22 October 2019
Accepted for publication 21 February 2020
Published 9 March 2020 Volume 2020:15 Pages 543—552
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Richard Russell
Lasse L Langholm,1,2 Sarah Rank Rønnow,1,3 Jannie MB Sand,1 Diana Julie Leeming,1 Ruth Tal-Singer,4 Bruce E Miller,4 Jørgen Vestbo,5 Morten A Karsdal,1 Tina Manon-Jensen1
1Nordic Bioscience A/S, Herlev, Denmark; 2University of Copenhagen, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, Copenhagen, Denmark; 3University of Southern Denmark, The Faculty of Health Science, Odense, Denmark; 4Respiratory Medical Innovation, Value Evidence & Outcomes, GSK R&D, Collegeville, PA, USA; 5Division of Infection, Immunity and Respiratory Medicine, University of Manchester, and Manchester University NHS Foundation Trust, Manchester, UK
Correspondence: Lasse L Langholm
Nordic Bioscience A/S, Herlev Hovedgade 205-207, Herlev 2730, Denmark
Tel +45 4452 5252
Fax +45 4452 5251
Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and lung tissue deterioration. Given the high vascularity of the lung, von Willebrand factor (VWF), a central component of wound healing initiation, has previously been assessed in COPD. VWF processing, which is crucial for regulating the primary response of wound healing, has not been assessed directly. Therefore, this study aimed to characterize wound healing initiation in COPD using dynamic VWF-processing biomarkers and to evaluate how these relate to disease severity and mortality.
Methods: A cross-sectional analysis of plasma samples from the ECLIPSE study collected at year 1 from moderate to very severe COPD subjects (GOLD 2– 4, n=984) was performed. We applied competitive neo-epitope ELISAs specifically targeting the formation of and ADAMTS13-processed form of VWF, VWF-N and VWF-A, respectively.
Results: VWF-A and VWF-N were significantly increased (VWF-N, p=0.01; VWF-A, p=0.0001) in plasma of symptomatic (mMRC score ≥ 2) compared to asymptomatic/mild symptomatic COPD subjects. Increased VWF-N and VWF-A levels were specifically associated with emphysema (VWF-N, p< 0.0001) or prior exacerbations (VWF-A, p=0.01). When dichotomized, high levels of both biomarkers were associated with increased risk of all-cause mortality (VWF-N, HR 3.5; VWF-A, HR 2.64).
Conclusion: We demonstrate that changes in VWF processing were related to different pathophysiological aspects of COPD. VWF-N relates to the chronic condition of emphysema, while VWF-A was associated with the more acute events of exacerbations. This study indicates that VWF-A and VWF-N may be relevant markers for characterization of disease phenotype and are associated with mortality in COPD.
Study Identifier: NCT00292552; GSK study code SCO104960.
Keywords: von Willebrand factor processing, COPD, emphysema, exacerbations, increased mortality risk
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