Essential Thrombocythemia

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Chapter 29 Essential Thrombocythemia

Ronald Hoffman, Marina Kremyanskaya, Vesna Najfeld, John Mascarenhas

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Figure 29-1 PROBABILITY OF THROMBOSIS-FREE SURVIVAL IN 114 PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA TREATED WITH HYDROXYUREA OR LEFT UNTREATED.

(From Cortelazzo S, Finazzi G, Ruggeri M, et al: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332:1132, 1995.)

Table 29-1 Frequency of Neurologic Complaints Associated With Essential Thrombocythemia

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Data from Jabaily J, Iland HJ, Laszlo J, et al: Neurologic manifestations of essential thrombocythemia. Ann Intern Med 99:513, 1983.

Table 29-2 Risk Stratification in Essential Thrombocythemia Based on Thrombotic Risk*

Risk Category Age >60 Years or History of Thrombosis Cardiovascular Risk Factors
Low No No
Intermediate No Yes
High Yes Yes

*Cardiovascular risk factors: hypertension, hypercholesterolemia, diabetes, smoking, and congestive heart failure. Extreme thrombocytosis (platelet count >1500 × 109/L) is a risk factor for bleeding. Its role as a risk factor for thrombosis in essential thrombocythemia is uncertain.

Data from Finazzi G, Barbui T: Risk-adapted therapy in essential thrombocythemia and polycythemia vera. Blood Rev 19:243, 2005.

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Figure 29-2 ESSENTIAL THROMBOCYTHEMIA (ET): PERIPHERAL BLOOD SMEAR AND BONE MARROW BIOPSY.

The peripheral blood smear in ET shows a marked thrombocytosis with anisocytosis (varying sizes) of the platelets (A). The bone marrow (B) is hypercellular and exhibits a marked proliferation of large and giant megakaryocytes in loose clusters with other hematopoietic elements in the background. The large megakaryocytes (C) tend to be extensively lobulated.

Table 29-3 Proposed Revised World Health Organization Criteria for the Diagnosis of Primary Myelofibrosis and Essential Thrombocythemia and British Committee for Standards in Hematology Criteria for Diagnosis of Essential Thrombocythemia

Proposed Revised WHO Criteria for Primary Myelofibrosis
Major Criteria

1. Presence of megakaryocyte proliferation and atypia,* usually accompanied by either reticulin or collagen fibrosis or in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased BM cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (i.e., prefibrotic cellular phase disease)

2. Not meeting WHO criteria for PV,† CML,‡ MDS,§ or other myeloid neoplasm

3. Demonstration of JAK2617V->F or other clonal marker (e.g., MPL515W->L/K) or in the absence of a clonal marker, no evidence of BM fibrosis caused by underlying inflammatory or other neoplastic diseases‖
Minor Criteria

1. Leukoerythroblastosis

2. Increase in serum LDH level

3. Anemia

4. Palpable splenomegaly
Diagnosis requires meeting all three major criteria and two minor criteria.
BM, Bone marrow; CML, chronic myeloid leukemia; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.
*Small to large megakaryocytes with an aberrant nuclear-to-cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and sense clustering.
†Requires the failure of iron replacement therapy to increase hemoglobin level to the PV range in the presence of decreased serum ferritin. Exclusion of PV is based on hemoglobin and hematocrit levels, and RBC mass measurement is not required.
‡Requires the absence of BCR-ABL.
§Requires absence of dyserythropoiesis and dysgranulopoiesis.
‖Secondary to infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. It should be noted that patients with conditions associated with reactive myelofibrosis are not immune to primary myelofibrosis, and the diagnosis should be considered in such cases if other criteria are met.
Degree of abnormality could be borderline or marked.
Proposed Revised World Health Organization Criteria for Essential Thrombocythemia

1. Sustained platelet count ≥450 × 109/L*

2. BM biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left shift of neutrophil granulopoiesis or erythropoiesis

3. Not meeting WHO criteria for PV,† PMF,‡ CML,§ MDS,‖ or other myeloid neoplasm

4. Demonstration of JAK2V617F or other clonal marker or in the absence of a clonal marker, no evidence for reactive thrombocytosis
Diagnosis requires meeting all four criteria.
From Tefferi A, Thiele J, Orazi A, et al: Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 110:1092, 2007.
BM, Bone marrow; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.
*During the workup period.
†Requires the failure of iron replacement therapy to increase hemoglobin level to the PV range in the presence of decreased serum ferritin. Exclusion of PV is based on hemoglobin and hematocrit levels, and red blood cell mass measurement is not required.
‡Requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral blood leukoerythroblastosis, or markedly hypercellular BM for age accompanied by megakaryocyte morphology that is typical for PMF—small to large with an aberrant nuclear-to-cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering.
§Requires the absence of BCR-ABL.
||‖Requires absence of dyserythropoiesis and dysgranulopoiesis.
Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if the first three criteria are met.
British Committee for Standards in Hematology Criteria for Diagnosis of Essential Thrombocythemia
Requires A1-A3 or A1+A3-A5

A1: Sustained platelet count >450 × 109/L

A2: Presence of an acquired pathogenetic mutation (e.g., in JAK2 or MPL)

A3: No other myeloid malignancy, especially PV, PMF, CML, or MDS

A4: No reactive cause for thrombocytosis and normal iron stores

A5: BM aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm

BM, Bone marrow; CML, chronic myeloid leukemia; JAK2, Janus kinase 2; MDS, myelodysplastic syndrome; MPL, thrombopoietin receptor; PMF, primary myelofibrosis; PV, polycythemia vera.

