Hemophilia and von Willebrand's disease: genetic considerations

Recent progress in the biochemical characterization of coagulation factors VIII and IX has greatly contributed to our understanding of the inheritance of hemophilia and von Willebrand's disease and facilitated the recognition of carriers of these disorders. Factor VIII is a molecular complex which may be quantitated immunologically as factor VIII-related antigen. Within this complex reside the von Willebrand factor, absent in von Willebrand's disease, and factor VIII procoagulant activity and antigen. Hemophilia is an x-linked disorder; female carriers may be recognized by a disproportionate increase in factor VIII-related antigen or procoagulant antigens in relation to procoagulant activity. Prenatal diagnosis of hemophilia has been accomplished by measurements of clotting activity and antigens in fetal blood. Von Willebrand's disease has been classified on the basis of laboratory abnormalities, the biochemical characteristics of the von Willebrand factor, and its patterns of inheritance. In the most commonly observed form, there is autosomal dominant inheritance, and most patients are heterozygotes. These individuals manifest variably prolonged bleeding times and concordantly reduced activities associated with factor VIII. Rarely, there is an autosomal recessive pattern in which the homozygotes have much more severe clinical disease, including hemathroses. However, the biochemical defects in the von Willebrand factor appear to be quite diverse, defying any simple classification of this disorder.