Pharmacokinetic Studies, Assessing the Efficiency of FVIII/VWF Concentrates and Intravenous Human Immunoglobulin, Revealed the Etiopathogenesis of Acquired von Willebrand Disease in Patient With MGUS

Abstract

Acquired von Willebrand Syndrome (AVWS) is a rare disorder characterized by a bleeding diathesis, with symptoms ranging from mild to severe. It differs from the congenital von Willebrand disease (vWD) due to the absence of personal and family history of haemorrhagic disorders, a late-onset bleeding tendency and the frequent association with haematological malignancies, autoimmune or cardiovascular diseases [1, 2]. Amongst lymphoproliferative disorders, monoclonal gammopathy of undetermined significance (MGUS) is the most frequently reported condition associated with AVWS, accounting for approximately 23% of all cases, according to the International Registry of the Subcommittee on von Willebrand factor [3]. In this regard, clinical attention should be given to most haematologic, malignant, and autoimmune disorders, with serum protein electrophoresis and a complete blood count being crucial to screen for monoclonal gammopathy and other haematologic disorders, respectively [4]. Despite the multiple pathophysiological mechanism involved, treatments for AVWS are focused on the eradication of the underlying disease, control of acute episodes and prevention of bleeding events, especially in high-risk situations, such as during surgery. Desmopressin (DDAVP), plasma-derived FVIII/VWF concentrates, antifibrinolytic, high-dose IVIG (Intravenous Immunoglobulin) and plasmapheresis are some of the therapeutic measures taken for this purpose [4]. Despite the multiple pathophysiological mechanisms that interfere with the normal functionality of the VWF molecule in AVWS, patients with MGUS can exhibit the presence of circulating autoantibodies directed against both functional and non-functional domains of VWF [5]. The pathogenesis of these antibodies encompasses: the presence of circulating antibodies neutralizing platelet-related domains of VWF (Inhibitors) or antibodies forming immuno-complexes with VWF, that are rapidly cleared from the circulation by the reticulo-endothelial systems (non-neutralizing antibodies) [6]. Since the presence of inhibitors is often associated with a more severe haemorrhagic phenotype, laboratory investigations can be challenging trying to distinguish between the two immunological mechanisms [6, 7]. Mixing studies and enzyme-linked immunosorbent assays (ELISA) are both suitable methods to identify the etiopathogenetic mechanism of these antibodies. However, since ELISA test is intricate and has not yet been adequately standardized, it is an option not yet fully utilized in haemostasis laboratories [6]; at the same time, the sole use of the mixing test can only confirm or exclude the presence of neutralizing antibodies, but does not allow the identification of antibodies increasing the clearance of the VWF. Here we report a case of AVWS secondary to MGUS IgG λ associated to the presence of non-neutralizing antibodies, whose etiopathogenic mechanism was identified with the help of pharmacokinetic and mixing studies. Our patient was a 73-year-old woman who referred to Regional Reference Center of Coagulation Disorders of Federico II University Hospital, Naples (Italy), following a massive post-operative haemorrhage embroiling the surgery site of a robotic cholecystectomy procedure due to cholelithiasis. No relevant haemorrhagic events were reported in family or personal medical history, apart from a recent haemothorax arisen after tracheal intubation subsequent to a hysterectomy with bilateral salpingo-oophorectomy procedure. Given her older age, the recent history of two bleeding events and the lack of previous bleeding diathesis, we suspected an acquired bleeding syndrome. In agreement with this hypothesis, we researched for a possible underlying pathology that triggered this bleeding episode. Serum protein electrophoresis studies revealed a peak in the gamma zone of the IgG λ type, probably associated to an underlying monoclonal gammopathy (data not showed). The complete blood count showed low levels of erythrocyt