in Three Generations of Women

A bleeding diathesis is described which is phenotypically indistinguishable from hemophilia A and which has been trans- mitted as a dominant trait in three gen- erations of women in a North Carolina kindred. The abnormal phenotype is char- acterized by clinical mildness and slightly abnormal clotting time, prothrombin con- sumption, and partial thromboplastin time. Bleeding time, platelet count, clot retraction, tourniquet test, and prothrom- bin time are normal. Concentrations of factors I, II, V, VII, IX, X, and XII are nor- mal, while factor VIII activity is reduced to 2%-5% of control values. Dc nova synthesis of factor VIII does not occur after transfusion; factor VIll-related antigen is normal; patients' plasmas aggregate platelets normally in the presence of nsto- cetin, and a typical protein pattern is seen when a chymotryptic digest of cryo- precipitate of the prebend is examined by SDS-polyacrylamide gel electrophoresis. Six possible genetic explanations are entertained. Balanced X-autosomal trans- location of hemophilia A heterozygotes has been excluded by cytogenetic analysis of metaphase chromosomes. Classic von Willebrand's disease (vWd) is probably excluded on the basis of the laboratory data, and extreme lyonization of hemo- philia A heterozygotes on probabilistic grounds. The genetic possibilities which cannot be excluded include a previously unrecognized variant mutation at the vWd locus, a dominant mutation at the hemo- philia A locus on the X chromosome, and dominant mutation at a hypothetical fourth locus involved in factor VIII syn- thesis and control. genetic control of blood coagulation factor VIII is very complex. Popula- tion geneticists have shown that the distribution of plasma factor VIII levels within the normal population is consistent with the activity of a polygenic sys- tem and that the levels within and between members of hemophilia A families are consistent with the existence of multiple alleles at the hemophilia locus on the X chromosome. Family studies have shown that coagulant factor VIII activity is reduced in some kindred as a result of mutation at a locus on an autosomal chromosome (von Willebrand's disease), conclusive genetic evidence that at least two loci are involved. The existence of persons having a combined defect of factors V and VIII, a phenotype radically different from all others, limited to a single sibship and apparently inherited as an autosomal recessive trait, implies that at least a third locus is involved in the control of factor VIII. Barrow and Graham have emphasized that the genetic situation is probably