Medical Care

Primary polycythemia

The goals of therapy are to maximize survival while minimizing the complications of therapy as well as of the disease itself. Phlebotomy and myelosuppressive chemotherapy are the cornerstones of therapy. Based on clinical trials in adults, these approaches have produced a median survival time of 9-14 years after the beginning of treatment. Current recommendations for treatment of young patients primarily rely on phlebotomy because the thrombosis is far less likely to occur in children and the long-term risks of leukemia over a longer life span are increased.

Phlebotomy

The goal of phlebotomy is to maintain normal red cell mass and blood volume, with a target hematocrit level of 42-46% for men and 39-42% for women. The mean survival time of adult patients treated solely with phlebotomy is 13.9 years; however, a high risk of thromboembolic complications is observed. To reduce the thrombotic risk, antiplatelet agents such as aspirin and dipyridamole were used in combination with phlebotomy. Initial studies demonstrated an increased risk of hemorrhage in the phlebotomy plus aspirin/dipyridamole arm. However, a large European study showed a decrease in thrombotic events in those patients receiving low-dose aspirin therapy and recommended aspirin therapy for those patients for whom no contraindications were noted.^[35]

Hydroxyurea

Hydroxyurea as a myelosuppressive agent is also widely used in high-risk patients with polycythemia vera (ie, >60 y, history of thrombosis) who require cytoreductive therapy, reducing the need for phlebotomy.^[2]Neutropenia and thrombocytopenia are expected adverse effects, both of which can be rapidly corrected after holding or reducing the medication dose. The incidence of thrombotic complications is less than compared with patients treated with phlebotomy alone. However, these patients also experience higher rates of malignancy. Historically, patients have been treated with chlorambucil and busulfan. However, these patients exhibited the highest rates of secondary malignancy including acute leukemia, lymphocytic lymphomas, and skin and GI carcinomas. The rates of malignancy appear lower with busulfan than with the other alkylating agents. Currently, these agents are rarely used.

Patients treated with phosphorus-32 (³² P) tolerate treatment well and have prolonged periods of remission. However, these patients also exhibit increased rates of acute leukemias (10-15%). The mean survival time with³² P treatment is 10.9 years; therefore, phosphorous is rarely used.

Interferon

Interferon-alpha is effective in eliminating JAK2^V617Fexpression and inducing hematologic remission. Its use is limited by side effects, cost, and route of administration. The pegylated form and low dose treatment has decreased the rate of discontinuation of the drug secondary to side effects. In a French study, patients with polycythemia vera treated with interferon alpha showed a high rate of hematologic and molecular response.^{[36, 37]}

Tyrosine kinase inhibitors

Imatinib is a BCR-ABL tyrosine kinase inhibitor, which has been used in some patients with polycythemia vera. It has been shown to decreased blood counts, splenomegaly, and need for phlebotomy.^{[38, 39, 40]}

Ruxolitinib is a JAK1/JAK2 inhibitor was initially approved for primary myelofibrosis, and was used in a phase II trial of patients with PV who were refractory to hydroxyurea therapy. In this study, reduction in hematocrit, thrombocytosis, leukocytosis, and splenomegaly was seen in the ruxolitinib group.^[41]

Secondary polycythemia

Phlebotomy is used for symptomatic hyperviscosity. The goal is to treat the underlying cause of polycythemia.

Surgical Care

Surgery is not typically indicated. Occasionally, splenectomy is performed late in the course of the disease if massive splenomegaly causes adverse effects such as early satiety, anemia, or thrombocytopenia from sequestration. Please note that these patients have a high risk of complications during surgical procedures.

Consultations

Consult a neurologist and neurosurgeon if evidence of a stroke is present.

Diet

Diet is unrestricted.

Activity

Contact sports and other activities should be limited for individuals in hypercoagulable and hypocoagulable states.

