Review Series INHERITED BLEEDING DISORDERS Diagnostic approach to von Willebrand disease

von Willebrand disease (VWD) is one of the most common inherited bleeding disorders, with a prevalence of symptomatic disease of;1 in 10 000. Given the complexity of the disease, the ability to accurately and appropriately diagnose individuals with VWD continues to be an important and much discussed topic of interest. In this review, we highlight the current status of clinical testing and diagnostic classifications that are useful to the clinician while also underscoring the current limitations of the existing tests. VWD, first described by Erik von Willebrand in a Scandinavian family, is characterized by abnormal quantity or quality of von Willebrand factor (VWF), a large glycoprotein synthesized by megakaryocytes and endothelial cells and released into the circulation through a constitutive pathway and also upon stimulation. VWF is the product of the VWF gene (VWF) on the short arm of chromosome 12 and is highly conserved across multiple species. The mature released molecule is 2050-aa long; in the intracellular space, it also has a 741-aa propeptide that is synthesized, cleaved, and released in equimolar concentrations with the VWFmonomer making it a useful marker for VWF clearance. The VWF monomer has multiple domains that deliver its unique hemostatic abilities, including the localization of platelet-binding sites in the A1, C1, and C2 domains, collagen binding in the A1 and A3 domains, and a FVIII-binding site in the D9, D3 domains. VWF has a remarkable ability tomultimerize via disulfide bonds at cysteine residues allowing for a range of VWF complexes that span from protomers (dimers) to multimers that contain.40 subunits (Figure 1). The highmolecular-weight multimers are the most effective forms of VWF at mediating platelet adhesion at sites of vascular injury. The biologic modulator of VWF is ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif), which can cleave VWF in the A2 domain when the VWF complexes are unraveled under shear conditions. The cleavage of ultra-large-molecular-weight multimers leads to production of smaller, lower-molecular-weight multimers that are inherently less hemostatically active. VWD is traditionally classified into type 1 and type 3, which describe mild to moderate and severe quantitative deficiencies of VWF, respectively, and type 2,which is characterized by qualitative deficits in VWF. The prevalence of VWD in published studies ranges from 1 in 100 to 1 in 10 000 depending on the method used to identify patients, either by population screening of persons at risk or actual patients seen at medical centers; therefore, it is reasonable to infer that the prevalence of individuals with clinically significant bleeding is likely in the range of 1:10 000.VWDaffects individuals of all ethnic backgrounds, and the clinical symptoms can present at any age. A large number of patients with VWD inherit the disease according to classic Mendelian genetics. Although VWD type 1 and 2 are generally inherited in an autosomal-dominant pattern, VWD type 3 is inherited in an autosomal-recessive pattern. Interestingly, not all individuals that have mutations in VWF exhibit clinical symptoms (a phenomenon known as incomplete penetrance), and although there is often a significant family history of bleeding associated with the diagnosis of VWD, many family members with low VWF levels may exhibit a range of bleeding symptoms (known as variable expressivity). Additionally, because mild bleeding is common in the general population and many individuals will have low to borderline levels of VWF, the association of these 2 traits may occur by chance in many occasions. The ability to identify a causative mutation in patients with VWD, particularly with type 1, is sometimes difficult. There are many patients, particularly with VWD type 1, for whom there is no causative mutation identified and geneticmodifiers outside of theVWF genemay play significant roles in themodulation of VWF quantity, function, and multimer status. Therefore, a significant number of patients diagnosed withVWDtype1mayhaveacomplexgeneticdisorder inwhich.1gene coupledwith environmental stressors is responsible for the phenotype.