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What is essential thrombocythemia?

Essential thrombocythemia (ET) is one of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), or chronic, progressive hematologic disorders in which there is abnormal production of blood cells by stem cells in the bone marrow. In ET, there is uncontrolled production of platelets, the cells that help the blood to clot. The excessive numbers of platelets in the blood may result in an increased risk of formation of blood clots that limit blood flow and supply to organs. This can lead to complications such as heart attack and stroke, if not treated.

Epidemiology

A recent study estimated the number of new cases of ET (or the incidence) in the United States in 2010 ranged from 22 to 31 per 100,000,1 and the number of people living with ET (or the prevalence) ranged from 38 to 57 per 100,000.2 In a recent study of 891 patients,3 the median age at ET diagnosis was 56 years (range 13-91 years). ET is more common in women than men.

Symptoms

There may be no symptoms of ET, which may be discovered during routine blood work that indicates an elevated platelet count. Symptoms of ET may include headache; dizziness or lightheadedness; visual disturbances; ringing in the ears; chest pain or discomfort; feeling of fullness or bloating in the left upper abdominal area that may indicate an enlarged spleen; numbness or tingling in the upper or lower extremities; or redness accompanied by a painful burning sensation in the upper or lower extremities (erythromyalgia). Less commonly, if platelet count is extremely high, nose bleeds, bruising, blood in the stool, and bleeding gums may occur.

Complications

The increased number of platelets in the blood result in an increased risk of thrombotic events, or cardiovascular complications that are due to the formation of blood clots. Thrombotic events in individuals with ET may include stroke, mini-stroke (transient ischemic attack), heart attack, or blood clots in peripheral arteries. Rarely, bleeding complications may occur in individuals with platelet counts at least 2½ times higher than normal. Management of ET includes controlling platelet counts to reduce the risks of thrombotic and bleeding complications.

Very rarely, other disorders of the blood may develop in individuals with ET. Approximately < 1% of patients with ET develop myelofibrosis, an MPN in which scarring (fibrosis) of the bone marrow ultimately results in impaired production of RBCs, and sometimes of WBCs and platelets, within 10 years.4 When myelofibrosis develops in a patient with ET, it is called post-essential thrombocythemia myelofibrosis (post-ET MF). Post-ET MF typically happens late in the course of ET. Acute myeloid leukemia (AML), a cancer of the blood, may develop in approximately < 1% of patients within 10 years.4

Diagnosis

Elevated platelet count is the hallmark of ET; however, there may be other causes of increased platelets in the blood that may or may not be associated with the way blood is formed in the bone marrow. Therefore, both physical examination and a series of laboratory tests are used to determine if signs and symptoms are consistent with ET and not due to another cause. Based on consensus, hematologists who are experts in the field of MPN have developed very specific criteria to confirm diagnosis of ET.

The World Health Organization (WHO) criteria for diagnosis of essential thrombocythemia5 are the current consensus criteria used for definitive diagnosis of ET by most hematologists. There are four criteria required for diagnosis of ET: (1) blood tests showing sustained, elevated platelet count; (2) samples of bone marrow (obtained via biopsy) showing increased numbers of the cells that form platelets and the absence of other cellular characteristics that might indicate another type of MPN; (3) ruling out the presence of another type of MPN or other neoplasm of the bone marrow; and (4) either the presence of a specific mutation on a gene called Janus kinase 2 (JAK2), the V617F mutation (present in approximately 55% of ET patients)6 or confirmation that the elevated platelet count is not due to iron deficiency, removal of the spleen, an inflammatory disease, or another type of malignancy.

Current Treatments

There is no cure for ET, but there are treatments aimed at managing the symptoms and reducing the risks of complications associated with ET. Treatments for ET that may be used depend on an individual’s age, cardiovascular history, and signs and symptoms of ET they are experiencing7; recent studies propose cardiovascular risk factors (e.g., hypertension, diabetes, cigarette smoking) and the presence of the JAK2 V617F mutation should also be considered in determining treatment for ET.3,8 These factors help hematologists classify patients with ET into various risk categories, ranging from low to high, for the purpose of determining the best individual treatment option. In individuals who are at a low risk for complications, no treatment may be necessary.

Hematologists who are experts in the field of MPN have developed consensus recommendations for the management and treatment of ET, based on both clinical practice and the body of evidence available from multiple research studies.7

The first goal of therapy is to avoid thrombotic and bleeding complications associated with ET, or to reduce the risk of them occurring again in individuals with previous events. This includes management of risk factors for cardiovascular disease that may be present regardless of ET, such as hypertension, obesity, diabetes, and high cholesterol, as well as smoking cessation.

Treatments for reducing the risk of thrombotic events specific to ET focus on reducing the number of platelets in the blood, and then maintaining them at normal levels. Treatment may include low-dose aspirin, which reduces the risk of formation of blood clots by inhibiting the production of a substance that binds platelets together. In individuals who are at a higher risk of thrombotic and bleeding complications from ET due to older age and prior history of such events, medications known as cytoreductive agents—or agents that reduce the excess number of cells—may be used in addition to aspirin. The cytoreductive drug of choice is hydroxyurea. In some cases, anagrelide may be used to reduce the number of platelets; however, pegylated interferon-alpha has recently been identified as second-line treatment of choice, particularly for younger patients.8 Busulfan may be used in selected patients.

In addition to reducing the risk for cardiovascular complications, some of these treatments may also help alleviate some of the symptoms associated with ET.

The safety and effectiveness of new drugs for the treatment of ET, including JAK2 inhibitors, are currently being evaluated in clinical trials.

As with any treatment, there may be side effects associated with treatments for ET. Hematologists use the consensus recommendations as guidelines while considering what the right treatment is for an individual. Decisions regarding whether to treat and the right treatment for ET should be made considering the benefits and risks of the treatment, and these considerations may change over time.

References

  1. Mesa RA, Mehta J, Wang H, Wang Y, Usman I, Neumann F, Zhang Y, Colton T. Epidemiology of myeloproliferative disorders in the US - A real world analysis. American Society Hematology; 2012; Atlanta, Georgia.
  2. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leukemia & Lymphoma. 2013;Early online: 1-6.
  3. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Gisslinger H, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Vannucchi AM, Tefferi A Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-5133.
  4. Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, Rodeghiero F, D'Amore ESG, Randi ML, Bertozzi I, Marino F, Vannucchi AM, Antonioli E, Carrai V, Gisslinger H, Buxhofer-Ausch V, Mullauer L, Carobbio A, Gianatti A, Gangat N, Hanson CA, Tefferi A. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: An international study. J Clin Oncol. 2011;29:3179-3184.
  5. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114:937-951.
  6. Tefferi A, Vainchenker W. Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies. JClinical Oncol. 2011;29(5):573-582.
  7. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. Feb 20 2011;29(6):761-770.
  8. Tefferi A, Barbui T. Personalized management of essential thrombocythemia—Application of recent evidence to clinical practice. Leukemia. 2013;27:1617-1620.