Acquired von Willebrand syndrome in association with multiple myeloma: remission after stem cell transplant

Abstract

Acquired von Willebrand syndrome is a rare bleeding disorder characterised by a later age of onset without a personal or family history of bleeding diathesis. It is vital to discern acquired von Willebrand syndrome from inherited von Willebrand disease and other acquired bleeding disorders as management differs significantly. Acquired von Willebrand syndrome is usually secondary to an underlying disorder such as lymphoproliferative disorder, myeloproliferative neoplasm, solid tumour, cardiovascular disorder, autoimmune disorders or hypothyroidism. Diagnosis is often delayed with a significant risk of morbidity and even mortality. Here we present a case of a 74-year-old man with an acquired bleeding disorder and work up suggestive of acquired von Willebrand syndrome secondary to immunoglobulin G kappa multiple myeloma. He was treated successfully with intravenous immunoglobulin, von Willebrand Factor/Coagulation Factor VIII Complex (human), myeloma directed chemotherapy and autologous stem cell transplantation. We also discuss the management strategies that are largely based on retrospective studies and case reports.

Background

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder of unknown prevalence. von Willebrand factor (VWF) is a glycoprotein produced by the vascular endothelium and megakaryocytes¹ that plays a critical role in primary haemostasis. VWF is responsible for the formation of an adhesive bridge between platelets and vascular subendothelium at sites of endothelial injury.¹ Moreover, VWF is a carrier protein for factor VIII (FVIII) and thus plays a role in fibrin clot production.¹ Clinical characteristics of AVWS that differentiate it from inherited von Willebrand disease include a later age of onset without a prior history of bleeding diathesis and a lack of family history.² It is vital to differentiate AVWS from inherited von Willebrand disease and other acquired bleeding disorders as management differs significantly. Here we present a case of AVWS secondary to IgG kappa multiple myeloma treated successfully at our institution.

Case presentation

A 74-year-old African American man was transferred from an outside hospital (OSH) due to intractable gross haematuria. His previous medical history included a diagnosis of mild haemophilia A diagnosed 3 years prior following postoperative haemorrhage after right hip arthroplasty. He subsequently required several right hip revisions secondary to prosthetic infections. He received perioperative FVIII replacement and desmopressin (DDAVP). He was admitted to the OSH with a 1-month history of gross haematuria. Prior to transfer to our institution, he underwent multiple cystoscopies, developed acute renal failure, bilateral hydronephrosis from distal urinary track obstruction secondary to haemorrhaging and clotting requiring bilateral nephrostomy tube placements. Renal biopsy and cystoscopies with biopsy did not show evidence of malignancy. He received recombinant FVIII replacement at 50 units/kg two times per day prior to transfer. FVIII level at baseline was 16%, and 89% after starting recombinant FVIII replacement. He was transferred to our institution due to persistent haematuria.

On arrival, we discovered a negative bleeding history until 3 years prior. Family history of bleeding disorders was negative. A CT scan of the abdomen and pelvis revealed new bilateral perinephric haematomas. Initial evaluation confirmed partial thromboplastin time of 52 s, normal prothrombin time, random FVIII activity of 15.4% with negative FVIII inhibitor. Von Willebrand antigen (VWF:Ag), VWF activity (VWF:Act) and multimer analysis were ordered. Recombinant FVIII replacement was restarted to achieve a goal peak FVIII activity level of 80%. Despite appropriate FVIII replacement, his haemoglobin continued to decrease and repeated CT angiography showed active bleeding from the left kidney with marked increase in size of the left perinephric haematoma. Subselective embolisation was performed in order to preserve left kidney function and control bleeding. Despite achieving target trough and peak FVIII levels, his bleeding continued. Subsequently, his von Willebrand studies resulted and confirmed VWF:Ag level of 24.3% and VWF:Act <19% with loss of high and intermediate molecular weight multimers. He received VWF/Coagulation FVIII Complex (human) (VWF/FVIII complex), with goal FVIII activity and VWF:Act trough of at least 50%. Despite appropriate dosing of VWF/FVIII complex, and obtaining target peak levels, he did not reach target trough levels of VWF:Ag and VWF:Act. Intravenous immunoglobulin (IVIg) at a dose of 0.4 g/kg/day for 5 days was administered. After the first dose of IVIg, trough levels of VWF:Ag improved (figure 1). Serum protein electrophoresis returned with an M spike of 0.8 g/dL, IgG kappa. Immunoglobulins were within normal range. Serum-free light chains confirmed a kappa of 64 mg/dL (normal range: 0.33–1.94 mg/dL), lambda of 32 mg/dL (normal range: 0.57–2.63 mg/dL) and ratio of 2 (normal range: 0.26–1.65). Bone marrow biopsy showed a hypercellular marrow (60%–70% cellularity) with kappa-restricted plasma cells expressing CD38, CD138, aberrant CD56, dim C117 and dim CD20, with complete loss of CD19 encompassing 10%–50% of the marrow elements. Cytogenetics revealed 45, X, Y in four metaphases and 46, XY in 26 metaphases with negative fluorescence in situ hybridization (FISH) studies. Myeloma-directed therapy with oral dexamethasone 40 mg/day for 4 days and subcutaneous bortezomib 1.3 mg/m² two times per week was initiated. Addition of cyclophosphamide was planned but was delayed while he was recovering from vancomycin-resistant enterococci bacteraemia. Due to an inability to completely wean off VWF/FVIII complex replacement, an IVIg course was repeated 15 days after the initial administration (figure 1). Factor replacement was then discontinued, and he was discharged after more than 1 week off VWF/FVIII complex replacement.

