Acquired von Willebrand syndrome (ORPHA:99147)
A rare bleeding disorder marked by the same biological anomalies as those seen in hereditary von Willebrand disease (VWD) but which occurs in association with another underlying pathology, generally in elderly patients without any personal or family history of bleeding anomalies.
Epidemiology
Prevalence is unknown, but Acquired von Willebrand syndrome (AVWS) is a rare disease that is underdiagnosed, with just over 300 cases reported in the literature so far.
Clinical description
The bleeding manifestations are similar to those occurring in hereditary VWD (prolonged bleeding after trauma, epistaxis, ecchymoses and gastrointestinal bleeding associated with angiodysplasia).
Etiology
Three principle pathogenic mechanisms have been described: 1) the presence of autoantibodies (inhibiting or noninhibiting) that form immune complexes with the von Willebrand factor (VWF) leading to rapid clearance of VWF from the circulation (the mechanism most commonly implicated in AVWS associated with monoclonal gammapathies and autoimmune diseases); 2) absorption of VWF onto malignant cell clones (the mechanism implicated in AVWS associated with neoplasia); 3) increased proteolysis of high molecular weight VWF multimers under abnormal hemorheologic conditions caused by cardiovascular malformations (such as aortic valve stenosis).
Diagnostic methods
The most accurate diagnostic tests rely on detection of abnormally low levels of VWF activity (ristocetin cofactor or collagen binding assays) in comparison to VWF antigen levels, and on demonstration of a selective deficiency of high molecular weight VWF multimers. Measurement of VWF propeptide levels may also be useful as they reflect the abnormally rapid clearance of VWF from the circulation. However, none of these tests allow AVWS to be distinguished from hereditary VWD. Detection of anti-VWF antibodies is pathognomonic of the acquired mechanism of VWF deficiency; however, these antibodies are only detected in 14% of suspected cases of AVWS. The finding of a monoclonal protein detected by serum protein electrophoresis is an argument for AVWS. Thus, it is the presentation of an acute bleeding disorder, in association with an underlying pathology (such as lympho- or myeloproliferative disorders, solid tumors, immunological or cardiovascular disorders) which generally leads to the diagnosis of acquired VWF deficiency.
Management and treatment
Management relies on identification and then treatment of the underlying pathology usually involving corticosteroids or immunosuppressors, chemotherapy, plasmapheresis or valve replacement. In cases when these treatments are not rapidly efficient, symptomatic treatment aiming to correct the VWF deficiency is used to prevent or to cure abnormal bleeding. The choice of treatment depends on the suspected physiopathology and clinical status: intravenous immunoglobulins (in case of IgG monoclonal gammopathy of undetermined significance), desmopressin or VWF concentrates (although pharmacokinetic studies may be required before any major surgical intervention as the half-life of endogenous or exogenous VWF may be significantly reduced), recombinant factor VIII concentrates (completely depleted of VWF) or, as a last-resort treatment option, recombinant activated factor VII.
Prognosis
The prognosis depends on the underlying pathology associated with the disease.

                            Last update: 
                            October 2008


                            - Expert reviewer(s): 
                            Pr Jenny GOUDEMAND  - Pr Agnès VEYRADIER