Acquired von Willebrand syndrome: an important bleeding complication to be considered in patients with lymphoproliferative and myeloproliferative disorders.

Abstract

Acquired von Willebrand Syndrome (AVWS) is a rare disorder that is characterized by excessive bleeding and a defect in vonWillebrand Factor (VWF) activity, as tested by Ristocetin cofactor (VWF:RCo) and/or collagen binding (VWF:CB) activities. In contrast to congenital von Willebrand Disease (VWD) patients, who are characterized by autosomal inherited pattern and lifelong bleeding episodes, AVWS usually occurs in individuals devoid of family and personal history of bleeding (Table 1). Since the ®rst report in a patient with systemic lupus erythematosus, nearly 300 cases have been described in patients with a variety of underlying diseases. ± 7 Although the syndrome may develop in patients with solid tumors, immunological diseases and cardiovascular disorders ± according to the literature and from the data of an international registry ± patients with lymphoproliferative (LPD) and myeloproliferative (MPD) disorders are particularly prone to be associated with AVWS. Diagnosis of AVWS is usually based on measurements of bleeding time (BT), ristocetin-induced platelet agglutination,VWF:RCoorVWF:CB, andVWF antigen (VWF:Ag), as well as on multimeric analysis of VWF in plasma and platelets. In addition, activity of VWF antigen II can sometimes be used to distinguish patients with AVWS from those with congenital VWD. Anti-FVIII/VWF activities must also be determined because their presence is very important for the treatment of patients with AVWS. In contrast to patients with acquired hemophilia A which is always the result of antiFVIII inhibitory activity, anti-VWF inhibitors are not frequently present in AVWS patients. Regarding the pathophysiology of AVWS, except for patients with hypothyroidism who are characterized by decreased VWF synthesis or release, most patients with AVWS show a normal synthesis of VWF. When VWF is normally synthesized, its accelerated removal from plasma occurs through the activity of speci®c autoantibodies that inactivate VWF; activity of non-speci®c antibodies that form circulating immune complexes with VWF; absorption of VWF onto malignant cell clones; increased proteolytic degradation of VWF; and/or loss of high VWF multimers under conditions of high shear stress. None of these mechanisms, however, is mutually exclusive and the same mechanism can be responsible for AVWS in patients with di€erent underlying disorders. Patients with AVWS may su€er from moderate-severe bleeding symptoms but life-threatening hemorrhages requiring hospitalization and frequent administration of blood components are not so infrequent. While treatment aims, wherever possible, to eliminate the underlying disease, e€orts have been directed speci®cally to control actual bleeding episodes and to prevent bleeding when an invasive procedure is necessary. Compared to congenital VWD patients who are treated only with desmopressin (DDAVP), and Factor VIII/VWF concentrates (Table 2), high-dose intravenous immunoglobulin (IV:Ig), plasmapheresis, corticosteroids and immunosuppressive drugs have been also used to treat patients with AVWS with varying e€ectiveness.