Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition

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.

Emerging roles for hemostatic dysfunction in malaria pathogenesis

“…However, several studies have reported that plasma ADAMTS13 antigen and activity levels are significantly reduced in CM. 26,32,33 Interestingly, only modest reductions in ADAMTS13 have been observed, with plasma levels generally remaining .30% normal values. 26,32,33 Previous in vitro studies suggest that these ADAMTS13 levels should be adequate to maintain normal plasma VWF multimer distribution.…”

“…26,32,33 Interestingly, only modest reductions in ADAMTS13 have been observed, with plasma levels generally remaining .30% normal values. 26,32,33 Previous in vitro studies suggest that these ADAMTS13 levels should be adequate to maintain normal plasma VWF multimer distribution. 61 Consequently, the significance of this modest reduction in plasma ADAMTS13 with respect to the accumulation of UL-VWF multimers in children with severe P falciparum malaria remains unclear.…”

“…24 A series of recent studies have shown that plasma levels of VWF antigen (VWF:Ag) and VWF propeptide (VWFpp) are both markedly elevated in patients with severe P falciparum malaria. [25][26][27][28][29] For example, Hollestelle et al observed that plasma VWF concentration at presentation in Ghanaian children with CM was approximately threefold higher than that observed in healthy age-matched controls. 25 Interestingly, plasma VWFpp levels were also threefold increased in children with CM.…”

“…26,32 Importantly, these UL-VWF multimers demonstrate significantly enhanced binding to platelets compared with monomers and consequently are more efficient in modulating platelet aggregation. Furthermore, a significant proportion of plasma VWF in patients with P falciparum infection circulates in an active confirmation that facilitates binding to platelet GpIb.…”

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

“…Further evidence suggests ADAMTS13 deficiency in patients with systemic inflammation and severe sepsis (9,(23)(24)(25). This deficiency is associated with an increase in ulVWF and is postulated to cause TMA in patients (9,23,26).…”