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

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          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.


          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.


          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).


          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.

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          Most cited references 31

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          Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.

          Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV(1)) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-alpha (TNF-alpha), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-alpha levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.
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            The lung is a site of platelet biogenesis and a reservoir for hematopoietic progenitors

            Platelets are critical for hemostasis, thrombosis, and inflammatory responses 1,2 , yet the events leading to mature platelet production remain incompletely understood 3 . The bone marrow (BM) is proposed to be a major site of platelet production although indirect evidence points towards a potential pulmonary contribution to platelet biogenesis 4-7 . By directly imaging the lung microcirculation in mice 8 , we discovered that a large number of megakaryocytes (MKs) circulate through the lungs where they dynamically release platelets. MKs releasing platelets in the lung are of extrapulmonary origin, such as the BM, where we observed large MKs migrating out of the BM space. The lung contribution to platelet biogenesis is substantial with approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature MKs along with hematopoietic progenitors that reside in the extravascular spaces of the lung. Under conditions of thrombocytopenia and relative stem cell deficiency in the BM 9 , these progenitors can migrate out of the lung, repopulate the BM, completely reconstitute blood platelet counts, and contribute to multiple hematopoietic lineages. These results position the lung as a primary site of terminal platelet production and an organ with considerable hematopoietic potential.
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              From COPD to chronic systemic inflammatory syndrome?

               L. Fabbri,  K. F. Rabe (2007)

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                09 March 2020
                : 15
                : 543-552
                [1 ]Nordic Bioscience A/S , Herlev, Denmark
                [2 ]University of Copenhagen, Faculty of Health and Medical Sciences, Department of Biomedical Sciences , Copenhagen, Denmark
                [3 ]University of Southern Denmark, The Faculty of Health Science , Odense, Denmark
                [4 ]Respiratory Medical Innovation, Value Evidence & Outcomes, GSK R&D , Collegeville, PA, USA
                [5 ]Division of Infection, Immunity and Respiratory Medicine, University of Manchester, and Manchester University NHS Foundation Trust , Manchester, UK
                Author notes
                Correspondence: Lasse L Langholm Nordic Bioscience A/S , Herlev Hovedgade 205-207, Herlev2730, DenmarkTel +45 4452 5252Fax +45 4452 5251 Email
                © 2020 Langholm et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 3, Tables: 3, References: 43, Pages: 10
                Original Research


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