Development and introduction of recombinant factor VIII - a clinician’s experience

Abstract

In this review concerning the state of treatment for persons with haemophilia A leading up to the development and introduction of recombinant factor VIII products, and beyond, I vividly recall my own feelings at the time. When I began my fellowship training in paediatric haematology in the mid-1960s, we almost always had numerous boys in the hospital, receiving large volumes of fresh frozen plasma every 6–8 h for joint or large soft tissue haemorrhages. If they developed an inhibitor, there was little that we could do. A short time later, we were able to obtain cryoprecipitates, and then, by 1970, intermediate purity, lyophilized FVIII concentrates. These seemed wonderful, allowing out-patient treatment, and even surgical procedures! However, it soon became apparent that there was a price to be paid for the use of these plasmaderived products as most of our patients developed hepatitis, and by the early 1980s, AIDS. As a result, there were attempts to make the lyophilized, plasmaderived FVIII concentrates safer (improved donor screening, dry heat treatment, solvent-detergent treatment, pasteurization); however, by 1987, when recombinant FVIII concentrates became available for prelicensure clinical trials, there was genuine excitement! Excitement by me and most of my colleagues throughout the U.S. and abroad, and also a great deal of excitement by our patients, many of whom had affected family members or friends who had developed the acquired immunodeficiency syndrome (AIDS). In the 1950s and much of the 1960s, bleeding episodes in persons with haemophilia were treated with fresh frozen plasma (FFP), as no one had come up with a method for separating F VIII or F IX from plasma. Patients with bleeding episodes were frequently hospitalized for infusions of large volumes of FFP given every 6–8 h in an attempt to stop bleeding without pushing them into congestive heart failure from fluid overload. A major breakthrough came in 1965, when Dr. Judith Poole described a simple way of separating FVIII (and vWF) from plasma which had been frozen and then thawed in the cold [1]. Almost overnight, cryoprecipitates (cold insoluble precipitates) were being produced by blood collection facilities, for treatment of persons with haemophilia A. These cryoprecipitates had to be stored in the frozen state prior to use, and varied in the amount of FVIII contained. A short time later, two pharmaceutical companies had developed technologies to separate FVIII (and FIX) from large pools of donor plasma, resulting in freeze-dried, lyophilized FVIII concentrates [2]. These early, intermediate purity FVIII concentrates were easier to use, as they did not need to be frozen for storage, and each bottle was labelled with the amount of FVIII contained. However, neither cryoprecipitates or these intermediate purity plasmaderived concentrates were treated for blood-borne viruses. Once these lyophilized concentrates became available, treatment for bleeding episodes was much easier, haemostatic levels of FVIII could easily be achieved and, in the early 1970s, home treatment programs sprung up. The latter resulted in earlier treatment of joint bleeds, and a greater feeling of independence for those with haemophilia. Many referred to this period as the ‘golden age’ for haemophilia. However, this feeling was short-lived, as in 1981 the Communicable Disease Center (CDC) described the first three persons with haemophilia A who developed the acquired immunodeficiency syndrome (AIDS), and these three were followed by more and more individuals with haemophilia, many of whom died of its complications [3–5]. In addition, it had become increasingly apparent that many persons with haemophilia had been infected with hepatitis viruses [5] (hepatitis B and socalled, ‘non-A, non-B’ hepatitis, subsequently called hepatitis C after the HCV was identified). These serious complications of treatment resulted in increased efforts to make treatment safer. Lyophilized, intermediate purity concentrates were treated with dry heat [5]. Cryoprecipitates were no longer recommended for treatment of haemophilia A, being considered less safe than heat-treated products [6]. In 1981 Haemate P, a pasteurized FVIII and vWF concentrate became available in Germany. Predominantly used in Europe, this product was the first effectively virus-inactivated FVIII product [7]. Shortly thereafter, other products of Haemophilia (2012), 18, 483–486 DOI: 10.1111/j.1365-2516.2012.02804.x