Immune Response to FVIII in Hemophilia A: An Overview of Risk Factors

Abstract

Development of inhibitors is perhaps the most serious complication of factor VIII (FVIII) replacement therapy, which can practically preclude efficient clinical management of patients with hemophilia A. Much effort therefore has been focused both in improving our understanding of the reasons for the formation of FVIII antibodies and to find alternative methods of treatment. Several patient-related factors have been related to the risk of inhibitor development such as ethnicity, FVIII gene mutation type, family history of inhibitors, HLA haplotype, polymorphisms in the promoter regions of IL 10 gene, single nucleotide polymorphisms of tumor necrosis factor alpha gene, and so on. In addition to the genetic determinants, there are several nongenetic factors which mainly include treatment characteristics like the type and purity of coagulation factor concentrates used for treatment, age at the time of initial treatment, initial doses of concentrate, mode of infusion, surgery, frequency of dosing prior to inhibitor development, and intensity of treatment or regular prophylaxis. Inflammatory processes in early childhood are under discussion as being an environmental factor that may modify the immune response to a foreign antigen. The genetic risks cannot be changed, while environmental factors may increase or decrease the inhibitor risk in an individual patient. In addition, there are other causes of inhibitor development against FVIII like stress, age, malignancy, infection, pregnancy, antibiotics, etc. Development of inhibitors in such cases happens in individuals who are not hemophilic and have normal plasma FVIII levels. Acquired inhibitors to FVIII in nonhemophiliacs (autoantibodies) pose a further challenge to treatment, as this is often associated with significant morbidity and mortality. Prognosis in case of autoantibodies is related to the underlying disease process and is associated with high mortality. Improved understanding of these complex interactions may lead to the development of preventive measures to minimize FVIII inhibitor formation. The modifiable risk factors for inhibitor formation may provide the key to predict and perhaps prevent the formation of inhibitors in hemophilia patients.

Factor VIII gene variants and inhibitor risk in African American hemophilia A patients

“…[32][33][34][35] A possibly increased inhibitor risk was seen for subjects with HLA-DR15 and the H2 haplotype (Table 5), but this was not seen for those with peak titers $5 BU/mL (supplemental Table 3). Future studies will evaluate additional genetic and environmental factors 34,[36][37][38] that influence race-associated differences in inhibitor risk.…”

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

“…[63][64][65][66][67] Risk factors for development of inhibitors in HA include genetic factors such as the type of F8 gene mutation, the severity of hemophilia, HLA haplotype, and polymorphisms in genes involved in immunoregulation 68 as well as environmental factors such as the intensity of FVIII exposure and concomitant immunologic "danger signals." 69 Identification of risk factors related to rFVIII vs plasma-derived FVIII has been more controversial. Product-specific differences that have been examined include amino acid sequence alterations, including B-domain deletion/truncation, glycosylation patterns, and a potential protective role of VWF.…”

Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice

“…In hemophilia A, formation of inhibitory antibodies (inhibitors) directed against factor VIII (F.VIII), a helper-T-cell-dependent response, occurs in 20-30% of patients (1). There is much progress in the risk assessment of inhibitor formation in patients early in therapy, using a combination of genotyping (e.g., determination of the underlying F.VIII mutation and polymorphisms in the promoters of the cytokine genes IL-10 and TNFα), family history of inhibitor formation, ethnicity, and intensity of early treatment (2). Inhibitors increase the risk for bleeding-related morbidity and mortality.…”