Best Practice & Research Clinical Haematology
Volume 19, Issue 3 , Pages 455-469 , September 2006

The diagnosis of polycythemia vera: New tests and old dictums

  • Ayalew Tefferi, MD (Professor of Hematology and Medicine Consultant)

      Affiliations

    • Corresponding Author InformationTel.: +1 507 284 3159; Fax: +1 507 266 4972.

References 

  1. Tefferi A. Polycythemia vera: a comprehensive review and clinical recommendations. Mayo Clinic Proceedings. 2003;78:174–194
  2. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. American Journal of Medical. 2004;117:755–761
  3. Chievitz E, Thiede T. Complications and causes of death in polycythemia vera. Acta Medica Scandinavica. 1962;172:513–523
  4. Berk PD, Wasserman LR, Fruchtman SM, Goldberg JD. Treatment of polycythemia vera: a summary of clinical trials conducted by the polycythemia vera study group. In:  Wasserman LR, et al. editor. Polycyhtemia Vera and the Myeloproliferative Disorders. London: W. B. Saunders; 1995;p. 166–194
  5. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. The New England Journal of Medicine. 2004;350:114–124
  6. 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;99:1144–1149
  7. Andreasson B, Lofvenberg E, Westin J. Management of patients with polycythaemia vera: results of a survey among Swedish haematologists. European Journal Haematology. 2005;74:489–495
  8. Isbister JP. The contracted plasma volume syndromes (relative polycythaemias) and their haemorheological significance. Baillieres Clinic Haematology. 1987;1:665–693
  9. Schwarcz TH, Hogan LA, Endean ED, et al. Thromboembolic complications of polycythemia: polycythemia vera versus smokers' polycythemia. Journal of Vascular Surgery. 1993;17:518–522
  10. Ammash N, Warnes CA. Cerebrovascular events in adult patients with cyanotic congenital heart disease. Journal of the American College Cardiology. 1996;28:768–772
  11. Fisher MJ, Prchal JF, Prchal JT, AD DA. Anti-erythropoietin (EPO) receptor monoclonal antibodies distinguish EPO-dependent and EPO-independent erythroid progenitors in polycythemia vera. Blood. 1994;84:1982–1991
  12. Le Couedic JP, Mitjavila MT, Villeval JL, et al. Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies. Blood. 1996;87:1502–1511
  13. Means RT, Krantz SB, Sawyer ST, Gilbert HS. Erythropoietin receptors in polycythemia vera. Journal of Clinical Investigation. 1989;84:1340–1344
  14. Ang SO, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genetics. 2002;32:614–621
  15. Moo-Penn WF, Schneider RG, Shih T, et al. Hemoglobin Ohio (beta 142 Ala replaced by): a new abnormal hemoglobin with high oxygen affinity and erythrocytosis. Blood. 1980;56:246–250
  16. Hoyer JD, Allen SL, Beutler E, et al. Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. American Journal of Hematology. 2004;75:205–208
  17. Sokol L, Luhovy M, Guan Y, et al. Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin. Blood. 1995;86:15–22
  18. Tyndall MR, Teitel DF, Lutin WA, et al. Serum erythropoietin levels in patients with congenital heart disease. The Journal of Pediatrics. 1987;110:538–544
  19. Milledge JS, Cotes PM. Serum erythropoietin in humans at high altitude and its relation to plasma renin. Journal of Applied Physiology. 1985;59:360–364
  20. DiMarco AT. Carbon monoxide poisoning presenting as polycythemia. The New England Journal of Medicine. 1988;319:874
  21. Coulthard MG, Lamb WH. Polycythaemia and hypertension caused by renal artery stenosis. Archives of Disease in Childhood. 2002;86:307–308
  22. Tanabe N, Ohnishi K, Fukui H, Ohno R. Effect of smoking on the serum concentration of erythropoietin and granulocyte-colony stimulating factor. Internal Medicine. 1997;36:680–684
  23. Hoffstein V, Herridge M, Mateika S, et al. Hematocrit levels in sleep apnea. Chest. 1994;106:787–791
  24. Samyn I, Fontaine C, Van Tussenbroek F, et al. Paraneoplastic syndromes in cancer: Case 1. Polycythemia as a result of ectopic erythropoietin production in metastatic pancreatic carcinoid tumor. Journal of Clinical Oncology. 2004;22:2240–2242
