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ADAMTS13 Deficiency with Elevated Levels of Ultra-Large and Active von Willebrand Factor in P. falciparum and P. vivax Malaria

A deficiency in ADAMTS13 (a von Willebrand factor [VWF] cleaving protease) is associated with accumulation of prothrombogenic unusually large VWF multimers (UL-VWF) in plasma. We studied VWF release and proteolysis in patients with symptomatic Plasmodium falciparum or P. vivax malaria on the Indonesian island Sumba. Malaria patients had significantly lower platelet counts and higher VWF concentrations and VWF activation factors than healthy hospital staff controls. The latter indicates that a higher amount of circulating VWF was in a conformation enabling spontaneous platelet binding. In addition, ADAMTS13 activity and antigen levels were reduced in both malaria groups, and this was associated with the appearance of UL-VWF. The mechanism behind this reduction and the role in malaria pathogenesis needs to be further elucidated. In malaria, endothelial cell activation with increased circulating amounts of active and ultra-large VWF, together with reduced VWF inactivation by ADAMTS13, may result in intravascular platelet aggregation, thrombocytopenia, and microvascular disease.

Received October 3, 2008. Accepted for publication November 17, 2008.

Acknowledgments: The authors thank all patients and staff at the Karitas Hospital in Weetabula, Sumba, Indonesia, for their support and participation. We also thank Dr. M. Roest and A. Barendrecht for determination of the P475S mutation and the ICAM-1 and IL-6 ELISAs.

Fiancial support: This study was supported in part by the Noaber and Hoge Dennen foundations. PBA is supported by NWO-WOTRO (WIZ93-465) through PRIOR. MGN is supported by a Vidi Grant of the Netherlands Organization for Scientific Research (NWO). The sponsors of this study are public or nonprofit organizations that support science in general. They had no role in gathering, analyzing, or interpreting the data.

^* Address correspondence to Quirijn de Mast, Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Room 456, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. E-mail: q.demast{at}aig.umcn.nl

Authors’ addresses: Quirijn de Mast, Department of General Internal Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, Tel: +31243618822, Fax: +31243566336, E-mail: q.demast{at}aig.umcn.nl. Evelyn Groot, Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands, Tel: +31887557769, Fax: +31887555418, E-mail: e.groot-6{at}umcu-trecht.nl. Puji B. Asih, Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia, E-mail: puji{at}eijkman.go.id. Din Syafruddin, Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia, E-mail: din{at}eijkman.go.id. Marije Oosting, Department of General Internal Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, Tel: +31243618822, Fax: +31243566336, E-mail: m.oosting{at}aig.umcn.nl. Silvie Sebastian, Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands, Tel: +31887557769, Fax: +31887555418, E-mail: s.a.e.sebastian{at}umcutrecht.nl. Bart Ferwerda, Department of General Internal Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, Tel: +31243618822, Fax: +31243566336, E-mail: b.ferwerda{at}aig.umcn.nl. Mihai G. Netea, Department of General Internal Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, Tel: +31243618822, Fax: +31243566336, E-mail: m.netea{at}aig.umcn.nl. Philip G. de Groot, Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands, Tel: +31887557769, Fax: +31887555418, E-mail: Ph.G.deGroot{at}umcutrecht.nl. Andre J. A. M. van der Ven, Department of General Internal Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, Tel: +31243618822, Fax: +31243566336, E-mail: a.vanderven{at}aig.umcn.nl. Rob Fijnheer, Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands, Tel: +31887557769, Fax: +31887555418, E-mail: Ph.G.deGroot{at}umcutrecht.nl.