Acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a rare disorder associated with low levels of VWF and FVIII, but in comparison with inherited VWD, bleeding symptoms appear later in life without a family history. The majority of cases are caused by lympho- or myeloproliferative disorders. Other causes include solid tumors, immunological disorders, increased shear stress, hypothyroidism, drugs and miscellaneous or unknown causes [1,2]. The pathophysiology is not always clear. In hypothyroidism, the synthesis of VWF is decreased but in most other conditions, synthesis seems to be normal, but clearance is increased through different possible mechanisms: specific autoantibodies, non-specific autoantibodies forming immune complexes, adsorption to malignant cell clones or increased proteolytic degradation. In contrast to acquired hemophilia, inhibiting antibodies can only rarely be demonstrated.

It may be difficult to distinguish AVWS from congenital VWD and the symptoms are similar, i.e. mostly mucocutaneous bleeds. However, usually there is an abrupt change in the bleeding pattern. Laboratory findings may vary between different causes of AVWS but it usually include mildly decreased VWF:Ag and FVIII:C and more pronounced decrease of the VWF activity assays. The VWF activity/VWF:Ag ratio is therefore frequently decreased. The large multimers are often lacking due to increased clearance. Thus, these patients often exhibit a laboratory phenotype that resembles VWD type 2A. However, it is important to note that patients with AVWS may have VWF antigen and activity levels above the cut-off for VWD. Inhibitors against VWF may be detected with Bethesda-like mixing studies and it is important to test for neutralization with both VWF activity assays (platelet-dependent and collagen binding) as only one of the activities may be affected.  Non-neutralizing antibodies may cause an increased clearance of VWF without inhibiting the functional VWF assays and these antibodies are detected with an appropriate ELISA assay. Measurement of the VWFpp levels may also be useful as the VWFpp/VWF:Ag ratio is increased in plasma to a greater extent than most VWD types (except VWD type 1C), but the assay is not generally available. Since 2004, ISTH has run an international register of AVWS, and today there are just over 200 patients included. There is also an ongoing initiative by NHC to collect retrospective data from patients diagnosed with AVWS in the Nordic countries. We encourage the participation in this type of data collection in order to increase our knowledge in this complex area.