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Polycythemia Vera

NORD is very grateful to Ayalew Tefferi, MD, Professor of Medicine and Hematology, Mayo Clinic, for assistance in the preparation of this report.

Synonyms of Polycythemia Vera

  • erythremia
  • Osler-Vaquez disease
  • polycythemia rubra vera
  • primary polycythemia
  • splenomegalic polycythemia
  • Vaquez-Osler disease

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Summary
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 blood. 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. The exact role that this mutation plays in the development of polycythemia vera is not yet known.

Introduction
Polycythemia vera was first reported in the medical literature in 1892. The term "myeloproliferative disorder" (MPD) was first used to described polycythemia vera and related disorders in 1951. In 2008, the World Health Organization reclassified MPDs to "myeloproliferative neoplasms" (MPNs) to reflect the consensus that these diseases are blood cancers (neoplasms).

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 MPNs: chronic myeloid leukemia, essential thrombocythemia and idiopathic myelofibrosis. Because MPNs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.

Symptoms

The symptoms of polycythemia vera usually develop slowly over many years. Often, the disorder is found incidentally on a blood test as part of a routine exam before noticeable symptoms occur. Occasionally, affected individuals may report vague, nonspecific symptoms that eventually lead to diagnosis of the disorder.

Many individuals with polycythemia vera slowly development a variety of general, nonspecific symptoms that are common to many disorders such as headaches, fatigue, weakness, dizziness, excessive sweating especially at night, and itchy skin that, in severe cases, may be worse after taking a shower or a warm bath. Additional symptoms may occur in some affected individuals including blurred vision, ringing in the ears (tinnitus), and abnormal redness of the skin especially on the face.

Eventually, the spleen becomes involved. The spleen is an organ located in upper left part of the abdomen that filters out worn out blood cells. It often becomes abnormally enlarged in individuals with polycythemia vera as it attempts to clear a greater number of blood cells than normal - a condition called splenomegaly. Splenomegaly may cause an affected individual to have a bloated or full feeling in the abdomen.

Less common symptoms associated with polycythemia vera include a tendency to bruise easily, frequent nosebleeds or bleeding from the gums, enlargement of the liver (hepatomegaly), and erythromelalgia, a condition characterized by a reddened or purplish appearance to the skin of the hands and feet. The skin may feel warm to the touch. Erythromelalgia can also cause a painful, burning sensation or swelling of the affected areas.

Some individuals with polycythemia vera may develop symptoms secondary to reduced blood flow (due to thickening of the blood) and abnormalities affecting the platelets, which can increase a person's risk of developing blood clots. Complications that occur due to blood clots may be referred as thrombotic events and, in rare cases, can be the first obvious sign of polycythemia vera. Specific symptoms depend upon where a blood clot forms. A blood clot can cause a stroke, chest pain (angina), a heart attack, deep vein thrombosis (DVT) or a pulmonary embolism. DVT occurs when a blood clot forms in the legs may cause the legs to become painful and swollen. A pulmonary embolism occurs when 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 polycythemia vera have developed 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).

The abnormal proliferation of red blood cells may also cause peptic ulcers, gout, and kidney stones. Peptic ulcers are open sores on the lining of the gastrointestinal tract, which may cause bleeding (hemorrhaging) within the gastrointestinal tract. Gout is an inflammation of the joints caused by a build up of uric acid. Abnormally high levels of uric acid can also cause kidney stones. Gout and kidney stone associated with polycythemia vera occur due to the high turnover of red blood cells, which results in higher-than-normal uric acid production.

Polycythemia vera may eventually "burn out" so that scar tissue replaces the marrow and the disorder resembles idiopathic myelofibrosis. This may also be referred to as the "spent phase" of polycythemia vera. When this occurs, the 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, polycythemia vera may eventually progress into a form of leukemia known as acute myeloid leukemia.

Causes

Polycythemia vera is caused by a malignant change in the genetic material (DNA) within a single cell of the bone marrow (clonal disorder). Bone marrow is the soft, spongy material found inside bone where most blood cell production occurs. The underlying reason why this malignant change occurs is unknown.

This change is acquired meaning that it occurs after conception and is not inherited. Researchers have determined that approximately 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. The exact role this specific mutation plays in the development of the disorder is unknown.

