Familial and congenital polycythemias: A diagnostic approach

Journal of Pediatric Hematology/Oncology

Volumn 26, Issue 7, 2004, Pages 407-416

  Van Maerken, Tom ^a   Hunninck, Kathleen ^a   Callewaert, Luc ^b   Benoit, Yves ^a   Laureys, Geneviève ^a   Verlooy, Joris ^a  

^a GHENT UNIVERSITY HOSPITAL   (Belgium)

^b Algemeen Ziekenuis Maria Middelares ^*  (Belgium)

Author keywords

Algorithm; Differential diagnosis; Erythropoietin; Familial and congenital polycythemias; Oxygen sensing

Indexed keywords

ERYTHROPOIETIN;

ADOLESCENT; CASE REPORT; CONGENITAL POLYCYTHEMIA; DIAGNOSTIC APPROACH ROUTE; ERYTHROID PRECURSOR CELL; FAMILIAL POLYCYTHEMIA; HEMATOCRIT; HUMAN; MALE; POLYCYTHEMIA; POLYCYTHEMIA VERA; PRIORITY JOURNAL; REVIEW; SYSTEMATIC REVIEW;

ADOLESCENT; ALGORITHMS; DIAGNOSIS, DIFFERENTIAL; HUMANS; POLYCYTHEMIA; RECEPTORS, ERYTHROPOIETIN; SIGNAL TRANSDUCTION;

EID: 3543102148     PISSN: 10774114     EISSN: None     Source Type: Journal    
DOI: 10.1097/00043426-200407000-00002     Document Type: Review

References (124)

