Glycocalyx biomarkers as early predictors of endotheliopathy in pediatric and young adult hematopoietic stem cell transplantation patients.

Introduction: Discovery of biomarkers predictive of endotheliopathy after hematopoietic stem cell transplant (HSCT) has the potential to more rapidly identify vulnerable patients, guide treatment decisions, track responses to therapy, and inform targets for novel treatment. This study aimed to evaluate the levels and predictive capabilities of glycocalyx biomarkers for endotheliopathy in the first 100 days following HSCT in pediatric and young adult patients. Methods: Parallel prospective observational pilot studies were performed to examine markers related to endothelial glycocalyx structure, function, and regulation at St. Jude Children's Research Hospital (SJCRH) and MD Anderson Cancer Center (MDACC). The MDACC study took a discovery-driven approach using a 55-biomarker panel performed at two early timepoints whereas the SJCRH study adopted a targeted approach evaluating a 6-biomarker panel at eight scheduled timepoints. Biomarker levels in patients' post-HSCT who did or did not develop endotheliopathy were compared at specific timepoints predicative value was assessed using Area Under the Curve (AUC) and Youden Index. Results: In the SJCRH study, Syndecan-1 and Angiopoietin-2 levels were found to be significantly different between cases of endotheliopathy and controls at multiple time points. Predictive values for both were good to excellent when comparing the time-point immediately before diagnosis of endotheliopathy in cases to standardized time-points of Days 7, 14, and 21 in controls. This was noted for endotheliopathy in general as well for sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) or transplant-associated thrombotic microangiopathy (TA-TMA). In the MDACC study, a signature of markers was found to be associated with endotheliopathy on Days 0 and 7. Specifically, Tissue inhibitor of metalloproteinases-1 (TIMP-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) had perfect performance (AUC of 1) for endotheliopathy. Discussion: Biomarkers of glycocalyx damage and dysregulation have significant potential to predict endotheliopathy in pediatric and young adult patients undergoing HSCT. The convergence of these two studies, one targeted and one unbiased, affirms the central role of endothelial injury in post-HSCT complications and provides a list of potential candidate predictors. Given small sample size and hence limited generalizability, further research is required to validate these findings in larger patient cohorts.