In the first 20 years of the third millennium, hemophilia therapy has advanced remarkably, although the innovation started with the 1946 description of plasma fractionation. The earliest attempts at replacement therapy were made in the early 1960s after the finding of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant. People with hemophilia (PWH) received concentrates infected by hepatitis A, hepatitis C, and human immunodeficiency virus as these concentrates were manufactured from enormous industrial pools of plasma collected from hundreds of donors, but there were no screening measures for viral infections. The issue of the immunogenicity of exogenously delivered concentrates still has to be fully resolved. The most serious side effect of replacement therapy is the formation of alloantibodies against FVIII in around 25–35 % of PWH. The cloning of the F8 and then F9 genes, which opened the possibility for the production of factor concentrates produced using recombinant DNA technology, was the next significant development.
