Size and Charge Characteristics of the Protein Leak in Dengue Shock Syndrome

Abstract

Background. The mechanism underlying the transient vascular leak syndrome of dengue hemorrhagic fever (DHF) is unknown. We aimed to determine whether molecular size and charge selectivity, which help restrict plasma proteins within the intravascular space, are altered in patients with DHF and whether a disturbance of the anionic glycosaminoglycan (GAG) layer on the luminal endothelial surface contributes to disease pathogenesis.Methods. We measured serial plasma levels and fractional clearances of proteins with different size and charge characteristics in 48 children with dengue shock syndrome (DSS) and urinary excretion profiles of heparan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate in affected children and healthy control subjects.Results. Compared with convalescent values, acute plasma concentrations of all proteins were reduced, with increased fractional clearances. Smaller proteins were more affected than larger molecules. Albumin, which is normally protected from leakage by its strong negative charge, demonstrated a clearance pattern similar to that of transferrin, a neutral molecule of similar size. Urinary heparan sulfate excretion was significantly increased in children with DSS.Conclusions. The endothelial size-dependent sieving mechanism for plasma proteins is at least partially retained, whereas selective restriction based on negative charge is impaired. The increased heparan sulfate excretion suggests a role for GAGs in the pathogenesis of the vascular leak.

Hemostatic Changes in Vietnamese Children with Mild Dengue Correlate with the Severity of Vascular Leakage Rather than Bleeding

“…26 During dengue infections the transcapillary filtration of albumin increases markedly. 27 It may be that fibrinogen filtration increases in a similar manner and that the low plasma concentrations measured simply reflect loss from the intravascular to the interstitial space. A pathologic process involving the endothelial surface glycocalyx could also offer a potential explanation for the increase in APTT seen in these patients.…”

Recent Advances in Deciphering Viral and Host Determinants of Dengue Virus Replication and Pathogenesis

“…For example, urinary levels of heparan sulfate (195) and plasma levels of pentraxin 3 (126), an acute-phase protein, were both significantly increased in children with DSS, whereas plasma levels of albumin were decreased (195). Additionally, levels of vascular endothelial growth factor were significantly elevated in patients with DHF compared with those in DF patients or control patients (185).…”

“…(22,52) and NO (24,141) are produced primarily by infected monocytes/macrophages and activate endothelial cells, which can contribute to increased vascular permeability (reviewed in reference 17). Changes in vascular permeability in DENV infections have classically been measured by monitoring levels of albumin in the plasma (195). IFN-␥ is produced primarily by NK and CD8 ϩ T cells and activates macrophages as well as CD4 ϩ T cells (17).…”

Pathogenesis of Dengue Haemorrhagic Fever and Its Impact on Case Management

“…e basic Starling principle still holds true in explaining microvascular ultra�l-tration based on the balance of the oncotic and hydrostatic pressures. However the glycocalyx, which is a gelatinous layer lining the vascular endothelium is also implicated in controlling �uid movement by the adherence of albumin molecules in to its matrix, damage of which, leads to loss of albumin into the extravascular compartment [8][9][10][11].…”

“…e role of the glycocalyx rather than the endothelial cells per se in controlling ultra�ltration in the microvasculature is increasingly recognised and in vivo animal studies have shown the permeation of �brinogen to the endothelial surface similar to albumin [11].…”