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A 62-year-old woman with increased bleeding tendency
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A 62-year-old white woman was initially evaluated in November 2006 for a new-onset bleeding episode. She had been followed for lymphocytosis for a few months and subsequently developed lymphadenopathy. A lymph node biopsy was done and confirmed the diagnosis of chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). The lymph node biopsy was complicated by excessive blood loss, which prompted the referral.
The patient denied any bleeding symptoms in the past such as epistaxis, gum bleeding or excessive bleeding after dental extractions. Prior to the onset of menopause 20 years ago, she did have moderate menorrhagia. She had never been pregnant. In the last couple of months, she had noticed easy bruising and one episode of spontaneous vaginal bleeding, which resolved without intervention.
There was no family history of bleeding disorder. Past medical history was significant for depression and osteoporosis. Her medications were alendronate sodium (Fosamax, Merck) and fluoxetine. She lived alone and denied alcohol or tobacco use. Physical examination was significant for bilateral cervical and axillary lymphadenopathy.
Her initial laboratory data revealed white blood cell count of 15.6, hemoglobin of 13.4, platelets of 334,000, prothrombin time of 12 seconds and partial thromboplastin time of 25.3 seconds. The Factor VIII activity, von Willebrand antigen and ristocetin co-factor activity levels over time are shown in table 1.
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A PET/CT scan done showed increased FDG uptake in axillary, nasopharyngeal, cervical, retroperitoneal and pelvic regions. The patients von Willebrand gel multimer assay showed loss of high molecular weight multimers. When challenged with desmopressin (DDAVP, Sanofi Aventis), she did not have a significant response in her von Willebrand factor antigen levels.
Due to lack of major spontaneous bleeding episodes, she was advised to use von Willebrand factor replacement therapy (Humate-P; CSL Behring) prophylactically prior to invasive procedures. Humate-P was administered before placement of a Mediport and prior to a colonoscopy. There were no bleeding complications.
Regarding the diagnosis of her CLL/SLL, the patient was followed conservatively until late 2008 when increasing adenopathy was noted; she then underwent treatment with rituximab (Rituxan, Genetech) and fludarabine for eight cycles, concluding in March 2009.
Case Discussion
Acquired von Willebrand’s disease (AvWD) is an uncommon bleeding disorder that requires a high index of clinical suspicion for diagnosis and is challenging to treat successfully. It is commonly seen in patients with an underlying lymphoproliferative disease or monoclonal gammopathy. These patients usually present with symptoms of bleeding without a prior personal or family history of a bleeding diathesis. Laboratory exam shows a low or normal antigen assay with low or absent ristocetin co-factor activity. Analysis of the multimeric structure of the patient’s von Willebrand factor often shows a decrease in the high molecular weight multimers.
Diseases associated with AvWD are monoclonal gammopathy of unknown significance, multiple myeloma, non-Hodgkin’s lymphoma, myeloproliferative disorders and chronic lymphocytic leukemia. Other disorders associated with this condition are Wilm’s tumor, adrenal carcinoma, autoimmune diseases such as hypothyroidism, systemic lupus erythematosus, scleroderma and drugs such as ciprofloxacin, griseofulvin, valproic acid and hydroxyethyl starch.
Multiple mechanisms have been postulated regarding pathophysiology of AvWD. These include antibody formation associated with decreased function or increased clearance of von Willebrand factor, proteolysis, binding to cells with increased clearance, and decreased synthesis as in hypothyroidism. In most cases, it is due to the development of an inhibitor. However, the antibody is directed against a nonfunctional domain on the von Willebrand factor multimer in contrast to acquired Factor VIII inhibitor.
In some cases, von Willebrand factor may be adsorbed onto cells (eg, in Wilm’s tumor, multiple myeloma and Waldenstrom’s macroglobulinemia), probably leading to increased clearance. In patients with myeloproliferative disorders, an inverse relationship has been observed between platelet counts and large von Willebrand factor multimers. This might be due to increased binding and removal of large von Willebrand factor multimers from plasma by the platelets.
Treatment of AvWD depends in part upon the pathogenetic mechanism. It may involve empiric trials to select the best treatment regimen (eg, demopressin, von Willebrand factor replacement therapy or intravenous immune globulin) as well as treatment of the underlying condition, if possible.
A trial of desmopressin should be considered, with monitoring of Factor VIII and von Willebrand factor levels at baseline, one, two, and four hours following administration to assess the response. It is less effective in patients with circulating inhibitors to von Willebrand factor.
If desmopressin is ineffective, the patient should consider a trial of von Willebrand factor replacement therapy. Patients with circulating inhibitors may require large doses of von Willebrand factor. High-dose intravenous immunoglobin (1 gm/kg per day for two days) has been used in patients with AvWD associated with autoimmune disease or monoclonal gammopathies who do not respond to desmopressin. It acts at least in part by increasing the half-life of circulating von Willebrand factor. There are case reports of patients successfully treated with recombinant Factor VIIa in whom treatment with desmopressin, von Willebrand factor and intravenous immunoglobulin were unsuccessful.
Ramya Varadarajan, MD, is a Medical Oncology Fellow at Roswell Park Cancer Institute, Buffalo, N.Y., and is a member of the HemOnc Today Editorial Board.