Essential Thrombocythemia

OVERVIEW

ESSENTIAL THROMBOCYTHEMIA IS A MYELOPROLIFERATIVE NEOPLASM CHARACTERIZED BY AN INCREASE IN MEGAKARYOCYTES AND PLATELETS

Essential thrombocythemia (ET) is a rare but serious myeloproliferative neoplasm (MPN) characterized by thrombocytosis with bone marrow megakaryocytic hyperplasia and a tendency to develop thrombotic and hemorrhagic complications.1-3

Prevalence/Demographics

ET CURRENTLY AFFECTS BETWEEN 71,000 AND 88,000 PEOPLE IN THE UNITED STATES

Between 71,000 and 88,000 people in the United States currently live with ET.4 ET is occasionally diagnosed in older children, but most often occurs in adults.5 The typical pattern of ET onset is bimodal, with one peak occurring during young adulthood in women and the other peak occurring between the ages of 50 and 70 years in both men and women.6

OLDER ADULTS AND PREGNANT WOMEN WITH ET MAY FACE SERIOUS COMPLICATIONS

ET can lead to serious complications, such as thrombosis, especially in patients3:

  • 60 years of age or older
  • with a history of major thrombosis
  • with elevated leukocyte counts at diagnosis
  • with hypertension
  • with diabetes

ET can also lead to complications in pregnancy. Pregnant women with ET have been reported to have live birth rates of 50% to 70% and spontaneous abortion rates of 25% to 50%.7

Pathophysiology

ET IS CHARACTERIZED BY BONE MARROW AND BLOOD CELL ABNORMALITIES

Essential thrombocythemia (ET) is a rare but serious myeloproliferative neoplasm (MPN) characterized by thrombocytosis with bone marrow megakaryocytic hyperplasia and a tendency to develop thrombotic and hemorrhagic complications.1-3

DYSREGULATED JAK SIGNALING PLAYS A ROLE IN THE PATHOPHYSIOLOGY OF ET

As in myelofibrosis and polycythemia vera, dysregulated signaling in the JAK pathway plays a role in the pathophysiology of ET.8,9 The JAK2V617F mutation occurs in about 55% of patients with ET,10-12 and a mutation in the thrombopoietin receptor gene MPL occurs in about 4% of affected patients.13

SIGNS AND SYMPTOMS

ET IS ASSOCIATED WITH A VARIETY OF NONSPECIFIC SIGNS AND SYMPTOMS

Symptoms and signs of ET include5:

  • Erythromelalgia (burning or throbbing pain in the feet)
  • Headache
  • Dizziness
  • Blood clots
  • Abnormal bleeding episodes
  • Weakness or numbness on one side of the body
  • Slurred speech
  • Enlarged spleen

DIAGNOSIS

ET SHARES CHARACTERISTICS WITH OTHER MPNS

ET may be difficult to diagnose because of its similarity to other MPNs.14 In patients with a JAK2V617F mutation, ET may be difficult to differentiate from polycythemia vera.14 In patients who are JAK2V617F-negative, ET may be difficult to differentiate from both primary myelofibrosis and chronic myelogenous leukemia.14 Furthermore, many patients with ET are asymptomatic, which may further complicate the diagnostic process.5

DIAGNOSTIC CRITERIA

Diagnostic criteria for the MPNs, including ET, polycythemia vera, and primary myelofibrosis, were established in 2008 by the World Health Organization (WHO).15

ET is diagnosed by ruling out reactive thrombocytosis caused by underlying conditions and clonal thrombocytosis associated with other MPNs (particularly primary myelofibrosis, BCR-ABL–positive chronic myelogenous leukemia, and myelodysplastic syndromes presenting with a high platelet count).14

PRESENCE OR ABSENCE OF MOLECULAR MARKERS MAY HELP TO DISTINGUISH ET FROM OTHER DISORDERS

The presence or absence of molecular markers, such as JAK2V617F, can be useful in making a diagnosis of ET. In JAK2V617F-negative patients, for example, the results of a bone marrow biopsy and cytogenetic testing can provide strong support for establishing a diagnosis of ET and may help to distinguish ET from primary myelofibrosis and chronic myelogenous leukemia.14

