Polycythemia Vera

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Continuing Education Activity

Polycythemia vera is a myeloproliferative disorder associated with a Janus kinase-2 (JAK2) mutation that causes the neoplastic proliferation of the hematopoietic progenitor cells. It causes elevated red blood cell production along with secondary white blood cell and platelet production. Disease complications are associated with increased blood viscosity, including thromboses. This activity reviews the evaluation and treatment of polycythemia vera and highlights the role of the interprofessional team in improving care for patients with this condition.


  • Identify the etiology of polycythemia vera.
  • Describe the presentation of polycythemia vera.
  • Outline treatment recommendations for polycythemia vera.
  • Review the importance of collaboration among the interprofessional team to achieve correct diagnosis and management to improve outcomes in patients with polycythemia vera.


Polycythemia vera (PV) is a myeloproliferative neoplastic disorder involving uncontrolled red blood cell production resulting in elevated red blood cell (RBC) mass. There is often a concurrent stimulation of myeloid and megakaryocytic lineages, leading to increased white blood cell and platelet production. The current understanding of pathophysiology involves increased sensitivity to growth factors due to an abnormal hematopoietic cell clone. Signs and symptoms, including headache, dizziness, claudication, thrombosis, are a consequence of increased blood viscosity.


The etiology of the disease process appears to be neoplastic proliferation. There is a signaling defect leading to an abnormal response to growth factors, and the abnormal clonal line interferes with normal lineage proliferation. The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of polycythemia vera (PV).[1] Cytogenetic studies show the presence of an abnormal karyotype in the hematopoietic progenitor cells in approximately 34% of patients with PV. At the time of diagnosis, 20% of patients have cytogenetic abnormalities, increasing to more than 80% for those with more than 10 years of follow-up care.


Polycythemia vera (PV) can affect all ethnic groups with no sex predilection, although there are slightly more cases in men than women.[2] It can occur in all age groups, but the median age of diagnosis is 60.[3] PV affects 0.6 to 1.6 per million people in the United States. There are fewer incidences in Japan than in the United States or Europe.[4]


The bone marrow of patients with polycythemia vera (PV) contains normal stem cells and contains abnormal clonal stem cells that suppress normal stem cell growth and maturation. The cause of panmyelosis is unregulated neoplastic proliferation. JAK2 kinase mutation likely leads to the signaling derangements resulting in PV. A valine to phenylalanine substitution at position 617 of the JAK2 gene, or JAK2V617F, leads to constitutively active cytokine receptors.[5] This mutation is observed in over 90% of patients with PV and 50% to 60% of primary myelofibrosis, and 50% of essential thrombocythemia.[1][6] This process leads to increased production of red blood cells and platelets with associated complications of thrombosis and bleeding.


Peripheral blood smear findings can be different based on the stage of the disease. In pre-polycythemia and overt polycythemia, normochromic and normocytic red blood cells are seen. A hypochromic and microcytic pattern can accompany concomitant iron deficiency. Platelets and white blood cells can also be elevated. Leukocytosis, predominantly with neutrophils, can be seen without blast activity. Myelofibrosis develops with teardrop red blood cells, poikilocytosis, and circulating nucleated red cells in the post-polycythemic stage.

Bone marrow sampling typically shows hypercellularity with panproliferation. Again, histopathology is dependent on the stage of the disease. Erythrocytosis is seen with pre-polycythemia, increased red cell mass in overt polycythemia, and increased reticulin deposition in post-polycythemia with fibrosis, ineffective production, and extramedullary hematopoiesis.[7]

