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

Hdl Handle:
http://hdl.handle.net/10147/94749
Title:
Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.
Authors:
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
Affiliation:
Haemostasis Research Group, Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland.
Citation:
Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. 2009, 5 (3):e1000349 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Mar-2009
URI:
http://hdl.handle.net/10147/94749
DOI:
10.1371/journal.ppat.1000349
PubMed ID:
19300493
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 (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:
en
MeSH:
ADAM Proteins; Child; Child, Preschool; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Humans; Infant; Malaria, Falciparum; Protein Multimerization; von Willebrand Factor
ISSN:
1553-7374

Full metadata record

DC FieldValue Language
dc.contributor.authorLarkin, Deirdreen
dc.contributor.authorde Laat, Basen
dc.contributor.authorJenkins, P Vinceen
dc.contributor.authorBunn, Jamesen
dc.contributor.authorCraig, Alister Gen
dc.contributor.authorTerraube, Virginieen
dc.contributor.authorPreston, Roger J Sen
dc.contributor.authorDonkor, Cynthiaen
dc.contributor.authorGrau, George Een
dc.contributor.authorvan Mourik, Jan Aen
dc.contributor.authorO'Donnell, James Sen
dc.date.accessioned2010-03-23T16:45:32Z-
dc.date.available2010-03-23T16:45:32Z-
dc.date.issued2009-03-
dc.identifier.citationSevere Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. 2009, 5 (3):e1000349 PLoS Pathog.en
dc.identifier.issn1553-7374-
dc.identifier.pmid19300493-
dc.identifier.doi10.1371/journal.ppat.1000349-
dc.identifier.urihttp://hdl.handle.net/10147/94749-
dc.description.abstractPlasmodium 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.-
dc.language.isoenen
dc.subject.meshADAM Proteins-
dc.subject.meshChild-
dc.subject.meshChild, Preschool-
dc.subject.meshEndothelial Cells-
dc.subject.meshEnzyme-Linked Immunosorbent Assay-
dc.subject.meshHumans-
dc.subject.meshInfant-
dc.subject.meshMalaria, Falciparum-
dc.subject.meshProtein Multimerization-
dc.subject.meshvon Willebrand Factor-
dc.titleSevere Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.en
dc.contributor.departmentHaemostasis Research Group, Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland.en
dc.identifier.journalPLoS pathogensen

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