RISK, PROGNOSIS, AND SURVIVAL

ET IS A CHRONIC DISEASE THAT MAY SHORTEN SURVIVAL OVER TIME

Prospective data regarding prognosis in ET are limited.3,13 In general, ET is a chronic disease that does not shorten life expectancy in the first decade following diagnosis; however, over longer periods of time, survival may be shortened.3 Median survival of ET is about 20 years.16

SEVERAL VARIABLES PREDICT SHORTENED SURVIVAL IN ET

Prognostic variables that are associated with shortened survival in patients with ET include the following3:

  • Age ≥60 years
  • History of arterial thrombosis
  • Occurrence of any major thrombosis at or after diagnosis
  • Tobacco use
  • Diabetes mellitus
  • Leukocyte count of ≥15 x 109/L at diagnosis

Shortened survival in ET can usually be attributed to thrombotic events, hemorrhage, progression to myelofibrosis, and transformation to acute leukemia.17

ET RISK IS BASED ON AGE, HISTORY OF THROMBOSIS, AND CARDIOVASCULAR (CV) RISK FACTORS

Patients with ET who have a history of thrombosis or who are 60 years of age or older are considered to be at high risk, whereas those who are younger than age 60 years or who lack a history of thrombosis but have CV risk factors (eg, diabetes, hypertension, or tobacco use) are considered to be at intermediate risk.18 Patients who are younger than age 60 years or who lack a history of thrombosis, have no CV risk factors, and have a platelet count of <1,000 x 109/L are considered to be at low risk.18

Progression
In some patients, ET may transform to myelofibrosis.19 If such a transformation occurs, a patient is said to have developed post-ET myelofibrosis, which is often fatal.19 ET transforms to secondary acute myelogenous leukemia in a small minority of patients.20

Clinical Considerations

ACCURATE DIAGNOSIS IS A KEY FACTOR IN CLINICAL DECISION-MAKING

ET may be difficult to diagnose because of its similarity to other MPNs,14 and misdiagnosis can have an impact on patient outcomes.21 The International Working Group for MPN Research and Treatment (IWG-WRT) subjected 1,104 cases of locally diagnosed ET to review by a central laboratory. The laboratory determined that 891 of the cases met the WHO criteria for ET, but 213 did not. They classified these cases as early/prefibrotic myelofibrosis. In terms of outcomes, these patients had worse overall survival, higher rates of transformation to leukemia, and higher rates of fibrotic progression. They also had a higher risk of bleeding.21 These results reinforce the importance of performing an accurate bone marrow biopsy for the differential diagnosis of ET from early/prefibrotic myelofibrosis.

ET remains an incurable disease. The focus of managing the disease is to13,16:

  • Avoid first occurrence and/or recurrence of thrombotic and bleeding complications
  • Minimize the risk of acute leukemia and post-PV myelofibrosis
  • Control systemic symptoms
  • Treat complications (thrombosis and hemorrhage)
  • Manage risk situations (eg, pregnancy, surgery)

FAQS

Q: What are the main characteristics of essential thrombocythemia (ET)?

A: ET is characterized by thrombocytosis with bone marrow megakaryocytic hyperplasia and a tendency to develop thrombotic and hemorrhagic complications.1-3

Q: What prognostic variables are associated with shortened survival in essential thrombocythemia (ET)?

A: Prognostic variables associated with shortened survival in patients with ET include3:
  • Age ≥60 years
  • History of arterial thrombosis
  • Occurrence of any major thrombosis at or after diagnosis
  • Leukocyte count of ≥15 x 109/L at diagnosis
  • Tobacco use
  • Diabetes mellitus

References

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  3. Wolanskyj AP, Schwager SM, et al. Mayo Clin Proc. 2006;81:159-166.
  4. Incyte Corporation. Myelofibrosis epidemiology: a preliminary overview of data from available literature. July 2013. (Data on file.)
  5. The Leukemia & Lymphoma Society. White Plains, NY; 2007. Number 12.
  6. The Merck Manual for Healthcare Professionals. Available at: http://www.merckmanuals.com/professional/hematology_and_oncology/myeloproliferative_disorders/essential_thrombocythemia.html. 2009. Updated February 2012. Accessed March 3, 2013.
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