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Von Willebrand disease type 3
A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a total or near-total absence of Willebrand factor (VWF) in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII (FVIII). It is the most severe form of VWD.
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 1/1,000,000 to 1/2,000,000 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, 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.
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. 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.