1. Prchal JT. Primary polycythemias. Curr Opin Hematol. 1995;2:146-152.
2. 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.
3. Braunwald E. Hypoxia, polycythemia, and cyanosis. In: Fauci AS, Braunwald E, Isselbacher KJ, et al., eds. Harrison's Principles of Internal Medicine, 14th ed. New York: McGraw-Hill, 1998:205-210.
4. Means RT. Polycythemia: erythrocytosis. In: Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology, 10th ed. Baltimore: Williams & Wilkins, 1998:1538-1554.
5. Blacklock HA, Royle GA. Idiopathic erythrocytosis: a declining entity. Br J Haematol. 2001;115:774-781.
6. Prchal JT, Sokol L. Benign erythrocytosis and other familial and congenital polycythemias. Eur J Haematol. 1996;57:263-268.
7. Prchal JT, Crist WM, Goldwasser E, et al. Autosomal dominant polycythemia. Blood. 1985;66:1208-1214.
8. Gregg XT, Prchal JT. Erythropoietin receptor mutations and human disease. Semin Hematol. 1997;34:70-76.
9. Sokol L, Prchal JF, Prchal JT. Primary familial and congenital polycythaemia [letter]. Lancet. 1993;342:115-116.
10. Emanuel PD, Eaves CJ, Broudy VC, et al. Familial and congenital polycythemia in three unrelated families. Blood. 1992;79:3019-3030.
11. Kralovics R, Prchal JT. Genetic heterogeneity of primary familial and congenital polycythemia. Am J Hematol. 2001;68:115-121.
12. Kralovics R, Sokol L, Prchal JT. Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia. J Clin Invest. 1998;102:124-129.
13. Prchal JF, Axelrad AA. Bone marrow responses in polycythemia vera [letter]. N Engl J Med. 1974;290:1382.
14. Eaves CJ, Eaves AC. Erythropoietin (Ep) dose-response curves for three classes of erythroid progenitors in normal human marrow and in patients with polycythemia vera. Blood. 1978;52:1196-1210.
15. Pearson TC, Messinezy M. The diagnostic criteria of polycythemia rubra vera. LeukLymphoma. 1996;22(Suppl 1):87-93.
16. Michiels JJ, Juvonen E. Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Semin Thromb Hemost. 1997;23:339-347.
17. Juvonen E, Ikkala E, Fyhrquist F, et al. Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin. Blood. 1991;78:3066-3069.
18. Kralovics R, Indrak K, Stopka T, et al. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood. 1997;90:2057-2061.
19. Sokol L, Prchal JF, D'Andrea A, et al. Mutation in the negative regulatory element of the erythropoietin receptor gene in a case of sporadic primary polycythemia. Exp Hematol. 1994;22:447-453.
20. 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.
21. Kralovics R, Sokol L, Broxson EH Jr, et al. The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia. Proc Assoc Am Physicians. 1997;109:580-585.
22. de la Chapelle A, Träskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci USA. 1993;90:4495-4499.
23. Furukawa T, Narita M, Sakaue M, et al. Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor. Br J Haematol. 1997;99:222-227.
24. Percy MJ, McMullin MF, Roques AW, et al. Erythrocytosis due to a mutation in the erythropoietin receptor gene. Br J Haematol. 1998;100:407-410.
25. Arcasoy MO, Sinning JG, Segal HM, et al. A novel mutation in the erythropoietin receptor (EPOR) gene leads to an extensive COOH-terminal truncation of the EPOR associated with familial erythrocytosis [abstract]. Blood. 1998;92:205a.
26. Arcasoy MO, Karayal AF, Segal HM, et al. A novel mutation in the erythropoietin receptor gene is associated with familial erythrocytosis. Blood. 2002;99:3066-3069.
27. Arcasoy MO, Degar BA, Harris KW, et al. Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood. 1997;89:4628-4635.
28. Watowich SS, Xie X, Klingmuller U, et al. Erythropoietin receptor mutations associated with familial erythrocytosis cause hypersensitivity to erythropoietin in the heterozygous state. Blood. 1999;94:2530-2532.
29. D'Andrea AD, Yoshimura A, Youssoufian H, et al. The cytoplasmic region of the erythropoietin receptor contains non-overlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991;11:1980-1987.
30. Klingmuller U, Lorenz U, Cantley LC, et al. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995;80:729-738.
31. Yi T, Zhang J, Miura O, et al. Hematopoietic cell phosphatase associates with erythropoietin (Epo) receptor after Epo-induced receptor tyrosine phosphorylation: identification of potential binding sites. Blood. 1995;85:87-95.
