What are the other Names for this Condition? (Also known as/Synonyms)

• Familial Essential Thrombocythemia
• Idiopathic Thrombocythemia
• Primary Thrombocythemia

What is Essential Thrombocythemia? (Definition/Background Information)

• Essential Thrombocythemia 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 (the soft tissue inside the hollow part of bones that helps form blood cells)
• In Essential Thrombocythemia, the body produces too many platelet cells. The signs and symptoms vary from person to person, but most people with Essential Thrombocythemia do not have any symptoms when the platelet cell count first increases. The main signs and symptoms include:
  • Increased production of megakaryocyte (a cell in the bone marrow that is responsible for making platelets)
  • Enlargement of the spleen (splenomegaly), and
  • Bleeding in several parts of the body and/or clotting episodes such as strokes, pain in the legs  and difficulty breathing
• Other symptoms may include weakness, headaches, or burning, tingling or prickling sensation in the skin. Some people have episodes of severe pain, redness, and swelling, especially in the hands and feet
• Essential Thrombocythemia is caused by mutations in the JAK2 (most frequently) and CALR genes, and rarely, the disease is caused by mutations in the MPL, THPO, and TET2 genes
• Treatment may include medication such as hydroxyurea, anagrelide, or interferon-alpha
• Most people with the disease can live long lives.  In very rare cases, Essential Thrombocythemia can transform into either primary myelofibrosis or acute myeloid leukemia

(Source: Essential Thrombocythemia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Essential Thrombocythemia? (Age and Sex Distribution)

• A majority of Essential Thrombocythemia cases are diagnosed during later adulthood (age over 60 years)
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Essential Thrombocythemia? (Predisposing Factors)

• A positive family history may be an important risk factor, since Essential Thrombocythemia is an inherited condition
• Currently, no other risk factors have been clearly identified for this blood disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Essential Thrombocythemia? (Etiology)

Essential Thrombocythemia may be caused by mutations in the JAK2 (most frequently) 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, and lead to the proliferation of blood cells, particularly platelets. It is believed that mutations in these genes lead to an increase in the production of platelets in the bone marrow
• The way by which mutations in the CALR and TET2 genes cause the symptoms of Essential Thrombocythemia is not known yet. 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
• 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
• Most cases of Essential Thrombocythemia are not inherited. Instead, the condition arises from gene mutations that occur in early blood-forming cells after conception. These alterations are called 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 disorder. When Essential Thrombocythemia is inherited, it is called Familial Essential Thrombocythemia
• In familial cases, an affected person has a 50% (or 1 in 2) chance of passing on the condition to each of his or her children

(Source: Essential Thrombocythemia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Essential Thrombocythemia?

The signs and symptoms of Essential Thrombocythemia may include:

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 mini-strokes (transient ischemic attack or 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 i.e., 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
• Abnormality of the skeletal system
• Acrocyanosis
• Hypertension
• Impaired platelet aggregation
• Myeloproliferative disorder
• Somatic mutation
• Thrombocytosis

Based on the frequency of symptoms observed, the following information may be noted:

Very frequently present symptoms in 80-99% of the cases:

• Abnormal platelet morphology
• Amaurosis fugax
• Arterial thrombosis
• Chest pain
• Increased megakaryocyte count
• Myocardial infarction
• Paresthesia
• Prolonged bleeding time
• Transient ischemic attack
• Venous thrombosis

Frequently present symptoms in 30-79% of the cases: Splenomegaly

Occasionally present symptoms in 5-29% of the cases:

• Acute leukemia 
• Myelodysplasia 
• Myelofibrosis

(Source: Essential Thrombocythemia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Essential Thrombocythemia Diagnosed?

While most cases of Essential Thrombocythemia are not inherited, genetic testing is available for some of the genes known to be associated with rare cases of Familial Thrombocythemia. This includes the THPO and MPL genes.

A diagnosis of Essential Thrombocythemia can be made when individuals meet all of the criteria below:

• 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"

And, more than three of the criteria given below:

• 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

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

(Source: Essential Thrombocythemia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Essential Thrombocythemia?

The complications of Essential Thrombocythemia may include:

• Blood clots leading to stroke and lung dysfunction
• Heart-related abnormalities including heart attack
• Increased susceptibility to leukemia

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Essential Thrombocythemia Treated?

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, and 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.

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.

(Source: Essential Thrombocythemia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Essential Thrombocythemia be Prevented?

Currently, Essential Thrombocythemia may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Essential Thrombocythemia? (Outcomes/Resolutions)

Because the symptoms of Essential Thrombocythemia 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

(Source: Essential Thrombocythemia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Essential Thrombocythemia:

Essential Thrombocythemia is also known by the following names: 

• Essential Thrombocytosis
• Hemorrhagic Thrombocythemia

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/