History and Physical

Symptoms of polycythemia vera (PV) are related to hyperviscosity and thrombosis, impairing oxygen delivery. Physical complaints can include fatigue, headache, dizziness, tinnitus, vision changes, insomnia, claudication, pruritus, gastritis, and early satiety. Aquagenic pruritus, which occurs during or after a hot shower, is a complaint in 40% of patients.[8][9] The mechanism is likely from mast cell and basophil degranulation, causing a histamine surge. In a 2013 study with 1545 patients, pruritis was associated with better survival.[10] Erythromelalgia is a burning pain in the hands and feet with erythema or pallor. This can be seen in PV or essential thrombocythemia and responds well to low-dose aspirin.[11] Bleeding and thrombotic complications are each observed in 1% of patients. Bleeding events can include epistaxis, gum bleeding, and gastrointestinal (GI) bleeding. Thrombotic events can include deep venous thrombosis (DVT), pulmonary embolism (PE), Budd-Chiari syndrome, splanchnic vein thrombosis, stroke, and arterial thrombosis.[12] Early satiety occurs from impaired gastric filling due to splenomegaly. GI discomfort and peptic ulcer disease are common, likely from increased histamine release from basophils and increased viscosity in gastrointestinal blood supply.[13]

Patients can display a plethora and flushing of the face and palms, conjunctival injection, and skin excoriation from pruritus on physical exam. Splenomegaly and hepatomegaly are also often observed.[14]


In the 1970s, the polycythemia vera study group (PVSG) set the first diagnostic criteria for polycythemia vera (PV). The diagnosis can be made if all three category A criteria are met, or if A1, A2, and two from category B are met.[15]

Category A

  • Total red blood cell mass more than or equal to 36 mL/kg in males or more than or equal to 32 mL/kg in females
  • Arterial oxygen saturation more than or equal to 92%
  • Splenomegaly

Category B

  • Platelets of more than 400,000/microliter
  • White blood cell count more than 12,000/microliter
  • Leukocyte alkaline phosphatase (ALP) more than 100 U/L
  • Serum vitamin B12 more than 900 pg/mL or binding capacity more than 2200 pg/mL

Measuring the red blood cell mass requires labeling with the 51Cr isotope, which is no longer readily available. Therefore, the PVSG guidelines have fallen out of favor, and the World Health Organization (WHO) published revised guidelines for diagnosing PV in 2016. These criteria are composed of three major and one minor criterion. Diagnosis can be made if all three major or two major and minor criteria are met.[16]


  • Hemoglobin (Hgb) more than 16.5 g/dL or hematocrit (Hct) more than 49% in men, Hgb more than 16 g/dL or Hct more than 48% in women; or red blood cell mass more than 25% above mean normal predicted
  • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
  • JAK2 V617For JAK2 exon 12 mutation


  • Serum erythropoietin level below the reference range for normal

These criteria should only be applied for diagnosis after secondary causes of polycythemia have been ruled out.

Treatment / Management

There is no cure for polycythemia vera (PV); treatment goals are aimed at symptom relief and reducing the risk of disease complications, including thrombosis, bleeding, and hematologic transformation. There are currently no means for preventing transformation into myelofibrosis or acute leukemia/myelodysplastic syndrome, but there are known agents to avoid that can increase this risk.[17]

Medical Treatment

  Patients under the age of 60 without a history of thrombotic events are considered low risk, and treatment recommendations include:

  • Phlebotomy: Target hematocrit to less than 45%. Each unit of phlebotomized blood (500 mL) should drop the hematocrit by 3% in an average-sized adult. Men may tolerate up to the removal of 1.5 to 2 units a week. Whereas women, the elderly, those who weigh less than 50 kg, or those with cardiovascular disease may only tolerate removal of 0.5 units a week. The goal of phlebotomy is to deliberately induce an iron-deficient state, which will, to some degree, limit the marrow's capacity for erythropoiesis; therefore, patients should not take iron supplements. Patients with hematocrits maintained at less than 45% have significantly fewer cardiovascular and thrombotic events compared to when the goal hematocrit is 50%.[18]
  • Low dose aspirin (40 mg to 100 mg) once or twice daily should be given, if no contraindications, to lower thrombotic risk.[19] Patients with platelets greater than 1 million/microliter can have increased bleeding risk due to acquired von Willebrand disease and, therefore, should not be placed on aspirin.[20]
  • Treat aspirin refractory symptoms.
  • Optimizing cardiovascular health such as weight loss, exercise, tobacco cessation, blood pressure control.

