The Role of Immunomodulation in the Management of Factor VIII Inhibitors

Abstract

With the development of factor VIII (FVIII) concentrates for which the risk of infectious agent transmission is negligible, the principal treatment-related complication in hemophilia A is now the formation of anti-FVIII antibodies (FVIII inhibitors).1 The occurrence of a FVIII inhibitor in a person with hemophilia significantly influences the clinical care of the patient from two aspects: the requirement of alternative approaches to effect hemostasis through the use of bypassing agents, and the need to initiate immunomodulatory therapy to induce immunological tolerance to FVIII. This review will address recent developments in this latter area of clinical management. Factor VIII Inhibitors: Background and PathogenesisSince their earliest recognition in the 1940s, the pathobiology and treatment of FVIII inhibitors has been an area of intense activity for the scientific and clinical hemophilia communities. The incidence of this adverse immunological event ranges in the literature from 15-50%, 2-5 thus prompting questions about why such diverse results have been obtained in these various studies. It is clear that a number of variables are likely to have contributed to this wide range of results. These include the frequency of testing for inhibitors, the type of laboratory test being used, the type of FVIII concentrate and its mode of administration, and the mix of patients in the study population.Best characterized of the patient variables is the FVIII genotype, with a spectrum of inhibitor risks ranging from > 75% for multi-domain deletions through a 20-30% risk with the common intron 22 inversion mutation, to < 10%

IgG subclasses of anti‐FVIII antibodies during immune tolerance induction in patients with hemophilia A

“…ITI treatment comprises frequent administration of high or intermediate doses of FVIII, which generally results in a gradual decline in inhibitor titre (Brackmann & Gormsen, 1977; Lollar, 2004; Reipert et al , 2007). Retrospective data from two international registries indicate that the success rate for ITI varies between 70–80% (DiMichele & Kroner, 2002; Mariani et al , 2003; Lillicrap, 2006). Outcome of ITI is influenced by the inhibitor titre at the onset of treatment, the historical peak titre and the peak titre during treatment (DiMichele & Kroner, 2002; Mariani et al , 2003; Lillicrap, 2006).…”

Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10

“…1 Several approaches for immune tolerance induction (ITI), leading to the control of the production of clotting factor inhibitors, are currently used in hemophilia patients. 2 However, the success of ITI is not absolute, and currently, at a time when viral contaminants in therapeutic products are a problem of the past, inhibitors have become a major complication for hemophilia treatment. This has led to an increasing interest in developing new protocols for the induction of tolerance to therapeutically administered clotting factors.…”

The immunogenicity of platelet-derived FVIII in hemophilia A mice with or without preexisting anti-FVIII immunity

“…Inhibitory antibody development against FVIII is not only a significant complication in protein replacement therapy in clinical care, [20][21][22][23] but also a major concern in gene therapy of HA. [24][25][26] In the clinic, up to 35% of severe HA patients develop inhibitors after FVIII protein infusion, rendering routine FVIII treatment useless.…”