Figure 1.

Graphical representation of VWF activity, antigen and factor VIII activity at various time points in relation to treatment and ASCT. ASCT, autologous stem cell transplant; IVIg, intravenous immunoglobulin; VWF, von Willebrand factor.

The patient’s subsequent clinical course was highlighted by achievement of a partial response of his IgG kappa multiple myeloma after six cycles of CyBorD (cyclophosphamide, bortezomib, dexamethasone). He subsequently underwent autologous stem cell transplantation (ASCT) with melphalan 140 mg/m² conditioning approximately 7–8 months from the original diagnosis. The levels of VWF:Ag, VWF:Act and FVIII activity normalised as shown in figure 1. The VWF multimeric analysis that showed loss of high and intermediate weight multimers at diagnosis normalised after starting myeloma directed therapy and have remained normal following ASCT.

Outcome and follow-up

VWF:Ag, VWF:Act, multimer analysis and FVIII activity remain normal. Patient continues to be in remission after ASCT for multiple myeloma.

Follow-up period: approximately 11 months after ASCT and approximately 18 months from original presentation.

Discussion

Our case highlights the complexity of the diagnosis and management of AVWS. Diagnosis of AVWS is often delayed or misdiagnosed as described in our case.

As per the International Society of Thrombosis and Hemostasis registry, lymphoproliferative disorders (48%) are the most common aetiology for AVWS.³ Other less common causes include cardiovascular disease (21%), myeloproliferative neoplasms (15%), solid tumours (5%), autoimmune disorders (2%)³ and rarely hypothyroidism.⁴ Various pathogenic mechanisms have been proposed. Autoantibodies directed against VWF inhibiting function of VWF⁵ or clearance antibodies leading to rapid clearance of VWF from plasma is seen in lymphoproliferative disorders.^{6 7} Adsorption of VWF on cancer cells is commonly seen in multiple myeloma or myeloproliferative neoplasm.⁸ Loss of high-molecular weight multimers of VWF due to exposure to high shear stress is seen in patients with aortic stenosis or left ventricular assist devices.⁹ Furthermore, decreased synthesis of VWF is a proposed mechanism in hypothyroidism.¹⁰

Our patient did not have antibodies against FVIII, thus ruling out acquired haemophilia. Further evaluation should include VWF studies such as VWF:Ag, VWF:Act and VWF multimer analysis. Reduction in VWF:Ag, VWF:Act, VWF:Act/Ag ratio and selective absence or decrease in high-molecular weight multimers should prompt further evaluation to differentiate AVWS from inherited VWD. Apart from late onset of bleeding diathesis and a negative family history, laboratory evaluation for detection of VWF antibodies and searching for an underlying aetiology could aid in the diagnosis. However, inhibitory antibodies that bind to the functional domain of VWF are infrequently detected¹¹ in AVWS. Alternatively, clearance antibodies that bind to the non-functional domain of VWF with rapid clearance by the reticuloendothelial system have been proposed as a mechanism of AVWS.¹¹ However, this phenomena do not occur in vitro and thus VWF:Act normalises with addition of normal plasma and clearance antibodies are not typically detected¹¹ in laboratory evaluation. In our patient, infusion of VWF/FVIII complex did not result in appropriate increase in trough values of VWF:Act and VWF:Ag, coupled with negative VWF inhibitor studies led us to consider increased clearance. Subsequently, the evaluation for an underlying aetiology confirmed IgG kappa multiple myeloma.

The treatment of AVWS consists of controlling and preventing bleeding in addition to treatment of the underlying aetiology. The options for treatment and prevention of bleeding in AVWF include DDAVP, recombinant Factor VIIa, VWF/FVIII complex, aminocaproic acid and IVIg. Responses to DDAVP are highly unpredictable and only transient.¹² Aminocaproic acid may be useful as adjunct therapy in patients with minor bleeding; however, should be avoided in urinary track bleeding where it can lead to clot formation and obstruction. Disadvantages of factor VIIa and VWF/FVIII concentrates include short half-life and a risk of thrombosis. Until he received IVIg, our patient did not achieve meaningful increases in trough levels of VWF:Ag and VWF:Act. Our findings are consistent with what is reported in the literature¹³ in patients with monoclonal gammopathy. IVIg has been used successfully in patients with AVWS secondary to IgG kappa MGUS or MM,^{12 14} but not in IgM or IgA paraproteinemia.^{12 15} The mechanisms by which IVIg diminishes clearance of circulating VWF in IgG MGUS is not fully established but may involve inhibition of pathogenic VWF antibodies by transfused anti-idiotype antibodies and blockage of macrophage Fc receptors.^{14 16} The response to IVIg is relatively long lasting and has been used every 20–30 days as needed to maintain the response.^{17 18}

Definitive treatment of the underlying aetiology may provide long term suppression of the paraprotein as well as remission of AVWS as seen in our case. Close monitoring of AVWS even after transplant is necessary, as relapse of AVWS can occur, particularly in the setting of relapsed multiple myeloma.¹⁹

Learning points.

• The diagnosis of acquired von Willebrand syndrome (AVWS) can be difficult and is often delayed.

• Because of the risk of bleeding accurate diagnosis and management is critical.

• Obtaining a thorough bleeding history is vital.

• Our case highlights the risk of significant morbidity and mortality associated with a delay in diagnosis.

• Physicians must be aware of AVWS associated disorders, the evaluation and treatment of which is necessary for long-term remission of AVWS.