Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients with Hemophilia A from the HEMFIL Study

Abstract

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.

High levels of anti–factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors

“…Anti-FVIII antibodies consist of a polyclonal population of antibodies mainly targeting antigenic sites within A2, A3, and C2 domains of FVIII [ 20 ]. In people with hemophilia A, they comprise both neutralizing (inhibitors) and nonneutralizing antibodies [ 21 ], mainly represented by IgG4 and IgG1, respectively [ 16 , 22 ]. Our results demonstrated that high levels of both anti-FVIII IgG total and IgG4 are hallmarks of ITI failure.…”

“…We used these 2 brands of target FVIII because these were the types of FVIII concentrates that people with hemophilia A used for the course of ITI. Tests were performed in duplicates, and results were expressed as mean [ 16 ].…”

HCV infection in hemophilia A patients is associated with altered cytokines and chemokines profile and might modulate the levels of FVIII inhibitor

“…The cytokine profile observed in this study for each analyzed group fits this model: INB− patients (NI INB− and HCV INB− groups) showed the lowest levels of Th1 and Th2 cytokines; NI INB+ patients presented high levels of Th1 and Th2 cytokines, including IFNγ and IL‐4; finally, HCV INB+ patients showed high levels of Th1 cytokines, but low production of IL‐4. Other studies also have been shown that cytokines may play an important role in inhibitor development 22–24 …”

“…Other studies also have been shown that cytokines may play an important role in inhibitor development. [22][23][24] The groups of HCV INB− and HCV INB+ in comparison to their counterparts NI INB− and NI INB+ presented different signatures of cytokines and chemokines. Despite a history of inhibitor development, HCV patients were characterized by a higher frequency of good secretors of chemokines (Figure 2), indicating that chemokines were associated with the viral infection as previously reported.…”

Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol

“…Thirdly, the BrazIT Study is aimed to identify new predictive factors related to ITI response, which includes not only clinical characteristics but also immune and genetic (other than F8 ) biomarkers. The involvement of immune modulators in the biogenesis of inhibitors has been described [ 51 , 52 ], but, to our concern, this is the first study targeting these biomarkers as potential predictors of ITI outcome. Fourthly, since inhibitor status is evaluated regularly among Brazilian PwHA, this study may determine both recurrence incidence and risk factors for relapse in PwHA who responded to ITI.…”