Von Willebrand disease type 2 (ORPHA:166081)
A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a qualitative deficiency and functional anomalies of the Willebrand factor (VWF). Depending on the type of functional abnormalities, this form is classified as type 2A, 2B, 2M or 2N.
Epidemiology
The subtypes of type 2 VWD account for between 20-45% of cases of VWD; the prevalence wordwide is estimated at 1/107,000.
Clinical description
Age of onset of the bleeding anomalies varies, with earlier onset being associated with more severe VWF deficiency. Four type 2 VWD subtypes have been described: types 2A, 2B and 2M are characterized by mucocutaneous manifestations (menorrhagia, epistaxis, gastrointestinal hemorrhage etc.); type 2N is mainly characterized by post traumatic soft tissue bleedings. There is an increased risk of abnormal bleeding following an invasive procedure associated with all type 2 subtypes.
Etiology
The VWF gene (12p13.3) anomalies that lead to type 2 VWD involve the well-defined functional domains of the VWF protein. Three of these subtypes are associated with anomalies in the interaction of VWF with platelets and/or the subendothelium, and are caused by decreased affinity for platelets in combination with VWF multimerization anomalies (type 2A), increased VWF affinity for platelets (type 2B), or decreased VWF affinity for platelets or collagen and normal VWF multimerization (type 2M). The fourth subtype (type 2N) is associated with decreased VWF affinity for factor VIII (FVIII); the interactions between the platelets and the vessel walls are often normal and the FVIII deficiency is usually only moderate.
Diagnostic methods
For subtypes 2A, 2B and 2M, diagnosis is suspected following detection of a notably more profound decrease in functional VWF levels than in VWF antigen levels. This discrepancy between the functional VWF levels and VWF antigen levels also allows the type 2 disease to be distinguished from VWD type 1. However, more specific laboratory tests (analysis of the structure and distribution of the multimers) are required to diagnose the exact type 2 subtype. A thrombocytopenia can be observed in type 2B. Diagnosis of type 2N is suspected when the decrease in FVIII levels is much greater than that of VWF, and confirmed by a factor VIII binding assay.
Differential diagnosis
Subtypes 2A, 2B and 2M can be differentiated from acquired von Willebrand syndrome (AVWS), clinically by the onset of bleeding manifestations at a young age, a family history of the disease and the absence of an underlying pathology, and through molecular analysis revealing a mutation in the VWF gene. The factor VIII binding assay, together with molecular analysis of the VWF gene, allows type 2N VWD to be distinguished from mild hemophilia A.
Genetic counseling
Most subtypes of type 2 VWD are transmitted in an autosomal dominant manner except for type 2N and some rare forms of type 2A which are autosomal recessive. 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. In case of recessive transmission where both parents are carriers of the disease-causing mutation, the at-risk couple should be informed that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Medication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone therapy for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. The response to desmopressin varies depending on the type 2 subtype, as the endogenous VWF released from the endothelial cells in response to this treatment displays the same functional anomalies as plasmatic VWF. Desmopressin is contraindicated in patients with subtype 2B. Preventative or curative treatment for abnormal bleeding events often involves substitution therapy with purified human VWF. Platelet concentrates may have to be transfused in some patients with type 2B.
Prognosis
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: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN