Essential thrombocythemia

Essential thrombocythemia may be caused by acquiring somatic mutations (not inherited mutations) in any of several genes, including the JAK2 gene (most frequently) and CALR gene. In rare cases, the disease is caused by mutations in the MPL, THPO, or TET2 gene. The proteins produced from the JAK2 , MPL , and THPO genes work together to regulate a signaling pathway called the JAK/STAT pathway, which transmits messages to the cell nucleus to produce blood cells. It is believed that mutations in these genes lead to an increase in the production of platelets in the bone marrow.

The reason that mutations in the CALR and TET2 genes cause essential thrombocythemia is not known. The CALR gene provides instructions for creating a protein called calreticulin that has many functions, such as aiding the functioning of the immune system and wound healing. The TET2 gene produces a protein that is thought to be important for the production of blood cells.

In some cases, no genetic mutation is identified in a person with essential thrombocthemia, and the cause is not known. It is thought that these cases may be due to mutations in genes that are not yet known to be associated with the disease.

The diagnosis of essential thrombocytemia can be made when people who meet criteria 1-5 and more than three of criteria 6-11:

1. Platelet count greater than 600,000/mm3 on two different occasions with a 1-month interval among them
2. No identifiable cause of secondary thrombocytosis
3. Having normal red blood cell mass
4. Bone marrow fibrosis that is less than one third of the bone marrow
5. Absence of the Philadelphia chromosome (Ph) by a blood exam that examines the chromosomes (karyotyping) or absence of the "bcr-abl fusion product"
6. Splenomegaly detected by physical examination or seen in ultrasonography
7. High number of cell in the bone marrow and increased size of the megakaryocyte
8. Abnormal blood producing cells in the bone marrow
9. Normal levels of CRP and IL-6
10. Absence of iron deficiency anemia
11. Clonal hematopoiesis in which stem cells that produce blood cells help to form blood cells that have a unique mutation because these cells are derived from a single founding cell and are genetic "clones" of the original cells.

Most of the time, the disease is found through blood tests, showing high number of platelets, done for other conditions before symptoms appear. Tests may include:

• Bone marrow biopsy
• Complete blood count (CBC)
• Genetic tests
• Uric acid level

Most cases of essential thrombocythemia are not inherited. Instead, the condition arises from gene mutations that occur after conception (somatic mutations).

Less commonly, essential thrombocythemia is inherited in an autosomal dominant pattern. This means that just one copy of the altered gene in each cell is sufficient to cause the condition. When essential thrombocythemia is inherited, it is called familial essential thrombocythemia. In familial cases, an affected person has a 50% (1 in 2) chance of passing on the condition to each of his or her children.

Because the symptoms vary from person to person, the prognosis is also different from person to person. In general, most people can live for long periods of time without complications and have a normal life expectancy. Few people can have more serious problems such as stroke, severe heart or respiratory problems, or bleeding episodes in several parts of the body. Also, in very rare cases, the disease can transform into either primary myelofibrosis or acute myeloid leukemia.

Before starting the treatment, it is 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 available treatments are not curative and do not prevent further evolution of the disease to acute myeloid leukemia or myelofibrosis (which only happens in very rare cases). The treatment of essential thrombocythemia is based in reducing the platelet count to avoid complications. The most common medication include hydroxyurea, interferon- alpha, Phosphorus 32, anagrelide. Aspirin in low doses can be used to control microvascular symptoms such as redness and pain in the fingers and toes, insufficient blood flow (ischemia), infections in the limbs (gangrene), strokes, syncopes, instability or visual disturbances.

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.

Recent studies have made the following recommendations:

• 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

Hydroxyurea is the preferred cytoreductive drug for most people, because it is less toxic and has a lower risk of producing myelofibrosis. However, in pregnant women and in those women who wish to become pregnant, interferon is used because hydroxyurea or anagrelide may cause birth defects.