Knowledge on rare diseases and orphan drugs

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.

The bleeding manifestations are similar to those occurring in hereditary VWD (prolonged bleeding after trauma, epistaxis, ecchymoses and gastrointestinal bleeding often associated with angiodysplasia).

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 gammopathies 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) or mechanical circulatory devices (such as ventricular assist devices or extracorporeal membrane oxygenation). Monoclonal gammopathy of undetermined significance (MGUS) is the most common underlying condition associated with AVWS.

The most accurate diagnostic tests rely on detection of abnormally low levels of VWF activity (VWF:GPIb- 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 neutralizing antibodies is pathognomonic of an AVWS; however, these antibodies are only detected in very few suspected cases of AVWS. The finding of a monoclonal protein detected by serum protein electrophoresis is a strong 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 AVWS.

Differentiation between VWD and AVWS is critical because therapeutic approaches can be very different. AVWS should be suspected in patients with late onset of bleeding and negative family. In uncertain cases, testing of family members and genetic analysis can be helpful.

The management goals in AVWS are: 1) to control acute bleeds; 2) to prevent bleeding in high-risk situations; and 3) to obtain long-term remission through the identification and treatment of the underlying disorder whenever possible (chemotherapy, immunosuppressive drugs, plasmapheresis or corrective surgery according to the etiology). In cases when these treatments are not rapidly efficient, symptomatic treatment aiming to correct the VWF deficiency is used to prevent or to treat abnormal bleeding. The choice of treatment depends on the suspected physiopathology and clinical status: intravenous immunoglobulins (in case of AVWS resulting from IgG monoclonal gammopathy), 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.

The long-term prognosis mainly depends on the underlying pathology associated with the disease. The short- and mid-term prognosis may be dependent on the severity of acute bleeding events.

Last update: September 2024 - Expert reviewer(s): Pr Antoine RAUCH | EuroBloodNet* - Pr Agnès VEYRADIER | EuroBloodNet*

* European Reference Network