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Essential Thrombocythemia (ET)

What is ET?
Symptoms
Diagnosis
Progression
Prognosis/Life Expectancy

Available Treatments
Possible Causes
Prevalence

What is ET?

Essential Thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by an increased number of platelets in the circulating blood. The disease is commonly diagnosed at the age of 60, predominately in women. ET is characterized by a proliferation of platelet precursors in the bone marrow, and its most common complications include tendencies toward blood clotting and/or bleeding; later but more rare consequences include a transformation to myelofibrosis (marrow scarring) or acute leukemia

Symptoms

Many patients are asymptomatic, diagnosed after blood counts as part of a routine check-up reveal a high platelet count. When symptoms are present, they may include fatigue, or may be related to small or large vessel disturbance or bleeding.

Small vessel disturbances (often considered vasomotor in nature) can lead to:

• Headache
• Vision disturbances or silent migraines 
• Dizziness or lightheadedness
• Coldness or blueness of fingers or toes 
• Burning, redness, and pain in the hands and feet

Thrombotic complications can be quite serious, leading to:
• Stroke
• Transient ischemic attack (TIA)
• Heart attack
• Deep vein thrombosis or Pulmonary Embolus (blood clot in the lung)

Bleeding can manifest as: 
• Easy bruising, nosebleeds or heavy periods 
• Gastrointestinal bleeding or blood in the urine

Diagnosis

ET is often diagnosed after a routine blood test shows that a patient has a high platelet count. Other patients may consult their physician as a result of one or more of the symptoms shown above. Based on diagnostic tests and a review of patient history and symptoms, a physician can determine whether a patient has ET, and whether his/her case can be categorized as having low or high risk.

Tests which may be done to diagnose ET include the following:

• Blood tests to exclude other causes of a high platelet count (“reactive”). This often includes tests for iron deficiency and indicators of inflammation; other mimicking blood diseases can be ruled out as well

• Tests for gene mutations JAK2 (occurring in approximately 50% of cases), CALR, or MPL ( occurring in up to 5% of cases)

• Bone marrow biopsy to look for classical signs of ET, including an increase in platelet precursors

Progression

A small minority of people with ET may later develop acute leukemia or myelofibrosis, both of which can be life-threatening:
Acute leukemia. Acute myelogenous leukemia (AML) is a type of blood and bone marrow cancer that progresses rapidly
Myelofibrosis. This progressive bone marrow disorder results in bone marrow scarring, severe anemia, and enlargement of your liver and spleen

Prognosis/Life Expectancy

Essential thrombocythemia patients have an excellent chance of living out a normal life span if properly monitored and treated as necessary. ET is a chronic hematologic malignancy and it is prudent to be monitored regularly by a hematologist. It is important to report any symptoms such as visual disturbances, unexplained pain, numbness, tingling or bruising to your physician. For those who have had symptoms from their ET, treatment will be required.

Possible Causes

No one knows exactly what triggers the start of essential thrombocythemia (ET) or other myeloproliferative neoplasms (MPNs). Recently, researchers discovered mutations that alter the activity of proteins that control signaling pathways in many patients with MPN. Signaling pathways are important regulators of cell growth and development.

About half of all people with essential thrombocythemia have a mutation called "JAK2V617F" (found in the JAK2 gene) within their blood-forming cells. This mutation leads to hyperactive JAK (Janus kinase) signaling and leads to many  of the characteristic features of the disease. The end result is that the body makes the wrong number of blood cells. Recently, clusters of families with MPN have been described, suggesting a familial predisposition in some patients.

About 23.5% of people with myelofibrosis have a mutation called Calreticulin, or CALR. This genetic marker was discovered in 2013 by two independent laboratories, including one funded by MPN Research Foundation. Research is still ongoing, but there are potential implications for prognosis and treatments for those with the CALR mutation.

Researchers now know that myelofibrosis is complex and is not caused by genetic mutations alone. There may be many contributing factors, including mutations of other genes in other pathways.

