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Last updated:
11/16/2023
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NORD gratefully acknowledges Ayalew Tefferi, MD, Professor of Medicine and Hematology, Mayo Clinic, for assistance in the preparation of this report.
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 patients. 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 variant (mutation) in the JAK2 gene. The exact role these variants play 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 describe 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.
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 the 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 to 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, sudden pain in 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.
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 variant in the JAK2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body.
The JAK2 gene produces a protein called a kinase, specifically Janus kinase 2. Kinases are very powerful drivers of cell growth. In people with polycythemia vera, the JAK2 gene is overactive because of the underlying genetic change.
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. Normally, the kidneys produce a hormone called erythropoietin. This hormone binds to receptors found on hematopoietic stem cells. Because the JAK2 gene is overactive, these cells derived from the original defective hematopoietic stem cell continue to grow and divide even in the absence of erythropoietin. These rapidly growing cells clog the bone marrow and when they break down and die, cause scar tissue to form.
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 variant 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.
Polycythemia vera affects slightly more males than females. The disorder is estimated to affect approximately 44 to 57 per 100,000 people in the US. 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.
Diagnosis of polycythemia vera may be made based upon a thorough clinical evaluation, detailed patient history and various specialized tests. In many people, 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 patients, surgical removal and microscopic examination of bone marrow tissue (biopsy) may also be used to diagnose 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 JAK2 gene variants 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 (phlebotomy), usually at regular intervals over several months. This is done 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 patients, phlebotomy may contribute to elevated platelet levels.
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 interferon 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).
Ruxolitinib (Jakafi) was approved by the U.S. Food and Drug Administration (FDA) in 2011 for treatment of patients with intermediate or high-risk myelofibrosis, including post-polycythemia vera myelofibrosis. In 2014, Jakafi was approved for PV patients who have had an inadequate response to or are intolerant of hydroxyurea. This medication inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning.
Information on current clinical trials is posted on the Internet at https://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
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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 variants 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
TEXTBOOKS
Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, et al. Eds. Williams Hematology. 7th ed. McGraw-Hill Companies. New York, NY; 2006:779-803.
Algazy KM, Bergman GE. Polycythemia Vera. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:411-412.
Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:102-1027.
JOURNAL ARTICLES
Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(9):1465-1487. doi:10.1002/ajh.27002 https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27002?domain=p2p_domain&token=HDGQBZNMGJWDDBVISUGU
Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92:94-108.
Barbui T, Thiele J, Vannucchi AM, Tefferei A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J. 2015;5:e337.
Stein BL, Moliterno AR, Tiu RV. Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014;93:1965-1976.
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
Nagalla S and Besa EC, Polycythemia Vera. Medscape. Updated: Aug 31, 2022. Available at: https://www.emedicine.com/MED/topic1864.htm Accessed Nov 16, 2023.
Mayo Clinic for Medical Education and Research. Polycythemia Vera. Feb. 11, 2022. Available at: https://www.mayoclinic.com/health/polycythemia-vera/DS00919 Accessed Nov 16, 2023.
Leukemia & Lymphoma Society. Polycythemia Vera Facts. Revised April 2015. Available at: https://www.lls.org/sites/default/files/file_assets/FS13_PolycythemiaVera_FactSheet_final5.1.15.pdf Accessed Nov 16, 2023.
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