Increased von Willebrand Factor Processing in COPD, Reflecting Lung Epithelium Damage, Is Associated with Emphysema, Exacerbations and Elevated Mortality Risk

Lasse L Langholm, Sarah Rank Rønnow, Jannie M B Sand, Diana Julie Leeming, Ruth Tal-Singer, Bruce E Miller, Jørgen Vestbo, Morten A Karsdal, Tina Manon-Jensen, Lasse L Langholm, Sarah Rank Rønnow, Jannie M B Sand, Diana Julie Leeming, Ruth Tal-Singer, Bruce E Miller, Jørgen Vestbo, Morten A Karsdal, Tina Manon-Jensen

Abstract

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: COPD; emphysema; exacerbations; increased mortality risk; von Willebrand factor processing.

Conflict of interest statement

RTS, BEM, and JV are part of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) study investigators. LLL, SRR, JMBS, DJL, MAK and TMJ are fulltime employees of Nordic Bioscience A/S. BEM is a fulltime employee and shareholder of GlaxoSmithKline (GSK). RTS is a former employee and current shareholder of GSK. JV is supported by the National Institute of Health Research Manchester Biomedical Research Centre (NIHR Manchester BRC). JV reports personal fees from AstraZeneca, grants from Boehringer-Ingelheim, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from GSK, and personal fees from Novartis, outside the submitted work. The authors report no other conflicts of interest in this work.

© 2020 Langholm et al.

Figures

Figure 1
Figure 1
VWF processing was increased in COPD and symptomatic disease. (A) VWF-N and VWF-A were significantly increased in COPD subjects (n=957) compared to smoker controls (n=203), but not non-smoker controls (n=96). (B) Both VWF-N and VWF-A were significantly increased in symptomatic (mMRC ≥2) COPD subjects (n=458) compared to non-symptomatic/mild COPD (n=462). Data presented as median + 95% CI. *p<0.05, ***p<0.001.
Figure 2
Figure 2
VWF processing was different between subjects with emphysema and exacerbations. (A) VWF-A but not VWF-N was increased in COPD subjects who suffered from one or more exacerbations within the previous year (n=522), compared to the no exacerbation group (n=418). (B) VWF-N but not VWF-A is increased in COPD subjects with emphysema (n=584) compared to non-emphysematous subjects (n=310). Data presented as median + 95% CI. *p<0.05, ***p<0.001.
Figure 3
Figure 3
Increased VWF processing was associated with increased risk of mortality. (A) VWF-N and VWF-A levels were increased in subjects that died within a two-year follow-up period (n=30) compared to survivors (n=910). (B) VWF biomarkers were dichotomized using AUROC analysis. Kaplan-Meier survival curves showed high biomarker levels associated with decreased survival time. Data presented as median + 95% CI. **p<0.01, ***p<0.0001.

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