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

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 si...

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Autores principales: Larkin, Deirdre, de 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.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652105/
https://www.ncbi.nlm.nih.gov/pubmed/19300493
http://dx.doi.org/10.1371/journal.ppat.1000349
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author Larkin, Deirdre
de 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.
author_facet Larkin, Deirdre
de 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.
author_sort Larkin, Deirdre
collection PubMed
description 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.
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spelling pubmed-26521052009-03-20 Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition Larkin, Deirdre de 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. PLoS Pathog Research Article 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. Public Library of Science 2009-03-20 /pmc/articles/PMC2652105/ /pubmed/19300493 http://dx.doi.org/10.1371/journal.ppat.1000349 Text en Larkin et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Larkin, Deirdre
de 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.
Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition
title Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition
title_full Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition
title_fullStr Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition
title_full_unstemmed Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition
title_short Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition
title_sort severe plasmodium falciparum malaria is associated with circulating ultra-large von willebrand multimers and adamts13 inhibition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652105/
https://www.ncbi.nlm.nih.gov/pubmed/19300493
http://dx.doi.org/10.1371/journal.ppat.1000349
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