American Society of Hematology

Case Study: Putting Two and Two Together

The following case study focuses on a 48-year-old G4P4 female admitted with severe symptomatic menorrhagia requiring transfusion despite IV premarin, tranexamic acid, and DDAVP. Test your knowledge by reading the background information below and making the proper selection.

No other mucocutaneous bleeding or hematoma and no gynecologic cause for the bleeding were noted. The patient was diagnosed with IgG-kappa monoclonal gammopathy of undetermined significance (MGUS) 10 years prior with an M-protein level of 26 g/L. A year later she noted a heavier period, which progressed to symptomatic anemia requiring transfusion. A bone marrow biopsy was performed at the time to investigate her anemia, which revealed trilineage hematopoiesis with 12 percent to 15 percent plasma cells. Over the ensuing years, her MGUS did not progress and her M-protein remained stable. She had dental surgeries, tonsillectomy, and cholecystectomy in the past with no peri-operative bleeding complications and no history of prolonged bleeding after trauma. The patient’s peri-partum course for all four of her pregnancies was unremarkable and her menses were also regular with normal flow up to nine years ago. Family history was not suggestive of a congenital bleeding disorder. Investigations on admission revealed Hb 5.7 g/dL, MCV 84.6, platelets 358,000 cells/µL, white blood cell count 9.62 x103 cells /µL, and absolute neutrophil count 6.72 x103 cells/µL. Prothrombin time was 11.5 s, activated partial thromboplastin time 38.0 s, thrombin time 7.6 s, and fibrinogen 104 mg/dL. vWF:Ag was 0.05 U/mL, vWF:RCo < 0.06 U/mL, fVIII activity 0.11 U/mL, and decreased ristocetin-induced platelet aggregation (RIPA) and multimer analysis showed absence of large and intermediate vWF multimers.

What is her diagnosis?

a. von Willebrand Disease (vWD)Type 1
b. vWD Type 2
c. vWD Type 3
d. Acquired von Willebrand Syndrome
e. Pseudo (platelet-type) vWD

What is the most effective therapy for this patient?

a. DDAVP
b. vWF concentrates
c. Intravenous immunoglobulin (IVIg)
d. Corticosteroids
e. Rituximab

Answers: 1. d; 2. c

Explanation

The patient’s laboratory findings suggest that her menorrhagia is related to a coagulopathy. The pattern of the vWF testing was not suggestive of a Type 1 vWD, since multimeric analysis and RIPA are normal in Type I. Also, it is not Type 3 vWD, because all multimers and RIPA are absent in Type 3. The pattern here is suggestive of Type 2A or 2B vWD, given the low vWF:Ag and vWF:RCo and vWF:RCo to vWF:Ag ratio is <0.7. Type 2M and 2N vWD have normal multimeric pattern, and Type 2N would have normal vWF:Ag and vWF:RCo. Pseudo (platelet-type) vWD would be indistinguishable from Type 2B vWD phenotypically. But the feature that distinguishes this case from all of the other congenital vWDs discussed previously is the patient’s bleeding history. The patient essentially had a normal bleeding history right up to nine years ago, coinciding with the diagnosis of her MGUS (i.e., it is acquired as opposed to being congenital).

As the name implies, acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is acquired later in life, as opposed to inherited like other types of vWD. The laboratory pattern of AVWS mimics Type 2B vWD. Etiologies of AVWS include lymphoproliferative disorders, myeloproliferative disorders, plasma cell dyscrasias, solid tumors, drugs (ciprofloxacin, valproic acid, griseofulvin, hydroxyethyl starch, cefotaximee), Epstein-Barr virus (EBV) infection, connective tissue disorders, and cardiovascular disorders. Three main mechanisms are responsible for AVWS: auto-antibodies against vWF, absorption of vWF onto malignant cells, and loss of high-molecular-weight vWF multimers under high shear stress, none of which are etiologically specific. The cause of this patient’s AVWS was the MGUS, usually a monoclonal IgG acting as an auto-antibody against vWF, although IgM has been described. Targets of inhibition by these auto-antibodies include preferential binding to large and intermediate vWF, collagen-binding sites (A1 and A3 domains) of vWF, and binding region of vWF to GPIb. The goals of treatment in AVWS are to control the current bleeding episode, prevent further bleeding in the future, and control the underlying disease. In cases of AVWS due to MGUS, DDAVP and vWF concentrates offer only a very transient response. This was hypothesized to be due to rapid clearance of IgG-vWF/fVIII antibody complex. These patients generally demonstrate poor response to immune suppression treatments, such as corticosteroids, rituximab, and chemotherapy. Intravenous immunoglobulin (IVIg) 1 g/kg/day x 2 days achieved good response in the IgG, but not IgM, subtype in a small therapeutic trial. Duration of response is typically six to 30 days. Some authors have advocated the concurrent use of DDAVP or vWF concentrates with IVIg in cases of emergency bleeding or surgery (Collins 2008), as IVIg usually normalizes plasma vWF/fVIII activity in 24 to 48 hours.

Further Reading

  1. Collins P, Budde U, Rand JH, et al. Epidemiology and general guidelines of the management of acquired haemophilia and von Willebrand syndrome. Haemophilia. 2008;14:49-55.
  2. van Genderen PJ, Vink T, Michiels JJ, et al. Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. Blood. 1994;84:3378-3384.
  3. Mohri H, Tanabe J, Ohtsuka M, et al. Acquired von Willebrand disease associated with multiple myeloma; characterization of an inhibitor to von Willebrand factor. Blood Coagul Fibrinolysis. 1995;6:561-566.
  4. Michiels JJ, Budde U, van der Planken M, et al. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol. 2001;14:401-436.
  5. Michiels JJ, Berneman Z, Gadisseur A, et al. Immune-mediated etiology of acquired von Willebrand syndrome in systemic lupus erythematosus and in benign monoclonal gammopathy: therapeutic implications. Semin Thromb Hemost. 2006;32:577-588.
  6. Grimaldi D, Bartolucci P, Gouault-Heilmann M, et al. Rituximab failure in a patient with monoclonal gammopathy of undetermined significance (MGUS)-associated acquired von Willebrand syndrome. Thromb Haemost. 2008;99:782-783.
  7. Huang YW, Saidi P. Acquired von Willebrand disease in a patient with monoclonal gammopathy of undetermined significance. Am J Med Sci. 2004;327:98-101.
  8. Federici AB, Stabile F, Castaman G, et al. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches. Blood. 1998;92:2707-2711.
  9. Haj MA, Murch N, Bowen DJ, et al. Cefotaxime as the potential cause of transient acquired von Willebrand syndrome. Eur J Haematol. 2006;76:440-443.

Case study submitted by Kevin Kuo, MD, University of Toronto.

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