The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics.

Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM" status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for any HLA class-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire.

Inhibitors of factor VIII in black patients with hemophilia.

Background: Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date.

Products for clotting factor replacement in developing countries.

Developing countries provide clotting factor replacement for hemophilia patients using one or more of the following strategies. (1) Production of domestic plasma and cryoprecipitate provides some self-sufficiency but depends heavily on the presence of an excellent blood transfusion service. The risk of transmitting donor infections is not completely obviated even with good serologic testing.

Advances in care of children with hemophilia.

Care for children with severe hemophilia has moved from pediatric hospital wards and rehabilitation services to the home, school, and community. Advances in hemophilia are due largely to the development of specialized hemophilia treatment centers, which created a system of comprehensive care and focused healthcare efforts on prevention and education. Parallel advances in coagulation resulted in identification of clotting factors VIII and IX, elucidation of the protein molecular and biochemical structures and functions, sequencing of their respective genes and transfer of the human genes for production of proteins by recombinant technology, and development of gene therapy.