Background: Features of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM.
Methods: Plasma from children with uncomplicated malaria (UM, n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-Platelet Factor 4/polyanion (anti-PF4/P), anti-Phospholipid, anti-Phosphatidylserine, anti-Myeloperoxidase, anti-Proteinase 3, anti-dsDNA, anti-Beta-2-Glycoprotein I (β2GPI), and anti-Cardiolipin. Non-malaria coma (NMC, n = 49) and healthy controls (HC, n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses.
Results: Median anti-PF4/P and anti-PS IgG levels were elevated with malaria infection relative to HC (P < 0.001) and NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in CM (median = 0.27, IQR: 0.19-0.41) compared to UM (median = 0.19, IQR: 0.14-0.22, P ≤ 0.0001). Anti-PS IgG levels did not differ between UM and CM (P = 0.39). When CM cases were stratified by malaria retinopathy (Ret) status, levels of anti-PF4/P IgG correlated negatively with peripheral platelet count in Ret+ CM cases (Rs = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from CM patients induced a greater platelet activation capacity in an ex-vivo assay relative to plasma from UM patients (P = 0.02). Platelet activation was associated with anti-PF4/P IgG levels (Rs = 0.293, P = 0.035).
Conclusions: Thrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.
Keywords: Autoimmune diseases; Infectious disease; Malaria; Microbiology; Platelets.