Treatment of Acquired von Willebrand Syndrome in Patients With Monoclonal Gammopathy of Uncertain Significance: Comparison of Three Different Therapeutic Approaches

Abstract

Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10 patients with MGUS and AvWS: 8 had IgGκ (3) or λ (5) MGUS and 2 IgM-κ MGUS. Three therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor (FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS, DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently. IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS associated with IgG-MGUS, but not with IgM-MGUS. © 1998 by The American Society of Hematology.

Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias

“…A framework for management decisions is presented in Fig 1. Most patients with lymphoproliferative diseases, including MGUS, will demonstrate a transient, or no, response to DDAVP or FVIII/VWF infusions, consistent with immune mediated in-vivo neutralization or rapid clearance of VWF, although some patients will have a clinical response, supporting their inclusion as initial therapies. IVIg infusions reliably produce laboratory and clinical improvements within several days, which can persist for 1-3 weeks and can be accelerated by infusing DDAVP or FVIII/VWF concentrate immediately following IVIg (Federici et al, 1998). Monthly maintenance IVIg infusions (1AE0 mg/kg) have been effective in a limited number of cases (Federici et al, 1998).…”

“…IVIg infusions reliably produce laboratory and clinical improvements within several days, which can persist for 1-3 weeks and can be accelerated by infusing DDAVP or FVIII/VWF concentrate immediately following IVIg (Federici et al, 1998). Monthly maintenance IVIg infusions (1AE0 mg/kg) have been effective in a limited number of cases (Federici et al, 1998). Some MGUS patients with AVWS respond poorly (Frank et al, 2002;Krebs et al, 2002) or not at all to IVIg, typically those with IgM M proteins (Federici et al, 1998) and plasmaphaeresis and rFVIIa (Friederich et al, 2001;Smaradottir, 2004) have effectively controlled haemorrhage in some cases.…”

“…Monthly maintenance IVIg infusions (1AE0 mg/kg) have been effective in a limited number of cases (Federici et al, 1998). Some MGUS patients with AVWS respond poorly (Frank et al, 2002;Krebs et al, 2002) or not at all to IVIg, typically those with IgM M proteins (Federici et al, 1998) and plasmaphaeresis and rFVIIa (Friederich et al, 2001;Smaradottir, 2004) have effectively controlled haemorrhage in some cases. Chronic immune suppression with prednisone or rituximab (Grimaldi et al, 2008) has been unsuccessful in MGUS-associated AVWS, as has chemotherapy (Michiels et al, 2006).…”

Haemostatic management of extreme challenges to haemostasis in acquired von Willebrand syndrome

“…1), an increase in VWF:Ag levels does not guarantee a functional increase in VWF activity. The use of IVIG has been reported to lead to sustained response, especially in cases of MGUS by IgG [8]. We were able to document the positive response to IVIG with increase in VWF:RCo up to haemostatic levels even before the use of VWF concentrate in a patient with AVWS which was refractory to standard immunossupressive and to VWF concentrate.…”

“…The most commonly used regimens are 1 g kg -1 for 2 days or 0.4 g kg -1 for 5 days. Applications every 21 days may be used to produce more durable responses [8].…”