Abstract
Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF∶Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF∶CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU/ml versus 1.9 IU/ml; p<0.005). This increased VWF∶CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF∶Ag and VWF∶CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (∼55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.
Highlights
In spite of the significant mortality associated with P. falciparum infection, the molecular mechanisms involved in its pathophysiology remain poorly understood
In children with cerebral (CM) and non-cerebral severe (SM) P. falciparum malaria, plasma von Willebrand factor (VWF):Ag levels were significantly elevated at presentation (Fig 1A)
Plasma VWF:Ag and VWF:CB were both increased in children with cerebral malaria (CM) or SM at initial presentation, the observed increase in VWF:CB was much greater compared to that in plasma VWF:Ag levels, so that the ratio of CB:Ag was consistently increased compared to that observed in healthy control children (Fig 1C)
Summary
In spite of the significant mortality associated with P. falciparum infection, the molecular mechanisms involved in its pathophysiology remain poorly understood. Previous studies have demonstrated that sequestration involves adhesion of IE to endothelial cell (EC) surfaces This process is mediated by various parasite-related ligands, including P. falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surface of IE [2]. A number of specific receptors expressed on EC surfaces are important in regulating IE adhesion, including thrombomodulin, CD36, thrombospondin, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), P-selectin and E-selectin. Expression of these receptors varies significantly between different vascular beds, and can be regulated in response to inflammatory cytokines (e.g. TNF and interleukin-1) [3,4]. EC activation plays a critical role in regulating IE cytoadherence [5]
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