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Essential Thrombocythemia

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NORD is very grateful to Kenneth M. Algazy, MD, Clinical Professor of Medicine, University of Pennsylvania School of Medicine, and Chief of Hematology/Oncology, Philadelphia VA Medical Center, for assistance in the preparation of this report.

Synonyms of Essential Thrombocythemia

Disorder Subdivisions

General Discussion

Essential thrombocythemia (ET) is a rare, chronic disorder characterized by the overproduction of platelets. Platelets (also known as thrombocytes) are specialized blood cells that clump together to form clots to stop bleeding at the site of injury to blood vessels Although the overproduction of platelets is the or characteristic of ET, red blood cells and white blood cells may be overproduced to some degree as well.

Individuals with ET are at risk for the formation of blood clots (thrombosis), which can restrict blood flow to vital organs, and episodes of uncontrolled bleeding (hemorrhaging). Additional symptoms associated with ET include headaches, dizziness, bleeding from the gums or gastrointestinal tract, an enlarged spleen (splenomegaly) and a condition known as erythromelalgia, which is characterized by a reddened or purplish appearance to the skin of the hands and feet sometimes associated with a painful, burning sensation. Approximately two-thirds of individuals with ET do not have symptoms (asymptomatic) when initially diagnosed. In fact, a diagnosis of ET is often made incidentally during a routine examination. Many individuals eventually present with symptoms related to small or large vessel thrombosis or minor bleeding. Presentation with a major bleeding episode is very unusual. The exact, underlying cause of ET is unknown. However, more than half of the people with this disorder have a mutation of the JAK2 gene. The exact role that this gene plays in the development of ET is not fully understood.

Essential thrombocythemia belongs to a group of diseases known as the myeloproliferative disorders (MPDs). This group of disorders is characterized by the overproduction (proliferation) of one or more of the three main blood cell lines - red or white blood cells or platelets. Red blood cells carry oxygen to the body. White blood cells fight infection. Platelets are involved in clotting of the blood in response to injury. Three other disorders are commonly classified as MPDs: chronic myelogenous leukemia, polycythemia vera and idiopathic myelofibrosis. Because the MPDs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.

Symptoms

The symptoms of essential thrombocythemia vary widely from one person to another. Many individuals do not have symptoms (asymptomatic) at the time of their diagnosis and remain symptom-free for many years. Affected individuals may develop vague, nonspecific symptoms common to many disorders including headaches, fatigue, excessive sweating and dizziness. Most symptoms of ET are related to the formation of blood clots (thrombosis) or episodes of unexpected or exaggerated bleeding (hemorrhaging).

Blood clots may lead to reduced blood flow and damage (ischemia) to the central nervous system, resulting in headaches, lightheadedness, visual problems such as double vision (diplopia) or the sudden development of blurred vision, and/or mini-strokes (transient ischemic attacks or TIAs) that can cause slurred speech (dysarthria), weakness on one side of the body and additional signs. Loss of consciousness (syncope), seizures, migraines and vertigo may result from reduce blood flow to the central nervous system.

If blood flow to the arms and legs is reduced because of blood clots in the arteries, serious damage to the tissues of the arm and/or leg (peripheral vascular ischemia) may also occur, possibly to the extent of tissue death (gangrene) in one or more limbs. Some individuals with ET develop erythromelalgia, a condition by a reddened or purplish appearance to the skin of the hands and feet that can also cause a painful, burning sensation or swelling of the affected areas. Affected skin may feel warm to the touch. Tingling, numbness or other abnormal sensations (paresthesias) of the hands and feet may also occur.

Additional symptoms can occur in ET depending upon the location of blood clots. Deep vein thrombosis is a condition that occurs when a blood clot forms in the legs, which may cause the legs to become painful and swollen. Some individuals may develop a pulmonary embolism, a condition in which a clot forms in the lungs or when a piece of a DVT breaks off and travels through the bloodstream eventually becoming stuck in the pulmonary artery. A pulmonary embolism can cause breathlessness, a sudden pain the chest, exhaustion, or life-threatening complications such as high blood pressure of the pulmonary artery.

