Background/Purpose:

Multiple lines of evidence identify thrombin as an important mediator of lung fibrosis in systemic sclerosis (SSc).  In addition to demonstrating dramatically high levels of thrombin activity in SSc bronchoalveolar lavage fluid (BALF), increased expression of the thrombin receptor PAR-1 in SSc-ILD tissue has also been shown.  Previous studies established that after brief exposure to thrombin in vitro, normal lung fibroblasts differentiate to a SSc-like myofibroblast phenotype.  In addition, it has been demonstrated that a direct thrombin inhibitor, dabigatran etexilate, prevents cleavage of the extracellular domain of the PAR-1 receptor, and in doing so inhibits thrombin-induced differentiation of lung fibroblasts to the myofibroblast phenotype, while also decreasing CTGF, α-SMA, and collagen type I in SSc lung fibroblasts.  Although there is much evidence to support a central role for thrombin in SSc-ILD, to date there has been no attempt to correlate thrombin activity to pulmonary function.  Our goal is to determine if the correlation between thrombin activity and decline in pulmonary function does exist. 

Methods:

Thrombin activity was measured using a fluorometric assay (Morita, et al.).  Samples were analyzed in duplicate.  Samples included existing specimens from MUSC patients, as well as stored BALF specimens from Scleroderma Lung Study (SLS-1) subjects (treated and untreated) for whom there were serial PFT data (baseline and every 3 months for up to 24 months).   A Wilcoxon rank sum test was used to compare the thrombin levels between cases and controls, and Spearman correlations were calculated to investigate the associations between thrombin and PFT metrics at various time points.  General linear mixed models (GLMMs) were also constructed to assess whether thrombin was associated with decline in PFT metrics over time among the SSc patients.

Results:

BALF samples were obtained from 75 patients with SSc. All patients fulfilled the 2013 ACR/EULAR classification for systemic sclerosis.  Four samples from patients without SSc served as controls.  Eighty-five percent of patients in our cohort were female, and the proportion of Caucasian and African American patients was equal (49%; 2% Hispanic).  As shown in the past, the thrombin level for cases was significantly higher than controls (p=0.02).  Thrombin levels were not meaningfully correlated with any of the PFT metrics at any point in time (all correlations <0.3, all p-values >0.15), and thrombin levels were not significantly (all p-values >0.22) associated with declines in PFT metrics over time.

Conclusion:

Thrombin activity may not be a useful biomarker for decline in pulmonary function, but is increased in SSc cases when compared to controls.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/scleroderma-bronchoalveolar-lavage-fluid-thrombin-activity-correlation-with-pulmonary-function/