Intravenous immunoglobulins and acquired von Willebrand syndrome

Abstract

Dear Sir, I read with interest the letter “Are intravenous immunoglobulins really inappropriate in the acquired von Willebrand syndrome?” by Federici et al1. Intravenous immunoglobulin (IVIG) is a fractionated blood product made from pooled human plasma. It was introduced in the late 1970s and rapidly subsumed the use of intramuscular preparations as replacement therapy in primary and secondary immunodeficiencies. It is increasingly important in replacement therapy and as an immunomodulatory agent in autoimmune disease and transplantation. IVIG is the market driver for the plasma industry in the developed world. The literature on this therapeutic agent increases exponentially and the burgeoning interest in therapeutic immunoglobulin is rapidly generating new evidence, both expanding and reducing current therapeutic indications, with varying levels of supportive evidence. In 1998, the effectiveness of IVIG was demonstrated in an open-label crossover study in patients with acquired von Willebrand syndrome associated with monoclonal gammopathy of uncertain significance of the IgG class2. In 2000, an in ternational registry series reported that one-third of the 63 patients treated with high-dose IVIG had a good response1. The currently limited evidence of the probable benefit of IVIG in the very rare bleeding disorder known as autoimmune acquired von Willebrand disease, though mainly coming from case reports and case series and not from large well-designed, prospective, randomised trials, is continuously growing, also thanks to the international registry of the International Society on Thrombosis and Haemostasis. Despite the low level of evidence case reports and case series can provide us with, they are still part of the evidence hierarchy in evidence-based practice and guide an important part of clinical practice. Case series are incorporated in a significant proportion of health technology assessments3. In 2007, the Australian Health Ministers’ Conference issued the “Criteria for the clinical use of intravenous immunoglobulin in Australia” and suggested that the management of autoimmune acquired von Willebrand syndrome includes the treatment of the underlying medical condition and should be undertaken only by or in consultation with haemophilia treatment centres keeping in mind that IVIG constitutes only part of the management of these complex patients4, who also require additional haemostatic support. This very rare and severe bleeding disorder is one of the conditions for which IVIG use is suggested in exceptional circumstances only. These circumstances include the management of bleeding and prior to invasive procedures, except cases associated with IgM paraprotein in which response is unlikely. The use of IVIG is also indicated in cases of failure to respond to chemotherapy/immunosuppressants or when there is insufficient time for chemotherapy/immunosuppressants to be given. In 2011, the guidelines of the United Kingdom Department of Health also recommended that IVIG treatment in this severe bleeding disorder be only undertaken in a comprehensive care centre for haemophilia. In addition, “IVIG is only recommended for patients with acquired von Willebrand syndrome with life- or limb-threatening haemorrhage who have not responded to other treatments, or prior to invasive procedures (grade B recommendation, level IIa evidence)” 5. For the above reasons, although more research is needed, undoubtedly autoimmune acquired von Willebrand syndrome deserves to be included in the rapidly growing list of non-recognised conditions in which IVIG has been utilised with some benefit, as suggested by Federici et al1.