title: Thrombocytopenia May Mediate Disease Severity in Plasmodium falciparum Malaria Through Reduced Transforming Growth Factor Beta-1 Regulation of Proinflammatory and Anti-inflammatory Cytokines.
abstract: BACKGROUND
  Transforming growth factor beta-1 (TGF-β1) is an important regulator of inflammation. Platelets are a major source of TGF-β1 and are reduced in severe malaria. However, the relationships between TGF-β1 concentrations and platelet counts, proinflammatory and anti-inflammatory cytokine and chemokine concentrations and disease severity in malaria have not been characterized.
  
  
  METHODS
  Platelet counts and serum concentrations of TGF-β1, interleukin-1beta (IL-1β), IL-6, IL-10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and RANTES were measured at the time of presentation in Ugandan children with cerebral malaria (CM, n = 75), uncomplicated malaria (UM, n = 67) and healthy community children (CC, n = 62).
  
  
  RESULTS
  TGF-β1 concentrations decreased with increasing severity of disease [median concentrations (25th, 75th percentile) in ng/mL in CC, 41.4 (31.6, 57.4); UM, 22.7 (14.1, 36.4); CM, 11.8 (8, 21); P for trend < 0.0001]. In children with CM or UM, TGF-β1 concentrations correlated positively with platelet count (CM, P < 0.0001; UM, P = 0.0015). In children with CM, TGF-β1 concentration correlated negatively with IFN-γ, IL-6 and IL-10 and positively with RANTES concentrations (all P < 0.01). TGF-β1 concentration was not associated with death or adverse neurologic or cognitive outcomes in children with CM.
  
  
  CONCLUSIONS
  TGF-β1 concentrations decrease with increasing Plasmodium falciparum disease severity. In CM, thrombocytopenia correlates with decreased TGF-β1, and decreased TGF-β1 correlates with cytokine/chemokine changes associated with increased disease severity and death. Thrombocytopenia may mediate disease severity in malaria through reduced TGF-β1-mediated regulation of cytokines associated with severe disease.
authors.affiliation: From the *Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and †Department of Paediatrics, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Hanisch
authors.forename: Paul
authors.initials: P
authors.lastname: Bangirana
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Park
authors.forename: Chandy C
authors.initials: CC
authors.lastname: John
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000150:complications* / Q000473:pathology*; D016778:Malaria, Falciparum / Q000150:complications* / Q000473:pathology*; D008297:Male; D013921:Thrombocytopenia / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000097:blood*; D014454:Uganda
chemical_list: D016207:Cytokines; D053773:Transforming Growth Factor beta1