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• W1978771401 abstract "Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder similar to inherited von Willebrand disease in terms of laboratory findings and clinical severity. It is characterized by a prolonged bleeding time and variably low plasma levels of von Willebrand factor (VWF) and factor VIII. The syndrome usually occurs in individuals with no personal or family history of bleeding. Data from large prospective studies are not available, and the actual incidence of AVWS in the general population is therefore unknown [1]. Mohri et al. [2] reported an incidence of approximately 10% in 260 patients with hematologic disorders studied by a single institution. Since the original description of AVWS in 1968, in a patient with systemic lupus erythematosus [3], more than 300 cases of AVWS have been reported, and data from an International Registry on AVWS are also available [4]. The majority of information pertaining to the clinical and laboratory features of the syndrome, as well as on different therapeutic approaches, has been derived from retrospective studies, often summarized in review articles [5-10]. Six categories of underlying disorders have been reported to occur frequently in patients with AVWS: lymphoproliferative and myeloproliferative disorders; solid tumors; immunologic and cardiovascular disorders; and miscellaneous conditions [4-10]. Taken together, lymphoproliferative and myeloproliferative disorders appear to be most frequently associated with AVWS in both the literature and the registry, accounting for 48–63% of cases. However, owing to the lack of studies specifically designed to evaluate prospectively patients with the underlying disorders usually associated with AVWS, the actual incidence of the disorder is certainly underestimated. Therefore, only the tip of the iceberg is apparent (Fig. 1), because most AVWS patients do not bleed until they are exposed to major trauma or major invasive procedures and surgery. Pictorial representation of the current information on acquired von Willebrand syndrome (AVWS). Only the tip of the iceberg can be seen, as most of the mild cases with clinical conditions associated with AVWS are hidden below the water, but will emerge only when serious trauma or major surgery can occur. To improve the management of AVWS among hematologists, a website on the International Registry on AVWS (http://www.intreavws.com) has been organized. Physicians and scientists interested in AVWS can obtain information about this disorder. If physicians have patients with suspected AVWS, they can submit their data online after a simple registration of their centers, indicating names and affiliations. A board of experts will evaluate their data and reply with advice and suggestions. VWF is synthesized normally in most AVWS patients, but not in those with hypothyroidism, who characteristically exhibit decreased VWF synthesis or release [4-11]. In patients with normal synthesis of VWF, low levels of this factor result from its accelerated removal from the plasma by three main pathogenetic mechanisms, as reported at the homepage dedicated to the International Registry online (http://www.intreavws.com): (i) specific or non-specific autoantibodies that form circulating immune complexes with, and inactivate, VWF (these complexes are cleared by Fc-bearing cells; (ii) absorption of VWF onto malignant cell clones; and (iii) loss of high molecular weight VWF multimers under conditions of high shear stress. In patients with autoantibodies [mechanism (i)], the entire native VWF, normally secreted from endothelial cells, is usually removed from the circulation; this results in very low concentrations of both VWF and VWF antigen (VWF:Ag), but normal levels of VWF propeptide are maintained [12]. When malignant cell clones [mechanism (ii)] and conditions of high shear stress [mechanism (iii)] cause AVWS, preferential removal of high molecular weight VWF multimers occurs. This results in reduced VWF activity with relatively normal VWF concentrations. An additional mechanism to be considered is the increased proteolytic degradation of VWF, which occurs in several clinical conditions characterized by the presence of circulating proteases [13, 14]. As compared with acquired hemophilia, which is always due to autoantibodies against FVIII, the pathogenetic mechanisms underlying AVWS are more heterogeneous. None of the proposed mechanisms appears to be disease-specific, and the same mechanism can be responsible for AVWS in different underlying disorders that are known to be associated with the syndrome [1, 4]. Diagnosis of AVWS is usually based on the laboratory parameters typical for inherited VWD in the absence of a family history of bleeding. VWF ristocetin cofactor activity (VWF:RCo) or collagen-binding assay (VWF:CB) in plasma compared with VWF:Ag, ristocetin-induced platelet agglutination, multimeric analysis in plasma and platelets and VWF propeptide have all been used to identify patients with AVWS [4]. Testing for anti-VWF antibodies should always be performed, because the presence of these inhibitors is clinically significant [2]. Testing for these antibodies can be carried out by measuring VWF activity after mixing experiments involving patient plasma and normal plasma incubated at 37 °C for 1–4 h. Some solid-phase tests have also been proposed by different authors [15]. Recently, an assay to test for anti-VWF antibodies using a sandwich enzyme-linked immunosorbent assay has been described [16]. The sensitivity of this assay is promising, but its specificity in screening for autoantibodies against VWF should be tested further in multicenter studies. A diagnostic flow chart, which can be used in cases of excessive bleeding or before surgery in patients with