Platelet Activation Determines Angiopoietin-1 and VEGF Levels in Malaria: Implications for Their Use as Biomarkers

Abstract

IntroductionThe angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity. Since platelets store large amounts of Ang-1 and VEGF, measurement of circulation levels of these proteins is sensitive to platelet number, in vivo platelet activation and inadvertent platelet activation during blood processing. We studied plasma Ang-1, Ang-2 and VEGF levels in malaria patients, taking the necessary precautions to avoid ex vivo platelet activation, and related plasma levels to platelet count and the soluble platelet activation markers P-selectin and CXCL7.MethodsPlasma levels of Ang-1, Ang-2, VEGF, P-selectin and CXCL7 were measured in CTAD plasma, minimizing ex vivo platelet activation, in 27 patients with febrile Plasmodium falciparum malaria at presentation and day 2 and 5 of treatment and in 25 healthy controls.ResultsLevels of Ang-1, Ang-2 and VEGF were higher at day 0 in malaria patients compared to healthy controls. Ang-2 levels, which is a marker of endothelial activation, decreased after start of antimalarial treatment. In contrast, Ang-1 and VEGF plasma levels increased and this corresponded with the increase in platelet number. Soluble P-selectin and CXCL7 levels followed the same trend as Ang-1 and VEGF levels. Plasma levels of these four proteins correlated strongly in malaria patients, but only moderately in controls.ConclusionIn contrast to previous studies, we found elevated plasma levels of Ang-1 and VEGF in patients with malaria resulting from in vivo platelet activation. Ang-1 release from platelets may be important to dampen the disturbing effects of Ang-2 on the endothelium. Evaluation of plasma levels of these angiogenic proteins requires close adherence to a stringent protocol to minimize ex vivo platelet activation.

Serum levels of soluble adhesion molecules in newly diagnosed acute myeloid leukemia and in complete remission suggest endothelial cell activation by myeloblasts

“…The literature suggests these cytokines are stored in platelet granules [11][12][13] , which explains their correlation with platelet count. In CR, P-SEL correlates with platelet count, which is probably due to physiological cleavage of surface P-SEL from platelets, and further with IL-8.…”

Important of Angiopoietic System in Evaluation of Endothelial Damage in Children with Crimean–Congo Hemorrhagic Fever

“…VEGF and its receptor VEGFR1 and the Ang family of molecules, Ang-1 and Ang-2 and their receptor Tie-2, are among the most widely studied molecules. [23][24][25] Ang-1 and Ang-2 and their endothelial tyrosine kinase receptor Tie-2 form a central signaling system in endothelial permeability. 24,25 VEGF and its 2 receptors, VEGFR1 and VEGFR2, are expressed in the endothelium of blood vessels and contribute to vascular development and regulation of vascular permeability.…”

“…[23][24][25] Ang-1 and Ang-2 and their endothelial tyrosine kinase receptor Tie-2 form a central signaling system in endothelial permeability. 24,25 VEGF and its 2 receptors, VEGFR1 and VEGFR2, are expressed in the endothelium of blood vessels and contribute to vascular development and regulation of vascular permeability. 25,26 The angiogenic protein VEGF is a strong inducer of vascular permeability, and several studies have reported circulating e202 | www.pidj.com © 2015 Wolters Kluwer Health, Inc. All rights reserved.…”

“…24,25 VEGF and its 2 receptors, VEGFR1 and VEGFR2, are expressed in the endothelium of blood vessels and contribute to vascular development and regulation of vascular permeability. 25,26 The angiogenic protein VEGF is a strong inducer of vascular permeability, and several studies have reported circulating e202 | www.pidj.com © 2015 Wolters Kluwer Health, Inc. All rights reserved. 27 High levels of VEGF and VEGFR1 determined especially in severe patients support the plasma leakage and can be used as a prognostic factor for children with CCHF.…”

“…8 Ang-1 is not only produced in pericytes and smooth muscle cells, but platelets also contain high quantities of Ang-1. 25 Thus, the number and activation status of circulating platelets may influence plasma Ang-1 levels. Evidence is increasing that platelets are important cells for maintaining vascular stability and platelet-derived Ang-1 may be one of the factors involved.…”