Age-related differences in circulating heparanase-1 activity in sepsis and correlation with systemic vascular endotheliopathy.

Heparanase-1 (HPSE)-mediated degradation of endothelial glycocalyx heparan sulfate (HS) contributes to vascular endotheliopathy in sepsis, yet age-dependent differences in HPSE biology remain undefined. Thus, we sought to determine age-related differences in circulating HPSE activity during sepsis and its association with markers of endotheliopathy and organ dysfunction. Heparanase-1 enzymatic activity and HS disaccharide levels were measured in plasma from children (10 sepsis, 10 controls) and adults (16 sepsis, 15 controls) from prospective observational cohorts using liquid chromatography-tandem mass spectrometry. Associations with plasma angiopoietin-2 levels and change in serum albumin (markers of endotheliopathy) in addition to organ failure scores were assessed using Spearman correlations. Heparanase-1 activity and circulating HS were elevated in both sepsis cohorts compared to controls, with moderate-to-strong correlations between HPSE activity and HS levels. However, adults with sepsis demonstrated approximately 10-fold higher plasma HPSE activity than children (median 1,256 vs. 116, p < 0.001), despite children exhibiting greater endotheliopathy and higher organ failure scores. In both age groups, HPSE activity correlated with angiopoietin-2, serum albumin decline, and organ failure scores. Adult non-survivors had higher HPSE activity than survivors; no pediatric deaths occurred. Predominant neutrophilic/monocytic activation in adults versus greater platelet consumption in children may suggest developmental differences in cellular sources of circulating HPSE. Heparanase-1-mediated glycocalyx degradation is a conserved feature of sepsis across the age spectrum, but the magnitude, cellular source, and clinical implications of circulating HPSE activity differ markedly by age, underscoring the need for age-stratified therapeutic approaches.