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
Authors: Monteiro Ana Carolina Costa , Flori Heidi , Dahmer Mary K. , Sim Myung Shin , Quasney Michael W. , Curley Martha A. Q. , Matthay Michael A. , Sapru Anil ,   for the BALI Study Investigators of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, Monteiro Ana Carolina Costa , Flori Heidi , Dahmer Mary K. , Sim Myung Shin , Quasney Michael W. , Curley Martha A. Q. , Matthay Michael A. , Sapru Anil , Bateman Scot T. , Berg M. D. , Borasino Santiago , Bysani G. Kris , Cowl Allison S. , Bowens Cindy Darnell , Faustino E. Vincent S. , Fineman Lori D. , Godshall A. J. , Hirshberg Ellie , Kirby Aileen L. , McLaughlin Gwenn E. , Medar Shivanand , Oren Phineas P. , Schneider James B. , Schwarz Adam J. , Shanley Thomas P. , Sorce Lauren R. , Truemper Edward J. , Vander Heyden Michele A. , Wittmayer Kim , Zuppa Athena , Wypij David 
Published: August 2021

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.