Knowledge on rare diseases and orphan drugs

The prevalence of Von Willebrand disease (VWD) in the general population is estimated at between 0.6 and 1.3% (including all forms) depending on the study, but the prevalence of symptomatic VWD that requires specific treatment is approximately 1/10 000. Type 3 VWD is much more rare (1/1 000 000).

Age of onset varies, with earlier onset being associated with more severe VWF deficiency. The disease manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, bleeding from minor wounds, etc.) but hematomas and hemarthrosis may occur in more severe forms.

VWD is caused by mutations in the VWF gene (12p13.3) encoding the multimeric VWF protein. The VWF protein has an intraplatelet, endothelial and plasmatic localization and plays essential roles both in the interaction of platelets with the injured vessel wall and in the transport and stabilization of factor VIII (FVIII).

Diagnosis relies on laboratory tests involving functional and immunological assays of VWF and FVIII levels. Determination of the type of VWD requires other specific tests such as studies of the distribution of VWF multimers.

Measurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A. However, these tests do not allow differentiation of type 2N VWD, which requires more specific assays. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic. The fact that individuals in the general population belonging to blood group O may also have moderately lower levels of VWF should also be taken into consideration in the differential diagnosis.

In at risk pregnancies, the identification of underlying VWF mutations may be used for prenatal diagnosis of type 3 VWD.

VWD is most often transmitted in an autosomal dominant manner, however, the mode of inheritance is autosomal recessive for type 3 VWD and for some of the type 2 subtypes. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. For couples at risk of having a child with type 3 disease, genetic counseling may be best discussed in a specialized multidisciplinary center.

Management depends on the type of VWD. Desmopressin is generally an effective preventative or curative treatment for abnormal bleeding in type 1 VWD. In patients with type 2 disease, the response to desmopressin is variable and substitution therapy with purified human VWF is often required. Desmopressin does not constitute an effective treatment for patients with type 3 disease, and thus these individuals require substitution therapy with purified human VWF associated, at least for the first injection, with FVIII.

For patients managed within specialized hemostasis hospital centers, the prognosis is favorable, even for those with the most severe forms of the disease.

Last update: November 2020 - Expert reviewer(s): Pr Sophie SUSEN