Prothrombotic autoantibodies targeting platelet factor 4/polyanion are associated with pediatric cerebral malaria
Iset M. Vera, … , Karl B. Seydel, Kami Kim
Iset M. Vera, … , Karl B. Seydel, Kami Kim
Published April 23, 2024
Citation Information: J Clin Invest. 2024;134(11):e176466. https://doi.org/10.1172/JCI176466.
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Clinical Research and Public Health Infectious disease Microbiology

Prothrombotic autoantibodies targeting platelet factor 4/polyanion are associated with pediatric cerebral malaria

Abstract

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–β-2-glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (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 in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti–PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14–0.22, P < 0.0001). Anti–PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti–PF4/P IgG correlated negatively with the peripheral platelet count in patients with Ret+ CM (Spearman’s rho [Rs] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02–275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed 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.

Authors

Iset M. Vera, Anne Kessler, Visopo Harawa, Ajisa Ahmadu, Thomas E. Keller, Stephen T.J. Ray, Terrie E. Taylor, Stephen J. Rogerson, Wilson L. Mandala, Morayma Reyes Gil, Karl B. Seydel, Kami Kim

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Figure 5

Anti-PS antibodies are elevated in malaria but do not vary with severity.

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Anti-PS antibodies are elevated in malaria but do not vary with severity...
(A) Plasma levels of anti–PS IgM antibodies measured in patients with UM (n = 39) versus patients with CM (n = 58). Shown are internal negative (neg) (n = 3) and positive (pos) (n = 3) controls. Dotted blue line across the y axis at 10 U/mL represents the predetermined assay clinical cutoff. (B) Plasma levels of anti–PS IgG in patients with UM (n = 74) versus patients with CM (n = 108) versus HCs (n = 34) versus patients with NMC (n = 48). (C) Plasma levels of anti–PS IgG in CM stratified by retinopathy status (Ret– or Ret+) and outcome (survival or death). Ret– survivors: n =19; Ret+ CM survivors: n = 63; Ret– CM deaths: n = 6; and Ret+ CM deaths: n = 12. (D) CD62p versus anti–PS IgG (n = 58), (E) sCD40L versus anti–PS IgG (n = 73), (F) HgB versus anti–PS IgG (n = 77), and (G) PCV versus anti–PS IgG (n = 79). Shown within scatter plots are linear regression curves with the 95% CI in the dotted line, the calculated Spearman’s Rs, and the associated P value. Shown are the median levels ± IQRs. Statistical significance was determined by Mann-Whitney U test (A) and Kruskal-Wallis test with Dunn’s multiple comparisons (B and C). Spearman correlation analysis of soluble markers in Ret+ CM patient plasma associated with platelet activation (D and E) or anemia (F and G) in relation to circulating levels of anti–PS IgG. Values were converted to log form to accommodate non-normal distribution.