Von Willebrand Disease (vWD)

Definition, Etiology, PathogenesisTop

Von Willebrand disease (vWD) is the most frequent inherited bleeding disorder. It is caused by a deficiency or dysfunction of von Willebrand factor (vWF), which affects both primary and secondary hemostasis (vWF is a cofactor in the adhesion of platelets to the exposed subendothelium and protects factor VIII from inactivation).

Classification:

1) Type 1 vWD (65%-75% of patients): Partial quantitative vWF deficiency with preserved function (plasma levels of antigen and activity are similar). The level of factor VIII is normal or decreased.

2) Type 2 vWD (20%-25% of patients): vWF dysfunction (depending on type of dysfunction, this is classified as subtype 2A, 2B, 2M, or 2N), which causes a reduction in vWF activity that is disproportionate to the decrease in its concentrations. The level of factor VIII is normal (2A, 2B, 2M) or decreased (2N).

3) Type 3 (severe) vWD: Undetectable activity of vWF with the factor VIII level usually <10% of normal.

Clinical FeaturesTop

Mucocutaneous bleeding (recurrent epistaxis and gingival bleeding, easy bruising, heavy and prolonged menstrual bleeding); hemorrhages after tooth extraction and surgical procedures; gastrointestinal bleeding (all types); bleeding into joints (hemarthrosis) and muscles almost exclusively in patients with type 3 vWD (this may cause arthropathy). Types 1 and 2 are mostly due to autosomal dominant gene defects, with many family members affected and a variable clinical phenotype.

DiagnosisTop

Diagnostic Tests

1. Screening tests: Prothrombin time (PT)/international normalized ratio (INR) and thrombin time (TT) are normal. Activated partial thromboplastin time (aPTT) may be prolonged and it corrects at mixing studies. Bleeding time and platelet function analyzer (PFA)-100 closure time are always prolonged in patients with type 3 vWD and may be prolonged or normal in patients with type 1 or type 2 vWD. The platelet count is normal, except for type 2B vWD, which may rarely cause intermittent thrombocytopenia during stress conditions or after desmopressin administration.

2. Studies confirming the diagnosis: The diagnosis of vWD is confirmed if the vWF activity is <30 IU/dL (<30%), regardless of the presence of bleeding. In the range of 30 to 50 IU/dL (30%-50%), the presence of bleeding is required for the diagnosis of vWD. An activity-to-antigen ratio ≥0.7 suggests type 1 vWD while <0.7 indicates type 2 vWD. The activity of factor VIII is decreased or normal.

3. Specialized studies: Specialized testing, including genetic analyses and analysis of the multimeric composition, are available and should be interpreted by experts, as the laboratory findings in vWD are pleomorphic.

Diagnostic Criteria

Diagnosis is made on the basis of the laboratory tests (see above). The types and subtypes of vWD are confirmed by specialized studies. Laboratory confirmation of mild vWD is fraught with controversy; many patients with a mild bleeding disorder phenotype are misdiagnosed with vWD based on inappropriate laboratory testing.

Differential Diagnosis

Hemophilia A (particularly the mild variant), acquired von Willebrand syndrome (most frequently occurring in the course of autoimmune diseases, valvular heart disease, lymphoid neoplasms, monoclonal gammopathies, polycythemia vera, or essential thrombocytosis), platelet-type (pseudo-) vWD (inherited abnormalities of the glycoprotein Ib platelet receptor causing its increased affinity to vWF, leading to thrombocytopenia and bleeding), platelet function disorders.

TreatmentTop

General Measures

1. Do not use antiplatelet agents; in particular, do not use acetylsalicylic acid (exceptions as in hemophilia A and hemophilia B).

2. Avoid intramuscular injections.

3. Major surgical procedures and treatment of severe bleeding should be performed, if possible, in a hospital capable of 24-hour measurements of vWF and factor VIII activity.

Pharmacotherapy in Case of Bleeding or Surgery

1. Desmopressin: A 30 minute IV infusion of 0.3 mg/kg every 12 to 24 hours. Desmopressin is the drug of choice in patients with type 1 vWD. It is also effective in some patients with type 2 vWD; however, in patients with type 2B disease it may rarely cause thrombocytopenia, and in most patients with type 3 vWD it is ineffective. Desmopressin causes a 2- to 5-fold increase in plasma vWF and factor VIII activity by releasing them from tissue stores. This pool can be exhausted after 3 to 7 days of continuous desmopressin treatment; in such situations, consider the administration of a factor VIII concentrate containing vWF (intermediate-purity plasma-derived factor VIII). In patients treated with desmopressin (especially children, pregnant women, and the elderly) the drug can induce water retention, hyponatremia, and occasionally seizures.

2. Plasma-derived concentrates containing vWF are used in patients in whom desmopressin is ineffective or contraindicated and in all patients requiring major surgery. IV administration of 1 IU of vWF/kg increases plasma vWF activity by ~2% of normal. Dosage: Table 1. In selected patients with recurrent bleeding, consider regular prophylaxis. Recombinant vWF is also approved in some jurisdictions.

3. Oral or IV tranexamic acid is used at a dose 10 to 15 mg/kg every 8 hours in patients with mucosal bleeding and in those undergoing a minor surgery or invasive procedure.

4. Combined (estrogen-progestogen) oral contraceptives or levonorgestrel-releasing intrauterine systems may prevent heavy menstrual bleeding.

TablesTop