Elevated plasma von Willebrand factor and propeptide levels in Malawian children with malaria

Abstract

Background: In spite of the significant mortality associated with Plasmodium falciparum infection, the mechanisms underlying severe disease remain poorly understood. We have previously shown evidence of endothelial activation in Ghanaian children with malaria, indicated by elevated plasma levels of both von Willebrand factor (VWF) and its propeptide. In the current prospective study of children in Malawi with retinopathy confirmed cerebral malaria, we compared these markers with uncomplicated malaria, non malarial febrile illness and controls.

Methods and findings: Children with cerebral malaria, mild malaria and controls without malaria were recruited into the study. All comatose patients were examined by direct and indirect ophthalmoscopy. Plasma VWF and propeptide levels were measured by ELISA. Median VWF and propeptide levels were significantly higher in patients with uncomplicated malaria than in children with non-malarial febrile illness of comparable severity, in whom levels were higher than in non-febrile controls. Median concentrations of both markers were higher in cerebral malaria than in uncomplicated malaria, and were similar in patients with and without retinopathy. Levels of both VWF and propeptide fell significantly 48 hours after commencing therapy and were normal one month later.

Conclusions: In children with malaria plasma VWF and propeptide levels are markedly elevated in both cerebral and mild paediatric malaria, with levels matching disease severity, and these normalize upon recovery. High levels of both markers also occur in retinopathy-negative 'cerebral malaria' cases, many of whom are thought to be suffering from diseases other than malaria, indicating that further studies of these markers will be required to determine their sensitivity and specificity.

Figure 1. Plasma concentration of von Willebrand factor (VWF) and VWF propeptide in various subsets of children with and without Plasmodium falciparum malaria.

Graphs showing median and scatter of plasma VWF and VWF propeptide levels in children with cerebral malaria (CM) and mild malaria (MM), and in non-malaria febrile illness (NMFI) and non-febrile illness (NFI) controls as measured by ELISA (Kruskal-Wallis, *** P<0.001; **P<0.01 after Bonferroni correction for post-hoc multiple pairwise testing). Dotted lines indicate median levels in local healthy Malawian adults.

Figure 2. Plasma concentration of VWF and propeptide in Plasmodium falciparum cerebral malaria patients during and after treatment.

Plasma levels of VWF and VWF propeptide were measured at admission, 2 days and 30 days post-treatment in a cohort of retinopathy positive children with cerebral malaria (Friedman Test, *P<0.05). Dotted lines indicate median levels in local healthy Malawian adults.

Figure 3. Plasma concentration of VWF and propeptide in severe Plasmodium falciparum malaria patients with and without retinopathy.

Graphs showing median and scatter of plasma VWF and VWF propeptide levels in cerebral malaria children with (+) and without (−) retinopathy as measured by ELISA (Mann Whitney U test, p = 0.832 and p = 0.143, respectively).

Figure 4. Plasma concentration of VWF and propeptide in Plasmodium falciparum cerebral malaria patients with retinopathy.

Graphs showing median and scatter of plasma VWF and VWF propeptide levels in retinopathy positive children with cerebral malaria who died (Died) or recovered (Recovered) as measured by ELISA (Mann Whitney U test, p = 0.873, p = 1.000, respectively).