Von Willebrand disease

Von Willebrand disease (vWD) is the most common inherited bleeding disorder. The prevalence of symptomatic vWD is approximately 0.01%. Identification of milder forms is complicated by the broad range of von Willebrand factor (vWF) levels in the normal population; it is important to recognize that the diagnosis of vWD requires the presence of bleeding symptoms (see Fig 37.1).

All vWD is caused by mutations in the gene for vWF. vWF is an adhesive glycoprotein secreted by endothelium and megakaryocytes (see also p. 12). It is a multimeric protein with a characteristic normal distribution of multimer sizes in plasma. vWF has two key functions: promotion of platelet adhesion to damaged endothelium and other platelets (Fig 37.2) and the transport and stabilisation of factor VIII. Thus, the clinical disorder of vWD is associated with excessive bleeding due to abnormal platelet function and low factor VIII activity. The relationship between the risk of bleeding and vWF level is not strong until the level is very low. The clinical and laboratory heterogeneity of vWD necessitates the definition of several subtypes.

Classification (Table 37.1 and Fig 37.3)

The current classification of vWD depends on electrophoretic analysis of vWF multimers. In type 1 vWD, the multimers appear to be normal in structure and function but decreased in concentration. In type 2 vWD there is a qualitative deficiency of vWF divisible into four subtypes. In type 2A there is an absence of high molecular weight vWF multimers and markedly reduced vWF binding to platelets. 2B refers to a variant where defective platelet adhesion results, paradoxically, from increased binding of vWF to platelets. In 2M there is decreased platelet-dependent vWF function despite a relatively normal multimer pattern while 2N is characterised by failure of vWF to bind factor VIII. In the rare type 3 form, there is an almost complete deficiency of vWF and the factor VIII level is markedly decreased.