Type IV collagen turnover is predictive of mortality in COPD: a comparison to fibrinogen in a prospective analysis of the ECLIPSE cohort

Abstract

Background Identifying subjects with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation and mortality is key to aid individual management of COPD. The only FDA approved blood-based drug development biomarker for patients at high risk of mortality, is plasma fibrinogen. In this study, we benchmarked two biomarkers of basement membrane remodeling, a characteristic of COPD, against plasma fibrinogen alone and as a combination. The biomarkers of basement membrane remodeling are two neoepitopes from of the alpha 3 chain of type IV collagen (COL4A3). Materials and methods COL4A3 degradation was assessed by the biomarkers C4Ma3 and tumstatin (TUM) in year 1 plasma samples in 984 COPD subjects, 95 non-smoking controls and 95 smoking controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. They were measured by competitive ELISA using monoclonal antibodies recognizing two specific MMP-generated cleavage site within COL4A3. The level of fibrinogen was previously assessed in year 1 plasma. Results In COPD subjects, plasma C4Ma3 levels were significantly correlated with plasma fibrinogen levels (0.389 ( P < 0.0001)). Cox proportional-hazards regression adjusted for relevant confounders showed that high levels of plasma C4Ma3, but not TUM, were related to a higher risk of mortality (hazard ratio 5.12 (95% CI 2.28–11.50), P < 0.0001). High levels of plasma fibrinogen were not associated with all-cause mortality in this subpopulation, contradictory to published results. Whereas plasma C4Ma3 multiplied by fibrinogen showed to be related to a higher risk of mortality (hazard ratio 5.74 (95% CI 2.65–12.41), P < 0.0001). Plasma C4Ma3 levels were related to the number of hospitalizations due to COPD exacerbations in the year before study start ( P = 0.0375). Fibrinogen levels were related to hospitalized exacerbations prior to study start ( P = 0.0058) and were also related to future exacerbations ( P < 0.0001). Conclusion We compared herein fibrinogen, C4Ma3 and TUM as biomarkers for COPD prognosis. Fibrinogen was related to future exacerbation, whereas C4Ma3 and the combination of C4Ma3 with fibrinogen were superior to fibrinogen alone in predicting mortality. This pilot study suggests that the assessment of plasma C4Ma3 could be important for identifying COPD patients with a poor prognosis. Trial registration NCT00292552 , GSK Study No. SCO104960. Electronic supplementary material The online version of this article (10.1186/s12931-019-1026-x) contains supplementary material, which is available to authorized users.

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

“…In this study, we utilized the biomarker X-FIB, a more accurate neo-epitope specific D-dimer assay. We have previously shown that in the current subset of ECLIPSE, high levels of plasma fibrinogen predicted mortality risk with an unadjusted hazard ratio of 3.3 [11]. Thus, the current data indicate that the combination of C4Ma3 and X-FIB may be an equally good, or potentially better, predictor of mortality.…”

Plasma fibrinogen in the diagnosis of periprosthetic joint infection

“…Plasma fibrinogen is a large (340 kDa) hexametric homodimer and is synthesized primarily in the liver; it can rapidly increase following injury and is essential for the infection process 30 . In addition, plasma fibrinogen is a better biomarker for COPD disease progression and wound healing and regulates nervous system functions 31 , 32 . Klim et al 33 found that plasma fibrinogen is a significant biomarker for detecting PJI due to a sensitivity of 0.90 and specificity of 0.66 through a prospective study.…”

Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort

“…ECM remodeling, including both formation and degradation of the lung tissue, has been shown to be increased in patients with COPD [22][23][24][25]. Furthermore, an accelerated rate of remodeling was associated with acute exacerbations of COPD and an elevated risk of mortality [18,[22][23][24][25][26]. Abdillahi et al showed that type VI collagen mRNA and protein are increased in the lungs of COPD patients when compared to controls [27].…”