Von Willebrand disease type 1 (ORPHA:166078)
A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a partial, quantitative plasmatic deficiency of an otherwise structurally and functionally normal von Willebrand factor (VWF).
Epidemiology
The type 1 disease is considered to be the most common form of VWD, accounting for between 50-75% of cases but its prevalence is probably overestimated.
Clinical description
Age of onset of bleeding anomalies varies, with earlier onset and more severe symptoms being associated with more severe VWF deficiency. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (menorrhagia, epistaxis, or prolonged bleeding after trauma or a surgical intervention). Hematomas and hemarthrosis are very rare.
Etiology
VWD is caused by mutations in the VWF gene (12p13.3). The anomalies responsible for type 1 VWD generally lead to intracellular retention or rapid clearance of VWF from the circulation. However, families have been described in which no mutations in the VWF gene have been detected indicating that other genetic factors are also implicated. To date, the main additional factor associated with the disease is the ABO blood group, with levels of VWF in blood group O being 25-35% lower than in non-O blood groups.
Diagnostic methods
The presence of bleeding manifestations in the patient and in at least one family member is obligatory for diagnosis. Laboratory diagnosis relies on detection of parallel decreases in functional and VWF antigen levels to values below 40% of normal, in the absence of notable anomalies in the distribution or structure of the VWF multimers. Moderate deficiency of factor VIII (FVIII) may also be present.
Differential diagnosis
Given the variation in VWF levels (particularly among individuals with blood group O) and the occurrence of abnormal bleeding events in the general population, it may be difficult to differentiate between unaffected individuals and those with type 1 VWD. Evaluation of patients using the bleeding score and studies of family history are therefore essential for diagnosis. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic, especially if the type 1 VWD is secondary to an increased clearance. Measurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A.
Genetic counseling
Type 1 VWD is transmitted in an autosomal dominant manner. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks (some patients may be carriers for the most severe form type 3), and to allow screening for detection of other affected family members.
Management and treatment
Medication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone treatment for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. Desmopressin (which triggers a transitory release of endogenous VWF stored in the epithelial cells) may be administered in cases when a specific curative or preventative treatment is required. The response to desmopressin is usually good for patients with type 1 disease. Substitution therapy with purified human VWF constitutes an alternative treatment in case of major bleeding problems, for patients in which desmopressin is contraindicated, those with a poor response to desmopressin, or those in which tachyphylaxis occurs.
Prognosis
Type 1 VWD is generally not life-threatening and does not lead to functional VWF impairment.

                            Last update: 
                            November 2020


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