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Polycythemia Vera

  • Author: Srikanth Nagalla, MBBS, MS, FACP; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
 
Updated: May 23, 2016
 

Practice Essentials

Polycythemia vera (PV) is a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. Its most prominent feature is an elevated absolute red blood cell mass because of uncontrolled red blood cell production.

Signs and symptoms

Impaired oxygen delivery due to sludging of blood may lead to the following symptoms:

  • Headache
  • Dizziness
  • Vertigo
  • Tinnitus
  • Visual disturbances
  • Angina pectoris
  • Intermittent claudication

Bleeding complications, seen in approximately 1% of patients with PV, include epistaxis, gum bleeding, ecchymoses, and gastrointestinal (GI) bleeding. Thrombotic complications (1%) include venous thrombosis or thromboembolism and an increased prevalence of stroke and other arterial thromboses.

Physical examination findings may include the following:

  • Splenomegaly (75% of patients)
  • Hepatomegaly (30%)
  • Plethora
  • Hypertension

Diagnosis

According to 2008 revised World Health Organization (WHO) guidelines, diagnosis of PV requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria.

Major WHO criteria are as follows:

  1. Hemoglobin > 18.5 g/dL in men and > 16.5 g/dL in women, or other evidence of increased red blood cell volume
  2. Presence of JAK2617V F or other functionally similar mutation, such as JAK2 exon 12 mutationMinor WHO criteria are as follows:

See the list below:

  • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
  • Serum erythropoietin level below the reference range for normal
  • Endogenous erythroid colony formation in vitro

Management

Treatment measures are as follows:

  • Phlebotomy – To keep hematocrit below 45%
  • Aspirin – 81 mg daily
  • Cytoreductive therapy – For patients at high risk for thrombosis
  • Splenectomy in patients with painful splenomegaly or repeated episodes of splenic infarction

Hydroxyurea is the most commonly used cytoreductive agent. If hydroxyurea is not effective or not tolerated, alternatives include the following:

  • Interferon alfa
  • Busulfan – In patients older than 65 years
  • Ruxolitinib (Jakafi)
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Background

Polycythemia vera (PV) is a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. Its most prominent feature is an elevated absolute red blood cell mass because of uncontrolled red blood cell production. This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation.[1, 2, 3]

For discussion of polycythemia in children, see Pediatric Polycythemia vera.

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Pathophysiology

Normal stem cells are present in the bone marrow of patients with polycythemia vera (PV), but also present are abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation. Evidence indicates that the etiology of panmyelosis is unregulated neoplastic proliferation. The origin of the stem cell transformation remains unknown. See the image below.

Bone marrow film at 100X magnification demonstrati Bone marrow film at 100X magnification demonstrating hypercellularity and increased number of megakaryocytes. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Progenitors of the blood cells in these patients display abnormal responses to growth factors, suggesting the presence of a defect in a signaling pathway common to different growth factors. The observation that in vitro erythroid colonies grow when no endogenous erythropoietin (Epo) is added to the culture and the presence of a truncated Epo receptor in familial erythrocytosis indicate that the defect is in the transmission of the signal. The sensitivity of polycythemia vera progenitors to multiple cytokines suggests that the defect may lie in a common pathway downstream from multiple receptors. Increased expression of BCLX suggests an additional decrease in cellular apoptosis.

Several reasons suggest that a mutation on the Janus kinase-2 gene (JAK2) is the most likely candidate gene involved in polycythemia vera pathogenesis, as JAK2 is directly involved in the intracellular signaling following exposure to cytokines to which polycythemia vera progenitor cells display hypersensitivity.[4] A recurrent unique acquired clonal mutation in JAK2 has been found in most patients with polycythemia vera and other myeloproliferative diseases (MPDs), including essential thrombocythemia and idiopathic myelofibrosis.

A unique valine-to-phenylalanine substitution at position 617 (V617F) in the pseudokinase JAK2 domain has been identified. The substitution, called JAK2V617F, leads to a permanently turned-on signaling at the affected cytokine receptors.[5, 6, 7, 8] How these mutations interact with the wild-type kinase genes and how they manifest into different forms of MPDs need to be elucidated.

Thrombosis and bleeding are frequent in persons with polycythemia vera, as a result of the disruption of hemostatic mechanisms because of (1) an increased level of red blood cells and (2) an elevation of the platelet count. There are findings that indicate the additional roles of tissue factor and polymorphonuclear leukocytes (PMLs) in clotting, the platelet surface as a contributor to phospholipid-dependent coagulation reactions, and the entity of platelet microparticles. Tissue factor is also synthesized by blood leukocytes, the level of which is increased in persons with MPD, which can contribute to thrombosis.

