Causes, Etiology and Diagnosis of Acquired von Willebrand Disease: A Prospective Diagnostic Workup to Establish the Most Effective Therapeutic Strategies

Abstract

Acquired von Willebrand disease (aVWD) occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative and myeloproliferative disorders, other malignancies, and cardiovascular disease. aVWD is a complex and heterogeneous defect with a multifactorial etiology and the pathophysiologic mechanisms remain unclear in many cases. Assays for anti-factor VIII (FVIII)/von Willebrand factor (VWF) activities often yield negative results although antibodies may be present in autoimmune disease and some lymphoproliferative disorders. Functional assays of VWF in patients’ plasma and particularly in heart valve disease, VWF multimer analysis are important for aVWD diagnosis. In patients with normal partial thromboplastin times and normal VWF activity, the diagnosis of aVWD is based on clinical suspicion and a careful bleeding history, which should prompt the clinician to initiate further laboratory investigations. Management of bleeding in aVWD relies mainly on desmopressin, FVIII/VWF concentrates and high-dose intravenous immunoglobulin. The half-life of VWF may be very short, and in bleeding episodes high doses of FVIII/VWF concentrates at short intervals may be necessary even when high-dose intravenous immunoglobulin was applied before. Since the optimal treatment strategy has not yet been defined for aVWD of different etiology, controlled multicenter trials aiming at the development of standardized treatment protocols are urgently needed.

Acquired von Willebrand Syndrome

“…Whenever the patient does not show the signs of active bleeding and the procedures with increased risk of bleeding can be postponed, treatment of a primary underlying condition is always a priority, since its remission is frequently associated with resolution of AvWS [45]. Individuals with autoimmune disorders are usually treated with glucocorticoids and other immunosuppressive agents (cyclophosphamide, azathioprine, cyclosporine) and patients with lymphoproliferative neoplasms (lymphoma, multiple myeloma) receive chemotherapy/immunochemotherapy, radiotherapy and immunomodulatory therapy.…”

“…Resolution of AvWS was also observed after the surgical removal of a malignancy, cardiac surgeries (valve replacement) and thyroxin substitution during the course of hypothyroidism [10,46,47]. Also withdrawing agents that might contribute to the development of AvWS (ciprofloxacin, griseofulvin, tetracycline, valproic acid, HES) may result in the remission of this condition [45].…”

“…However, the application of these agents may be limited due to their multiple side effects and delayed therapeutic effect [14,45].…”

Treatment of acquired von Willebrand syndrome in childhood

“…4 The pathophysiology of AVWS is heterogeneous and includes antibody-mediated destruction, decreased production, adsorption of VWF to tumor, or destruction from sheer stress ( Figure 1). 5,6 Common etiologies in adults, such as lymphoproliferative disorders and myeloproliferative diseases, 7 are uncommon in children 8 while AVWS associated with cardiovascular disease is common in both adults and children. In contrast, neoplasia (Wilms tumor), hypothyroidism, and autoimmunity are more often associated with AVWS in children.…”

Diagnosis and management of chronic ITP: comments from an ICIS expert group

“…In patients with unexpected bleeding, additional laboratory tests should be performed to identify platelet dysfunction [20] or an additional haemostatic abnormality e.g. underlying von Willebrand disease [21,22].…”