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What is polycythemia vera?
Polycythemia vera (PV) is one of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), or chronic, progressive hematologic disorders in which there is abnormal production of blood cells by stem cells in the bone marrow. In PV, there is uncontrolled production of red blood cells (RBCs), the cells that carry oxygen to the tissues. This leads to an increase in the concentration of RBCs in the blood, reflected by abnormally high hematocrit and hemoglobin (the protein in RBCs that carries oxygen) levels. In some cases, there may also be excessive concentrations of white blood cells (WBCs; the cells that help the body fight infection), and platelets (the cells that help the blood to clot) in the blood. The high concentrations of RBCs and other blood cells make the blood very thick (viscous). This thickness inhibits blood flow through the veins and arteries, and may result in an increased risk of thrombosis (formation of blood clots), which can lead to complications such as heart attack, stroke, or deep vein thrombosis, if not treated.
A recent study estimated the number of new cases of PV (or the incidence) in the United States in 2010 ranged from 22 to 27 per 100,000,1 and the number of people living with PV (or the prevalence) ranged from 48 to 57 per 100,000.2 PV typically is diagnosed later in life. In a recent study of 1545 patients,3 the median age at PV diagnosis was 61 years (range 18-95 years), with 10% of subjects diagnosed at age 40 years or younger. Some studies have indicated a roughly similar frequency of PV in men and women,3but other studies indicate a higher prevalence among men.2
PV develops over several years. Initially, there may be no symptoms of PV, which may be discovered during routine blood work that indicates an elevated hematocrit (the concentration of RBCs in blood). Symptoms that may develop as PV progresses include headache; dizziness; visual disturbances; severe itching, often triggered by a bath or shower; ruddy (or red) skin tone; abdominal pain; feeling of fullness or bloating in the left upper abdominal area that may indicate an enlarged spleen; difficulty breathing when lying down; fatigue; numbness, tingling or burning in upper or lower extremities; or gout, a condition in which a build-up of uric acid results in inflammation and pain in the joints, especially the big toe.
Because the high viscosity of the blood characteristic of PV inhibits blood flow through the veins and arteries, patients may have an increased risk of thrombotic events, which are cardiovascular complications that are due to the formation of blood clots. As a result, in about one-third of patients, PV may be discovered after such an event has occurred.4 Thrombotic events most commonly observed in studies of PV patients include inflammation from blood clots just below the surface of the skin (typically following placement of a needle or catheter), deep vein thrombosis (a blood clot that forms in a vein deep inside the body), mini-stroke (transient ischemic attack), stroke, blood clots in the peripheral arteries, heart attack, or pulmonary embolism (blockage of an artery in the lung). The risks of having such complications tend to be higher for individuals who are older and those with a prior history of thrombotic events.5 Management of PV includes controlling hematocrit levels and sometimes normalizing other blood cell counts to reduce the risks of thrombotic and bleeding complications.
Approximately 10% of patients with PV develop myelofibrosis,6 an MPN in which scarring (fibrosis) of the bone marrow ultimately results in impaired production of RBCs, and sometimes of WBCs and platelets, within 10 years. When myelofibrosis develops in a patient with PV, it is called post-polycythemia vera myelofibrosis (post-PV MF). Post-PV MF typically happens late in the course of PV. Risk factors for developing post-PV MF include a very high WBC count and advanced age.6 Acute myeloid leukemia (AML), a cancer of the blood, may develop very rarely in patients with PV (in a recent study, 3% of patients developed AML at a median of approximately 10 years).
Elevated hematocrit indicating excessive production of RBCs is the hallmark of PV; however, there may be other causes of increased RBCs that are not associated with the way blood is formed in the bone marrow. Therefore, both physical examination and a series of laboratory tests are used to determine if signs and symptoms are consistent with PV. Based on consensus, hematologists who are experts in the field of MPN have developed very specific criteria to confirm diagnosis of PV.
