End-product of fibrinogen is elevated in emphysematous chronic obstructive pulmonary disease and is predictive of mortality in the ECLIPSE cohort

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by abnormal epithelial repair process that may result in intra-airway accumulation of fibrin. Given that plasma fibrinogen is the only FDA approved biomarker that predicts mortality and COPD exacerbations, we hypothesized that changes in the processing of fibrinogen may provide additional characterization of disease phenotype and COPD progression. Methods: A subpopulation of subjects with COPD, (n ¼ 983) smoker (n ¼ 205) and non-smoker controls (n ¼ 98) were included from The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. Two biomarkers that specifically target the thrombin-mediated conversion of fibrinogen into fibrin (PRO-FIB), and plasmin-mediated degradation of cross-linked fibrin (X-FIB) were measured and compared with fibrinogen measurements. Results: X-FIB had a predictive value for two-year mortality, with an adjusted hazard ratio of 1.48 per SD (n ¼ 980; 95% Cl 1.18-1.84; p < 0.0001), and comparable to the fibrinogen hazard ratio of 1.59 per SD (n ¼ 983; 95% Cl 1.29-1.96; p ¼ 0.0003). X-FIB (p < 0.001), fibrinogen (p < 0.0001) and PRO-FIB (p < 0.05) were significantly elevated in symptomatic COPD (mMRC � 2) as compared to asymptomatic COPD. X-FIB was the only biomarker that was associated with emphysema (p < 0.001), and only plasma fibrinogen (p < 0.05) was associated with exacerbations. Conclusion: There is a need for biomarkers to characterize the heterogeneity of COPD, to continuously improve clinical trial design and to identify disease progressors for efficient health care utilization. Each of three fibrinogen biomarkers studied provide information representing distinct aspects of COPD which may be used to characterize disease endotypes and to assess mortality risk in COPD.

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

“…We have recently compared biomarkers of fibrinogen turnover to fibrinogen measured in the ECLIPSE study. 27 Plasma fibrinogen is currently the only FDA approved prognostic marker for all-cause mortality in COPD. 26 Indeed, fibrinogen was found to be an independent predictor of mortality, comparable to the results obtained for the VWF biomarkers in this paper.…”

“…5 We have discussed fibrinogen in relation to wound healing in this cohort more thoroughly elsewhere. 27 To address the difference in age between the disease and control groups we included this parameter in our analyses. Interestingly, although age was found to be associated with mortality, both VWF-N and VWF-A were found to be independently associated with increased mortality risk, when adjusting for confounders, including age.…”

Combining biomarkers of clot resolution and alveolar basement membrane destruction predicts mortality in the ECLIPSE COPD cohort

“…The rationale for this combination was that whereas the body may have wound healing in many places at the same time, represented by tissue nonspecific X-FIB, combining it with C4Ma3, a more tissue specific biomarker mainly localized in the lungs and kidney, could improve assessment of lung remodeling driven by wound healing. Elevated levels of C4Ma3 and X-FIB individually have previously been associated with increased mortality risk in COPD [ 11 , 12 ], and C4Ma3 levels were additionally elevated during acute exacerbations of COPD [ 14 ], indicating a role of wound healing and alveolar BM destruction in disease progression.…”

“…The study design of Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) ( clinicaltrials.gov identifier NCT00292552; GSK study code SCO104960) has previously been described [ 13 ]. C4Ma3 [ 14 ] and X-FIB [ 15 ] plasma levels were assessed at the year 1 time point in a subpopulation of 982 COPD participants out of the total of 2164, as previously described [ 11 , 12 ]. Only patients with both C4Ma3 and X-FIB data were included in the current analyses.…”

“…We previously showed that high levels of C4Ma3 and X-FIB individually were independently associated with increased risk of mortality in COPD [ 11 , 12 ]. We hypothesized that having high levels of two biomarkers that reflect different aspects of pathology, rather than one, would increase prognostic accuracy.…”