Hemophilia. Strategies for the treatment of inhibitor patients

Abstract

Symptomatic treatment of patients with hemophilia A and hemophilia B has now reached high levels of safety and efficacy. In consequence, at present the most prominent clinical complication is the development of inhibitors, which are alloantibodies directed against the coagulation factor demanded for substitution therapy in the management and prevention of bleeds. When de novo inhibitors are detected for the first time in a patient, several questions are raised. Since the clinical picture with inhibitors is dominated by an excessive tendency to bleed and reduced or lost efficacy of the usual factor concentrate, acute bleeding will often be a problem. Major questions from the patient and his next of kin are whether the inhibitors will disappear, and whether there is a therapy available that can cure this complication. Over the last 20-25 years, treatment programs have been established that seem to offer a reasonably good chance of suppressing inhibitors in hemophilia. Some protocols suggest the use of very high daily doses of factor VIII, whereas others propose much lower doses of factor VIII, seemingly with quite comparable rates of success. Therefore, controlled prospective clinical studies, focusing on the dosage aspect, are urgently required. Control of bleeding is another issue of great importance. In inhibitor patients with a low responder state, substitution with increased doses of factor VIII or IX may successfully arrest bleeding. In some hemophilia A patients with a high responder state, but with actual inhibitor titers in the lower range, a porcine factor VIII concentrate could be useful. In these cases the patient's anti-factor VIII antibody should display no major cross-reactivity towards the porcine factor VIII molecule. In patients with high-responder inhibitors, so-called bypassing agents may be used to control bleeding. There are two major classes of bypassing agents. Concentrates have been produced for more than two decades derived from plasma and characterized by a high content of vitamin K-dependent coagulation factors. Examples are the prothrombin complex concentrates (PCC), and the activated prothrombin complex concentrates (aPCC). A newly introduced recombinant activated factor VII molecule (rFVIIa) has gained approval in numerous countries based primarily on results from emergency use in a substantial number of individuals with inhibitors. Other, still experimental, products have been proposed, but no human clinical studies are available as of yet Inhibitors remain a challenge to patients and their physicians.