Temporary relief of symptomatic Von Willebrand disease by multiple myeloma


J.J.A. Auwerda, Erasmus MC, Department of Hematology, 3000 CA Rotterdam, PO Box 2040, the Netherlands.
Tel.: 31 10 4633740; fax: 31 10 4635814; e-mail: jja.auwerda@ikazia.nl

Multiple myeloma can be associated with various hemostatic abnormalities which predispose the patient to either venous thromboembolism or hemorrhage. In this journal, Minnema et al. reported increased levels of von Willebrand factor (VWF) and factor VIII (FVIII) in patients with multiple myeloma which may result in a prothrombotic state [1].

Recently a 55-year old male patient was referred to our hospital for treatment of multiple myeloma. In his youth he had presented with a bleeding diathesis as a result of type 2A von Willebrand disease (VWD). Laboratory investigation in the past showed FVIII:C of 0.23 U mL−1 (normal 0.6–1.4), VWF:Antigen (VWF:Ag) 0.12 U mL−1 (normal 0.6–1.4 U mL−1), VWF:Ristocetin cofactor activity (VWF:RCo) < 0.10 U mL−1 (normal 0.6–1.4), and VWF:collagen-binding activity (VWF:CB) < 0.05 U mL−1 (normal 0.6–1.4). Multimer analysis performed by sodium dodecyl sulfate–agarose gel electrophoresis, showed the absence of high-molecular-weight VWF multimers. He had recurrent episodes of epistaxis for which he was treated regularly with tranexamic acid. In addition he underwent several surgical interventions after infusion of FVIII/VWF concentrate (Haemate-P, ZLB Behring, Zaventem, Belgium), with normal recovery of FVIII and VWF. In his family several other members were also diagnosed with VWD, including his father, brother, son and daughter, and two grandchildren, which was indicative of an autosomal dominant trait. This confirms the hereditary nature of VWD and excludes an acquired von Willebrand syndrome.

In 2003 he noticed that the frequency of epistaxis had diminished while symptoms of fatigue and fever occurred. Laboratory investigations revealed an increased erythrocyte sedimentation rate (67 mm h−1) and a raised serum monoclonal immunoglobulin Gκ (IgGκ; 65 g L−1). In the bone marrow aspirate infiltration by monoclonal plasma cells (> 60%) confirmed the diagnosis of multiple myeloma. Laboratory investigations at that time revealed increased plasma levels of FVIII:C of 1.29 U mL−1, VWF:Ag of 0.9 U mL−1, and VWF:CB of 0.56 U mL−1. The VWF:RCo level remained low (0.18 U mL−1). The patient received three courses of thalidomide, adriamycin and dexamethasone according to the prospective phase III HOVON 50/GMMG-HD3 study. During treatment IgGκ levels decreased to 9 g L−1, resulting in a good partial response. This coincided with a decrease of FVIII:C and VWF antigen and activity to pre-existing levels (Fig. 1). In addition he again encountered several episodes of epistaxis.

Figure 1.

Plasma levels of VWF, Factor VIII and IgG during the course of treatment (A) and sodium dodecyl sulfate–agarose gel electrophoresis of VWF multimers pattern (B).

Multiple myeloma has primarily been associated with a bleeding tendency as a result of acquired von Willebrand syndrome, factor X deficiency or thrombocytopenia [2,3]. Recently however, an increased risk of venous thromboembolism has been reported in patients with multiple myeloma, in particular during treatment with doxorubicin and thalidomide [4,5]. The mechanism of the increased thrombotic tendency has not yet been fully elucidated. In multiple myeloma patients high levels of FVIII:C have been reported and a causal relationship has been suggested [1]. It is already known from population-based studies that high FVIII:C levels may be associated with an increased risk of venous thromboembolism [6]. The increase in FVIII:C in multiple myeloma is probably caused by an increased half-life because of high levels of VWF, the carrier protein of FVIII. It has been hypothesized that bone marrow microvessel density increases because of neovascularization in multiple myeloma [7,8], which in turn results in an increase in vascular endothelium. Because endothelium is the main source of VWF in the circulation [9], this may explain the increased VWF levels in multiple myeloma. However, it remains to be proven whether a direct relation of neovascularization with increased levels of VWF exists. Interestingly, we analyzed in retrospect a serum sample taken 1 year before the diagnosis of multiple myeloma, and found a M-protein IgGκ of < 5 g L−1, indicating a pre-existing monoclonal gammopathy of undetermined significance (MGUS). This was not accompanied by changes in FVIII:C or VWF:Ag levels compared to laboratory results obtained in the past. This demonstrates that the transformation of the MGUS to multiple myeloma resulted in the increased FVIII:C and VWF:Ag levels.

In our patient with inherited type 2A VWD, VWF:Ag and FVIII:C levels increased to normal levels at the time of diagnosis of multiple myeloma. VWF:RCo however, remained low because of the underlying qualitative disorder of the VWF molecule. The multimeric pattern before and after the start of therapy exhibited predominantly low-molecular-weight multimers, indicative of active proteolysis of VWF (Fig. 1). The rate of proteolysis of VWF may be influenced by plasma ADAMTS13 activity which is a recently discovered metalloprotease. In our patient, ADAMTS13 activity was 0.63 U mL−1 (normal 0.6–1.4) and did not change significantly during treatment (at diagnosis of multiple myeloma 0.51, after treatment 0.51). In patients with VWD the bleeding tendency is not only related to VWF levels in plasma, but is also dependent on FVIII:C levels. This is exemplified in patients with VWD treated with FVIII/VWF concentrate, in whom FVIII:C levels are of the main importance for clinical efficacy [10]. Therefore we suggest that in our patient, the increased FVIII:C and VWF associated with multiple myeloma resulted in the relief of his VWD symptoms and that the successful treatment of the multiple myeloma re-induced the bleeding tendency related to VWD.

We believe this to be the first report of a temporary relief of symptomatic VWD as a result of multiple myeloma. This report increases the understanding of hemostatic alterations in multiple myeloma, and may provide additional insight into the thrombotic tendency seen in these patients.