  25. Drenou B, Le Tulzo Y, Caulet-Maugendre S, et al. Pheochromocytoma and secondary erythrocytosis: role of tumour erythropoietin secretion. Nouvelle Revue française d'Hématologie. 1995;37:197–199
  26. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. The New England Journal of Medicine. 2004;350:482–492
  27. Jelkmann W. Erythropoietin. Journal of Endocrinological Investigation. 2003;26:832–837
  28. Pearson TC, Messinezy M. Idiopathic erythrocytosis, diagnosis and clinical management. Pathologie Biologie (Paris). 2001;49:170–177
  29. Blacklock HA, Royle GA. Idiopathic erythrocytosis—a declining entity. British Journali of Haematology. 2001;115:774–781
  30. Fairbanks VF, Tefferi A. Normal ranges for packed cell volume and hemoglobin concentration in adults: relevance to apparent polycythemia. European Journal of Haematology. 2000;65:285–296
  31. Fairbanks VF. Myeloproliferative disease: polycythemia vera: the packed cell volume and the curious logic of the red cell mass. Hematology. 2000;4:381–395
  32. Brown SM, Gilbert HS, Krauss S, et al. Spurious (relative) polycythemia: A non-existent disease. American Journal of Medicine. 1971;50:220–227
  33. Fessel WJ. Odd men out: individuals with extreme values. Archives of Internal Medicine. 1965;115:736–737
  34. Fairbanks VF, Klee GG, Wiseman GA, et al. Measurement of blood volume and red cell mass—re-examination of Cr-51 and I-125 methods (corrected version of Vc666). Blood Cells Molecules and Diseases. 1996;22:169–186
  35. Geisbock F. Die Bedeutung der Blutdruckmessung fur die Praxis. Archives Clinical Medicine (Leipzig). 1905;83:
  36. Lawrence JH, Berlin NI. Relative polycythemia-the polycythemia of stress. The Yale Journal of Biology and Medicine. 1952;24:498–505
  37. Bentley SA, Lewis SM. The relationship between total red cell volume, plasma volume and venous haematocrit. British Journali of Haematology. 1976;33:301–307
  38. Burge PS, Johnson WS, Prankerd TA. Morbidity and mortality in pseudopolycythaemia. Lancet. 1975;1:1266–1269
  39. Jonsson V, Bock JE, Nielsen JB. Significance of plasma skimming and plasma volume expansion. Journal of Applied Physiology. 1992;72:2047–2051
  40. Hering E. Versuche, die Schnelligkeit des Blutlaufs und der Absonderung zu Bestimmen. The Journal of Physiology. 1829;3:85–126
  41. Stewart GN. Researches on the circulation time and on the influences which affect it IV. The output of the heart. The Journal of Physiology. 1897;22:
  42. Keith NM, Rowntree LG, Geraghty JT. A method for the determination of plasma and blood volume. Archives of Internal Medicine. 1915;xvi:547–557
  43. Hamilton WF, Moore JW, Kinsman JM, Spurling RG. Simultaneous detrmination of the pulmonary and systemic circulation times in man and of a figure related to cardiac output. American Journal of Physiology. 1928;84:338–344
  44. Rowntree LG, Brown GE, Roth GM. Volume of Blood and Plasma in Health and Disease. London: W B Saunders; 1929;
  45. Wright RR, Tono M, Pollycove M. Blood volume. Seminars in Nuclear Medicine. 1975;5:63–78
  46. Pearson TC, Guthrie DL, Simpson J, et al. Interpretation of measured red cell mass and plasma volume in adults: Expert Panel on Radionuclides of the International Council for Standardization in Haematology. British Journal of Haematology. 1995;89:748–756
  47. Standard techniques for the measurement of red-cell and plasma volume . A report by the international committee for standardization in hematology (ICSH): panel on diagnostic applications of radioisotopes in haematology. British Journal of Haematology. 1973;25:801–814
  48. Balga I, Solenthaler M, Furlan M. Should whole-body red cell mass be measured or calculated?. Blood Cells Molecules and Diseases. 2000;26:25–31[discussion 32–26]
  49. Fairbanks VF. Commentary: should whole-body red cell mass be measured or calculated. Blood Cells Molecules and Diseases. 2000;26:32–36
  50. Hlad CJ, Tanz R. An analysis of technical errors in radioalbumin blood volume methods and presentation of a modified method. Journal of Laboratory and Clinical Medicine. 1958;52:289–298
