Abstract
BackgroundMalaria is a major cause of morbidity and mortality in sub-Saharan Africa, and poor outcomes have been associated with endothelial activation. In this study, biomarkers of endothelial activation, haemostasis, and thrombosis were measured in Ugandan children with severe malaria who participated in a clinical trial, in order to investigate associations between these processes.MethodsSerum and plasma were collected from participants at baseline (day 1), and on days 2, 3, 4, and 14. Von Willebrand factor (VWF) antigen was measured in stored plasma samples from all trial participants, and its association with mortality and changes over time were analysed. VWF multimer patterns were evaluated in baseline serum samples by gel electrophoresis followed by Western blotting. Levels of angiopoietins 1 and 2, VWF antigen, total active VWF, ADAMTS13, platelet counts, apolipoprotein A1, and syndecan-1 were measured in stored serum samples from 12 survivors at baseline and day 4.ResultsVWF antigen levels were associated with mortality, and decreased over time in survivors. Baseline VWF antigen and total active VWF levels were elevated, and very large multimers were present in the baseline serum of several patients. Higher platelet counts were associated with higher angiopoietin-1 and apolipoprotein A1 levels, while lower platelet counts were associated with higher syndecan-1, a marker of endothelial damage. Higher angiopoietin-2 to angiopoietin-1 ratio and higher syndecan-1 levels were correlated with lower apolipoprotein A1 levels. There were no correlations between total active VWF, VWF antigen, or ADAMTS13 levels and the other biomarkers at baseline. Changes in biomarker levels between baseline and day 4 were not correlated.ConclusionsThese results confirm that severe malaria is associated with endothelial activation, and suggest that endothelial activation contributes to microvascular thrombosis and endothelial damage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1106-z) contains supplementary material, which is available to authorized users.
Highlights
Malaria is a major cause of morbidity and mortality in sub-Saharan Africa, and poor outcomes have been associated with endothelial activation
Published work by the authors of this paper has demonstrated that plasma high-density lipoprotein (HDL) and apolipoprotein A1 (ApoA1) dose-dependently decrease the extent of Von Willebrand factor (VWF) self-association, in the process significantly decreasing the binding of platelets to the vessel wall [13]
Biomarkers of endothelial activation, haemostasis and thrombosis, including angiopoietin 1 and 2 (Ang-1 and Ang-2) levels, VWF antigen, total active VWF, and ADAMTS13, platelet counts, syndecan-1 levels, and ApoA1 levels, were measured among Ugandan children with severe malaria (SM) who participated in a clinical trial [16], in order to investigate associations between these processes
Summary
Malaria is a major cause of morbidity and mortality in sub-Saharan Africa, and poor outcomes have been associated with endothelial activation. Malaria is a major cause of morbidity and mortality in sub-Saharan Africa, where over 90 % of all malaria deaths occur [1]. Fatality rates for children with severe malaria (SM) and CM have been estimated at approximately 8.5 and 18 % despite treatment with intravenous artesunate, the current standard of care [2]. Graham et al Malar J (2016) 15:56 neurocognitive deficits, including epilepsy, behavioural disorders, and motor, sensory or language deficits [3]. These outcomes suggest that adjunctive therapy targeting mechanistic pathways mediating severe disease is needed
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