In Vivo Characterization of Recombinant Factor VIII in a Canine Model of Hemophilia A (Factor VIII Deficiency)

• Published in: Blood 1988-07, Vol.72 (1), p.335-339
• Main Authors: Giles, Alan R., Tinlin, Shawn, Hoogendoorn, Hugh, Fournel, Michael A., Ng, Paul, Pancham, Nazreen
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Disease Models, Animal; Dogs; Factor VIII - administration & dosage; Factor VIII - metabolism; Factor VIII - physiology; Half-Life; Hematologic and hematopoietic diseases; Hemophilia A - blood; Hemophilia A - therapy; Macromolecular Substances; Medical sciences; Platelet diseases and coagulopathies; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Recombinant Proteins - physiology; von Willebrand Factor - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V72.1.335.335

Infusion studies of recombinant factor VIII were performed in hemophilic (factor Vlll-deficient) animals. Functional activity was determined using a standardized model of bleeding and kinetic characteristics charted by performing assays of factor VIII functional and antigenic activities over time. To obtain an adequate comparison with plasma-derived factor VIII, a crossover study in two animals was performed in which each animal received either recombinant factor VIII or a highly purified plasma-derived factor VIII on day 1 and the alternative three days later (day 4). Both factor VIII preparations were functionally effective with complete correction of the cuticle bleeding time occurring one hour after infusion. The observed recovery was full and close to predicted for both preparations. The survival curves obtained for both functional and antigenic activities for both preparations were virtually identical and within the anticipated range determined from previous experiments using infusions of conventional factor VIII preparations. The plasma half-disappearance time (T ½) for recombinant factor VIII and plasma-derived factor VIII was 9.2 and 7.9 hours, respectively. Plasma samples obtained following infusion were subjected to chromatography on Sepharose 4B. The elution profile of factor VIII antigen activity was compared with that obtained with the infusates. A clear shift in profile was observed with the plasma samples, suggesting complexing of the infused factor VIII material with circulating canine von Willebrand factor (vWF). The elution profile of vWF antigen was superimposable, thus providing further evidence in support of this assumption. The study provided evidence that recombinant factor VIII possesses full functional activity in vivo, binds to circulating vWF, and exhibits normal recovery and survival characteristics.