Medication

Mondal H, Budh DP. Hematocrit (HCT). StatPearls. 2020 Jan. [QxMD MEDLINE Link]. [Full Text].
Zhan H, Spivak JL. The diagnosis and management of polycythemia vera, essential thrombocythemia, and primary myelofibrosis in the JAK2 V617F era. Clin Adv Hematol Oncol. 2009 May. 7(5):334-42. [QxMD MEDLINE Link].
Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood. 2013 Aug 15. 122 (7):1122-8. [QxMD MEDLINE Link].
Greer JP, Foerster J, Rodgers GM, et al. Erthrocytosis. Pine JW, Jacobs AE,. Wintrobe's Clinical Hematology. Twelfth. Lippincott, Williams and Wlkins; 2009.
Tefferi A. JAK2 mutations in polycythemia vera--molecular mechanisms and clinical applications. N Engl J Med. 2007 Feb 1. 356(5):444-5. [QxMD MEDLINE Link].
Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007 Feb 1. 356(5):459-68. [QxMD MEDLINE Link].
Cario H, Pahl HL, Schwarz K, et al. Familial polycythemia vera with Budd-Chiari syndrome in childhood. Br J Haematol. 2003 Oct. 123(2):346-52. [QxMD MEDLINE Link].
Sarkar S, Rosenkrantz TS. Neonatal polycythemia and hyperviscosity. Semin Fetal Neonatal Med. 2008 Aug. 13(4):248-55. [QxMD MEDLINE Link].
Hopfeld-Fogel A, Kasirer Y, Mimouni FB, Hammerman C, Bin-Nun A. Neonatal Polycythemia and Hypoglycemia in Newborns: Are They Related?. Am J Perinatol. 2020 Feb 6. [QxMD MEDLINE Link].
Ma X, Vanasse G, Cartmel B, Wang Y, Selinger HA. Prevalence of polycythemia vera and essential thrombocythemia. Am J Hematol. 2008 May. 83(5):359-62. [QxMD MEDLINE Link].
Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014 Mar. 55(3):595-600. [QxMD MEDLINE Link].
Titmarsh GJ, Duncombe AS, McMullin MF, O'Rorke M, Mesa R, De Vocht F, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol. 2014 Jun. 89(6):581-7. [QxMD MEDLINE Link].
Johansson P. Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. Semin Thromb Hemost. 2006 Apr. 32(3):171-3. [QxMD MEDLINE Link].
Mimouni FB, Merlob P, Dollberg S, Mandel D. Neonatal polycythaemia: critical review and a consensus statement of the Israeli Neonatology Association. Acta Paediatr. 2011 Oct. 100(10):1290-6. [QxMD MEDLINE Link].
Sankar MJ, Agarwal R, Deorari A, Paul VK. Management of polycythemia in neonates. Indian J Pediatr. 2010 Oct. 77(10):1117-21. [QxMD MEDLINE Link].
Vlug RD, Lopriore E, Janssen M, Middeldorp JM, Rath ME, Smits-Wintjens VE. Thrombocytopenia in neonates with polycythemia: incidence, risk factors and clinical outcome. Expert Rev Hematol. 2015 Feb. 8 (1):123-9. [QxMD MEDLINE Link].
Adamson JW, Fialkow PJ, Murphy S, et al. Polycythemia vera: stem-cell and probable clonal origin of the disease. New England Journal of Medicine. 1976. 295:913-916. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28. 352(17):1779-90. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
Vainchenker W, Constabtinescu S. A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases. Hematology. 2005. 195-200. [QxMD MEDLINE Link]. [Full Text].
Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005 Jun 17. 280(24):22788-92. [QxMD MEDLINE Link].
Cario H, Schwarz K, Herter JM, Komrska V, McMullin MF, Minkov M. Clinical and molecular characterisation of a prospectively collected cohort of children and adolescents with polycythemia vera. Br J Haematol. 2008 Aug. 142(4):622-6. [QxMD MEDLINE Link].
Smith CA, Fan G. The saga of JAK2 mutations and translocations in hematologic disorders: pathogenesis, diagnostic and therapeutic prospects, and revised World Health Organization diagnostic criteria for myeloproliferative neoplasms. Hum Pathol. 2008 Jun. 39(6):795-810. [QxMD MEDLINE Link].
Teofili L, Foa R, Giona F, Larocca LM. Childhood polycythemia vera and essential thrombocythemia: does their pathogenesis overlap with that of adult patients?. Haematologica. 2008 Feb. 93(2):169-72. [QxMD MEDLINE Link].
Teofili L, Giona F, Martini M, et al. Markers of myeloproliferative diseases in childhood polycythemia vera and essential thrombocythemia. J Clin Oncol. 2007 Mar 20. 25(9):1048-53. [QxMD MEDLINE Link].
Rives S, Pahl HL, Florensa L, Bellosillo B, Neusuess A, Estella J. Molecular genetic analyses in familial and sporadic congenital primary erythrocytosis. Haematologica. 2007 May. 92(5):674-7. [QxMD MEDLINE Link].
Rumi E, Passamonti F, Della Porta MG, et al. Familial chronic myeloproliferative disorders: clinical phenotype and evidence of disease anticipation. J Clin Oncol. 2007 Dec 10. 25(35):5630-5. [QxMD MEDLINE Link].
Barbui T, Thiele J, Vannucchi AM, Tefferi A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J. 2015 Aug 14. 5:e337. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007 Aug 15. 110(4):1092-7. [QxMD MEDLINE Link].
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19. 127 (20):2391-405. [QxMD MEDLINE Link]. [Full Text].
Gaston RS, Julian BA, Curtis JJ. Posttransplant erythrocytosis: an enigma revisited. Am J Kidney Dis. 1994 Jul. 24 (1):1-11. [QxMD MEDLINE Link].
Cacemiro MDC, Cominal JG, Berzoti-Coelho MG, et al. Differential cytokine network profile in polycythemia vera and secondary polycythemia. Sci Rep. 2020 Apr 27. 10 (1):7032. [QxMD MEDLINE Link]. [Full Text].
