Factor VIII

Gene therapy

Trials of gene therapy in hemophilia A and B, to determine safety and efficacy, are under way [ ]. The hazards of current vectors include the development of inhibitors, as observed in substitution therapy, insertion mutagenesis (for example through disruption of a regulatory gene such as a tumor suppressor gene), and transmission of genes to germ cells [ ]. In the various phase I trials performed in patients with hemophilia such adverse events have not been observed [ ]. Other theoretical hazards are immunogenesis, hepatotoxicity, and carcinogenic effects. In particular, retroviral vectors have a considerable carcinogenic potential. Adenoviruses, which do not integrate into the genome and consequently have only a transient effect, are considered to be safer. Also adeno-associated viruses have a low pathogenic potential in humans, as do lentiviruses.

The death of a young patient who took part in a clinical gene therapy study, probably caused by an adverse reaction to the viral vector [ , ], has led to increased interest in the application of non-viral techniques for gene therapy. When factor VIII genes were introduced into autologous skin cells in culture by electroporation, and thereafter implanted in the omentum in six patients with hemophilia A, no adverse events were reported [ ].

Cardiovascular

Thromboembolic complications developed in two of 81 patients with Von Willebrand disease treated with a high-purity factor VIII/Von Willebrand factor (VWF) concentrate [ ]. Four cases of venous thrombosis were reported in patients with Von Willebrand disease treated with an intermediate-purity factor VIII/VWF concentrate. Use of pure VWF concentrate is preferable [ ].

Respiratory

In a retrospective study of 29 treatments with porcine factor VIII in 18 patients with hemophilia A with inhibitors, the initial bolus administration of porcine factor VIII before continuous infusion caused bronchospasm in one patient [ ].

Nervous system A 71-year-old man with acquired hemophilia and high titers of antibodies to factor VIII developed a fatal thrombotic stroke while receiving porcine factor VIII [ ].

Hematologic

Porcine factor VIII, used for the treatment of patients with inhibitors of factor VIII, can cause thrombocytopenia, which is dose-related and occurs during intensive treatment for severe bleeding or surgery [ , ].

During continuous infusion of porcine factor VIII in patients with hemophilia A with inhibitors there is a smaller fall in platelet count and fewer other adverse effects and reactions than during the period after the initial bolus administration, as was shown in a retrospective study of 29 treatments with porcine factor VIII of 18 patients with hemophilia A with inhibitors [ ]. The authors attributed these differences to the dose of factor VIII and the rate of administration.