Knowledge on rare diseases and orphan drugs

The type 3 disease is the rarest form of VWD, accounting for less than 5% of all cases. The average prevalence in Europe and the USA is approximately 1/500,000; however, the prevalence worldwide, including within Europe, can vary depending on the country of origin and the level of consanguinity, and can be as frequent as 1/200,000.

Onset usually occurs during the neonatal period or in infancy, but later onset has been reported. The bleeding anomalies are mainly characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, postpartum hemorrhage, gastrointestinal bleeding etc.) and prolonged bleeding after surgical interventions. As in hemophilia patients, hematomas and hemarthrosis may occur in individuals with type 3 VWD due to the severe FVIII deficiency. Cerebral hemorrhage has also been reported.

The disease is caused by homozygous or compound heterozygous mutations (mainly missense or large mutations) in the VWF gene (12p13.3) that lead to synthesis of a truncated protein or allele silencing.

Diagnosis is straightforward and is based on the absence of detectable VWF measured by all available methods (including functional and immunologic assays and agarose gel electrophoresis), accompanied by a secondary FVIII deficiency with a decrease to between 1 and 10% of normal levels.

Measurements of VWF levels generally allow VWD type 3 to be distinguished from moderate hemophilia A. Type 3 VWD is also generally easy to distinguish from other hereditary forms of VWD.

In at risk pregnancies, when the pathogenic variants have been previously identified in a family member, the identification of underlying VWF mutations may be used for prenatal diagnosis.

The pattern of inheritance is autosomal recessive. Genetic counseling should be recommended for at risk couples (where both parents are unaffected carriers) informing them that the risk of having an affected child is 25% for each pregnancy.

Patients with type 3 VWD do not respond to desmopressin and therefore substitution therapy with purified human VWF associated, at least for the first injection, with FVIII is the principle preventative or curative treatment. Long-term prophylactic treatment with regular injections of purified human VWF may be required for patients with recurrent bleeding events. Some patients (5-10 % of cases) develop alloantibodies against VWF rendering the substitution treatment ineffective; the formation of immune complexes is sometimes associated with an anaphylactic response. In these cases, alternative treatments, such as continuous infusion of recombinant factor VIII or recombinant activated factor VII, should be considered. There are some preliminary reports of use of emicizumab in allo-immunized type 3 patients.

Type 3 VWD is the most severe form of VWD and, in the absence of appropriate management in specialized hemostasis hospital centers, the manifestations can be life-threatening and lead to functional impairment.

Last update: January 2021 - Expert reviewer(s): Pr Sophie SUSEN