What have we learned from large population studies of von Willebrand disease?

Von Willebrand factor (VWF) is a critical regulator of hemostatic processes, including collagen binding, platelet adhesion, and platelet aggregation. It also serves as a carrier protein to normalize plasma factor VIII synthesis, release, and survival. While VWF protein measurements by immunoassay are reasonably comparable between institutions, the measurement of VWF ristocetin cofactor activity (VWF:RCo) has significant variability. Other tests of VWF function, including collagen binding or platelet glycoprotein IIb-IIIa binding, are not universally available, yet these functional defects may cause major bleeding even with normal VWF antigen (VWF:Ag) and VWF:RCo assays. This results in both the overdiagnosis and underdiagnosis of VWD. Newer assays of VWF function (using recombinant glycoprotein Ib rather than whole platelets) have been developed that may improve interlaboratory variability. Some of these tests are not uniformly available and may not be licensed in the United States. Large longitudinal studies of VWF in von Willebrand disease (VWD) patients are not available. Patients are sometimes diagnosed with a single diagnostic VWF panel. Plasma VWF levels increase with age, but it is not clear if this results in less bleeding or whether different normal ranges should be used to identify age-related decreases in VWF. In order to quantitatively compare bleeding symptoms in VWD patients and normal individuals, recent studies in the European Union, Canada, United Kingdom, Holland, and the United States have used semiquantitative bleeding assessment tools (BATs). Even with careful centralized testing, including functional assays of VWF, addition of a BAT does not solve all of the problems with VWD diagnosis. No matter where the line is drawn for diagnosis of VWD, VWF is still a continuous variable. Thus, VWD can be a severe hemorrhagic disease requiring frequent treatment or a mild condition that may not be clinically relevant. As will be discussed by Dr. Goodeve in her presentation, genetics has helped us to diagnose type 2 functional variants of VWD but has not been helpful for the many patients who are at the interface of normal and low VWF and carry the possible diagnosis of type 1 VWD. The hematologist’s management of patients with reduced levels of VWF still requires both the art and science of clinical medicine.