McMullin MF, Bareford D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005 Jul. 130(2):174-95. [QxMD MEDLINE Link].
Landolfi R, Marchioloi R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. New England Journal of Medicine. 2004. 350:114-124. [QxMD MEDLINE Link]. [Full Text].
Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008 Oct 15. 112(8):3065-72. [QxMD MEDLINE Link].
Silver RT. Treatment of polycythemia vera with recombinant interferon alpha (rIFNalpha) or imatinib mesylate. Curr Hematol Rep. 2005. 4:235-237. [QxMD MEDLINE Link].
Jones CM, Dickinson TM. Polycythemia vera responds to imatinib mesylate. Am J Med Sci. 2003 Mar. 325(3):149-52. [QxMD MEDLINE Link].
Cortes J, Giles F, O'Brien S, Thomas D, Albitar M, Rios MB, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer. 2003 Jun 1. 97(11):2760-6. [QxMD MEDLINE Link].
Jones AV, Silver RT, Waghorn K, Curtis C, Kreil S, Zoi K, et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood. 2006 Apr 15. 107(8):3339-41. [QxMD MEDLINE Link].
Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, Rumi E, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer. 2014 Feb 15. 120(4):513-20. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Cario H. Childhood polycythemias/erythrocytoses: classification, diagnosis, clinical presentation, and treatment. Ann Hematol. 2005 Mar. 84(3):137-45. [QxMD MEDLINE Link].
Perrotta S, Cucciolla V, Ferraro M, Ronzoni L, Tramontano A, Rossi F, et al. EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors. PLoS One. 2010 Aug 5. 5(8):e12015. [QxMD MEDLINE Link]. [Full Text].
Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005 Mar 19-25. 365(9464):1054-61. [QxMD MEDLINE Link].
Cario H, McMullin MF, Bento C, Pospisilova D, Percy MJ, Hussein K, et al. Erythrocytosis in children and adolescents-classification, characterization, and consensus recommendations for the diagnostic approach. Pediatr Blood Cancer. 2013 Nov. 60 (11):1734-8. [QxMD MEDLINE Link].
Johansson PL, Safai-Kutti S, Kutti J. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol. 2005 Jun. 129(5):701-5. [QxMD MEDLINE Link].
Jones AV, Silver RT, Waghorn K, et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood. 2006 Apr 15. 107(8):3339-41. [QxMD MEDLINE Link].
Kwaan HC, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities. Semin Thromb Hemost. 2003 Oct. 29(5):451-8. [QxMD MEDLINE Link].
Pappas A, Delaney-Black V. Differential diagnosis and management of polycythemia. Pediatric Clinics of North America. 2004. 51:1063-86. [QxMD MEDLINE Link].
Passamonti F, Malabarba L, Orlandi E, et al. Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia. Haematologica. 2003 Jan. 88(1):13-8. [QxMD MEDLINE Link].
Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004 Nov 15. 117(10):755-61. [QxMD MEDLINE Link].
Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera. J Clin Oncol. 2009 Oct 13. [QxMD MEDLINE Link].
Rosenkrantz TS. Polycythemia and hyperviscosity in the newborn. Seminars in Thrombosis and Hemostasis. 2003. 29:515-527. [QxMD MEDLINE Link].
Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002 Dec 15. 100(13):4272-90. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008 Jun. 83(6):491-7. [QxMD MEDLINE Link].
Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013 Sep. 27(9):1874-81. [QxMD MEDLINE Link]. [Full Text].
Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008 Jan. 22(1):14-22. [QxMD MEDLINE Link].

Media Gallery

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.

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Author

May C Chien, MD Clinical Assistant Professor, Department of Medicine, Division of Hematology, Clinical Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, Associate Director, Hematology Block, Science of Medicine Course, Stanford University School of Medicine

May C Chien, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Kathleen M Sakamoto, MD, PhD Shelagh Galligan Professor, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, Society for Pediatric Research, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Scott S MacGilvray, MD Clinical Professor, Department of Pediatrics, Division of Neonatology, The Brody School of Medicine at East Carolina University

Scott S MacGilvray, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Joseph K Park, MD, PhD Paul and Yuanbi Ramsay Endowed Postdoctoral Fellow, Division of Hematology/Oncology, Lucile Packard Children's Hospital at Stanford

Disclosure: Nothing to disclose.

Krysta D Schlis, MD Clinical Assistant Professor of Pediatrics, Lucile Packard Children’s Hospital, Stanford University School of Medicine

Krysta D Schlis, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Acknowledgements

Kristin Baird, MD Staff Clinician, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health

Disclosure: Nothing to disclose.

Sun H Choo, MD Resident Physician, Department of Pediatrics, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.