Pathogenesis of Haemorrhage Associated With Dengue Infection in Adults in Vietnam

Abstract

Clinical experience suggests that adults with dengue manifest a pattern of complications different from those observed in children, but direct comparisons among populations experiencing the same exposure have rarely been published. I conducted a large prospective descriptive study of dengue across all age-groups presenting to a single institution in an endemic country during a defined time-period. Vascular leakage was more severe in the paediatric patients and DSS developed much more frequently in this age-group. In contrast haemorrhagic manifestations and severe organ involvement were more common in adults. Similar to the established findings in children, typical coagulation abnormalities were apparent in the adults - i.e. prolonged APTT with reduced fibrinogen levels but without evidence of true disseminated intravascular coagulation. However thrombocytopenia was significantly worse among the adults throughout the evolution of the disease, even after adjusting for the higher rate of secondary infections in this group, and platelet counts after recovery remained lower than in the children. Clinically severe liver involvement was seen only in adults and was infrequent but usually resulted in severe bleeding. Chronic hepatitis B co-infection was associated with modestly but significantly increased levels of alanine aminotransferase, but did not otherwise impact the clinical picture. To investigate the mechanisms underlying the increase in APTT I carried out APTT Mixing Studies confirming that deficiency of coagulation factors is a major contributory factor. Since there is little evidence for procoagulant activation the most likely mechanism for this would be leakage of coagulation proteins, many of which are of a similar size to albumin. An additional explanation for the increased APTT could be the presence of a circulating anticoagulant. I found very high levels of heparan sulfate (HS) in the dengue plasma, but was not able to show that the HS exerts an anticoagulant effect. I also used FACS analysis to demonstrate that circulating endothelial cells (CECs) are increased during dengue infections and that percentage CECs correlate with the severity of the coagulopathy and with bleeding. Parallel increases in both CECs and HS levels support the theory that disruption of the endothelial cell/glycocalyx complex occurs during dengue infections - i.e. CECs appear to be shed from the endothelial layer while HS may be shed from the surface glycocalyx. These disruptions likely affect the function of the complex and could contribute to the pathogenesis of the systemic vascular leak syndrome