Interactive Registry on Acquired von Willebrand Syndrome

On behalf of the Scientific Subcommittee on vWF
The acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease. Unlike the congenital form, the syndrome usually occurs in individuals with no personal or family history of bleeding. Large studies on this syndrome are not available, diagnosis is still difficult and treatment empirical. Data in the literature and from a previous retrospective international registry (2000) indicate that the syndrome is especially frequent in lympho- or myeloproliferative disorders, so that it should be suspected and diagnosed with the appropriate laboratory tests when there is excessive bleeding in patients with these hematological disorders. AVWS is also associated with solid tumors, immunological and cardiovascular disorders as well as other miscellaneous conditions. However, no prospective studies have been organized in these clinical conditions. Diagnosis of the AVWS is based on assays measuring ristocetin cofactor activity or collagen binding, which are usually abnormally low, while factor VIII coagulant activity is sometimes normal. FVIII/VWF inhibiting activities are found in only a minority of cases, but better tests to measure anti-FVIII/VWF autoantibodies are needed to screen patients with AVWS. Bleeding episodes in AVWS are mostly of the mucocutaneous type and can be managed with desmopressin, plasma-derived factor VIII/von Willebrand factor (FVIII/VWF) concentrates and intravenous immunoglobulin. Recombinant activated factor VII, plasmapheresis, corticosteroids and immunosuppressors combined with chemotherapy are also useful in some cases. In conclusion, the AVWS, although rare, is certainly underestimated in clinical practice and further prospective studies on its frequency, diagnosis and management are required.

Aims of this IntReAVWS: Aims of this updated version of the Registry are to enroll new cases of AVWS directly from the physicians who have followed such patients since January 2000 and to provide online the best diagnostic and therapeutic approaches of these new patients. The organization of prospective studies on the frequency of AVWS within specific underlying disorders and of new therapeutic approaches will be also encouraged. Annual updates on the number of cases enrolled and on studies ongoing will be reported during the meeting of the Subcommittee on VWF of the Scientific Standardization Committee of the International Society on Thrombosis and Haemostasis.

Pathogenetic mechanisms causing acquired von Willebrand Syndrome (AVWS) Pictorial representation of the three main pathogenetic mechanisms causing acquired von Willebrand Syndrome (AVWS). In the lower panel of the figure, the normal VWF biosynthesis and release from the endothelial cells is described: note that all the high molecular weight multimers (HMV VWF) are present in the released VWF after the cleavage of VWF pro-peptide (Pro-peptide of VWF) that can be found in circulation in equal amounts as native VWF. In the middle part of the figure, the three main mechanisms causing AVWS are described: a) specific or nonspecific auto-antibodies that inactivate VWF. These auto-antibodies form circulating immune complexes with VWF and are cleared, together with VWF, by Fc-bearing cells; b) absorption of VWF onto malignant cell clones; c) loss of high VWF multimers under conditions of high shear stress occurring in several heart valves abnormalities. In the upper part of the figure, the effects of these three mechanisms on VWF structure and function are described: in case of auto-antibodies (mechanism a), the entire native VWF normally secreted from the endothelial cells is usually removed from the circulation: this results in very low concentrations of both VWF activities and antigen but normal levels of VWF pro-peptide; when malignant cell clones (mechanism b) and conditions of high shear stress (mechanism c) cause AVWS, a preferential removal of high molecular weight (HMW) VWF multimers occurs: this results in reduced VWF activities with relatively normal VWF concentrations.