Essential thrombocythemia is a condition characterized by an increased number of platelets (thrombocythemia). Platelets (thrombocytes) are blood cells involved in blood clotting. While some people with this condition have no symptoms, others develop problems associated with the excess platelets.

Abnormal blood clotting (thrombosis) is common in people with essential thrombocythemia and causes many signs and symptoms of this condition. Clots that block blood flow to the brain can cause strokes or temporary stroke-like episodes known as transient ischemic attacks. Thrombosis in the legs can cause leg pain, swelling, or both. In addition, clots can travel to the lungs (pulmonary embolism), blocking blood flow in the lungs and causing chest pain and difficulty breathing (dyspnea).

Another problem in essential thrombocythemia is abnormal bleeding, which occurs more often in people with a very high number of platelets. Affected people may have nosebleeds, bleeding gums, or bleeding in the gastrointestinal tract. It is thought that bleeding occurs because a specific protein in the blood that helps with clotting is reduced, although why the protein is reduced is unclear.

Other signs and symptoms of essential thrombocythemia include an enlarged spleen (splenomegaly); weakness; headaches; or a sensation in the skin of burning, tingling, or prickling. Some people with essential thrombocythemia have episodes of severe pain, redness, and swelling (erythromelalgia), which commonly occur in the hands and feet.

Essential thrombocythemia is more common (80% of cases) in older people. Most cases are diagnosed around 60 years of age. Around 25-33% of people with this disease may not have any symptoms. The symptoms are varied and may include:

• Blood clots that may form in several organs of the body, and may result in:
  • Symptoms such as headache, dizziness, chest pain, fainting, numbness or tingling sensations of the hands and feet
  • Redness, throbbing and burning pain in the hands and feet (erythromelalgia)
  • Blood clot occurring in the arteries that supply the brain and may cause ministrokes (transient ischemic attack (TIA), or strokes, leading to weakness or numbness of the face, arm or leg, trouble speaking, and vision problems
  • Thrombosis in the legs can cause leg pain, swelling, or both
  • Clots that can travel to the lungs (pulmonary embolism), blocking blood flow in the lungs and causing chest pain and difficulty breathing (dyspnea)
• Bleeding episodes (when platelet count is very high (more than 1 million platelets per microliter of blood) that usually don't require transfusions, and may include:
  • nosebleeds
  • easy bruising
  • bleeding from the mouth or gums
  • bloody stool or anal bleeding due to bleeding in the intestines (40% of cases)
• Enlarged spleen (splenomegaly)
• Weakness
• Swollen lymph nodes (rare)
• Prolonged bleeding caused by surgical procedures or removal of a tooth
• Ulcers of the fingers or toes
• Microvascular occlusions (in arteries or small caliber veins) in fingers or toes leading to gangrene
• Unpleasant moods (dysphoria)
• Seeing spots or lights (Scotomas)
• Complications in pregnancy that can result in abortion.

Essential thrombocythemia may be caused by acquiring somatic mutations (not inheritedmutations) 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 cellnucleus 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.

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.

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

• Platelet count greater than 600,000/mm3 on two different occasions with a 1-month interval among them
• No identifiable cause of secondary thrombocytosis
• Having normal red blood cell mass
• Bone marrow fibrosis that is less than one third of the bone marrow
• Absence of the Philadelphia chromosome (Ph) by a blood exam that examines the chromosomes (karyotyping) or absence of the "bcr-abl fusion product"
• Splenomegaly detected by physical examination or seen in ultrasonography
• High number of cell in the bone marrow and increased size of the megakaryocyte
• Abnormal blood producing cells in the bone marrow
• Normal levels of CRP and IL-6
• Absence of iron deficiency anemia
• 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

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.

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.