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Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

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  • Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Parasitology, and Division of Human Genetics, Center for Biomedical Research, Dr. Kariadi Hospital and Faculty of Medicine, Diponegoro University, Semarang, Indonesia; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands; Angiogenesis Laboratory, Department of Medical Oncology, VUMC-Cancer Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands

The pathogenesis of plasma leakage during dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is largely unknown. Angiopoietins are key regulators of vascular integrity: Angiopoietin-1 is stored in platelets and maintains vascular integrity, and endothelium-derived angiopoietin-2 promotes vascular leakage. We determined angiopoietin-1 and angiopoietin-2 levels in a cohort of children in Indonesia with DHF/DSS and related them to plasma leakage markers. Patients with DHF/DSS had reduced angiopoietin-1 and increased angiopoietin-2 plasma levels on the day of admission when compared with levels at discharge and in healthy controls. There was an inverse correlation between angiopoietin-1 and markers of plasma leakage and a positive correlation between angiopoietin-2 and markers of plasma leakage. Angiopoietin-1 levels followed the same trend as the soluble platelet activation marker P-selectin and correlated with platelet counts. Dengue-associated thrombocytopenia and endothelial activation are associated with an imbalance in angiopoietin-2: angiopoietin-1 plasma levels. This imbalance may contribute to the transient plasma leakage in DHF/DSS.

Author Notes

* Address correspondence to Meta Michels, Department of Internal Medicine, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. E-mail: m.michels@aig.umcn.nl

Financial support: M. Michels is supported by a junior researcher grant from the Radboud University Nijmegen Medical Centre.

Disclosure: None of the authors has any commercial or other associations that might pose a conflict of interest.

Authors' addresses: Meta Michels, André J. A. M. van der Ven, and Quirijn de Mast, Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands, E-mails: m.michels@aig.umcn.nl, a.vanderven@aig.umcn.nl, and q.demast@aig.umcn.nl. Kis Djamiatun, Department of Parasitology, Faculty of Medicine, Diponegoro University, Semarang, Indonesia, E-mail: ramus64@yahoo.com. Rob Fijnheer, Philip G. de Groot, and Silvie Sebastian, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands, E-mails: r.fijnheer@umcutrecht.nl, ph.g.degroot@umcutrecht.nl, and s.a.e.sebastian@umcutrecht.nl. Arjan W. Griffioen, Angiogenesis Laboratory, Department of Medical Oncology, VUMC-Cancer Centre, VU University Medical Center, Amsterdam, The Netherlands, E-mail: aw.griffioen@vumc.nl. Sultana M. H. Faradz, Division of Human Genetics, Center for Biomedical Research, Kariadi Hospital and Faculty of Medicine, Diponegoro University, Semarang, Indonesia, E-mail: smhfaradz@yahoo.com.

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