32. Jiao H, Berrada K, Yang W, et al. Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol Cell Biol. 1996;16:6985-6992.
33. Barber DL, D'Andrea AD. The erythropoietin receptor and the molecular basis of signal transduction. Semin Hematol. 1992;29:293-304.
34. Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993;74:227-236.
35. Miura O, Nakamura N, Quelle FW, et al. Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. Blood. 1994;84:1501-1507.
36. Matsumoto A, Masuhara M, Mitsui K, et al. CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood. 1997;89:3148-3154.
37. Livnah O, Stura EA, Middleton SA, et al. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science. 1999;283:987-990.
38. Remy I, Wilson IA, Michnick SW. Erythropoietin receptor activation by a ligand-induced conformation change. Science. 1999;283:990-993.
39. Dusanter-Fourt I, Casadevall N, Lacombe C, et al. Erythropoietin induces the tyrosine phosphorylation of its own receptor in human erythropoietin- responsive cells. JBiol Chem. 1992;267:10670-10675.
40. Damen JE, Krystal G. Early events in erythropoietin-induced signaling. Exp Hematol. 1996;24:1455-1459.
41. Tilbrook PA, Ingley E, Williams JH, et al. Lyn tyrosine kinase is essential for erythropoietin-induced differentiation of J2E erythroid cells. EMBOJ. 1997;16:1610-1619.
42. Chin H, Arai A, Wakao H, et al. Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood. 1998;91:3734-3745.
43. Hanazono Y, Chiba S, Sasaki K, et al. Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells. Blood. 1993;81:3193-3196.
44. Duprez V, Blank U, Chretien S, et al. Physical and functional interaction between p72(syk) and erythropoietin receptor. J Biol Chem. 1998;273:33985- 33990.
45. Machide M, Mano H, Todokoro K. Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain. Oncogene. 1995;11:619-625.
46. Damen JE, Wakao H, Miyajima A, et al. Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J. 1995;14:5557-5568.
47. Gobert S, Chretien S, Gouilleux F, et al. Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. EMBO J. 1996;15:2434-2441.
48. Klingmuller U, Bergelson S, Hsiao JG, et al. Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Proc Natl Acad Sci USA. 1996;93:8324-8328.
49. Quelle FW, Wang D, Nosaka T, et al. Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Mol Cell Biol. 1996;16:1622-1631.
50. Ihle JN. Cytokine receptor signalling. Nature. 1995;377:591-594.
51. Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995;11:69-74.
52. Bittorf T, Jaster R, Ludtke B, et al. Requirement for JAK2 in erythropoietin-induced signalling pathways. Cell Signal. 1997;9:85-89.
53. Bittorf T, Jaster R, Brock J. Rapid activation of the MAP kinase pathway in hematopoietic cells by erythropoietin, granulocyte-macrophage colony-stimulating factor and interleukin-3. Cell Signal. 1994;6:305-311.
54. Todokoro K, Sugiyama M, Nishida E, et al. Activation of mitogen-activated protein kinase cascade through erythropoietin receptor. Biochem Biophys Res Commun. 1994;203:1912-1919.
55. Miura Y, Miura O, Ihle JN, et al. Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. J Biol Chem. 1994;269:29962-29969.
56. Barber DL, Corless CN, Xia K, et al. Erythropoietin activates Raf1 by an Shc-independent pathway in CTLL-EPO-R cells. Blood. 1997;89:55-64.
57. Nagata Y, Nishida E, Todokoro K. Activation of JNK signaling pathway by erythropoietin, thrombopoietin, and interleukin-3. Blood. 1997;89:2664-2669.
58. Nagata Y, Moriguchi T, Nishida E, et al. Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3. Blood. 1997;90:929-934.
59. Tauchi T, Feng GS, Shen R, et al. Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. J Biol Chem. 1995;270:5631-5635.
60. Tauchi T, Damen JE, Toyama K, et al. Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis. Blood. 1996;87:4495-4501.
61. He TC, Zhuang H, Jiang N, et al. Association of the p85 regulatory subunit of phosphatidylinositol 3-kinase with an essential erythropoietin receptor subdomain. Blood. 1993;82:3530-3538.
62. Miura O, Nakamura N, Ihle JN, et al. Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J Biol Chem. 1994;269:614-620.
