Factor VIII Inhibitors in Patients with Hemophilia A: Epidemiology of Inhibitor Development and Induction of Immune Tolerance for Factor VIII

Abstract

Factor (F) VIII inhibitor development remains one of the most serious complications in the treatment of hemophilia A. Former and recent studies on inhibitor development revealed that patients with severe hemophilia A and positive inhibitor family history are at highest risk of developing an inhibitor. Comparison of recent inhibitor incidence studies on previously untreated patients indicate that the risk of inhibitor development under treatment with recombinant FVIII concentrates is comparable to the inhibitor incidence under FVIII substitution by plasma-derived concentrates. However, longer observation periods are necessary to draw final conclusions. Since inhibitor development may result in inefficacy of FVIII concentrates in the treatment of severe bleedings, the induction of immune tolerance (IT) is still of main concern. Various regimens to induce IT by application of FVIII concentrates have been conducted up to now. Success rate appears to be influenced by low to high responder status, number of exposure days before onset of treatment, and dosage of therapeutic regimen. Especially, discontinuation of IT therapy seems to be associated with failure of therapy. Taking into account available data on IT therapy, we recommend early onset of a high dosage regimen in high responder patients as soon as possible after inhibitor detection, as this is associated with higher success rate and shorter elimination time.

Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system

“…12 Inhibitors complicate treatment of bleeding episodes by rapidly inactivating infused FVIII, but in many cases this problem can be overcome by induction of immune tolerance via daily infusions of high-dose FVIII. 12,27 Immune tolerance induction can be achieved in hemophilia A mice by injecting neonates with recombinant hFVIII within 24 hours of birth, 16,17 when the immune system is very susceptible to immune tolerance induction. 16,17,[28][29][30] Therefore, we tolerized newborn (1-day-old) hemophilia A mice by injection of 0.1 U g Ϫ1 recombinant hFVIII into the facial temporal vein to evaluate the efficacy of gene delivery.…”

“…Immune response to FVIII has been a persistent clinical problem for clotting factor replacement therapy 12 and gene therapy studies in animal models. 9,[13][14][15] In FVIII vector-treated hemophilia A mice, anti-FVIII antibodies rapidly clear FVIII from the circulation, thereby complicating the assessment of the efficacy of gene therapy vectors.…”

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

“…Despite these advantages, successful FVIII replacement has been complicated by the development of inhibitory antibodies to various epitopes of the FVIII molecule. Inhibitor development occurs in B30-50% of patients receiving protein replacement therapy, 6,7 and in over 80% of animals receiving gene therapy. 3,[8][9][10][11][12] FVIII inhibitors rapidly inactivate FVIII and dramatically decrease the efficacy of treatment; therefore approaches to eliminate the formation of inhibitors are of significant interest to scientists and clinicians treating hemophilia.…”

Induction of tolerance to human factor VIII in mice

“…[4][5][6] The mechanism responsible for development of the anti-FVIII inhibitor remains unclear, although several factors may affect its formation, including the type of FVIII mutation, the FVIII product used, and patients' immune response. [4][5][6] Currently, patients with the inhibitor are treated with induction of immune tolerance 7 or administration of porcine FVIII, 8 activated factor complexes, 9 immunosuppressive agents, 10 or activated factor VIIa. 11,12 Successful induction of immune tolerance can be achieved by continuous infusion of a high-dose FVIII concentrate to "desensitize" patients.…”