Acquired von Willebrand Syndrome Associated to Secondary IgM MGUS Emerging after Autologous Stem Cell Transplantation for AL Amyloidosis
1 Department of Medicine, University of Alberta, Edmonton, AB, Canada.
2 Southern Alberta Rare Blood & Bleeding Disorders Comprehensive Care Program, Department of Medicine, Calgary, AB, Canada.
3 Tom Baker Cancer Center, Department of Medical Oncology and Hematology, Calgary, AB, Canada.
Received: February 15, 2017
Accepted: April 10, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017034 DOI 10.4084/MJHID.2017.034
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von Willebrand syndrome (AVWS) is a rare hemorrhagic disorder that
occurs in patients with no prior personal or family history of
bleeding. Here, we describe a case of AVWS occurring after autologous
stem cell transplantation (ASCT). Interestingly, AVWS developed after
bortezomib-based induction and conditioning regimens. Recent evidence
suggests that the proximity of the bortezomib therapy to the collection
of stem cells with consequent depletion of regulatory T cells after the
conditioning regimen could explain some of the unusual autoimmune
complications reported in patients receiving bortezomib prior to ASCT.
In addition, this patient developed a secondary MGUS post-ASCT, which
may have also contributed to the AVWS. To the best of our knowledge,
this is the first case of post-ASCT AVWS reported. Prospective data is
needed to better elucidate the mechanisms by which these unusual
complications occur in patients receiving bortezomib prior to ASCT.
Lupus type inhibitor was not detected, and fibrinogen and all other measured factor levels were normal. Other lab testing revealed: Hemoglobin 75 g/L, Platelets 110 x10e9, creatinine 139 umol/L, ANA-, RF-, Hep B and Hep C negative, cryoglobulin and agglutinin testing negative. Based on these investigations, the patient was diagnosed with Acquired von Willebrand syndrome (AVWS). No coagulation factor replacement was required and desmopressin (DDAVP) challenge test demonstrated a good increase in von Willebrand factor and factor VIII levels, without rapid clearance (Factor levels were measured at 30 mins, 1 and 4 hours) (Table 1). The patient was treated with prednisone at 1 mg/Kg with slow dose tapering. No further bleeding has been reported and normalization of von Willebrand factor levels is maintained at 12 months. (Figure 1).
|Table 1. VWF, VWFpp, and VWFpp:Ag at diagnosis, during DDAVP testing, and in remission.|
|Figure 1. Levels of von Willebrand factor VIII Ag and Ristocetin Cofactor activity. (In the X axis, days from episode of bleeding is shown, while in the Y axis levels in U/mL are recorded).|
|Figure 2. Multimer gel image demonstrated the presence of high molecular weight multimers.|
The treatment goals in AVWS are to control acute bleeds, to prevent bleeding in high-risk situations, and to obtain long-term remission. In this case, DDAVP was able to stimulate enough endogenous secretion of VWF to overcome the clearance caused by the anti-VWF antibody, and maintain normal VWF levels at 1 and 4 hours following DDAVP administration. In other cases of AVWS, DDAVP is often ineffective for treatment as the anti-VWF antibody is either neutralizing, or the clearance of VWF:Ag by the anti-VWF antibody is much greater than the amount of endogenous VWF:Ag that can be secreted by Weibel-Palade bodies. However, in our case, the anti-VWF antibody is non-neutralizing and clearance by this antibody is not so rapid such that the DDAVP-stimulated release of endogenous VWF can overcome the anti-VWF antibody-mediated clearance. This is evidenced by the increased VWF levels following DDAVP stimulation and the decreased VWFpp:Ag ratio.
Bleeding and bruising are common in immunoglobulin light chain (AL) amyloidosis and can occur through a number of mechanisms, thus AVWS is not often considered when bleeding symptoms occur. Kos et al, recently reported a small series of cases where the association of active AL amyloid and the appearance of AWVS was noted. In our current report, in contrast, this association was observed even in the setting of complete haematological response. To our knowledge this is the first case report of post-transplant IgM lambda secondary MGUS treated with high dose prednisone. However, a previous report by Lazarchick et al., described a 41 y/o male who after undergoing allogeneic bone marrow transplantation for the treatment of acute myeloid leukemia was admitted with worsening chronic GVHD and subsequently was found to have markedly reduction of von Willebrand factor antigen consistent with a diagnosis of AVWS. Our current report also illustrates the emerging complications for patients with AL amyloidosis receiving bortezomib-containing regimens prior to stem cell transplantation. Further data in this regard is needed to better understand the mechanisms by which these complications occur and how to minimize the morbidity related to these events.
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