Biomarkers in Pediatric ARDS: Future Directions

Orwoll, Benjamin E.; Sapru, Anil

Platelets, also critical to the function of the coagulation system, are dysregulated in ARDS (93, 94) , and thrombocytopenia at ARDS onset has been reported to correlate with increased morbidity and mortality (95) in both adults and children (96) . However, in addition to these familiar markers of coagulation, multiple, more novel biomarkers have been evaluated in children with ARDS. Plasminogen activator inhibitor 1 (PAI-1) is an antifibrinolytic enzyme that is activated in the setting of inflammation. Depressed fibrinolytic activity, demonstrated by elevated PAI-1 levels in the BAL fluid and blood from adults with ARDS, is associated with increased mortality and decreased VFDs (97) (98) (99) . PAI-1 has also been evaluated as a marker in pediatric patients, and among a cohort of pediatric patients with ARDS, elevated plasma PAI-1 was also associated with increased mortality and decreased VFDs (25) . Among cohorts of critically ill children, PAI-1 levels from BAL fluid were also able to discriminate patients with ventilator-associated pneumonia (VAP) compared with colonized patients (65) , and plasma levels were significantly elevated in patients with septic shock, purpura, and ARDS (26) . In addition to PAI-1, another important regulator of coagulation activity in lung disease is soluble urokinase-type plasminogen activator receptor (suPAR). This protein binds urokinase (uPA) at the cell surface and facilitates the further proteolytic activation of plasminogen and pro-uPA, while the soluble form may have additional roles in inflammation (100) . Plasma suPAR levels were elevated in a large study of critically ill, ventilated adults and were associated with mortality (101) . In a neonatal study, blood suPAR levels were elevated among those who developed BPD compared with controls, and correlated with disease severity (27) . Similarly, suPAR levels were shown to correlate with severity in a cohort of children with pneumonia, though none of that cohort developed ARDS (28) . Decreased plasma levels of antithrombin-III, which mediates heparin's anticoagulant effect, early in the course of ARDS have also been associated with increased mortality in both adults and children (24, 102) . Though protein C, an important regulator of the activity of thrombin, has been investigated as both a biomarker (103) and as a therapeutic agent in the form of activated protein C (APC) (104) (105) (106) in adult ARDS patients, additional studies are needed to clarify its role in children with ARDS. Further investigation into biomarkers of coagulation and fibrinolysis pathways, including the roles of tissue factor (TF) and its pathway inhibitor (TFPI), may further advance our understanding of the pathogenesis of ARDS in children and provide for new therapeutic targets.