Rusak et al evaluated the hemostatic balance in patients using thromboelastography and also studied the effect of isovolemic erythrocytapheresis on patients with polycythemia vera. They concluded that thromboelastography may help to assess the thrombotic risk in patients with polycythemia vera.[9]

Hyperhomocystinemia is a risk factor for thrombosis and is also widely prevalent in patients with MPD (35% in controls, 56% in persons with polycythemia vera).

Acquired von Willebrand syndrome is an established cause of bleeding in persons with MPD, accounting for approximately 12-15% of all patients with this syndrome. von Willebrand syndrome is largely related to the absorption of von Willebrand factor onto the platelets; reducing the platelet count should alleviate the bleeding from the syndrome.

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Epidemiology

Frequency

United States

Polycythemia vera (PV) is relatively rare, occurring in 0.6-1.6 persons per million population.

Race-, Sex-, and Age-related Demographics

Originally, Jewish persons were thought to have a higher predilection for polycythemia vera than members of other ethnic groups. Subsequently, however, many studies have shown that this condition occurs in all ethnic groups.

Polycythemia vera has no sex predilection, although the Polycythemia Vera Study Group (PVSG) found that slightly more males than females are affected.[3]

The peak incidence of polycythemia vera is age 50-70 years. However, this condition occurs in persons of all age groups, including early adulthood and childhood, albeit rarely.

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Contributor Information and Disclosures
Author

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Koyamangalath Krishnan, MD, FRCP, FACP Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

References
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  2. Landolfi R. Bleeding and thrombosis in myeloproliferative disorders. Curr Opin Hematol. 1998 Sep. 5(5):327-31. [Medline].

  3. 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. [Medline]. [Full Text].

  4. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28. 434(7037):1144-8. [Medline].

  5. Kralovics R, Teo SS, Buser AS, et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood. 2005 Nov 15. 106(10):3374-6. [Medline]. [Full Text].

  6. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005 Apr. 7(4):387-97. [Medline]. [Full Text].

  7. Guglielmelli P, Barosi G, Pieri L, et al. JAK2V617F mutational status and allele burden have little influence on clinical phenotype and prognosis in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis. Haematologica. 2009 Jan. 94(1):144-6. [Medline]. [Full Text].

  8. Mustjoki S, Borze I, Lasho TL, et al. JAK2V617F mutation and spontaneous megakaryocytic or erythroid colony formation in patients with essential thrombocythaemia (ET) or polycythaemia vera (PV). Leuk Res. 2009 Jan. 33(1):54-9. [Medline].

  9. Rusak T, Ciborowski M, Uchimiak-Owieczko A, Piszcz J, Radziwon P, Tomasiak M. Evaluation of hemostatic balance in blood from patients with polycythemia vera by means of thromboelastography: The effect of isovolemic erythrocytapheresis. Platelets. 2011 Nov 18. [Medline].

  10. Spivak JL, Considine M, Williams DM, Talbot CC Jr, Rogers O, Moliterno AR, et al. Two clinical phenotypes in polycythemia vera. N Engl J Med. 2014 Aug 28. 371(9):808-17. [Medline].

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  13. National Cancer Institute. PDQ® Chronic Myeloproliferative Neoplasms Treatment. National Cancer Institute. Available at http://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq#link/_5. October 21, 2015; Accessed: December 20, 2015.

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  15. Alvarez-Larrán A, Martínez-Avilés L, Hernández-Boluda JC, Ferrer-Marín F, Antelo ML, Burgaleta C, et al. Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea. Ann Hematol. 2014 Jul 2. [Medline].

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  18. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, et al. Cardiovascular events and intensity of treatment in polycythemia vera. The New England Journal of Medicine. 2013 Jan 3. 368(1):22-33. [Medline].

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  20. Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Eur J Haematol. 1994 Mar. 52(3):134-9. [Medline].

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  22. Huang BT, Zeng QC, Zhao WH, Li BS, Chen RL. Interferon a-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. Leuk Res. 2014 Jul 15. [Medline].

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  24. Verstovsek S, Kiladjian J, Griesshammer M, et al. Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): the RESPONSE trial. Presented at the 2014 ASCO Annual Meeting, May 30 – June 3, 2014; Chicago, IL. J Clin Oncol 32:5s, 2014 (suppl; abstr 7026). [Full Text].

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  26. Siebolts U, Breuhahn K, Hennecke A, Schultze JL, Wickenhauser C. Imbalance of DNA-dependent protein kinase subunits in polycythemia vera peripheral blood stem cells. Int J Cancer. 2009 Feb 1. 124(3):600-7. [Medline].

 
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Bone marrow film at 100X magnification demonstrating hypercellularity and increased number of megakaryocytes. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Blood film at 400X magnification demonstrating polyglobulia and thrombocytosis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
This blood film at 10,000X magnification shows a giant platelet and an eosinophil. Erythrocytes show signs of hypochromia as a result of repeated phlebotomies. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
 
 
 
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