title: Endothelial activation, haemostasis and thrombosis biomarkers in Ugandan children with severe malaria participating in a clinical trial.
abstract: BACKGROUND
  Malaria is a major cause of morbidity and mortality in sub-Saharan Africa, and poor outcomes have been associated with endothelial activation. In this study, biomarkers of endothelial activation, haemostasis, and thrombosis were measured in Ugandan children with severe malaria who participated in a clinical trial, in order to investigate associations between these processes.
  
  
  METHODS
  Serum and plasma were collected from participants at baseline (day 1), and on days 2, 3, 4, and 14. Von Willebrand factor (VWF) antigen was measured in stored plasma samples from all trial participants, and its association with mortality and changes over time were analysed. VWF multimer patterns were evaluated in baseline serum samples by gel electrophoresis followed by Western blotting. Levels of angiopoietins 1 and 2, VWF antigen, total active VWF, ADAMTS13, platelet counts, apolipoprotein A1, and syndecan-1 were measured in stored serum samples from 12 survivors at baseline and day 4.
  
  
  RESULTS
  VWF antigen levels were associated with mortality, and decreased over time in survivors. Baseline VWF antigen and total active VWF levels were elevated, and very large multimers were present in the baseline serum of several patients. Higher platelet counts were associated with higher angiopoietin-1 and apolipoprotein A1 levels, while lower platelet counts were associated with higher syndecan-1, a marker of endothelial damage. Higher angiopoietin-2 to angiopoietin-1 ratio and higher syndecan-1 levels were correlated with lower apolipoprotein A1 levels. There were no correlations between total active VWF, VWF antigen, or ADAMTS13 levels and the other biomarkers at baseline. Changes in biomarker levels between baseline and day 4 were not correlated.
  
  
  CONCLUSIONS
  These results confirm that severe malaria is associated with endothelial activation, and suggest that endothelial activation contributes to microvascular thrombosis and endothelial damage.
authors.affiliation: Department of Medicine, University of Washington, Box 359909, 325 Ninth Avenue, Seattle, WA, 98104, USA. grahamsm@uw.edu.|Department of Global Health, University of Washington, Seattle, WA, USA. grahamsm@uw.edu.|Department of Epidemiology, University of Washington, Seattle, WA, USA. grahamsm@uw.edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Graham
authors.affiliation: Bloodworks Research Institute, Seattle, WA, USA. JunmeiC@BloodWorksNW.org.
authors.forename: Junmei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bloodworks Research Institute, Seattle, WA, USA. Chung@BloodWorksNW.org.
authors.forename: Dominic W
authors.initials: DW
authors.lastname: Chung
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. kevin.barker@mail.utoronto.ca.|University Health Network-Toronto General Hospital, Toronto, ON, Canada. kevin.barker@mail.utoronto.ca.|Sandra Rotman Centre for Global Health, Toronto, ON, Canada. kevin.barker@mail.utoronto.ca.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Barker
authors.affiliation: Department of Medicine, Indiana University, Indianapolis, IN, USA. andrea.conroy@gmail.com.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Conroy
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada. mthawkes@ualberta.ca.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hawkes
authors.affiliation: Jinja Regional Referral Hospital, Jinja, Uganda. somnamasopo@yahoo.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Namasopo
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Kevin.Kain@uhn.ca.|University Health Network-Toronto General Hospital, Toronto, ON, Canada. Kevin.Kain@uhn.ca.|Sandra Rotman Centre for Global Health, Toronto, ON, Canada. Kevin.Kain@uhn.ca.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
authors.affiliation: Department of Medicine, University of Washington, Box 359909, 325 Ninth Avenue, Seattle, WA, 98104, USA. JoseL@BloodWorksNW.org.|Bloodworks Research Institute, Seattle, WA, USA. JoseL@BloodWorksNW.org.|Department of Biochemistry, University of Washington, Seattle, WA, USA. JoseL@BloodWorksNW.org.
authors.forename: José A
authors.initials: JA
authors.lastname: López
authors.affiliation: Department of Medicine, University of Washington, Box 359909, 325 Ninth Avenue, Seattle, WA, 98104, USA. wcliles@uw.edu.|Department of Global Health, University of Washington, Seattle, WA, USA. wcliles@uw.edu.|Department of Pathology, University of Washington, Seattle, WA, USA. wcliles@uw.edu.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
mesh_terms: D000071120:ADAMTS13 Protein / Q000097:blood; D042683:Angiopoietin-1 / Q000097:blood; D042702:Angiopoietin-2 / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D005260:Female; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D007223:Infant; D008288:Malaria / Q000097:blood* / Q000503:physiopathology*; D008297:Male; D053668:Syndecan-1 / Q000097:blood; D013927:Thrombosis / Q000097:blood* / Q000503:physiopathology; D014454:Uganda / Q000453:epidemiology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015415:Biomarkers; D053668:Syndecan-1; D014841:von Willebrand Factor; D000071120:ADAMTS13 Protein
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