63. Damen JE, Cutler RL, Jiao H, et al. Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the P85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem. 1995;270:23402-23408.
64. Klingmuller U, Wu H, Hsiao JG, et al. Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors. Proc Natl Acad Sci USA. 1997;94:3016-3021.
65. Bouscary D, Pene F, Claessens YE, et al. Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. Blood. 2003;101:3436-3443.
66. Ren HY, Komatsu N, Shimizu R, et al. Erythropoietin induces tyrosine phosphorylation and activation of phospholipase C-gamma 1 in a human erythropoietin-dependent cell line. J Biol Chem. 1994;269:19633-19638.
67. Damen JE, Liu L, Cutler RL, et al. Erythropoietin stimulates the tyrosine phosphorylation of Shc and its association with Grb2 and a 145-Kd tyrosine phosphorylated protein. Blood. 1993;82:2296-2303.
68. He TC, Jiang N, Zhuang H, et al. Erythropoietin-induced recruitment of Shc via a receptor phosphotyrosine-independent, Jak2-associated pathway. J Biol Chem. 1995;270:11055-11061.
69. Damen JE, Liu L, Rosten P, et al. The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc Natl Acad Sci USA. 1996;93:1689-1693.
70. Mason JM, Beattie BK, Liu Q, et al. The SH2 inositol 5-phosphatase Shipl is recruited in an SH2-dependent manner to the erythropoietin receptor. J Biol Chem. 2000;275:4398-4406.
71. Odai H, Sasaki K, Iwamatsu A, et al. The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells. J Biol Chem. 1995;270:10800-10805.
72. Ravichandran KS, Lorenz U, Shoelson SE, et al. Interaction of Shc with Grb2 regulates association of Grb2 with mSOS. Mol Cell Biol. 1995;15:593-600.
73. Hanazono Y, Odai H, Sasaki K, et al. Proto-oncogene products Vav and c-Cbl are involved in the signal transduction through Grb2/Ash in hematopoietic cells. Acta Haematol. 1996;95:236-242.
74. Odai H, Hanazono Y, Sasaki K, et al. The signal transduction through Grb2/Ash in hematopoietic cells. Leukemia. 1997;11(Suppl 3):405-407.
75. Miura O, Miura Y, Nakamura N, et al. Induction of tyrosine phosphorylation of Vav and expression of Pim-1 correlates with Jak2-mediated growth signaling from the erythropoietin receptor, Blood. 1994;84:4135-4141.
76. Barber DL, Mason JM, Fukazawa T, et al. Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Blood. 1997;89:3166-3174.
77. Chin H, Saito T, Arai A, et al. Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochem Biophys Res Commun. 1997;239:412-417.
78. Nosaka Y, Arai A, Miyasaka N, et al. CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3. J Biol Chem. 1999;274:30154-30162.
79. Arai A, Kanda E, Nosaka Y, et al. CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor signaling. J Biol Chem. 2001;276:33282-33290.
80. Lecoq-Lafon C, Verdier F, Fichelson S, et al. Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Blood. 1999;93:2578-2585.
81. Wickrema A, Uddin S, Sharma A, et al. Engagement of Gab1 and Gab2 in erythropoietin signaling. J Biol Chem. 1999;274:24469-24474.
82. Verdier F, Chretien S, Billat C, et al. Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation. J Biol Chem. 1997;272:26173-26178.
83. Wakioka T, Sasaki A, Mitsui K, et al. APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia. 1999;13:760-767.
84. Arcasoy MO, Harris KW, Degar BA, et al. Prolonged STAT5 activity associated with a naturally occurring truncation mutation of the human erythropoietin receptor [abstract]. Blood. 1996;88:53a.
85. Arcasoy MO, Harris KW, Forget BG. A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation. Exp Hematol. 1999;27:63-74.
86. Masuhara M, Sakamoto H, Matsumoto A, et al. Cloning and characterization of novel CIS family genes. Biochem Biophys Res Commun. 1997;239:439-446.
87. Yoshimura A. The CIS/JAB family: novel negative regulators of JAK signaling pathways. Leukemia. 1998;12:1851-1857.
88. Sasaki A, Yasukawa H, Shouda T, et al. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. JBiol Chem. 2000;275:29338-29347.
89. Wojchowski DM, Gregory RC, Miller CP, et al. Signal transduction in the erythropoietin receptor system. Exp Cell Res. 1999;253:143-156.