Some individuals with ET may develop Budd-Chiari syndrome, a condition in which a blood clot forms in the main blood vessel leading to the liver (hepatic vein thrombosis). Symptoms of Budd-Chiari syndrome include pain in the upper right part of the abdomen, an abnormally enlarged liver (hepatomegaly), yellowing of the skin and the whites of the eyes (jaundice), and/or accumulation of fluid in the space (peritoneal cavity) between the two layers of the membrane that line the stomach (ascites).

Bleeding (hemorrhaging) episodes associated with ET are usually mild. The gastrointestinal tract is most often affected and some individuals may have traces of blood in the stools (melena) or urine (hematoemesis). Chronic gastrointestinal bleeding may result in iron-deficiency anemia, a condition characterized by insufficient numbers of healthy red blood cells to deliver oxygen throughout the body. Individuals with iron-deficiency anemia may tire easily and have a pale skin complexion. Individuals with ET may have also other bleeding complications such as a tendency to bruise easily or occasional nosebleeds (epitaxis) or bleeding from the gums. Major bleeding episodes in individuals with ET are rare, but can occur.

Affected individuals may develop an abnormally enlarged spleen (splenomegaly) and, less often, an abnormally enlarged liver (hepatomegaly). Additional symptoms that may occur in some cases include unintended weight loss, itchy skin (pruritis) and fever.

Women with ET may be at risk for certain complications during pregnancy including growth delays of a developing fetus, premature delivery and the early separation of the placenta from the uterus (placental abruption). The risk of spontaneous abortion is also increased in women with ET.

ET may eventually progress to resemble myelofibrosis, a condition in which scar tissue slowly replaces bone marrow. Eventually, the bone marrow can no longer produce blood cells resulting in low levels of healthy, functioning red blood cells (anemia), platelets (thrombocytopenia) and white blood cells (leukopenia). In rare cases, ET may eventually progress into an acute form of leukemia or myelodysplasia.

Causes

The exact cause of essential thrombocythemia is not fully understood. Approximately 50 percent of individuals with ET have a mutation of the JAK2 gene. The specific role this mutation plays in the development of the disorder is unknown.

ET is characterized by a malignant change in a single, immature blood cell known as a megakaryocyte. These cells are found in the bone marrow - the soft spongy material within bones where most blood cell formation takes place. Megakaryocytes are called "giant cells" because the large cells eventually break apart with the shards developing into platelets. The underlying reason for the malignant change in a megakaryocyte is not known, but it causes the defective megakaryocyte to continually reproduce itself. This overproduction of megakaryocytes results in too many platelets being created and released into the bloodstream. Too many platelets in the bloodstream causes affected individuals to be at risk for developing blood clots for no reason. If the platelets are defective they can also cause uncontrolled bleeding episodes.

Because ET arises from an early cell that can develop into certain types of any of the three major blood cell types, some individuals have elevated levels of red blood cells and white blood cells in addition to elevated levels of platelets.

ET is classified as a clonal disorder, which is a disorder that arises from a single defective cell. However, some women with ET seem to have a form that arises from multiple defective cells (polyclonal disorder).

ET and some similar disorders have, in rare cases, occurred in multiple members of the same family suggesting that genetic factors in addition to a JAK2 gene mutation may play a role in the development of the disorder. However, researchers have not determined which, if any, genetic factors may predispose individuals to developing ET.

Affected Populations

Essential thrombocythemia affects women approximately twice as often as men. It is estimated to affect approximately 1 to 3 people out of every 100,000 in the general population. However, because many people with ET do not have obvious symptoms, determining the disorder's true frequency in the general population is difficult. ET usually affects individuals between 50-70 years of age, but can affect individuals of any age. It is estimated about 20 percent of cases of ET occur in individuals under the age of 40.

