Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.
Authors
Larkin, Deirdrede Laat, Bas
Jenkins, P Vince
Bunn, James
Craig, Alister G
Terraube, Virginie
Preston, Roger J S
Donkor, Cynthia
Grau, George E
van Mourik, Jan A
O'Donnell, James S
Affiliation
Haemostasis Research Group, Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland.Issue Date
2009-03MeSH
ADAM ProteinsChild
Child, Preschool
Endothelial Cells
Enzyme-Linked Immunosorbent Assay
Humans
Infant
Malaria, Falciparum
Protein Multimerization
von Willebrand Factor
Metadata
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Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. 2009, 5 (3):e1000349 PLoS Pathog.Journal
PLoS pathogensDOI
10.1371/journal.ppat.1000349PubMed ID
19300493Abstract
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 (approximately 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.Language
enISSN
1553-7374ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1000349
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