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.

There is correlation between the subtype and the mode of inheritance. Type 1 vWD is the most common form of the disease (80% of cases) and inheritance is often autosomal dominant. Type 2 vWD (15% of cases) may be dominant or recessive and the type 3 variant is recessive. Because inherited deficiencies of vWF function are common the accidental co-inheritance of otherwise recessive vWD alleles may occur (‘compound heterozygosity’). There is currently no genotypic classification of vWD. More than 250 mutations of all types have been identified. These include large and small deletions, nonsense and missense mutations and splicing abnormalities.

Clinical features

Severe vWD is characterised by spontaneous bleeding, particularly epistaxes, gum bleeding and menorrhagia. Easy bruising is also common but (with the exception of type 3) haemarthroses and muscle haematomas are rare. Milder disease often presents with excessive bleeding following trauma or surgical procedures and the diagnosis can easily be missed. A thorough history is crucial and must include assessment of the severity of recent bleeding, the existence of previous bleeding problems (particularly after surgery, dental extractions and childbirth) and the presence of a family history of easy bleeding. A standard questionnaire can be used to generate a quantitative ‘bleeding score’. Death from bleeding is rare but it may follow massive gastrointestinal haemorrhage.

Other inherited coagulation disorders