From Harrison CN, Bareford D, Butt N, et al: Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 149:352, 2010.

Table 29-4 Clinical and Laboratory Features Helpful in Distinguishing Essential Thrombocythemia from Reactive Thrombocytosis* (Revised)

Feature ET RT
Chronic platelet increase + −
Known causes of RT − +
Thrombosis or hemorrhage + −
Splenomegaly + −
BM reticulin fibrosis + −
BM megakaryocyte clusters + −
Abnormal cytogenetics + −
Increased acute phase reactants − +
Spontaneous colony formation† + −
JAK2V617F mutation + −

BM, bone marrow; ET, essential thrombocythemia; RT, reactive thrombocytosis.

*Acute phase reactants include C-reactive protein and fibrinogen.

†Erythroid colonies.

Modified from Tefferi A, Hoagland HC: Issues in the diagnosis and management of primary thrombocythemia. Mayo Clin Proc 69:651, 1994.

Table 29-5 Risk Factors for Thrombosis in 100 Patients With Essential Thrombocythemia

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CI, Confidence interval; NS, not significant.

* Reference category.

Data from: Finazzi G, Barbui T: Risk-adapted therapy in essential thrombocythemia and polycythemia vera. Blood Rev 19:243, 2005.

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Figure 29-3 EVENT-FREE SURVIVAL IN A HYDROXYUREA-TREATED GROUP COMPARED WITH AN ANAGRELIDE-TREATED GROUP.

Primary end points were arterial or venous thrombosis, serious hemorrhage, or death from any of these causes.

(From Harrison CN, Campbell PJ, Buck G, et al: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353:33, 2005.)

Table 29-6 Choice of Drugs for Treatment of Patients With High-Risk Essential Thrombocythemia

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Personal Approach to Therapy of Essential Thrombocythemia

The optimal therapy for patients with ET remains uncertain. Therapy is geared toward interventions to reduce the potential for developing thrombotic episodes. Patients with the greatest risk of developing a thrombus have a number of characteristics, including age 60 years or older, history of a thrombotic event, leukocytosis (WBC ≥11,000 × 109/L), and cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus, obesity). Patients with ET or prefibrotic form of MF can frequently present with elevated platelet counts and are treated in a similar fashion by us. No known therapy is available that is capable of reversing the BM fibrosis in such patients or delaying or eliminating evolution to MF. Certain concepts, however, apply to all patients. All patients with ET should stop smoking to minimize the risk factors associated with atherosclerotic disease. Indiscriminant use of high doses of NSAIDs should be avoided because this practice can lead to an increased risk of hemorrhage. Use of such agents is particularly frequent in elderly patients in whom ET is common. In patients with a life-threatening thrombotic or hemorrhagic episode, plateletpheresis should be initiated in addition to starting them on hydroxyurea therapy.

In high-risk patients, cytoreductive therapy has been shown to lessen the chance of developing additional thrombotic events with the reduction of extreme thrombocytosis to platelet counts below 600,000 × 109/L. High-risk patients include patients older than 60 years of age and patients with a history of a previous thrombotic episode, including erythromelalgia, transient ischemic attacks, or large vessel thrombosis. Even though this treatment philosophy has been considered common practice, the recommendation to treat patients older that the age of 60 years who have not experienced a thrombotic episode with cytoreductive therapy is not based on robust data from multiple randomized trials. Asymptomatic high-risk patients without cardiovascular risk factors may not necessarily benefit from this treatment, and the decision on how to treat them should be based on individual assessment.

At present, no therapy is indicated in asymptomatic patients younger than 60 years of age. If a patient has a platelet count greater than or equal to 1500 × 109/L and acquired von Willebrand syndrome with bleeding symptoms, platelet reduction therapy is indicated to avoid the high risk of hemorrhage. In totally asymptomatic patients with platelet counts greater than 1500 × 109/L, we frequently observe the patients and do not feel compelled to treat them. Patients with acquired von Willebrand syndrome should clearly avoid the use of aspirin.

