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.

Acquired von Willebrand Disease

“…The most frequently observed association is with dysproteinemias ( Table 1). These range from monoclonal gammopathy of undetermined significance (MGUS), a common scenario, 4,16,27,68 to plasma cell proliferative disorders such as Waldenström macroglobulinemia 17,18,68 and multiple myeloma. [19][20][21] The presence of a monoclonal protein is not always essential, as seen in certain low-grade lymphoproliferative disorders such as chronic lymphocytic leukemia, 9,10 hairy cell leukemia, 12 and non-Hodgkin lymphoma.…”

“…35 Intravenous immunoglobulin (IVIG) has been used in patients with AvWD 35,36,90 and seems to be useful in some patients with an MGUS; it can produce a more sustained response than desmopressin or factor concentrates. 16,95 However, patients with IgM-MGUS appear to be less responsive to IVIG than those with IgG-MGUS. 16 The mechanism of action of IVIG in this setting is unclear but may be related to its effect on the clearance of the vWFantibody complex, 95 such as blocking reticuloendothelial Fc receptors in the spleen and increasing catabolism of autoantibodies, as is observed in other conditions in which IVIG is effective.…”

“…16,95 However, patients with IgM-MGUS appear to be less responsive to IVIG than those with IgG-MGUS. 16 The mechanism of action of IVIG in this setting is unclear but may be related to its effect on the clearance of the vWFantibody complex, 95 such as blocking reticuloendothelial Fc receptors in the spleen and increasing catabolism of autoantibodies, as is observed in other conditions in which IVIG is effective. In several situations in which use of desmopressin or factor concentrates did not control bleeding, IVIG was effective.…”

“…96,97 Responses lasting up to a month have been observed after treatment with a single dose of IVIG, and this agent has been used repeatedly every 3 to 4 weeks to maintain normal hemostasis in patients with AvWD who are not responding to desmopressin or vWF concentrates. 16,97,98 The high cost of IVIG limits routine use.…”

Acquired Von Willebrand’s Syndrome in Systemic Lupus Erythematosus

“…Although IVIG can produce a more sustained response than DDAVP or factor concentrates, it requires 24–48 hours to normalize plasma VWF-FVIII activity; thus DDAVP or VWF-FVIII concentrates can be given together with IVIG to achieve hemostasis immediately in cases of emergency bleeding [ 22 , 25 ]. Repeated doses of IVIG every 21 days can produce consistent responses, as has been shown in patients with IgG-MGUS [ 41 , 43 ].…”