Dataset Information

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

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.

SUBMITTER: Langholm LL

PROVIDER: S-EPMC7069584 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Langholm Lasse L LL Rønnow Sarah Rank SR Sand Jannie M B JMB Leeming Diana Julie DJ Tal-Singer Ruth R Miller Bruce E BE Vestbo Jørgen J Karsdal Morten A MA Manon-Jensen Tina T

International journal of chronic obstructive pulmonary disease 20200309

<h4>Background</h4>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 dynami ...[more]

PMID: 32210548

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Project description:BACKGROUND: Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation. METHODS: We reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis and compared plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). RESULTS: During a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21, and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2.36 SD ± 0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD ± 0.82 IU/ml vs. 2.20 SD ± 0.77 IU/ml; p = 0.024). This difference remained significant for recurrent events (mean 2.78 SD ± 0.75; p = 0.043). sCD14 was positively correlated with LPS (r = 0.255; p = 0.003). CONCLUSION: The incidence of venous thrombosis was two-fold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels as well as a correlation of vWF to first and recurrent venous thrombo-embolic events. These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis.

Project description:Essentials von Willebrand factor (VWF) is synthesized in endothelial cells and platelet precursors. Type 3 patients with Pro2808Leufs*24 have lower bleeding scores than other type 3s. The Pro2808Leufs*24 variant was examined in patient platelets and endothelial cells. Type 3s with this variant contain releaseable VWF, possibly reducing bleeding. SUMMARY:Background A novel variant, p.Pro2808Leufs*24, in the von Willebrand factor (VWF) gene was previously identified in the Canadian von Willebrand disease (VWD) patient population. Clinical observations of type 3 VWD patients with this variant indicate a milder bleeding phenotype compared with other type 3 patients. Objective To assess the effect of the Pro2808Leufs*24 variant on the molecular pathogenesis of VWD and correlate this with the phenotype observed in patients. Patients/Methods Phenotypic data from individuals in the Canadian type 3 VWD study were analyzed. VWF expression in platelets and plasma was assessed via immunoblotting. Cellular expression of VWF in platelets and blood outgrowth endothelial cells (BOEC) was examined via immunofluorescence microscopy and biochemical analysis in a type 3 index case and family member with Pro2808Leufs*24. Results Twenty-six individuals with the Pro2808Leufs*24 variant (16 type 3 VWD homozygous or compound heterozygous and 10 heterozygous family members) were studied. Bleeding scores were lower in type 3 patients with Pro2808Leufs*24 compared with type 3 patients with other variants, confirming a milder bleeding phenotype. Immunoblotting of platelet lysates detected VWF in the platelets of type 3 patients with Pro2808Leufs*24. Examination of an index case detected VWF within platelets via immunofluorescence microscopy, and in vitro experiments showed that this VWF was released upon platelet activation. Patient BOECs showed decreased VWF synthesis and secretion, although some VWF-containing granules were observed. Conclusion Type 3 VWD patients with the Pro2808Leufs*24 have bioavailable platelet-derived VWF that may produce a milder bleeding phenotype than other type 3s.

Dataset Information

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

Publications

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

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