The original defective cell in the bone marrow of individuals with polycythemia vera is a hematopoietic stem cell - a specialized cell that grows and eventually develops into one of the three main types of blood cells: red blood cells, white blood cells or platelets. A change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself eventually becoming the predominant hematopoietic stem cell in the bone marrow.

Polycythemia vera and some similar disorders have, in rare cases, affected 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 established a strong familial predisposition in association with polycythemia vera.

The symptoms of polycythemia vera occur because of abnormalities affecting the formation of blood cells that result in an overproduction of red blood cells and, to a lesser extent, the overproduction of white blood cells and platelets.

Affected Populations

Polycythemia vera affects slightly more men than women. The disorder is estimated to affect approximately 2 people per 100,000 in the general population. It occurs most often in individuals more than 60 years old, but can affect individuals of any age. It is extremely rare in individuals under 20.

Related Disorders

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

Secondary polycythemia is a general term for the overproduction of red blood cells that occurs as a result of (secondary to) a known cause. Such causes include genetic disorders, certain tumors that may secrete erythropoietin (a hormone that stimulates red blood cell production), conditions that deprive the body of oxygen such as certain lung or heart diseases. Some people living in high altitudes may develop secondary polycythemia in response to poor oxygenation of tissue. Certain kidney disorders can result in the excessive production of erythropoietin and, in turn, overproduction of red blood cells. Therapy in individuals with secondary polycythemia involves treating the underlying disorder or cause of the polycythemia.

Primary 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 primary 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 primary 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 "primary myelofibrosis" as your search term in the Rare Disease Database.)

Essential thrombocythemia (ET) is one of four rareMPNs. Myeloproliferative means uncontrolled production of cells by the bone marrow. Each of the four myeloproliferative neoplasms is characterized by over-production of a different, but essential, type of blood cell resulting in a high concentration of these cells in the blood. Essential thrombocythemia is characterized by overproduction of the precursor cells to blood platelets (megakaryocytes) which, in turn, leads to a vastly increased number of platelets in the blood. Platelets are specialized cells in blood essential for the normal process of clotting. In addition to over-production of platelets, other symptoms and signs of ET may include an enlarged spleen (splenomegaly); bleeding from the gut, gums and/or nose (hemorrhaging); and constricted or blocked arteries (thrombosis). As many as two-thirds of patients are without symptoms (asymptomatic) upon initial examination. Most patients present with symptoms related to small or large vessel thrombosis or minor bleeding. Presentation with a major bleeding episode is very unusual. Clots may occur in the small arteries of the toes and fingers, leading to pain, warmth, tissue death (gangrene) and/or classic erythromelalgia. Erythromelalgia refers to a syndrome of redness and burning pain in the extremities. The incidence of the thrombotic and bleeding episodes is minimized, but not eliminated, with reduction of the platelet count to normal. In some instances, this chronic disorder may be progressive, evolving in relatively rare cases into acute leukemia or myelofibrosis. (For more information on this disorder, choose "essential thrombocythemia" as your search term in the Rare Disease Database.)

Chronic myelogenous leukemia is a rare myeloproliferative neoplasm 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.

Standard Therapies

Diagnosis
Diagnosis of polycythemia vera may be made based upon a thorough clinical evaluation, detailed patient history, and various specialized tests. In many cases, the disorder may be detected from blood tests conducted during a routine examination. A complete blood count (CBC) may demonstrate elevated numbers of red blood cells and sometimes platelets and white blood cells.

Blood tests may also measure hemoglobulin and hematocrit. Hemoglobin is the protein within red blood cells that carry oxygen. Hematocrit is the percentage of red blood cells in the total blood volume. If these measures are elevated it may indicate polycythemia vera.

Physicians may also measure the levels of erythropoietin (EPO), a hormone that causes the bone marrow to produce red blood cells. In individuals with polycythemia vera, EPO levels are abnormally low. This test is usually done to distinguish polycythemia vera from secondary polycythemia, in which EPO levels are not affected.

In some cases, surgical removal and microscopic examination of bone marrow tissue (biopsy) may also be used to diagnose of polycythemia vera. The sample tissue is tested to determine whether the marrow is functioning properly.

A variety of specialized tests can be used to identify the JAK2 mutation in blood cells, which is also diagnostic of polycythemia vera.

