Essential thrombocythemia

Clinical picture

Essential thrombocythemia (ET) is a rare disease in which the body produces too many blood platelets (thrombocytes). ET belongs to a group of conditions called myeloproliferative disorders. Myeloproliferative disorders cause platelets, white blood cells and red blood cells to grow abnormally in the bone marrow. Normally there is control over the amount of new platelets that are produced in the bone marrow. However, a mutation in a certain protein (called JAK2) causes an uncontrolled growth of platelet cells.

Having too many platelets may cause disruptions in blood circulation and increases the risk of blood clots in the veins (venous thrombosis) or arteries (arterial thrombosis). Bleeding can also occur as too many immature and non-functioning platelets enter the blood stream.

Essential thrombocytosis is a rare disease with about 120 new patients per year in Belgium. It is mainly found in older (50-60 years) patients and somewhat more common in women. However, the condition can manifest itself at all ages.

Symptoms

Essential thrombocythemia may be asymptomatic. The disease is often diagnosed as part of a routine check-up, after a blood test reveals a high platelet count. Symptoms present may be related to small or large vessel disturbance, the formation of blood clots in the vessels, or bleeding.

Common symptoms related to small vessel disturbances may include:

headache
dizziness or lightheadedness
chest pain
fainting
vision disturbances or silent migraines
redness, throbbing and burning pain in the hands and feet (erythromelalgia)
coldness or blueness of fingers or toes
numbness or tingling of the hands and feet

Thrombotic complications can also occur. These are due to the temporary interruption of blood flow to specific parts of the body resulting in:

stroke
heart attack
deep vein thrombosis or pulmonary embolus (blood clot in the lung)
blood clotting in unusual locations, such as the abdominal veins

A transient ischemic attack (TIA) or mini-stroke occurs when a blood clot is formed in the arteries that supply the brain. Signs and symptoms of a stroke or TIA develop suddenly and include:

weakness or numbness of your face, arm or leg, usually on one side of your body
difficulty speaking or understanding speech (aphasia)
blurred, double or decreased vision

Essential thrombocythemia may cause bleeding, especially if the platelet count is extremely high (more than 1 million platelets per microliter of blood). Bleeding can manifest as:

easy bruising, nosebleeds or heavy periods
gastrointestinal bleeding or blood in the urine
bleeding from your mouth or gums

Cause

In essential thrombocythemia, precursor cells for platelets (megakaryocytes) in the bone marrow are more sensitive to growth factors. This may be caused by mutations in the JAK2 and CALR genes. In rare cases, the disease is caused by mutations in the MPL, THPO, and TET2 genes. The proteins produced from the JAK2, MPL, and THPO genes work together to turn on the signaling pathway called the JAK/STAT pathway that transmits chemical signals from outside the cell to the cell’s nucleus. This leads to the proliferation of blood cells in the bone marrow, particularly platelets.

A mutation in the JAK2 kinase is present in 40–50% of cases and is diagnostic if present. There are several cases where no mutation can be detected and it is thought that these cases may be due to mutations in genes that are not yet identified.

Diagnosis

Essential thrombocythemia is often suspected after a routine blood test shows that a patient has a high platelet count. Because there can be many causes for an increased number of platelets in the blood, extensive research must be carried out in order to be able to diagnose essential thrombocytosis.

Common tests for diagnosing ET include:

careful registration of symptoms and medical history
physical examination and recording of liver and spleen size by means of an echo
blood tests to exclude other causes of a high platelet count, including:
- platelet count
- platelet size
- activity of platelets
- iron level
- markers of inflammation
bone marrow biopsy, to look for an increase in platelet precursors (megakaryocytes)
gene mutation analysis like JAK2 (occurring in approximately 50% of cases), CALR (occurring in 23.5% of cases) or MPL (occurring in up to 5% of cases)
specific genetic flaws, such as the JAK2, CALR or MPL gene mutation
iron levels
bone marrow tests
cardiovascular research to map the risk of cardiovascular disease
echo of the spleen

Treatment

Essential thrombocythemia can’t be cured, however, there are treatments available. Treatments for essential thrombocythemia is usually based in reducing the platelet count to avoid complications. Available treatments are not curative and do not prevent further evolution of the disease to acute myeloid leukemia or myelofibrosis. When treated, lifespan is expected to be normal despite the disease.

While some ET patients may be asymptomatic and require no treatment, others may require various treatments and therapies, based on the symptoms and the results of routine monitoring. Treatment depends on the risk of blood-clotting or bleeding episodes. It is therefore recommended to determine the risks of having complications according to the age, medical history and the presence of specific mutations to decide which the best treatment should be.

The classification of the disease according to the risks is as following:

High-risk disease: People who had thrombosis at any age and/or who are older than 60 years of age and have a JAK2 V617F mutation
Intermediate-risk disease: People who are older than 60 years of age, who do not have a JAK2 mutation and who never had thrombosis
Low-risk disease: People who are 60 years of age or younger, and who have a JAK2 mutation and never had thrombosis
Very-low-risk disease: People who are 60 years of age or younger without a JAK2 mutation and never had thrombosis.

Recommendations based on risk are as follows:

People who have a high risk of thrombosis or who had thrombosis should use a cytoreductor in combination with an anticoagulant.
People with high or intermediate risk, should be treated with a cytoreductor in combination with aspirin at low doses.
People who are at low risk should be treated with low doses of aspirin or are only observed carefully without any type of treatment.

When treatment is necessary, the available treatment options include:

Low-dose aspirin to reduce the risk of blood clotting. Aspirin may also help relieve the burning sensation that some ET patients experience in their hands and feet (erythromelalgia, along with other vasomotor symptoms).
Hydroxyurea to suppress bone marrow production of blood cells, including platelets. It is often used for patients at high risk for clotting (over 60 years-old or patients with a prior blood clot). It is the preferred cytoreductive drug, because it is less toxic and has a lower risk of producing myelofibrosis.
- In pregnant women and in those women who wish to become pregnant, interferon is used because hydroxyurea or anagrelide may cause birth defects.
Anagrelide to lower platelet counts. It is frequently used after a patient has demonstrated intolerance or experienced complications with Hydroxyurea.
Interferon alfa (Intron A) or peginterferon alpha-2a (Pegasys) is sometimes prescribed for ET patients. Women of childbearing age are often treated with interferon because it hasn’t been shown to cause birth defects.
Platelet pheresis, only used in emergencies, such as after a stroke or other dangerous blood clotting. It temporarily lowers platelet count.