Management of haemophilia A-inhibitor patients: clinical and regulatory perspectives.
Inhibitors to factor VIII (FVIII) are alloantibodies directed against epitopes able to neutralise FVIII procoagulant activity. They may render FVIII replacement therapy ineffective. They represent the most severe complication of haemophilia A. At least three mechanisms of FVIII neutralisation activity by anti-FVIII antibodies have been described: (1) steric hindrance; (2) recognition of neo-epitopes and (3) catalytic activity. The Nijmegen modification of the Bethesda is the recommended method for inhibitor surveillance. The occurrence of inhibitors is a relatively frequent and early event in previously untreated patients. Conversely, it is rare in previously treated patients. Therapeutic strategies for managing inhibitors include: inhibitor eradication, haemostatic management of bleeding episodes and/or surgery and supportive care. For high responding inhibitors, immune tolerance induction (ITI) is the strategy for achieving antigen-specific tolerance to FVIII. ITI success rate ranges commonly between 60% and 80%. For treatment of patients with high-titre, high-responding inhibitors, 'by-pass' therapy is generally recommended. Activated prothrombin complex concentrates represent the historically primary 'by-pass' treatment. Recombinant factor VIIa has also been widely used as a by-passing agent. Considering the small patient population, it has to be considered that full immunogenicity data cannot be collected premarketing authorisation. Thus, stringent follow-up of patients in the post-authorisation phase is required.
Tellier
Zera
Z
Laboratoire Français du Fractionnement et des Biotechnologies, Les Ulis, France, tellier@lfb.fr
André
Marie-Hélène
MH
Polack
Benoît
B
D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000276:immunology / Q000627:therapeutic use; D006467:Hemophilia A / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007518:Isoantibodies / Q000097:blood / Q000276:immunology; D016896:Treatment Outcome
D057134:Antibodies, Neutralizing; D019774:Blood Coagulation Factor Inhibitors; D007518:Isoantibodies; D005169:Factor VIII