Extracellular histones are cytoxic and cause endothelial cell injury and dysfunction [46]. The cytotoxicity primarily occurs within the microcirculatory system, and causes ultrastructural changes and dysfunction. Altered flow dynamics cause further endothelial cell damage and glycocalyx shedding [47] Inflammatory conditions with high concentrations of extracellular histones and cytokines damage the endothelial glycocalyx accompanied by its degradation shedding of syndecan-1, heparan sulfate, and hyaluronan [47].