Essential Thrombocythemia

Disease Overview

ET, or primary thrombocythemia, is a chronic MPD characterized by a clonal proliferation of megakary-ocytes in the bone marrow. The peripheral blood platelet counts exceed 600,000/pL and can be greater than 1 million. This disease is characterized by an

Table 12.11 O Key Facts for Essential Thrombocythemia

• Marked thrombocytosis (platelet count >600 X 109/L)

• Usually no fibrosis

• Neurological manifestations

• Abnormal platelet function

• Megakaryocyte fragments in both peripheral blood and bone marrow

• Absent Philadelphia chromosome increased platelet count, a megakaryocytic hyperplasia, and an absence of increased RCM. The clinical course is complicated by hemorrhage or thrombotic episodes. Etiology is unknown, and the disorder usually occurs between the ages of 50 and 70.1 Table 12.11 summarizes the key factors for ET.

Pathophysiology

ET is considered to be a clonal disorder of the multipotential stem cell.35 ET has many biological characteristics in common with PV and the other myeloproliferative disorders. This disorder can affect all three cell lines, but the main characteristic is the increase in the megakaryocyte. Bone marrow and peripheral blood are the principal sites of involvement in this disorder. Megakaryocytes are hypersensitive to several cytokines, including IL-3, IL-6, and thrombopoietin, which leads to increased platelet production.40 Platelet survival and platelet aggregation studies are normal.

The increased platelet count can cause increased thrombotic and hemorrhagic episodes. Qualitative abnormalities in the platelet contribute to the increased risk of thrombotic and hemorrhagic complications. Age, previous thrombotic event, increased or greater than 600 X 109/L platelet counts, duration of diseases, and prior symptoms are considered high-risk factors. The increase in thrombotic risk with age has been attributed to vascular disease or hypercoagulable platelets.

Clinical Features and Symptoms

Most often, patients present asymptomatic at the time of diagnosis. The elevated platelet count is discovered on a routine CBC. The clinical signs and symptoms are similar to those of PV The most frequent symptoms are weight loss, low-grade fever, weakness, pruritus, hemorrhage, headache, and dizziness. Bleeding is usually mild and may present as epistaxis and the tendency to bruise easily. The gastrointestinal tract is the primary site for bleeding complications. Patients who present with microvascular occlusion may have transient ischemic attacks with symptoms of unsteadiness, syncope, and seizures. Thrombosis of the large veins and main arteries is common. Occlusion of the leg arteries and renal arteries may be involved.

Approximately 50% of the patients at the time of diagnosis will present with an enlarged spleen and approximately 20% of patients will present with an enlarged liver.1

Peripheral Blood and Bone Marrow Findings

The hallmark for ET is an unexplained elevated platelet count. The blood platelet count is usually in excess of 1 million. The platelets will have anisocytosis ranging from small to large forms. Figure 12.5 illustrates the increased platelet count. The peripheral blood may reveal a leukocytosis with an occasional immature cell (myelocytes and metamyelocytes), erythrocytosis, and a mild normocytic, normochromic anemia. A mild basophilia and eosinophilia may be seen. Leukoery-throblastosis and teardrop cells are not features of ET.

The bone marrow shows an increase in cellularity. Megakaryocytic hyperplasia is the most striking feature. Giant megakaryocytes and clusters of megakaryocytes are frequently seen. The megakaryocytes have abundant, mature cytoplasm and hyperlobulated nuclei. Proliferation of erythroid precursors may be found in some cases. The network of reticulin fibers is normal or slightly increased.1 Increased reticulin or collagen fibrosis points more toward MMM than ET. Stainable iron is present.

Figure 12.5 Increased thrombocytes in ET.

Table 12.12 O Causes of Relative Thrombocytosis

• Inflammatory states

• Postsplenectomy

• Acute hemorrhage

• Malignancy

• Postoperative

• Hemolytic anemia

Diagnosis

Discriminating ET from reactive thrombocytosis and the other myeloproliferative disorders is a diagnostic challenge. For the diagnosis of ET, reactive thrombocytosis needs to be excluded. Secondary or reactive thrombocytosis is associated with many acute and chronic infections. Table 12.12 summarizes the causes of relative thrombocytosis. In reactive thrombocytosis, the platelet count is less than 1 million and is transient. Leukocytes and erythrocytes are normal. Platelet function is normal, and the spleen and liver are not enlarged.

Diagnostic requirements for ET include a normal RBC mass (increased with PV), a hemoglobin of less than 13 g/dL (elevated in PV), absence of the Philadelphia chromosome (associated with CML), and the absence of teardrop RBCs or significant increase in bone marrow fibrosis (as seen in MMM). Diagnosis for ET follows the gold standard criteria of the PVSG.3 Table 12.13 summarizes the diagnostic criteria for ET.3,41

There are no characteristic cytogenetic or molecular abnormalities associated with or that establish the diagnosis for patients with ET.41,42

Treatment

The goal of treatment of ET is to prevent or reduce the risk of complications from vaso-occlusion or hemorrhage. The treatment of ET can vary from no treatment, if patients are asymptomatic, to low-dose aspirin for low-risk patients, to treatment with hydroxyurea, ana-grelide, or alfa-interferon to reduce the platelet count.43,44 Patients with life-threatening hemorrhagic or thrombotic events should be treated with platelet phoresis in combination with myelosuppressive therapy to reduce the platelet count below 1 million.40 The maintaining of a platelet count of less than 400,000/pL is needed to reduce the risk of a thrombotic event.

198 Part III • White Cell Disorders

Table 12.13 O Diagnostic Criteria for Essential Thrombocythemia

I. Platelet count >600 X 109/L

II. Hematocrit <40 or normal RBC mass (males <36 mL/kg, females <32 mL/kg)

III. Stainable iron in marrow or normal serum ferritin or normal RBC mean corpuscular volume

IV Absent Philadelphia chromosome or BCR-ABL gene rearrangement

V Collagen fibrosis of marrow

A. Absent or

B. <1/, of biopsy involved and neither marked splenomegaly nor a leukoerythroblastic reaction

VI. No cytogenetic or morphological evidence for a myelodysplastic syndrome

VII. No cause for reactive thrombocytosis

Adapted from Murphy S, Peterson P, Iland H, Laszio J. Experience of the Polycythemia Vera Study Group with essential thrombocythemia: A final report on diagnostic criteria, survival and leukemic transition by treatment. Semin Hematol 34:29, 1997; and Nimer S. Essential thrombocythemia: Another "heterogeneous disease" better understood? Blood 93:415-416, 1999.

Prognosis

Prognosis is dependent on the age of the patient and the history of thrombotic events (Table 12.14). The survival rate is 10 years for 64% to 80% of the patients, particu larly the younger patients.4,46 Less than 10% of patients with ET will convert to AML and less than 5% will convert to MMM.47 Most patients die from thrombotic complications.

Table 12.14

Differentiation of Myeloproliferative Disorders

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