 Patients 60 years of age or older and/or who have a history of thrombosis are considered high risk. In high-risk patients, cytoreductive therapy is recommended in addition to phlebotomy and aspirin. The first-line agent is hydroxyurea (HU) due to its safety profile, cost, and efficacy.[21] Initial dosing is 15 mg/kg of actual body weight per day divided into twice-daily dosing. The goal is to reduce platelets to 100,000 to 400,000/microliter without excessive neutropenia and anemia. Dosing should not be adjusted more frequently than once weekly because it takes three to five days for a dose modification to achieve the therapeutic effect. Patients failing hydroxyurea therapy or who are intolerant may try pegylated interferon or busulfan. Other alternatives include ruxolitinib, anagrelide, pipobroman, and radioactive phosphorus.[17][20]

The FDA approved a JAK inhibitor (ruxolitinib) in 2014 to treat patients with PV who have an inadequate response or are intolerant of hydroxyurea. A great proportion of patients on ruxolitinib achieved complete hematological remission.

To manage pruritus, initial treatment should include antihistamines and selective serotonin reuptake inhibitors (SSRIs). If ineffective, INF-a can be attempted, followed by JAK2 inhibitors for highly resistant cases.[17]

Surgical Treatment

Splenectomy may be appropriate in the setting of painful splenomegaly or recurrent splenic infarcts.

Budd-Chiari syndrome, or hepatic venous outflow thrombosis, is a potential complication requiring surgical intervention such as transjugular intrahepatic portosystemic shunt (TIPS), portocaval shunt, mesocaval shunt, portocaval/cavoatrial shunt, or mesoatrial shunt.[22]

Differential Diagnosis

Primary polycythemia vera (PV) must demonstrate increased production in all three cell lines to make the diagnosis. Increased red blood cell mass alone is not enough for diagnosis because other conditions such as chronic hypoxia and erythropoietin-secreting tumors can lead to polycythemia. Secondary polycythemia (from hypoxia or smoking) is much more common than primary PV and must be ruled out before the diagnosis of primary PV can be made.[3] A rare mutation of the erythropoietin (EPO) receptor can mimic the basic presentation of PV, including increased red cell mass and decreased EPO. However, the mechanism is an over-sensitive receptor to EPO rather than EPO independence.[23][24] Isolated granulocytosis can occur from infections or leukemoid reactions. Thrombocytosis alone can result from bleeding or iron deficiency.

Differential diagnoses to consider include:

  • Essential thrombocythemia
  • Chronic myelogenous leukemia
  • Agnogenic myeloid metaplasia
  • Chronic myelogenous leukemia
  • Primary myelofibrosis
  • Secondary polycythemia

Toxicity and Adverse Effect Management

Older patients and those with cardiovascular disease should have a smaller volume of blood removed during phlebotomy sessions to minimize orthostatic effects. Normal saline may be given post phlebotomy to replace the volume lost. Patients need to stay well-hydrated and limit aggressive physical activity within the first 24 hours of phlebotomy.

Higher dose aspirin (more than 100 mg/day) is associated with an increased risk of bleeding, and 900 mg daily is associated with a high rate of gastrointestinal bleeding.[25][19][26]

Adverse effects of hydroxyurea include cytopenias, oral ulcers, GI upset, peripheral neuropathy, and rare but severe pulmonary toxicity. If HU is not tolerated, cytoreductive therapy should be changed to other agents listed above.


The average survival of untreated polycythemia vera (PV) is 18 months, whereas median survival is 14 years overall and 24 years if younger than 60 for those undergoing treatment.[17][20][27] According to one study, mortality in PV is higher than in age and sex-matched populations. Five-year survival in the overall cohort was 79.5%, but patients are at a high risk of second primary malignancies and leukemic transformation, which may compromise long-term survival.[28]


Polycythemia vera-related complications and mortality are related to thrombosis, hemorrhage, peptic ulcer disease, myelofibrosis, acute leukemia, or myelodysplastic syndrome (MDS).