  51. Hinghofer-Szalkay H, Greenleaf JE. Continuous monitoring of blood volume changes in humans. Journal of Applied Physiology. 1987;63:1003–1007
  52. Leslie WD, Dupont JO, Peterdy AE. Effect of obesity on red cell mass results. The Journal of Nuclear Medicine. 1999;40:422–428
  53. Wasserman LR. The treatment of polycythemia. A panel discussion. Blood. 1968;32:483–487
  54. Shih LY, Lee CT, Ou YC. Prediction of clinical course in patients with idiopathic erythrocytosis by endogenous erythroid colony assay but not by serum erythropoietin levels. Experimental Hematology. 1997;25:288–292
  55. Adamson JW, Fialkow PJ, Murphy S, et al. Polycythemia vera: stem-cell and probable clonal origin of the disease. The New England Journal of Medicine. 1976;295:913–916
  56. Thiele J, Kvasnicka HM, Muehlhausen K, et al. Polycythemia rubra vera versus secondary polycythemias. A clinicopathological evaluation of distinctive features in 199 patients. Pathol Res Pract. 2001;197:77–84
  57. Temerinac S, Klippel S, Strunck E, et al. Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. Blood. 2000;95:2569–2576
  58. Bettinotti MP, Olsen A, Stroncek D. The use of bioinformatics to identify the genomic structure of the gene that encodes neutrophil antigen NB1, CD177. Clinical Immunology. 2002;102:138–144
  59. Teofili L, Martini M, Luongo M, et al. Overexpression of the polycythemia rubra vera-1 gene in essential thrombocythemia. Journal of Clinical Oncology. 2002;20:4249–4254
  60. Bodni RA, Sapia S, Galeano A, Kaminsky A. Indolent systemic mast cell disease: immunophenotypic characterization of bone marrow mast cells by flow cytometry. Journal of the European Academy of Dermatology Venereology. 2003;17:160–166
  61. Griesshammer M, Klippel S, Strunck E, et al. PRV-1 mRNA expression discriminates two types of essential thrombocythemia. Annals of Hematology. 2004;83:364–370
  62. Klippel S, Strunck E, Temerinac S, et al. Quantification of PRV-1 mRNA distinguishes Polycythemia vera from secondary erythrocytosis. Blood. 2003;102:3569–3574
  63. Kralovics R, Buser AS, Teo SS, et al. Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders. Blood. 2003;102:1869–1871
  64. Alcocer L. Statins for everybody? New evidence on the efficacy and safety of the inhibitors of HMG Co-A reductase. American Journal of Therapeutics. 2003;10:423–428
  65. Cilloni D, Carturan S, Gottardi E, et al. Usefulness of the quantitative assessment of PRV-1 gene expression for the diagnosis of polycythemia vera and essential thrombocythemia patients. Blood. 2004;103:2428;[author reply 2429]
  66. Florensa L, Besses C, Zamora L, et al. Endogenous erythroid and megakaryocytic circulating progenitors, HUMARA clonality assay, and PRV-1 expression are useful tools for diagnosis of polycythemia vera and essential thrombocythemia. Blood. 2004;103:2427–2428
  67. Passamonti F, Pietra D, Malabarba L, et al. Clinical significance of neutrophil CD177 mRNA expression in Ph-negative chronic myeloproliferative disorders. British Journal of Haematology. 2004;126:650–656
  68. Zhang J, Pellagatti A, Campbell L, et al. Neutrophil PRV-1 gene expression in myeloproliferative, myelodysplastic and reactive blood disorders. British Journal of Haematology. 2004;125:17
  69. Tanaka C, Kuruma I, Kuramoto A. Histochemical demonstration of 5-hydroxytryptamine in platelets and megakaryocytes. Blood. 1967;30:54–61
  70. Tranzer JP, Prada Md, Pletscher A. Storage of 5-hydroxytryptamine in megakaryocytes. The Journal of Cell Biology. 1972;52:191–197
  71. Pareti FI, Gugliotta L, Mannucci L, et al. Biochemical and metabolic aspects of platelet dysfunction in chronic myeloproliferative disorders. Thrombosis and Haemostasis. 1982;47:84–89
  72. Chauveau J, Fert V, Morel AM, Delaage MA. Rapid and specific enzyme immunoassay of serotonin. Clinical Chemistry. 1991;37:1178–1184
  73. Maurer-Spurej E, Dyker K, Gahl WA, Devine DV. A novel immunocytochemical assay for the detection of serotonin in platelets. British Journal of Haematology. 2002;116:604–611
