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Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients with Hemophilia A from the HEMFIL StudyFunding This study was funded by FAPEMIG (CDS – APQ-04185–10 and CDS – PPM-00205–14), CAPES (grant number 88881.068041/2014–01), and CNPq (grant number 456080/2014–7).
Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB −/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB −/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.
L.M.M.O. and L.L.J. performed the research, analyzed the data, and wrote the manuscript; M.P.S., M.H.C., C.S.L., and V.K.B.F. selected the patients and collected the clinical data; L.W.Z. performed the molecular tests; D.G.C. and S.M.R. designed the research, contributed to data analysis, and wrote the manuscript. All authors revised and approved the final version of the manuscript.
* These authors contributed equally to the work.
Received: 19 August 2020
Accepted: 21 November 2020
10 January 2021 (online)
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