Von Willebrand's disease (vWd) is an hereditary disorder of hemostasis which is autosomally transmitted and is characterized by a reduction in Factor VIII coagulant activity (VIII:C), F.VIII-related antigen (VIIIR:Ag) and F.VIII-related Willebrand factor activity (VIIIR:WF). It differs from classic hemophilia A, the X-linked disorder expressed through F.VIII, in that while VIII:C is reduced in hemophilia A, VIIIR:Ag and VIIIR:WF are normal. Detection of the vWd heterozygote is difficult since many presumably heterozygous transmitters are phenotypically normal. Recently, multivariate procedures employing three to five variables have been developed which permit identificaion of transmitters with a low rate of misclassification. A preliminary study in one large vWd kindred using the multivariate procedure has suggested linkage of the vWd locus to the GPT (glutamic-pyruvic-transaminase) locus at 13 rec units with a lod score of 1.02. We propose to examine additional vWd kindred to see whether this relationship can be confirmed. If established, linkage of the vWd locus to this highly polymorphic marker will be very valuable in basic studies of F.VIII, in genetic studies of vWd kindred and in counseling members of such kindred. The recognition of an allotypic marker within the vWd locus would be even more useful than establishment of a linkage relationship. Such a marker will be sought using heteroantisera raised to purified F.VIII protein prepared from single donors. If there is polymorphism within the normal vWd locus it might well be uncovered.