Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.
de Laat, Bas
Jenkins, P Vince
Craig, Alister G
Preston, Roger J S
Grau, George E
van Mourik, Jan A
O'Donnell, James S
AffiliationHaemostasis Research Group, Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland.
Enzyme-Linked Immunosorbent Assay
von Willebrand Factor
MetadataShow full item record
CitationSevere Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. 2009, 5 (3):e1000349 PLoS Pathog.
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.
- ADAMTS13 deficiency with elevated levels of ultra-large and active von Willebrand factor in P. falciparum and P. vivax malaria.
- Authors: de Mast Q, Groot E, Asih PB, Syafruddin D, Oosting M, Sebastian S, Ferwerda B, Netea MG, de Groot PG, van der Ven AJ, Fijnheer R
- Issue date: 2009 Mar
- Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13.
- Authors: Löwenberg EC, Charunwatthana P, Cohen S, van den Born BJ, Meijers JC, Yunus EB, Hassan MU, Hoque G, Maude RJ, Nuchsongsin F, Levi M, Dondorp AM
- Issue date: 2010 Jan
- Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome.
- Authors: Hulstein JJ, van Runnard Heimel PJ, Franx A, Lenting PJ, Bruinse HW, Silence K, de Groot PG, Fijnheer R
- Issue date: 2006 Dec
- Reduced ADAMTS13 in children with severe meningococcal sepsis is associated with severity and outcome.
- Authors: Bongers TN, Emonts M, de Maat MP, de Groot R, Lisman T, Hazelzet JA, Leebeek FW
- Issue date: 2010 Jun
- Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.
- Authors: Bridges DJ, Bunn J, van Mourik JA, Grau G, Preston RJ, Molyneux M, Combes V, O'Donnell JS, de Laat B, Craig A
- Issue date: 2010 Feb 18