Thrombosis is a major complication of polycythemia vera (PV), and current treatment recommendations aim to minimize these risks. In the setting of a first thrombotic event, an appropriate dose and length of anticoagulation are recommended. There is currently no difference in treatment recommendations for patients with underlying PV.[29]

Bleeding is another common complication of the disease process, but major bleeding is rare. The risk for bleeding increases with severe thrombocytosis and high-dose aspirin (more than 100 mg/day) or anticoagulation.[25]

Myelofibrosis worsens with the progression of the disease. Recommended treatment for secondary myelofibrosis is the same as primary myelofibrosis. Transformation to myelodysplasia and acute leukemia yields a poor prognosis. Treatment is the same as primary MDS and acute myeloid leukemia (AML).


It is recommended that a hematologist be involved in the care of patients with polycythemia vera (PV).

Deterrence and Patient Education

Polycythemia vera (PV) is a condition where the bone marrow goes into “overdrive” and makes too many red blood cells, along with too many white blood cells and platelets. This can put you at risk for life-threatening blood clots, bleeding, and certain blood cancers. It is, therefore, important to have frequent follow up with a hematologist for close monitoring and treatment to lower these risks. Treatment options include phlebotomy, daily aspirin, and certain medications to suppress the bone marrow.

Enhancing Healthcare Team Outcomes

Polycythemia vera (PV) may initially present with vague symptoms including headache, dizziness, fatigue, insomnia, GI complaints, pruritus, etc., and patients may initially bring this to the attention of the general practitioner. A combination of these symptoms, along with abnormal hematologic labs, warrants a referral to a hematologist for further workup for the underlying condition. Early diagnosis and treatment of PV can increase survival by decreasing morbidity from disease complications. The role of the interprofessional team to achieve correct diagnosis and management to improve outcomes in patients with polycythemia vera is crucial. This interprofessional team is comprised of clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all working collaboratively and exercising open communication to achieve optimal patient results. [Level 5]

Article Details

Article Author

Xiao Lu

Article Editor:

Richard Chang


4/24/2023 12:41:32 PM



Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kröger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek S, Tefferi A, European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011 Feb 20:29(6):761-70. doi: 10.1200/JCO.2010.31.8436. Epub 2011 Jan 4     [PubMed PMID: 21205761]


Anía BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ 3rd. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. American journal of hematology. 1994 Oct:47(2):89-93     [PubMed PMID: 8092146]


Berlin NI. Diagnosis and classification of the polycythemias. Seminars in hematology. 1975 Oct:12(4):339-51     [PubMed PMID: 1198126]


Johansson P. Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. Seminars in thrombosis and hemostasis. 2006 Apr:32(3):171-3     [PubMed PMID: 16673273]


James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28:434(7037):1144-8     [PubMed PMID: 15793561]


Spivak JL, Silver RT. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood. 2008 Jul 15:112(2):231-9. doi: 10.1182/blood-2007-12-128454. Epub 2008 Apr 9     [PubMed PMID: 18401028]


Wasserman LR. The management of polycythaemia vera. British journal of haematology. 1971 Oct:21(4):371-6     [PubMed PMID: 4941523]


Lelonek E, Matusiak Ł, Wróbel T, Szepietowski JC. Aquagenic Pruritus in Polycythemia Vera: Clinical Characteristics. Acta dermato-venereologica. 2018 Apr 27:98(5):496-500. doi: 10.2340/00015555-2906. Epub     [PubMed PMID: 29437189]


Saini KS, Patnaik MM, Tefferi A. Polycythemia vera-associated pruritus and its management. European journal of clinical investigation. 2010 Sep:40(9):828-34. doi: 10.1111/j.1365-2362.2010.02334.x. Epub 2010 Jul 1     [PubMed PMID: 20597963]


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,Müllauer L,Pardanani A,Thiele J,Passamonti F,Barbui T, Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013 Sep;     [PubMed PMID: 23739289]


Michiels JJ. Erythromelalgia and vascular complications in polycythemia vera. Seminars in thrombosis and hemostasis. 1997:23(5):441-54     [PubMed PMID: 9387203]


Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. British journal of haematology. 2013 Sep:162(6):730-47. doi: 10.1111/bjh.12461. Epub 2013 Jul 15     [PubMed PMID: 23855810]


