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 Medicine 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 2

Anti–PF4/P IgG levels are elevated in pediatric CM.

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Anti–PF4/P IgG levels are elevated in pediatric CM. (A) Plasma levels of...
(A) Plasma levels of anti–PF4/P IgM/IgA antibodies in patients with UM (n = 38) versus patients with CM (n = 54). (B) Plasma levels of anti–PF4/P IgG in HCs (n = 56) versus UM (n = 124) versus CM (n = 136) versus NMC (n = 49) patients. (C) Plasma levels of anti–PF4/P IgG in CM survivors (Ret– CM, n = 27; Ret+ CM, n = 87) and patients with fatal CM (Ret– CM, n = 9; Ret+ CM n = 13). (D) Pair-wise comparison of anti–PF4/P IgG in acute versus convalescent plasma from patients with CM 30 days after admission (30d) (n = 39). (E and F) Pairwise analysis of neutralization of anti–PF4/P IgG binding in patient plasma with (E) 100 U/mL HDH (n = 24) or (F) 200 μg/mL dsDNA (n = 24). (G) Pearson’s correlation analysis between neutralization of anti-PF4/P binding by dsDNA versus HDH (n = 22). Shown within the graph is the Pearson’s rho coefficient (r) and the associated P value. In A–C, the assay cutoff threshold of OD above 0.4 is depicted by a dashed blue line. Shown are the median levels ± IQRs. Statistical significance was determined by Mann-Whitney U test (A and D), Kruskal-Wallis test with Dunn’s multiple comparisons (B and C), and a parametric paired t test (E and F).