The World Health Organization (WHO) criteria for diagnosis of polycythemia vera7 are the current consensus criteria used for definitive diagnosis of PV by hematologists. There are two major criteria (which are present in approximately 98% patients with PV)4 and three minor criteria, all based on laboratory tests (blood tests and samples of bone marrow [obtained via biopsy], if available). The major criteria are based on hemoglobin or hematocrit levels (measures of red cell volume) and the presence of specific mutations on a gene called Janus kinase 2 (JAK2), including the V617F mutation (present in more than 95% of PV patients)8 or a less common mutation, known as exon 12 (sometimes present in some patients who do not have the V617F mutation).4,7,9 The minor criteria are based on characteristics of bone marrow and levels of hormone in the blood (erythropoietin) that stimulates stem cells in the bone marrow to make more RBCs. A diagnosis of PV requires either (1) the presence of both major criteria and one minor criterion or (2) the presence of the first major criterion (that is, excessive red cell volume) and two minor criteria.
There is no cure for PV, but there are treatments aimed at managing the symptoms and reducing the risks of complications associated with PV. Treatments for PV that may be used depend on an individual’s age, cardiovascular history, and signs and symptoms of PV they are experiencing. These factors help hematologists classify patients with PV into various risk categories, ranging from low to high, for the purpose of determining the best individual treatment option.
Hematologists who are experts in the field of MPN have developed consensus recommendations for the management and treatment of PV, based on both clinical practice and the body of evidence available from multiple research studies.10
The first goal of therapy is to avoid thrombotic complications associated with PV, or to reduce the risk of them occurring again in individuals with previous events. This includes management of risk factors for cardiovascular disease that may be present regardless of PV, such as hypertension, obesity, diabetes, and high cholesterol, as well as smoking cessation.
Treatments for reducing the risk of thrombotic events specific to PV focus on reducing the concentration of RBCs, and then maintaining them at normal levels. Phlebotomy is a procedure that involves withdrawing a certain amount blood through a vein to reduce the concentration of RBCs (the hematocrit) to a specific target level. The procedure of withdrawing blood is similar to what is done during blood donation. Phlebotomy is repeated over a period of time until the target hematocrit is reached, and blood counts are monitored regularly to confirm that the hematocrit stays at the target level.
Phlebotomy is used together with a low dose of aspirin, which reduces the risk of formation of blood clots by inhibiting the production of a substance that binds platelets (the cells that help the blood to clot) together.
In individuals who need very frequent phlebotomy or who do not tolerate the procedure well, or those with more advanced and symptomatic PV, medications known as cytoreductive agents—or agents that reduce the excess number of cells—may be used. Initial cytoreductive agents that may be used include hydroxyurea and pegylated interferon-alpha. In some cases, busulfan may be used.
In addition to reducing the risk for cardiovascular complications, some of these treatments may also help alleviate some of the symptoms associated with PV.
The safety and effectiveness of new drugs for the treatment of PV, including JAK2 inhibitors, are currently being evaluated in clinical trials.
As with any treatment, there may be side effects associated with treatments for PV. Hematologists use the consensus recommendations as guidelines while considering what the right treatment is for an individual. Decisions regarding the right treatment for PV should be made considering the benefits and risks of the treatment, and these considerations may change over time.
- Mesa RA, Mehta J, Wang H, Wang Y, Usman I, Neumann F, Zhang Y, Colton T. Epidemiology of myeloproliferative disorders in the US – A real world analysis. American Society Hematology; 2012; Atlanta, Georgia.
- Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leukemia & Lymphoma. 2013;Early online: 1-6.
- Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, Randi ML, Vaidya R, Cazzola M, Rambaldi A, Gisslinger B, Pieri L, Ruggeri M, Bertozzi I, Sulai NH, Casetti I, Carobbio A, Jeryczynski G, Larson DR, Mullaur L, Pardanani A, Thiele J, Passamonti F, Barbui T. Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia. 2013;27:1874-1881.
- Passamonti F. How I treat polycythemia vera. Blood. 2012;120:275-284.
- Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105(7):2664-2670.
- Passamonti F, Rumi E, Caramella M, Elena C, Arcaini L, Boveri E, Del Curto C, Pietra D, Vanelli L, Bernasconi P, Pascutto C, Cazzola M, Morra E, Lazzarino M. A dynamic prognostic model to predict survival in post-polychythemia vera myelofibrosis. Blood. 2008;111:3383-3387.
- Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114:937-951.
- Tefferi A, Vainchenker W. Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol. 2011;29(5):573-582.
- Tefferi A. Myeloproliferative neoplasms 2012: The John M. Bennett 80th birthday anniversary lecture. Leukemia Research. 2012;36:1481-1489.
- Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770.