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

Prevalence of hepatitis C virus (HCV) is high in hemophilia A patients and the development of FVIII inhibitor is another challenge in the management of these individuals. The influence of HCV infection in the occurrence of inhibitors was investigated by the comparison of clinical and laboratory data from noninfected (NI, n = 96) and chronically HCV-infected (HCV, n = 58) hemophilia A patients. Concentrations of plasmatic cytokines (IL-2, IL-4, IL-6, IL-10, TNF, IFN-gamma, and IL-17A) and chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10) were quantified from patients' samples. The results showed that older age, use of cryoprecipitate and fresh frozen plasma, and severe hemophilia were associated with HCV infection, whereas exclusive use of virus inactivated clotting factors was a protector factor to acquiring HCV infection. HCV infection was strongly associated with low levels of inhibitor (OR = 20.53, p < 0.001). Patients with a history of inhibitor (INB+) presented a mixed immune profile characterized by higher levels of pro-and anti-inflammatory cytokines than those without a history of inhibitor (INB-). The highest levels of CCL2 and CXCL8 were seen in HCVINB-, whereas CXCL9 and CXCL10 in HCVINB+. Heatmap analysis of the set of cytokines and chemokines concentration distributed HCV patients into two distinct clusters, HCVINB+ and HCVINB-, both characterized by low concentrations of IL-4, while noninfected patients were grouped in a single block regardless of inhibitor development history (NIINB-/INB+). This finding suggests that the strong association between HCV infection and low levels of factor VIII inhibitors might be due to the modulation of the cytokine and chemokine network established by the antiviral response.