Some epidemiological risk factors associated with ET include the following:
• Gender -- Women are 1.5 times more likely than men to develop the condition
• Age -- People older than 60 are most likely to develop the condition, although 20% of those with this condition are under 40
• Environment – Exposure to chemicals or to electrical wiring may increase an individual's risk for the condition

Available Treatments

You should consult your doctor about available treatments that may be appropriate for you. Essential thrombocythemia (ET) is different in every person. If you don’t have a lot of symptoms, your doctor may decide that you don't need treatment yet. Instead, your doctor will observe and monitor your condition.

Current treatments for ET patients who require treatment include the following:

Low-dose aspirin is usually given to reduce the risk of blood clotting. Aspirin may also help relieve the burning sensation that some people get in their hands and feet (erythromelalgia, along with other vasomotor symptoms)
Hydroxyurea is often used in essential thrombocythemia in people at high risk for clotting (age over 60 and those with a prior blood clot), and is usually considered the first line agent in those that require treatment
Anagrelide is another option to lower the platelet count, often chosen after a patient has intolerance or complications with Hydroxyurea
Interferon is sometimes prescribed for ET patients. Younger women of childbearing age are often treated with interferon because it hasn't been shown to cause birth defects. A pegylated version may be associated with less side effects and easier administration

The decision to use platelet lowering agents depends on a variety of risk factors including platelet count, history of bleeding or thrombosis, vascular risk, and severity of symptoms. The choice of treatments is generally based on a variety of risk factors including age, history or thrombotic events, and drug tolerance.

Potential new treatments for ET are currently being developed and tested as a result of the discovery of the link between the JAK2 mutation and incidence of ET. These drugs, referred to as JAK2 Inhibitors, are currently in early stages of testing for ET. Pegylated interferon is also being considered as a treatment in those with high risk disease.

Prevalence

Prevalence refers to the total number of patients living with MPNs at any given time. Incidence refers to the number of patients newly diagnosed each year. Previous studies estimated the prevalence of MPNs at 176,000 people in the US.

Researchers from Mayo Clinic, Boston University School of Public Health, and the pharmaceutical company Sanofi’s department of Global Evidence & Value Development, recently concluded a study of the prevalence of the myeloproliferative neoplasms in the United States. Their findings were reported at the American Society of Hematology annual meeting in 2012 and in a recent scientific publication.

Two major US health insurance claims databases (with over 70m enrollees/year) were used to retrospectively identify unique patients with MF, PV and ET between 1/1/08 and 12/31/10.

This is the first study utilizing two large national US claims databases to estimate prevalence of MPN disorders (IMPACT and MARKETSCAN). In the US, MF prevalence ranged from 3.6-5.7 per 100,000 patients on 12/31/10. PV prevalence estimates ranged from 45-57 cases and ET prevalence ranged from 39-57 cases per 100,000 patients on 12/31/10.

Table: Age Adjusted Prevalence (per 100,000) for MPN subgroups of interest for two large US health plans, 2008-2010.

*unique patients only    MF=Myelofibrosis; PV=Polycythemia vera; ET=Essential thrombocythemia


Using the Marketscan (lower than Impact) estimates from 2010, the projected prevalence for the MPNs in the US on December 31, 2010 is:

MF – 12, 812
PV – 148, 363
ET – 134, 534

The data provides compelling evidence to suggest that prevalence of MPNs is higher than has been reported in the past. Additional research using other national databases and/or study designs is needed to substantiate these findings.

References:
Epidemiology of Myeloproliferative Disorders in US – a real world analysis Poster presented at
ASH 2012 Ruben A. Mesa1, Jyotsna Mehta2*, Hongwei Wang2*, Yanxin Wang2*, Usman Iqbal2*,
Frank Neumann3, Yanzhen Zhang3* and Theodore Colton4*

Epidemiology of Myeloproliferative neoplasms (MPN) in the United States. Leuk Lymphoma. Epub 2013 Jyotsna Mehta1, Hongwei Wang2, Usman Iqbal2, Ruben Mesa1 http://www.ncbi.nlm.nih.gov/pubmed/23768070

1Mayo Clinic Arizona, Scottsdale, AZ
2Global Evidence & Value Development, Sanofi, MA
3Research and Development, Sanofi, Oncology, Cambridge, MA
4Department of Epidemiology, Boston University, Boston, MA

 

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