Treatment
The treatment of polycythemia vera is aimed at reducing the levels of red blood cells and preventing the complications of the disorder especially blood clot (thrombosis) formation. Treatment options include phlebotomy and drug therapy.

Most individuals with polycythemia vera will have their blood drawn (similar to as is done when donating blood) usually at regular intervals over several months. Phlebotomy is used to reduce the volume of circulating red blood cells so that blood can flow and function properly. Phlebotomy may resolve symptoms associated with thickened blood and increased red blood cell production. Phlebotomy may be the only treatment necessary for some people, for many years. However, this procedure does not treat elevated platelet levels (thrombocythemia), elevated white blood cell levels (leukocytosis), itchy skin or gout. In some cases, phlebotomy may contribute to elevated platelet levels. Phlebotomy is also known as venesection.

Many individuals with polycythemia vera will also receive treatment with certain drugs that suppress the formation of blood cells by the marrow (myelosuppressive drugs). A chemotherapy drug known as hydroxyurea is most often used. Another chemotherapy drug used is busulfan. Other drugs such as chlorambucil and radioactive phosphorous have been used in the past, but these drugs, especially in individuals requiring long-term therapy, have been associated with increased risk of developing leukemia.

Anagrelide is a drug used to lower the number of platelets and reduce the risk of blood clot formation. Another drug, called interfeon alfa, stimulates the immune system to suppress blood cell production.

Additional therapies used for polycythemia vera include low-dose aspirin to decrease the risk of blood clot formation, a drug called allopurinol to treat high uric acid levels, and antihistamines or ultraviolet light therapy to treat severe, persistent itchiness.

Individuals who enter the "spent phase" of polycythemia vera, in which the bone marrow no longer produces healthy, functioning blood cells, may require periodic blood transfusions to maintain sufficient levels of blood cells. During the spent phase, the spleen may become significantly enlarged and painful, potentially requiring its removal through surgery (splenectomy).

Jakafi (ruxolitinib) was approved by the FDA in 2011 for treatment of patients with intermediate or high risk myelofibrosis, including post-polycythemia vera myelofibrosis. This medication inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning. Jakafi is manufactured by Incyte Corp. For more information contact http://www.jakafi.com/ or 1-855-4-Jakafi (855-452-5234).

Investigational Therapies

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:

Toll-free: (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

Investigators are studying the anti-cancer drug imatinib mesylate (Gleevec®) in individuals with polycythemia vera. Gleevec has been successfully in treating individuals with chronic myelogenous leukemia, a related MPN. More research is necessary to determine the long-term effectiveness and safety of this potential therapy for individuals with polycythemia vera.

The identification of the JAK2 mutation has led to new research initiatives for individuals with polycythemia vera 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.

Contact for additional information about polycythemia vera:
Ayalew Tefferi, MD
Professor of Medicine and Hematology
Department of Hematology
Mayo Clinic Transplant Center
Mayo Clinic
Rochester, Minnesota
507-538-3270
tefferi.ayalew@mayo.edu

Polycythemia Vera Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Algazy KM, Bergman GE. Polycythemia Vera. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:411-412.

Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, et al. Eds. Williams Hematology. 7th ed. McGraw-Hill Companies. New York, NY; 2006:779-803.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:102-1027.

JOURNAL ARTICLES
Tefferi A. JAK2 mutations in polycythemia vera ? molecular mechanisms and clinical applications. N Engl J Med. 2007;356:444-445.

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.

Finazzi G, Barbui T. How I treat patients with polycythemia vera. Blood. 2007;109:5104-5111.

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.

Stuart BJ, Viera AJ. Polycythemia vera. Am Fam Physician. 2004;69:2139-44.

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

Kwaan HC, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities. Semin Thromb Hemost. 2003;29:451-58.

INTERNET
Besa EC, Woermann U. Polycythemia Vera. Emedicine Journal. January 10, 2012. Available at: http://www.emedicine.com/MED/topic1864.htm Accessed April 24, 2013.

Mayo Clinic for Medical Education and Research. Polycythemia Vera. April 2, 2011. Available at: http://www.mayoclinic.com/health/polycythemia-vera/DS00919 Accessed April 24, 2013.

Leukemia & Lymphoma Society. Polycythemia Vera Facts. June, 2012. Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/polycythemiavera.pdf Accessed April 24, 2013.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2013/05/08 00:00:00 GMT+0

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