90. Correa P, Axelrad A. Circulating erythroid progenitors in polycythemia vera are hypersensitive to IGF-1 [abstract]. Blood. 1991;78:381a.
91. Kralovics R, Tze L, Guan Y, et al. Two unique EPOR mutations associated with primary familial and congenital polycythemias [abstract]. Blood. 1995;86:18a.
92. Prchal JT, Semenza GL, Prchal JF, et al. Familial polycythemia [letter]. Science. 1995;268:1831-1832.
93. Whitcomb WH, Peschle C, Moore M, et al. Congenital erythrocytosis: a new form associated with an erythropoietin-dependent mechanism. Br J Haematol. 1980;44:17-24.
94. Adamson JW. Familial polycythemia. Semin Hematol. 1975;12:383-396.
95. Stephens AD. Polycythaemia and high-affinity haemoglobins. Br J Haematol. 1977;36:153-159.
96. Labie D, Leroux JP, Najman A, et al. Familial diphosphoglyceratemutase deficiency. Influence on the oxygen affinity curves of hemoglobin. FEBS Lett. 1970;9:37-40.
97. Cartier P, Labie D, Leroux JP, et al. Déficit familial en diphosphoglycérate-mutase: étude hématologique et biochimique. Nouv Rev Fr Hémat. 1972;12:269-287.
98. Galacteros F, Rosa R, Prehu M, et al. Déficit en diphosphoglycerate mutase: nouveaux cas associés à une polyglobulie. Nouv Rev Fr Hémat. 1982;26:69-74.
99. Zürcher C, Loos JA, Prins HK. Hereditary high ATP content of human erythrocytes. Folia Haem Leipzig. 1965;83:366-376.
100. Jaffe ER. Enzymopenic hereditary methemoglobinemia: a clinical/biochemical classification. Blood Cells. 1986;12:81-90.
101. Mansouri A, Lurie AA. Concise review: methemoglobinemia. Am J Hematol. 1993;42:7-12.
102. 5. N Engl J Med. 1986;314:757-761.
103. 5 gene from a patient with congenital methemoglobinemia and pseudohermaphrodism. Hum Genet. 1994;93:568-570.
104. Balcerzak SP, Bromber PA. Secondary polycythemia. Semin Hematol. 1975;12:353-382.
105. Prchal JT, Goldwasser E, Prchal JF, et al. Congenital polycythemia due to increased sensitivity of oxygen sensor responsible for epo production? [abstract] Blood. 1993;82:225a.
106. Sokol L, Kralovics R, Ren S, et al. Secondary polycythemia with putative defect in HIF-1 transcription activation pathway [abstract]. Blood. 1995;86:312a.
107. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447-5454.
108. Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem. 1993;268:2513-2518.
109. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13:167-171.
110. Wiesener MS, Maxwell PH. HIF and oxygen sensing; as important to life as the air we breathe? Ann Med. 2003;35:183-190.
111. Ang SO, Kralovics R, Adelina S, et al. Chuvash polycythemia: an autosomal recessive disorder of dysregulated oxygen sensing [abstract]. Blood. 2000;96:5a.
112. Ang SO, Chen H, Gordeuk VR, et al. Endemic polycythemia in Russia: mutation in the VHL gene. Blood Cells Mol Dis. 2002;28:57-62.
113. Ang SO, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet. 2002;32:614-621.
114. Sergeyeva A, Gordeuk VR, Tokarev YN, et al. Congenital polycythemia in Chuvashia. Blood. 1997;89:2148-2154.
115. Kralovics R, Prchal JT. Congenital and inherited polycythemia. Curr Opin Pediatr. 2000;12:29-34.
116. Gordeuk VR, Sergueeva AI, Miasnikova GY, et al. Congenital disorder of oxygen-sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 2004;103:3924-3932.
117. Polyakova LA. Familial-Hereditary Erythrocytosis. Moscow: Scientific Research Institute of Hematology and Blood Transfusion, 1977.
118. Pastore YD, Jelinek J, Ang S, et al. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood. 2003;101:1591-1595.
119. Pastore Y, Jedlickova K, Guan Y, et al. Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet. 2003;73:412-419.
120. Erslev AJ. Erythropoietin titers in health and disease. Semin Hematol. 1991;28:2-8.
121. Percy MJ, McMullin MF, Jowitt SN, et al. Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry. Blood. 2003;102:1097-1099.
122. Liu E, Percy MJ, Amos CI, et al. The worldwide distribution of the VHL 598C>T mutation indicates a single founding event. Blood. 2004;103:1937-1940.
123. Berlin NI, Wasserman LR. Polycythemia vera: a retrospective and reprise. J Lab Clin Med. 1997;130:365-373.
124. Lichtman MA, Murphy MS, Adamson JW. Detection of mutant hemoglobins with altered affinity for oxygen. A simplified technique. Ann Intern Med. 1976;84:517-520.