Studies of the Antihemophilic Factor (AHF,Factor VIII) Produced in von Willebrand's Disease. ∗

Abstract

In 1959 one of us pointed out that the apparent dependence of plasma antihemophilic factor (AHF, F. VIII) level on the activity of 2 genetic loci must have significance with respect to AHF synthesis(l). At that time only structural genes were generally considered operative in protein synthesis. This coupled with the widespread acceptance of the “one gene—one enzyme” concept impeded consideration of models for AHF synthesis involving 2 loci. Since then it has become apparent that both structural and regulatory genes function in bacteria(2) and that 2, non-allelic structural genes are sometimes involved in protein synthesis in mammals, e.g., hemoglobin in humans.

It has been found experimentally that the 2 mutant phenotypes showing reduced plasma AHF levels, hemophilia A and von Willebrand's disease (v.W.d.), do not “complement” in vitro as do hemophilias A and B, for example. This is in fact the basis for the assertion that AHF is “deficient” in v.W.d. A paradoxical type of “complementation” does occur in vivo, however. Plasma from persons with autosomal von Willebrand's disease is ineffective when transfused into persons having X-linked hemophilia A(3), but the reciprocal transfusion has a striking effect. When plasma from a person with X-linked hemophilia A and low AHF is transfused into a person with v.W.d. with low plasma AHF, large amounts of AHF appear in the blood (4). The quantity of AHF appearing is so large that it has been interpreted as new synthesis, and the observation has been confirmed in several laboratories (5,6). This finding has led to a considerable elaboration of the possible models of AHF synthesis. The locus on the X-chromosome has been suggested as a structural locus coding for the peptide sequence of AHF, while the locus on the (as yet unidentified) autosomal chromosome has been suggested as regulatory(7,8).