  74. Zerbinati P, Randi ML, Rossi C, et al. Two methods for intraplatelet serotonin evaluation—their use in thrombocytosis. Clin Appl Thromb Hemost. 1997;3:144–146
  75. Fabris F, Randi ML, Casonato A, et al. Clinical significance of beta-thromboglobulin in patients with high platelet count. Acta Haematologica. 1984;71:32–38
  76. Koch CA, Lasho TL, Tefferi A. Platelet-rich plasma serotonin levels in chronic myeloproliferative disorders: evaluation of diagnostic use and comparison with the neutrophil PRV-1 assay. British Journal of Haematology. 2004;127:34–39
  77. Reid CD. The significance of endogenous erythroid colonies (EEC) in haematological disorders. Blood Reviews. 1987;1:133–140
  78. Prchal JF, Axelrad AA. Letter: Bone-marrow responses in polycythemia vera. The New England Journal of Medicine. 1974;290:1382
  79. Juvonen E, Partanen S, Ruutu T. Colony formation by megakaryocytic progenitors in essential thrombocythaemia. British Journal of Haematology. 1987;66:161–164
  80. Zwicky C, Theiler L, Zbaren K, et al. The predictive value of clonogenic stem cell assays for the diagnosis of polycythaemia vera. British Journal of Haematology. 2002;117:598–604
  81. Partanen S, Juvonen E, Ikkala E, Ruutu T. Spontaneous erythroid colony formation in the differential diagnosis of erythrocytosis. European Journal of Haematology. 1989;42:327–330
  82. Dobo I, Donnard M, Girodon F, et al. Standardization and comparison of endogenous erythroid colony assays performed with bone marrow or blood progenitors for the diagnosis of polycythemia vera. The Hematology Journal. 2004;5:161–167
  83. Shih LY, Lee CT, See LC, et al. In vitro culture growth of erythroid progenitors and serum erythropoietin assay in the differential diagnosis of polycythaemia. European Journal of Clinical Investigation. 1998;28:569–576
  84. Dobo I, Mossuz P, Campos L, et al. Comparison of four serum-free, cytokine-free media for analysis of endogenous erythroid colony growth in polycythemia vera and essential thrombocythemia. The Hematology Journal. 2001;2:396–403
  85. Horikawa Y, Matsumura I, Hashimoto K, et al. Markedly reduced expression of platelet C-Mpl receptor in essential thrombocythemia. Blood. 1997;90:4031–4038
  86. Moliterno AR, Hankins WD, Spivak JL. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. The New England Journal of Medicine. 1998;338:572–580
  87. Yoon SY, Li CY, Tefferi A. Megakaryocyte c-Mpl expression in chronic myeloproliferative disorders and the myelodysplastic syndrome: immunoperoxidase staining patterns and clinical correlates. European Journal of Haematology. 2000;65:170–174
  88. Le Blanc K, Andersson P, Samuelsson J. Marked heterogeneity in protein levels and functional integrity of the thrombopoietin receptor c-mpl in polycythaemia vera. British Journal of Haematology. 2000;108:80–85
  89. Tefferi A, Yoon SY, Li CY. Immunohistochemical staining for megakaryocyte c-mpl may complement morphologic distinction between polycythemia vera and secondary erythrocytosis. Blood. 2000;96:771–772
  90. Duensing S, Duensing A, Meran JG, et al. Molecular detection of c-mpl thrombopoietin receptor gene expression in chronic myeloproliferative disorders. Molecular Pharmacology. 1999;52:146–150
  91. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–1061
  92. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature, in press.
  93. Kralovics R, Passamonti F, Buser AS, et al. A gain of function mutation in Jak2 is frequently found in patients with myeloproliferative disorders. The New England Journal of Medicine. 2005;352:1779–1790
  94. 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;7:387–397
  95. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. The Journal of Biological Chemistry. 2005;
  96. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both Atypical myeloproliferative disorders and the myelodysplastic syndrome. Blood. 2005;[Blood First Edition Paper, prepublished online April 28, 2005]
  97. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;[Blood First Edition Paper, prepublished online May 26, 2005]
