title: Laboratory evidence of disseminated intravascular coagulation is associated with a fatal outcome in children with cerebral malaria despite an absence of clinically evident thrombosis or bleeding.
abstract: BACKGROUND
  A procoagulant state is implicated in cerebral malaria (CM) pathogenesis, but whether disseminated intravascular coagulation (DIC) is present or associated with a fatal outcome is unclear.
  
  
  OBJECTIVE
  To determine the frequency of overt DIC, according to ISTH criteria, in children with fatal and non-fatal CM.
  
  
  METHODS
  Malawian children were recruited into a prospective cohort study in the following diagnostic groups: retinopathy-positive CM (n = 140), retinopathy-negative CM (n = 36), non-malarial coma (n = 14), uncomplicated malaria (UM), (n = 91), mild non-malarial febrile illness (n = 85), and healthy controls (n = 36). Assays in the ISTH DIC criteria were performed, and three fibrin-related markers, i.e. protein C, antithrombin, and soluble thrombomodulin, were measured.
  
  
  CONCLUSIONS
  Data enabling assignment of the presence or absence of 'overt DIC' were available for 98 of 140 children with retinopathy-positive CM. Overt DIC was present in 19 (19%), and was associated with a fatal outcome (odds ratio [OR] 3.068; 95% confidence interval [CI] 1.085-8.609; P = 0.035]. The levels of the three fibrin-related markers and soluble thrombomodulin were higher in CM patients than in UM patients (all P < 0.001). The mean fibrin degradation product level was higher in fatal CM patients (71.3 μg mL(-1) [95% CI 49.0-93.6]) than in non-fatal CM patients (48.0 μg mL(-1) [95% CI 37.7-58.2]; P = 0.032), but, in multivariate logistic regression, thrombomodulin was the only coagulation-related marker that was independently associated with a fatal outcome (OR 1.084 for each ng mL(-1) increase [95% CI 1.017-1.156]; P = 0.014). Despite these laboratory derangements, no child in the study had clinically evident bleeding or thrombosis. An overt DIC score and high thrombomodulin levels are associated with a fatal outcome in CM, but infrequently indicate a consumptive coagulopathy.
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.|Malawi-Liverpool Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: C A
authors.initials: CA
authors.lastname: Moxon
authors.affiliation: Malawi-Liverpool Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: N V
authors.initials: NV
authors.lastname: Chisala
authors.affiliation: University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: R
authors.initials: R
authors.lastname: Mzikamanda
authors.affiliation: Malawi-Liverpool Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.|University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: I
authors.initials: I
authors.lastname: MacCormick
authors.affiliation: Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Harding
authors.affiliation: Roald Dahl Haemostasis & Thrombosis Centre, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: C
authors.initials: C
authors.lastname: Downey
authors.affiliation: Malawi-Liverpool Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.|Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Molyneux
authors.affiliation: College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.|Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: K B
authors.initials: KB
authors.lastname: Seydel
authors.affiliation: College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.|Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: T E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.|Malawi-Liverpool Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: R S
authors.initials: RS
authors.lastname: Heyderman
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.|Roald Dahl Haemostasis & Thrombosis Centre, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: C-H
authors.initials: CH
authors.lastname: Toh
mesh_terms: D015415:Biomarkers / Q000032:analysis; D001786:Blood Glucose / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D003128:Coma / Q000097:blood / Q000209:etiology; D004211:Disseminated Intravascular Coagulation / Q000209:etiology*; D005260:Female; D005334:Fever / Q000097:blood; D005337:Fibrin / Q000096:biosynthesis; D006403:Hematologic Tests; D006801:Humans; D007223:Infant; D007773:Lactates / Q000097:blood; D016779:Malaria, Cerebral / Q000097:blood* / Q000401:mortality; D016778:Malaria, Falciparum / Q000097:blood* / Q000401:mortality; D008295:Malawi; D008297:Male; D018512:Parasitemia / Q000097:blood / Q000401:mortality; D011446:Prospective Studies; D012166:Retinal Hemorrhage / Q000097:blood / Q000469:parasitology; D012307:Risk Factors; D018180:Thrombomodulin / Q000032:analysis
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007773:Lactates; C546931:THBD protein, human; D018180:Thrombomodulin; D005337:Fibrin
keywords: blood coagulation; disseminated intravascular coagulation; endothelial cell protein C receptor; fibrin; malaria, cerebral