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Von Willebrand disease type 3
Type 3 von Willebrand disease (type 3 VWD) is the most severe form of VWD (see this term) characterized by a bleeding disorder associated with a total or near-total absence of Willebrand factor (von Willebrand factor; VWF) in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII (FVIII).
ORPHA:166096Classification level: Subtype of disorder
- Synonym(s): -
- Prevalence: 1-9 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: D68.0
- OMIM: 277480
- UMLS: C1264041
- MeSH: D056729
- GARD: -
- MedDRA: -
The type 3 disease is the rarest form of VWD, accounting for less than 5% of all cases. Annual incidence varies between countries ranging from 1/2,000,000 to 1/350,000 in Europe and the USA and with estimates of around 1/500,000 in countries where consanguinity is more frequent.
Onset usually occurs during the neonatal period or in infancy. 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 (in case of consanguinity) or composite 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.
The differential diagnosis with acquired von Willebrand syndrome (AVWS; see this term) is straightforward due to early onset of the bleeding manifestations in the hereditary form and to differences in the laboratory findings (in AVWS, VWF antigen levels remain within detectable limits and residual multimers are visible on agarose gels). Type 3 VWD is also generally easy to distinguish from other hereditary forms of VWD.
Prenatal diagnosis may be offered for future pregnancies to parents who already have a child with type 3 VWD or to consanguineous couples with a family history of VWD. This diagnosis is best managed in a specialized multidisciplinary centre and is more straightforward if the disease-causing mutations in the family have already been identified.
Transmission is autosomal recessive. Genetic counseling is essential for providing information on the risks associated with the disease and management strategies, and should also lead to identification of relatives who are carriers of the disease-causing mutation.
Management and treatment
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. Some patients (7.5-9.5% of cases) develop alloantibodies against VWF rendering the substitution treatment ineffective and resulting in an anaphylactic response associated with the formation of immune complexes. In these cases, alternative treatments, such as continuous infusion of recombinant factor VIII or recombinant activated factor VII, should be considered. Long-term prophylactic treatment with regular injections of purified human VWF may be required for patients with recurrent bleeding events.
Type 3 VWD is the most severe form of VWD and in the absence of appropriate management in specialized hemostasis and thrombosis hospital centers the manifestations can be life-threatening and lead to functional impairment.