In patients requiring platelet reduction therapy, the choice among the use of anagrelide, INF-α, pegylated INF, or hydroxyurea therapy is based on patient age, ease of administration, and drug-related toxicity. Randomized trials comparing these treatments in high-risk patients are ongoing. Until the results are available, we use the following strategy. In patients older than 50 years, hydroxyurea therapy is the treatment of choice, but in younger patients, we prefer to initiate therapy with INF-α. INF therapy should be avoided in patients with a history of depression, autoimmune disorders, or retinitis. If the patient cannot tolerate INF-α or it is not available, we feel comfortable treating symptomatic patients younger than 50 years of age with anagrelide or hydroxyurea. Although we remain concerned about the leukemogenic potential of hydroxyurea, the risk appears to be low if not associated with the prior use of an alkylating agent. The development of malleolar ulcers is a frequent complication of hydroxyurea treatment and is a signal for the elimination of hydroxyurea as a therapeutic agent for that particular patient.

Patients who initially receive hydroxyurea and no longer respond to this agent or experience toxicity and require another agent should not receive an alkylating agent. This sequence of administration is associated with an extremely high risk of leukemic transformation. Patients who have had a trial of hydroxyurea and require further treatment should receive either anagrelide, INF-α, or pegylated INF. Doses of each of these agents required for disease control will, of course, be dependent on the target platelet level that one hopes to achieve. Strict control to a platelet count of lower than 600 × 109/L does not appear to be necessary. In these patients, the addition of low-dose aspirin (81 mg/day) should be considered; it is less clear to us if patients who achieve better platelet control with cytoreductive therapy should also be so treated. However, in studies from Europe addressing this question in PV, the approach of combining aspirin with cytoreduction therapy appears to minimize thrombotic complications. The use of anagrelide and aspirin in combination should be avoided because of the high risk of a hemorrhage. In patients with thrombotic episodes, especially episodes involving the microcirculation or large vessels, we administer low-dose aspirin (81 mg/day). This dose of aspirin does increase the number of bleeding episodes to a modest degree but is effective in the treatment of thrombotic events. This low-dose aspirin therapy is given in addition to an agent, which reduces platelet numbers.

Hydroxyurea can be started at a dose of 1 g/day and then adjusted to achieve the target platelet count (≤600 × 109/L) without developing leukopenia. Anagrelide is initiated at 0.5 mg twice daily and increased by 0.5 mg/day every 5 to 7 days if platelet counts do not begin to drop. The usual dose to achieve platelet number control is 2.0 to 2.5 mg/day. Alternatively, combination therapy with anagrelide and hydroxyurea may be considered. Some patients do not tolerate either hydroxyurea or anagrelide. In this patient group, INF-α therapy is initiated at 3 million units three times per week subcutaneously or consideration to therapy with a pegylated form of interferon (peg-IFNα-2a) should be given. Another choice is busulfan at 4 mg/day for 2-week courses every time the platelet count rises above the normal range. Busulfan therapy is reserved for patients older than 70 years.

Complications even in young, otherwise healthy patients with platelet counts greater than 2000 × 109/L are unusual. However, these marked elevations of platelet numbers can be anxiety-provoking situations for the patient and the clinician.

In certain situations, in young, low-risk patients, treatment should be instituted. Surgery can increase the risk of thrombosis, and the use of antiinflammatory agents can increase the risk of bleeding postoperatively. Under these circumstances, the platelet count should be lowered to the normal range. In pregnant patients with ET, low-dose aspirin therapy is the first treatment option. If the patient develops symptoms as a result of thrombosis, platelet reduction therapy is necessary, and INF-α therapy is the treatment of choice.

In a patient with ET and a serious acute hemorrhagic event, the site of bleeding should be determined immediately, and any antiplatelet aggregating agents should be stopped. Although the platelet count may be high, these platelets should be considered to be qualitatively abnormal, leading to defective hemostasis. The patient may have acquired von Willebrand syndrome. In patients with acquired von Willebrand syndrome, DDAVP (desmopressin) or factor VIII concentrates containing von Willebrand factor can be used immediately at the same time chemotherapy is being administered. If acquired von Willebrand syndrome is not present, the transfusion of normal platelets is suggested. In patients with persistent hemorrhage, immediate reduction of the platelet count can be achieved by platelet pheresis. If this approach fails, some consideration to the use of activated factor VIIa should be given. Hydroxyurea at 2 to 4 g/day for 3 to 5 days should be administered immediately and then reduced to 1 g/day. All patients receiving hydroxyurea should be monitored for the onset of granulocytopenia or thrombocytopenia. Reduction of platelet counts is usually observed within 3 to 5 days of hydroxyurea treatment.

In contrast, patients with acute arterial thrombosis require immediate institution of platelet antiaggregating agents. Aspirin at a dose of 81 mg/day is suggested. Patients with erythromelalgia or transient ischemic attacks will have a rapid cessation of symptoms after the use of low-dose aspirin. In a patient with a life-threatening arterial thrombosis, the platelet count should be lowered with either a combination of apheresis and hydroxyurea or with hydroxyurea alone, depending on the severity of the event. If the arterial thrombosis involves the microcirculation and is not life threatening (transient ischemic attacks or erythromelalgia), immediate low-dose aspirin therapy is indicated, and platelet reduction therapy (hydroxyurea, anagrelide, or INF-α) can be initiated using a standard dose and schedule.

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