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Severe Plasmodium falciparum malaria is associated with circulating ultra-large von willebrand multimers and ADAMTS13 inhibition

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Larkin, D., De Laat, B., Jenkins, P. V., Bunn, J., Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Terraube, V., Preston, R. J. S., Donkor, C., Grau, G. E., Van Mourik, J. A. and O'Donnell, J. S. (2009) 'Severe Plasmodium falciparum malaria is associated with circulating ultra-large von willebrand multimers and ADAMTS13 inhibition'. PLoS Pathogens, Vol 5, Issue 3, e1000349.

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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 lU/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.

Item Type: Article
Subjects: QX Parasitology > Protozoa > QX 135 Plasmodia
QX Parasitology > Insects. Other Parasites > QX 510 Mosquitoes
QX Parasitology > Insects. Other Parasites > QX 515 Anopheles
QX Parasitology > Insects. Other Parasites > QX 650 Insect vectors
WA Public Health > WA 105 Epidemiology
WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries
WB Practice of Medicine > Medical Climatology > WB 710 Diseases of geographic areas
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 680 Tropical diseases (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 695 Parasitic diseases (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 312 Hemorrhagic disorders (General)
WS Pediatrics > By Age Groups > WS 421 Diseases of newborn infants
WS Pediatrics > By Age Groups > WS 430 Infancy
WS Pediatrics > By Age Groups > WS 440 Preschool child
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.ppat.1000349
Depositing User: Mary Creegan
Date Deposited: 02 Jun 2010 11:47
Last Modified: 06 Feb 2018 12:59
URI: http://archive.lstmed.ac.uk/id/eprint/316

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