Gilbert HS, Warner RR, Wasserman LR. A study of histamine in myeloproliferative disease. Blood. 1966 Dec:28(6):795-806     [PubMed PMID: 5959473]


Accurso V, Santoro M, Raso S, Contrino AD, Casimiro P, Piazza FD, Perez A, Russo A, Siragusa S. Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study. Hematology reports. 2019 Nov 29:11(4):8281. doi: 10.4081/hr.2019.8281. Epub 2019 Dec 4     [PubMed PMID: 31871612]


Streiff MB, Smith B, Spivak JL. The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood. 2002 Feb 15:99(4):1144-9     [PubMed PMID: 11830459]


Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19:127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11     [PubMed PMID: 27069254]


Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm 2018. Blood cancer journal. 2018 Jan 10:8(1):3. doi: 10.1038/s41408-017-0042-7. Epub 2018 Jan 10     [PubMed PMID: 29321547]


Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T, CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. The New England journal of medicine. 2013 Jan 3:368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8     [PubMed PMID: 23216616]


van Genderen PJ, Mulder PG, Waleboer M, van de Moesdijk D, Michiels JJ. Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin. British journal of haematology. 1997 Apr:97(1):179-84     [PubMed PMID: 9136963]


Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. American journal of hematology. 2015 Feb:90(2):162-73. doi: 10.1002/ajh.23895. Epub     [PubMed PMID: 25611051]


Büyükaşık Y, Ali R, Turgut M, Saydam G, Yavuz AS, Ünal A, Ar MC, Ayyıldız O, Altuntaş F, Okay M, Çiftçiler R, Meletli Ö, Soyer N, Mastanzade M, Güven Z, Soysal T, Karakuş A, Yiğenoğlu TN, Uçar B, Gökçen E, Tuğlular T. Patterns of Hydroxyurea Prescription and Use in Routine Clinical Management of Polycythemia Vera: A Multicenter Chart Review Study. Turkish journal of haematology : official journal of Turkish Society of Haematology. 2020 Aug 28:37(3):177-185. doi: 10.4274/tjh.galenos.2020.2019.0431. Epub 2020 Feb 20     [PubMed PMID: 32075363]


Slakey DP, Klein AS, Venbrux AC, Cameron JL. Budd-Chiari syndrome: current management options. Annals of surgery. 2001 Apr:233(4):522-7     [PubMed PMID: 11303134]


Tefferi A, Spivak JL. Polycythemia vera: scientific advances and current practice. Seminars in hematology. 2005 Oct:42(4):206-20     [PubMed PMID: 16210034]


Arcasoy MO, Degar BA, Harris KW, Forget BG. Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood. 1997 Jun 15:89(12):4628-35     [PubMed PMID: 9192789]


Ruggeri M, Rodeghiero F, Tosetto A, Castaman G, Scognamiglio F, Finazzi G, Delaini F, Micò C, Vannucchi AM, Antonioli E, De Stefano V, Za T, Gugliotta L, Tieghi A, Mazzucconi MG, Santoro C, Barbui T, Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Chronic Myeloproliferative Diseases Working Party. Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood. 2008 Jan 15:111(2):666-71     [PubMed PMID: 17909074]


Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T, European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. The New England journal of medicine. 2004 Jan 8:350(2):114-24     [PubMed PMID: 14711910]


CHIEVITZ E, THIEDE T. Complications and causes of death in polycythaemia vera. Acta medica Scandinavica. 1962 Nov:172():513-23     [PubMed PMID: 14020816]


Khanal N, Giri S, Upadhyay S, Shostrom VK, Pathak R, Bhatt VR. Risk of second primary malignancies and survival of adult patients with polycythemia vera: A United States population-based retrospective study. Leukemia & lymphoma. 2016:57(1):129-33. doi: 10.3109/10428194.2015.1071492. Epub 2015 Sep 1     [PubMed PMID: 26159045]


Ruggeri M, Gisslinger H, Tosetto A, Rintelen C, Mannhalter C, Pabinger I, Heis N, Castaman G, Missiaglia E, Lechner K, Rodeghiero F. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. American journal of hematology. 2002 Sep:71(1):1-6     [PubMed PMID: 12221665]