ASH Image Bank (2001); doi:10.1182/ashimagebank-2001-100172
Copyright © 2001 by the American Society of Hematology.
Essential Thrombocythemia: Acquired von Willebrand Syndrome
John Lazarchick, MD
Medical University of South Carolina
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Figure 1. Peripheral smear showing marked thrombocytosis with large platelets present. Hypochromic red blood cells (RBCs) are reflective of iron deficiency resulting from this patient's bleeding diathesis.
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Figure 3. Bone marrow aspirate showing megakaryocytic hyperplasia with large multilobated, dysplastic forms present.
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Figure 4. Bone marrow biopsy showing clustering of megakaryocytes with mature cytoplasm, and variable nuclear lobulations.
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Figure 5. Variability in megakaryocyte nuclear size, nuclear lobulations, and degree of displasia can better be seen in this cluster group.
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Figure 6. Immunohistochemical stain of megakaryocytes on bone marrow biopsy with antibody to von Willebrand factor antigen.
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Figure 7. Immunohistochemical stain of megakaryocytic cytoplasm using antibody to VWF antigen. Note clustering of cells.
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Figure 8. von Willebrand factor protein multimer analysis on agarose gel electrophoresis. Lane 1: normal control plasma; high molecular weight forms at the top; low molecular weight forms at the bottom. Lane 2: Type 2B (for illustration); high molecular weight multimers are absent. Lane 3: patient with acquired von Willebrand syndrome (AVWS) secondary to ET. Note both high and intermediate molecular weight multimers are absent.
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Clinical Summary
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A 10-year-old African American girl was seen by her pediatrician because of a two-day history of intermittent oozing and frank bleeding from the site of a recent dental procedure. She related that the bleeding began several hours after the procedure. She had no previous history of a bleeding diathesis and her family history was also negative. She has had no other surgical procedures in the past. Medications included Tylenol 2 to 3 days prior to the dental procedure.
A complete blood cell count (CBC) done in the pediatrician's office revealed a platelet count of 1.8M/uL.
Upon examination, no active bleeding was noted except for oozing from the gums at the site of the dental procedure. The spleen was palpable and splenomegaly was confirmed on ultrasound of the abdomen. There was significant adenopathy and the liver was not enlarged.
Lab: Hemoglobin (Hgb) 12.8, white blood cells (WBC) 9400/uL with normal diff.
Platelet count 1.7M/uL; prothrombin time (PT) was normal but the activated partial thromboplastin time (aPTT) was slightly prolonged. Mixing studies with normal plasma showed correction of the aPTT, consistent with a coagulation factor deficiency. Factor VIII was 36%. von Willebrand factor (VWF) studies included a Ristocetin cofactor activity of 17%, vWF antigen of 66%, and VWF multimer pattern consistent with Type 2A von Willebrand disease (VWD).
With lack of previous bleeding history, probable diagnosis of essential thrombocythemia (ET) (cytogenetics were 46XX), VWF:Ag II level was measured to distinguish between hereditary versus acquired VWD. The level was normal, confirming that this was an acquired bleeding disorder secondary to ET. The patient is being followed by her pediatric hematologist and only being treated symptomatically at the present time.
Sex
Female
Age
10
Ethnicity
African American
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Diagnosis
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Chronic myelogenous leukemia, Polycythemia Vera, Myelodysplastic syndrome, Reactive thrombocytosis.
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Discussion
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Essential thrombocythemia (ET) is a clonal myeloproliferative disorder primarily involving the megakaryocytic lineage. It is characterized by sustained thrombocytosis and marked increase in megakaryocytes in the bone marrow. Clinically, most patients are asymptomatic, but approximately 20% will have evidence of either arterial or venous thrombosis or a hemorrhagic diathesis, which are the major causes of morbidity and mortality in this disorder. It has a bimodal occurrence being seen most often in the 6th decade and an earlier peak in the 4th decade. It is uncommon in children.
Thrombosis can involve any size vessel but is most common in the cerebral, coronary, and peripheral vasculature with stroke, myocardial infarction, and digital ischemia or gangrene often present. Hepatic or splenic vein thrombosis is not uncommon. The hemorrhagic diathesis is related to platelet dysfunction and is manifested by mucocutaneous bleeding, which is either spontaneous, after minor trauma, or post-operatively.
Platelet counts range from 500,000 to 1 million/uL and platelets are of variable size with many large forms present on examination of the peripheral smear. Many appear dysplastic being hypogranular or having pseudopods. The bone marrow is normo- or hypercellular with marked proliferation of megakaryocytes being the most prominent feature. Many of these larger-than-normal megakaryocytes are multilobated and appear in clusters. Reticulin is not increased.
The vast majority of the bleeding episodes in these patients can be attributed to impaired platelet hemostatic function. The bleeding time is prolonged and there is a decreased aggregation response suggestive of an acquired storage pool defect. An unusual hemorrhagic syndrome in this disorder is the development of acquired von Willebrand syndrome.
This rare syndrome is most commonly associated with hematoproliferative disorders, especially monoclonal gammopathies and lymphoid malignancies. Clonal myeloproliferative disorders are much less common, but of these, it is seen most often in ET. The mechanism is presumed to be adsorption of the high molecular weight VWF multimers to glycoprotein Ib on activated platelets. Laboratory studies are similar to those seen in hereditary VWD: prolonged bleeding time, prolonged aPTT, deficiency of factor VIII activity, reduced von Willebrand factor antigen (VWF:Ag) and Ristocetin co-factor activity. VWF:Ag multimer analysis shows either decreased levels of all multimers (Type 1) or selective reduction of large multimers (Type 2A). Unlike in hereditary VWD where plasma VWF propeptide levels are decreased or absent, in this disorder the VWF propeptide levels are normal or increase.
Although ET is an indolent disease with a median survival of 10 to 15 years, thromboembolism or hemorrhage in this disorder can be life-threatening. Standard anticoagulation therapy is indicated for the former. Platelet pheresis should be used to reduce abruptly the platelet count in the case of severe hemorrhage and the patient begun on hydroxyurea, anagrelide, or recombinant interferon a. Therapy of acquired von Willebrand syndrome is difficult. In addition to the improvement noted by therapy directed at the primary disorder, brief improvement has been reported by the use of DDAVP and IVIg.
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Differential Diagnosis
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Chronic myelogenous leukemia, Polycythemia Vera, Myelodysplastic syndrome, Reactive thrombocytosis
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Chapter 8: Myeloproliferative disorders
Copyright © 2001 by the American Society of Hematology.
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