Related Disorders

Symptoms of the following disorders can be similar to those of essential thrombocythemia. Comparisons may be useful for a differential diagnosis.

Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). The overproduction of red blood cells is most dramatic, but the production of white blood cells and platelets are also elevated in most cases. Since red blood cells are overproduced in the marrow, this leads to abnormally high numbers of circulating red blood cells (red blood mass) within the circulatory system. Consequently, the blood thickens and increases in volume, a condition called hyperviscosity. Thickened blood may not flow through smaller blood vessels properly. A variety of symptoms can occur in individuals with polycythemia vera including nonspecific symptoms such as headaches, fatigue, weakness, dizziness or itchy skin; an enlarged spleen (splenomegaly); a variety of gastrointestinal issues; and the risk of blood clot formation, which may prevent blood flow to vital organs. More than 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. (For more information on this disorder, choose "polycythemia vera" as your search term in the Rare Disease Database.)

Idiopathic myelofibrosis is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In idiopathic myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets. The symptoms associated with idiopathic myelofibrosis vary and are related to the abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged (spleen) is a common finding. An enlarged liver (hepatomegaly) may also occur. (For more information on this disorder, choose "idiopathic myelofibrosis" as your search term in the Rare Disease Database.)

Chronic myelogenous leukemia is a rare myeloproliferative disorder characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. There are two phases to chronic myelogenous leukemia. The first phase, or chronic phase, is characterized by a slow, progressive overproduction of white blood cells. An advanced phase is called the acute phase or blast crisis. At this point, over 50 percent of the cells in the bone marrow are immature malignant cells (blast cells or promelocytes). In the acute phase, the leukemia is very aggressive and does not respond well to therapy. Approximately 85 percent of all individuals with chronic myelogenous leukemia enter the acute phase if not treated, but with the advent of Gleevec, conversion to acute leukemia is markedly delayed or even prevented changing the entire outlook. (For more information on this disorder, choose "chronic myelogenous leukemia" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
In many individuals, a diagnosis of essential thrombocythemia may first be suspected when blood tests, given as part of a routine examination, show elevated platelet levels. The major criteria for a diagnosis of ET are a persistent elevation in the number of circulating platelets; bone marrow biopsy showing overproduction of platelet precursor cells (megakaryocytes); no evidence of the presence of any other myeloproliferative disease; and the absence of any identifiable underlying condition that might cause secondary thrombocythemia, such as malignancy, infection, inflammatory disease, or iron deficiency. A bone marrow biopsy is a procedure in which a needle is inserted in a bone (usually the hip bone) and a small amount of marrow tissue is taken out. This sample tissue is viewed under a microscope where elevated levels of megakaryocytes or masses of platelets may be visible. Genetic studies are also obtained to rule out similar appearing disorders (chronic myelogenous leukemia)

Treatment
The treatment of essential thrombocythemia varies depending on an individual's risk for blood clots or bleeding complications as measured by platelet counts per microliter of blood. Individuals with a higher risk of complications include individuals who have had a previous history of blood clots or bleeding episodes, are over the age of 60, have white blood cell counts over 15,000, hemoglobins <12, have additional cardiovascular risk factors (e.g., high cholesterol, diabetes), have a platelet count greater than 1.5 million platelets per microliter of blood and smoke.

Low-risk individuals who exhibit few or no symptoms (asymptomatic) may not require any treatment at all. These individuals are carefully monitored periodically to detect any change or progression of their disease (watchful waiting).

When treatment is necessary, drug therapy with drugs that reduce the number of platelets in the blood is usually administered. The main drug used to treat individuals with ET is hydroxyurea. Hydroxyurea is usually sufficient to control the disease for an extended period of time in most individuals. When hydroxyurea is ineffective, a different drug, anagrelide may be used but because of potential complications has fallen into disfavor. Small amounts (doses) of aspirin may also be used to help control platelet hyperfuction in some individuals, especially those classified as low risk. The target platelet count is < 400,000.