underlying disorders known to be associated with AVWS, has been proposed [4]. In a report that appears in this issue of the journal, Thiede et al. tested their diagnostic approach retrospectively in 35 patients with AVWS followed at the Hannover Medical School between 1999 and 2005. The aims of the study were to analyze the capability of laboratory tests to identify patients with AVWS. Inclusion criteria were a history of recent onset of bleeding, a negative family history of VWD and, for the first time, abnormal plasma VWF multimers. Multimeric analyses were centralized in the laboratory of Budde, who is one of the recognized experts in this field. The first novel feature of this retrospective study is the relatively high association found with cardiovascular disorders (46%) in comparison to monoclonal gammopathy (31%), which is usually reported as the more frequent association [4]. The second novel feature is the relatively high sensitivity (86%) of VWF multimeric analyses to diagnose AVWS, which was similar to the combination of the three following assays: VWF:Ag < 50 U dL−1 (23%), VWF:RCo/Ag ratio < 0.7 (26%), and VWF:CB/Ag ratio < 0.7 (46%). These data are of interest, but the sensitivity of VWF multimeric analysis for the diagnosis of AVWS should be confirmed by multicenter prospective studies. There are three treatment goals in AVWS: to control current bleeding episodes; to prevent bleeding when an invasive procedure is necessary; and, when possible, to control the underlying disease. In several disorders associated with AVWS, surgery, chemotherapy, radiotherapy or discontinuation of the responsible drugs [17-34] can sometimes control the underlying disease, with resolution of the bleeding diathesis and normalization of the laboratory parameters. Unfortunately, in some cases of AVWS, the underlying disorders cannot be identified. In others, such as AVWS associated with monoclonal gammopathy of undetermined significance, the underlying disease is usually not treated. Hence, in such cases, the best approach to stop bleeding episodes and/or to prevent bleeding during surgery must be identified. A variety of therapeutic approaches have been used to treat patients with AVWS, including desmopressin (DDAVP), VWF concentrates, high-dose intravenous immunoglobulin (IVIg), plasmapheresis, corticosteroids, and immunosuppressive drugs [1, 4]. Desmopressin, VWF concentrates and high-dose IVIg have been tested prospectively in 10 patients with AVWS associated with monoclonal gammopathy of undetermined significance, with particular attention to the short-term and long-term administration of IVIg [35]. The therapeutic doses of IVIg for AVWS are 1 g kg−1 day−1 for 2 days or 0.4 g kg−1 day−1 for 5 days. Repeated doses of IVIg given every 21 days (long-term therapy) can produce consistent responses in VWF measurements, but high doses seem to be essential. Recombinant activated FVII (rFVIIa; NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) is another useful therapeutic approach. This agent has been successfully used when bleeding associated with AVWS has been unresponsive to standard therapy [36]. An updated version of the International Registry on AVWS has been established online (http://www.intreavws.com) to promote direct registration of new cases. The aim is to gain a better understanding of the basic mechanisms of AVWS (through the use of new assays), the limits of standard therapies, and the efficacy of novel and experimental therapeutic approaches. The contribution of the three main underlying clinical conditions associated with AVWS, namely lymphomyeloproliferative, immunologic and cardiovascular disorders, will also be established. Experts on AVWS should work with relevant specialists to design appropriate screening algorithms for patients at risk of bleeding. New interesting cases should be enrolled into this registry online to promote this international investigator-driven prospective study on AVWS organized on behalf of the Sub-Committee on VWF of the Scientific and Standardization Sub-Committee of the International Society on Thrombosis and Haemostasis. The use of more sensitive and specific assays should be encouraged to determine the role of anti-VWF autoantibodies in AVWS: a Working Party on standardization of these assays has recently started this activity with the task of promoting the best diagnostic approach for the identification and characterization of these anti-VWF inhibitors. As described above, management of bleeding in AVWS relies mainly on DDAVP, VWF concentrates and high-dose IVIg, but no single approach is effective for all AVWS cases. As bleeding episodes are sometimes life-threatening and require prolonged hospitalization with the infusion of large doses of blood products, the organization of large, prospective, multicenter studies in patients with AVWS is required. It is hoped that preliminary information will be gathered within 2008, 40 years after the description of the first case [3]. We wish to thank all the members of the Sub-Committee on VWF of the International Society on Thrombosis and Haemostasis Scientific and Standardization Sub-Committee who participated in this registry and contributed to the preparation of the guidelines for diagnosis and therapy of AVWS [4]. We acknowledge the work of L. Flaminio Ghilardini, who prepared Fig. 1. This work was partially supported by the Explorative Action on International Registry on AVWS grant given to A. B. Federici by the University of Milan. The author state that they have no conflict of interest." @default.
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• W1978771401 title "Acquired von Willebrand syndrome: is it an extremely rare disorder or do we see only the tip of the iceberg?" @default.
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