Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management

Acquired von Willebrand syndrome (AVWS) associated with hypothyroidism is o f type I, results from a decreased synthesis of factor VIII and von Willebr and factor (VWF), responds to desmopressin with normal half-life times for factor VIII and VWF parameters, and disappears after treatment with I-thyro xine. AVWS type I or III, which occurs in a minority of patients with Wilms ' tumour in the complete absence of an inhibitor against VWF and no absorpt ion of factor VIII or VWF onto nephroblastoma cells, responds to chemothera py and/or tumour resection. Hyaluronic acid produced by nephroblastoma cell s may be the causative factor in atypical AVWS in Wilms' tumour. AVWS assoc iated with thrombocythaemia of various myeloproliferative disorders is char acterized by normal factor VIII and von Willebrand factor antigen (VWF:Ag) levels and a selective deficiency of functional ristocetin co-factor activi ty (VWF: RCo) and collagen-binding activity (VWF:CBA). AVWS type II in thro mbocythaemia is caused by a platelet-dependent proteolysis of large VWF mul timers, given the inverserelationship between platelet count and large VWF multimers in plasma and specific increases in the number of proteolytic VWF fragments in plasma. The laboratory findings of AVWS associated with systemic lupus erythematosu s or IgG benign monoclonal gammopathy are characterized by a prolonged blee ding time and activated partial thromboplastin time, decreased or absent ri stocetin-induced platelet activity, low to very low levels of Factor VIII c oagulant activity (mean 15%), VWF:Ag (mean 10.7%) and VWF:RCo (mean 6.2%), and a type II multimeric pattern of VWF. Neutralizing and nonneutralizing a nti-VWF autoantibodies, usually IgG, have been detected in patient plasma e ither free or tightly bound to the intermediate and high molecular weight V WF factor VIII particles. The bound auto antibody-antigen complex is rapidl y cleared from the circulation, resulting in low levels of factor VIII, VWF parameters as documented by a poor response to desmopressin and VWF factor VIII concentrate. High-dose intravenous immunoglobulin transiently correct s the Factor VIII coagulant and VWF levels, lasting For a few weeks in AVWS type II associated with systemic lupus erythematosus or IgG benign monoclo nal gammopathy. Prednisolone is effective in AVWS associated with autoimmun e disorder. Prednisolone and chemotherapy will not affect AVWS associated w ith IgG benign monoclonal gammopathy because the monoclonal IgG protein rem ains to act as an anti-VWF autoantibody. An absorption of VWF to malignant cells has been documented in a few patien ts with various lymphoproliferative disorders or adrenal carcinoma and sugg ested to result in a depletion of VWF. The clinical picture of AVWS associa ted with early-stage IgG multiple myeloma, chronic lymphocytic leukaemia or non-Hodgkin's lymphoma without a paraprotein or no detectable underlying d isorder is similar to that of AVWS type II in IgG benign monoclonal gammopa thy but poorly documented with regard to the underlying immune mechanism of AVWS. The mechanical destruction of large VWF multimers may be of relevanc e in conditions in which the shear rate of flowing blood is increased, as m ay occur in cases of aortic stenosis, other heart valve defects or stenosed vessels. Drug-induced AVWS has been described in association with the use of pesticides valproic acid, ciprofloxacin, griseofulvin, tetracycline, thr ombolytic agents and hydroxyethyl starch.