The use of anti-platelet therapies discussed above is somewhat controversial. While hydroxyurea, anagrelide and low-dose aspirin all help reduce or control the levels of platelets in the blood, they can have the unwanted effect of increasing the likelihood of bleeding complications. Certain individuals may be at greater risk for bleeding complications then thrombotic complications. Affected individuals should discuss with their physician and healthcare team about the best therapy for their particular case.

Other drugs such as busulfan and radioactive phosphorous have been used to treat ET in the past, but are no longer used as frequently. These drugs have been associated with increased risk of developing leukemia, especially in individuals requiring long-term therapy.

Jakafi (ruxolitinib) was approved by the FDA in 2011 for treatment of patients with intermediate or high risk myelofibrosis, including post-essential thrombocythemia myelofibrosis. This medication inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning. It does not lower the platelet count but treats resultant splenomegally. Jakafi is manufactured by Incyte Corp. For more information contact http://www.jakafi.com/ or 1-855-4-Jakafi (855-452-5234).

Individuals with ET may be at risk for developing other myeloproliferative disorders. Physicians may closely monitor an affected individual to ensure early detection and appropriate treatment. Bone marrow evaluations may be given periodically to inspect for changes that may occur in the bone marrow.

Investigational Therapies

Interferon-alfa and pegylated interferon, immunosuppressive agents, has also been used to treat individuals with ET. There is disagreement within the medical community as to whether interferon is an effective treatment option for ET and more research is necessary to determine long-term safety and effectiveness of interferon as a treatment for individuals with ET.

Another therapy rarely used for people with ET is plateletpheresis, which involves the removal of platelets from the circulating blood. Plateletpheresis is usually used in the most severe cases of ET. More research is necessary to determine long-term safety and effectiveness of this treatment.

Investigators are studying the anti-cancer drug imatinib mesylate (Gleevec®) in individuals with ET. Gleevec has been successfully in treating individuals with chronic myelogenous leukemia, a related myeloproliferative disorder. Gleevec is classified as a tyrosine kinase inhibitor because it blocks the activity of certain proteins known tyrosine kinases. More research is necessary to determine the long-term effectiveness and safety of Gleevec and similar drugs for individuals with ET.
Pipobroman (similar to alkylating agents) is available for use in Europe.

The identification of the JAK2 mutation has led to new research initiatives for individuals with ET and related disorders. Medications that block or stop the activity of the protein product of this gene (which may help stimulate abnormal blood cell growth) may prove beneficial for affected individuals in the future. Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Essential Thrombocythemia

References

TEXTBOOKS
Algazy KM. Idiopathic Thrombocytosis. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:420-421.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1023-1027.

JOURNAL ARTICLES
Scott LM, Tong W, Levine RL, et al. JAK2 Exon 12 mutations in polycythemia vera and essential thrombocythemia. N Engl J Med. 2007;356:459-468.

Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006;355:452-466.

Tefferi A. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. Hematology Am Soc Hematol Educ Program. 2006;240-5.

Campbell PJ, Green AR. Management of polycythemia vera and essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2005;208-201.

Elliot MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br. J. Haematol. 2005;128:275-90.

Chomienne C, Rain JD, Briere JD, et al. Risk of leukemic transformation in PV and ET patients. Pathol Biol (Paris). 2004;52:289-93.

Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology (Am Soc Hematol Educ Program). 2003;200-24.

FROM THE INTERNET
Lal A. Essential Thrombocytosis. Emedicine Journal, October 4, 2009. Available at: http://www.emedicine.com/MED/topic2266.htm Accessed on: December 21, 2011.

National Heart, Lung And Blood Institute. Thrombocythemia and Thrombocytosis. October 1, 2010. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/thrm/thrm_what.html Accessed On: December 21, 2011.

Leukemia & Lymphoma Society. Essential or Primary Thrombocythemia. May 2007. Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/essentialprimarythrombocythemia.pdf Accessed On: December 21, 2011.

Report last updated: 2012/01/03 00:00:00 GMT+0