Thrombomodulin is associated with increased mortality and organ failure in mechanically ventilated children with acute respiratory failure: biomarker analysis from a multicenter randomized controlled trial

Abstract

Background Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. Methods This was a prospective observational study of 432 patients aged 2 weeks—17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. Results sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n = 432, adjusted HR = 1.003, p = 0.02) and worse OI in the first 5 days after intubation (n = 252, Estimate = 0.02, p < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p < 0.0001; and slope, Estimate = 0.01, p = 0.0009, n = 386). Conclusions Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. Trial registration: https://clinicaltrials.gov/ct2/show/NCT00814099. In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

“…Another category of biomarkers of the exudative phase of ALI are epithelial markers, including such molecules as surfactant proteins [ 355 ], Krebs von den Lungen-6 protein [ 356 ], vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF) performing both marker and prognostic functions [ 358 , 385 ] ( Table 3 ). Additionally, components of the coagulation/fibrinolysis system, such as plasminogen activator inhibitor-1 (PAI-1) [ 386 ] and the activator of anticoagulant protein C thrombomodulin [ 361 ], have been shown to be associated with an increase in overall mortality and worse clinical outcome in critically ill ALI patients ( Table 3 ).…”

Endotheliopathy is associated with slower liberation from mechanical ventilation: a cohort study

“…sTM was not associated with in-hospital mortality in a small observational study of patients with acute lung injury ( n = 50) [ 30 ], nor with development of acute respiratory failure in a posthoc analysis of a large RCT of septic patients ( n = 1103) [ 19 ]. In contrast, sTM correlated with: fewer ventilator-free days in an unadjusted analysis of a small RCT ( n = 75) [ 26 ]; increased 60-day mortality in an adjusted analysis of an RCT including patients with ARDS ( n = 449) [ 27 ]; ICU mortality in children with indirect causes of ARDS in a larger observational study after adjustment ( n = 243) [ 28 ]; and 90-day mortality and oxygenation index in children with ARDS in a prospective cohort ( n = 432) [ 29 ]. Our findings add to the existing evidence of sTM being an endotheliopathy biomarker that correlates well with outcomes of acute respiratory failure.…”

“…Together, Syndecan-1, sTM, and PECAM-1 reflect three important aspects of endotheliopathy: shedding of the endothelial glycocalyx (Syndecan-1); direct damage to the endothelial cells (sTM); and disruption of the tight junctions between the endothelial cells (PECAM-1). Syndecan-1 and sTM—alone and in conjunction—have been associated with the risk of developing acute respiratory failure as well as outcomes of manifest respiratory failure [ 23 – 29 ]. However, those results are not unanimous [ 19 , 30 ], and PECAM-1 has not previously been included in studies of endotheliopathy in acute respiratory failure.…”

Association and predictive value of soluble thrombomodulin with mortality in patients with acute respiratory distress syndrome: systematic review and meta-analysis

“…The correlation between sTM and ARDS has been investigated by some researchers, and the results are conflicting. Elevated levels of sTM were observed in nonsurvivors, and/or elevated levels of sTM were independently associated with ARDS mortality (10,11), but this finding was contradictory with other research (12,13). Furthermore, the predictive accuracy of sTM for ARDS hospital mortality was unclear, and mild to moderate predictive value was reported (14,15).…”

“…Thirteen studies were included in the study (10)(11)(12)(13)(14)(15)(23)(24)(25)(26)(27)(28)(29). The characteristics of the included studies are presented in Table 1.…”