Choice of replacement therapy for hemophilia

Abstract

Dear Sir, In the February issue of the Journal, Giangrande and Mannucci ostensibly take opposite sides on the following subject: ‘Recombinant factors only? Yes or no?’[1, 2]. In a careful reading of their contributions, it is interesting to note that both prefer to use recombinant products for their patients, but both also believe that plasma-derived products should continue to be produced. Giangrande makes the argument that if physicians in developed countries use recombinant clotting-factor concentrates then plasma-derived products might well become cheaper and made available to patients in developing or underdeveloped countries. Mannucci makes the same argument in a slightly different fashion. He points out that since the developing world cannot afford recombinant products, plasma-derived products should be available for the treatment of hemophilic patients in undeveloped areas of the world. I have long been persuaded that the best choice for treatment of hemophilic patients is recombinant products. This preference is based largely on the belief that clotting factor concentrates prepared by recombinant technology are probably safer than plasma-derived products because they are manufactured under more controlled conditions and are not reliant on donor plasma from several thousand individuals. Both Mannucci and Giangrande imply that there is always the possibility that as yet unknown transmissible agents may contaminate the blood supply and not be inactivated by current technology. This is probably the legacy of the AIDS crisis when the hemophilic population was exposed to a transmissible agent that resulted in an incurable disease with exceedingly high morbidity and mortality. None of us wishes to see a repeat of such a colossal tragedy, and, for this reason, many of us are sensitized to the possibility, no matter how small, of an AIDS-like tragedy in the future. Even though many physicians, including myself, prefer recombinant clotting-factor concentrates for the treatment of patients with hemophilia, rigid dogmatism that insists upon the sole use of recombinant products may be very unwise since dogmatism precludes a rational approach to future choice of therapy for hemophilic patients. Some potential developments in plasma fractionation that offer increased yields of cryoprecipitate and factor (F)VIII from plasma is promising, especially since some might be adaptable to local blood bank technology. Dr Ed Shanbrom and his colleagues have recently described a method for obtaining ‘supercryo’[3]. He has found that the yield of cryoprecipitate and FVIII can be increased to approximately 100% by increasing the citrate concentration of the starting plasma. More than that, the FVIII can be easily extracted from the cryoprecipitate, leaving most of the fibrinogen and von Willebrand factor to be used as a source of fibrin glue. Moreover, it seems feasible that an iodine column developed by his group to remove infectious agents might also be adaptable for use in local blood banks to remove infectious particles from FVIII preparations. If such procedures are confirmed, they may permit the accessibility of FVIII concentrates in those parts of the world that cannot afford recombinant products. It is also interesting that an economic model sponsored by Baxter Bioscience but developed independently by Evans and colleagues suggests that plasma-derived FVIII and IX concentrates may, in the long run, be economically feasible and safer than currently available cryoprecipitate fractions [4]. The model is ‘evidenced based’ and predicts that ‘screened’ cryoprecipitate could be contaminated by infectious agents not detectable in the window period by currently available screening techniques, including hepatitis viruses, HIV, and other infectious agents. Thus, the patients exposed over a lifetime to screened cryoprecipitate could be infected by such agents. The debate on the source of clotting-factor concentrates for the treatment of hemophilia, highlighted by Giangrande and Mannucci, emphasizes the need to make safe and effective clotting factor concentrates available to all hemophilia patients, whatever their geographic location or economic status.