Von Willebrand's disease and the molecular pathology of hemostasis
Blood Coagulation Factors
von Willebrand Diseases
von Willebrand Factor
Over 50 yr ago, Eric von Willebrand (Finsk Lakaresallsk Handl. 1926, 68, 87) described a severe hereditary bleeding disorder in an Åland Island family. The abnormality, which he referred to as 'pseudo hemophilia', was characterized by a prolonged bleeding time and was associated with an autosomal inheritance pattern. About 25 yr later, the hemostatic defect was described: reduced factor VIII procoagulant activity (antihemophilic factor) and a prolonged bleeding time. In factor VIII, 3 functionally distinct components have been recognized: a clot-promoting activity that corrects the coagulation abnormality of plasma from a patient with classic hemophilia A; an antigen that is generally detected in precipitin assays by heterologous antiserums and decreased in the plasma of patients with von Willebrand's disease but normal in hemophilia; and von Willebrand factor, an activity synthesized by endothelial cells, that corrects a platelet-function defect in von Willebrand's disease. In classic severe von Willebrand's disease, all 3 components are proportionally decreased, but variant forms have been recognized with increasing frequency. In this issue of the Journal, 5 patients are reported who had combined quantitative and qualitative protein abnormalities. It is not clear what the primary protein abnormality is in these patients. It appears that the molecular diseases of hemostasis involving the factor VIII system may well resemble the hemoglobinopathies. At least some of the forms of von Willebrand's disease will turn out to be a consequence of an autosomal gene mutation that leads to endothelial-cell synthesis of a structurally compromised factor VIII molecule. However, the possibility should also be considered that the impaired von Willebrand factor in some patients represents a 'monoclonal' hypertrophy of a normal minor subpopulation of molecules found ordinarily within the heterogeneous multimeric forms of factor VIII protein in normal plasma.