Diagnosis
Von Willebrand disease is diagnosed based on three criteria: an increased bleeding tendency, a family history and laboratory assays showing reduced von Willebrand factor activity (< 35 IU/dL) on repeated testing (9, 10). A thorough clinical history, including bleeding history and family background, should therefore always guide laboratory investigations. A standardised bleeding assessment tool has been developed for the systematic evaluation of bleeding tendency, but it is extensive and highly detailed. Nordic guidelines recommend that it only be used by trained personnel in the specialist health service (9, 11).
The disease is subdivided into categories according to severity and whether the reduced von Willebrand factor activity is the result of a quantitative deficiency or a qualitative dysfunction (Figure 2). Activated partial thromboplastin time is usually normal but may be prolonged if coagulation factor VIII is also reduced.
Type 1 von Willebrand disease is the most common form, accounting for 70–80 % of cases (12). It is characterised by a quantitative deficiency of von Willebrand factor, with activity levels < 35 IU/dL.
Type 2 accounts for approximately 20 % of cases and comprises several subtypes, all characterised by a qualitative dysfunction of von Willebrand factor (12). Functionally, this is indicated by a reduced ratio of von Willebrand factor activity to antigen (< 0.7), and both platelet-binding and collagen-binding von Willebrand factor activity should be assessed. In types 2A and 2B, the largest von Willebrand factor multimers are absent, while type 2M usually exhibits a normal multimer pattern. Type 2B is also characterised by increased binding of von Willebrand factor to platelets, accompanied by thrombocytopenia. In type 2 N, there is reduced binding of von Willebrand factor to coagulation factor VIII, resulting in decreased factor VIII activity, which can be mistaken for mild haemophilia A. The Section for Haemostasis and Thrombosis in the Department of Medical Biochemistry at Oslo University Hospital has national responsibility for these specialised coagulation assays.
Type 3 von Willebrand disease is characterised by a severe quantitative deficiency, with von Willebrand factor being virtually undetectable (< 5 IU/dL). Coagulation factor VIII is therefore also markedly reduced (< 10 IU/dL). Type 3 is rare (< 5 %) (12), but this was the variant originally described by von Willebrand (1).
Von Willebrand disease is usually inherited in an autosomal dominant pattern, except for types 2 N and 3, which are inherited in an autosomal recessive pattern. Genetic analyses to identify underlying mutations are performed at the Section for Medical Genetics in the Department of Laboratory Medicine at Telemark Hospital Trust.