  98. Lamy T, Devillers A, Bernard M, et al. Inapparent polycythemia vera—an unrecognized diagnosis. American Journal of Medicine. 1997;102:14–20
  99. Messinezy M, Westwood NB, El-Hemaidi I, et al. Serum erythropoietin values in erythrocytoses and in primary thrombocythaemia. British Journal of Haematology. 2002;117:47–53
  100. Mossuz P, Girodon F, Donnard M, et al. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. Haematologica. 2004;89:1194–1198
  101. Diez-Martin JL, Graham DL, Petitt RM, Dewald GW. Chromosome studies in 104 patients with polycythemia vera. Mayo Clinic Proceedings. 1991;66:287–299
  102. Andreasson B, Löfvenberg E, Westin J. Management of patients with polycythaemia vera: Results of a survey among Swedish haematologists. European Journal of Haematology, in press, available online.
  103. Galacteros F, Rosa R, Prehu MO, et al. Diphosphoglyceromutase deficiency: new cases associated with erythrocytosis. Nouvelle Revue française d'Hématologie. 1984;26:69–74
  104. Gordeuk VR, Stockton DW, Prchal JT. Congenital polycythemias/erythrocytoses. Haematologica. 2005;90:109–116
  105. Cario H. Childhood polycythemias/erythrocytoses: classification, diagnosis, clinical presentation, and treatment. Annals of Hematology. 2004;
  106. Vanuxem D, Guillot C, Fornaris E, et al. Secondary polycythaemia in chronic respiratory insufficiency. Thorax. 1977;32:317–321
  107. Smith JR, Landaw SA. Smokers' polycythemia. The New England Journal of Medicine. 1978;298:6–10
  108. Hudgson P, Pearce JM, Yeates WK. Renal artery stenosis with hypertension and high haematocrit. British Medical Journal. 1967;1:18–21
  109. Matsuyama M, Yamazaki O, Horii K, et al. Erythrocytosis caused by an erythropoietin-producing hepatocellular carcinoma. Journal of Surgical Oncology. 2000;75:197–202
  110. Ndububa DA, Ojo OS, Adetiloye VA, et al. The incidence and characteristics of some paraneoplastic syndromes of hepatocellular carcinoma in Nigerian patients. European Journal of Gastroenterol and Hepatology. 1999;11:1401–1404
  111. Wiesener MS, Seyfarth M, Warnecke C, et al. Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma. Blood. 2002;99:3562–3565
  112. Skultety FM, Sorrell MF, Burklund CW. Hemangioblastoma of the cerebellum associated with erythrocytosis and an unusual blood supply. Case report. Journal of Neurosurgery. 1970;32:700–705
  113. Weinstein RS. Parathyroid carcinoma associated with polycythemia vera. Bone. 1991;12:237–239
  114. Suzuki M, Takamizawa S, Nomaguchi K, et al. Erythropoietin synthesis by tumour tissues in a patient with uterine myoma and erythrocytosis. British Journal of Haematology. 2001;113:49–51
  115. Jermanovich NB. Polycystic kidney disease and polycythemia vera. Occurrence in a patient receiving hemodialysis. Archives of Internal Medicine. 1983;143:1822–1823
  116. Bruneval P, Sassy C, Mayeux P, et al. Erythropoietin synthesis by tumor cells in a case of meningioma associated with erythrocytosis. Blood. 1993;81:1593–1597
  117. Spivak JL. Erythropoietin use and abuse: When physiology and pharmacology collide. Advances in Experimental Medicine and Biology. 2001;502:207–224
  118. Dickerman RD, Pertusi R, Zachariah NY, Schaller F. Androgen-induced erythrocytosis. American Journal of Hematology. 1998;59:263–264
  119. Wickre CG, Norman DJ, Bennison A, et al. Postrenal transplant erythrocytosis: a review of 53 patients. Kidney International. 1983;23:731–737
  120. Glicklich D, Kapoian T, Mian H, et al. Effects of erythropoietin, angiotensin II, and angiotensin-converting enzyme inhibitor on erythroid precursors in patients with posttransplantation erythrocytosis. Transplantation. 1999;68:62–66
  121. Mrug M, Julian BA, Prchal JT. Angiotensin II receptor type 1 expression in erythroid progenitors: implications for the pathogenesis of postrenal transplant erythrocytosis. Seminars in Nephrology. 2004;24:120–130

PII: S1521-6926(05)00093-9

doi: 10.1016/j.beha.2005.07.005

Best Practice & Research Clinical Haematology
Volume 19, Issue 3 , Pages 455-469 , September 2006