Factor VIII, Small Active Factor VIII Fragments, and von Willebrand Factor

Abstract

Factor VIII activity of human, canine, and bovine preparations is associated with a molecule of high molecular weight. These preparations dissociate almost completely in 0.25 M Ca2+, yielding a small active fragment with factor VIII activity, and a high molecular weight fraction (carrier protein) with almost no factor VIII activity. With Ca2+ absent, the small active fragment recombines with the carrier protein to form a large protein with factor VIII activity. Mixtures of normal human small active fragment with human hemophilic carrier protein give normal recombination. Comparable experiments with human von Willebrand and canine “carrier protein fractions” show no recombination. The data suggest a working model of a small active fragment(s) linked by noncovalent bonds to a carrier molecule, comprised of repeating subunits, deficient in von Willebrand’s disease.Thrombin increases the activity of factor VIII preparations or the small active fragment obtained by Ca2+ dissociation. When a factor VIII preparation is treated with thrombin and subjected to gel chromatography or ultracentrifugation, the factor VIII activity appears to be associated with a small molecule. Factor VIII activity of this small molecule is not enhanced by thrombin. These and other data will be discussed.