Diagnosis and treatment of BCR/ABL-negative myeloproliferative diseases – principles and rationale of CZEMP recommendations

Czech version

Authors: J. Schwarz ¹; M. Penka ²; V. Campr ^1,3; D. Pospíšilová ⁴; L. Křen ⁵; L. Nováková ¹; C. Bodzásová ⁶; Y. Brychtová ⁷; O. Černá ⁸; P. Ďulíček ⁹; A. Jonášová ¹⁰; J. Kissová ²; Z. Kořístek ⁷; M. Schutzova ¹¹; I. Vonke ¹²; L. Walterová ¹³
Authors‘ workplace: Klinický úsek Ústavu hematologie a krevní transfuze Praha, přednosta doc. MUDr. Petr Cetkovský, Ph. D. ¹; Oddělení klinické hematologie FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Miroslav Penka, CSc. ²; Ústav patologie a molekulární medicíny 2. lékařské fakulty UK a FN Motol Praha, přednosta prof. MUDr. Roman Kodet, CSc. ³; Dětská klinika Lékařské fakulty UP a FN Olomouc, přednosta prof. MUDr. Vladimír Mihál, CSc. ⁴; Ústav patologie Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta doc. MUDr. Josef Feit, CSc. ⁵; Ústav klinické hematologie FN Ostrava, přednosta prim. MUDr. Jaromír Gumulec ⁶; Interní hematoonkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Mayer, CSc. ⁷; Oddělení klinické hematologie FN Královské Vinohrady Praha, přednosta doc. MUDr. Tomáš Kozák, Ph. D., MBA ⁸; Oddělení klinické hematologie II. interní kliniky Lékařské fakulty UK a FN Hradec Králové, přednosta prof. MUDr. Jaroslav Malý, CSc. ⁹; I. interní klinika 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Marek Trněný, CSc. ¹⁰; Hemato-onkologické oddělení FN Plzeň, přednosta prim. MUDr. Vladimír Koza ¹¹; Oddělení klinické hematologie Nemocnice České Budějovice, přednosta prim. MUDr. Ivan Vonke, MBA ¹²; Oddělení klinické hematologie Krajské nemocnice Liberec, přednostka prim. MUDr. Lenka Walterová ¹³
Published in: Vnitř Lék 2011; 57(2): 189-213
Category: Reviews

Overview

In 2009, the recommendations of the Czech Collaborative Group for Ph- Myeloproliferative Diseases (CZEMP) for diagnosis and treatment of BCR/ABL-negative myeloproliferative diseases (MPD), i.e. essential thrombocythemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF) were updated and extended. The present article gives the rationale of the recommendations in full detail. The CZEMP diagnostic criteria for ET and PMF are based on histopathological (HP) findings, which must unconditionally be in line with the given clinical and laboratory characteristics of ET or of a certain stage of PMF, respectively. The platelet count is not decisive for diagnosis. In cases lacking an adequately taken and read HP finding, the Polycythemia Vera Study Group (PVSG) criteria are recommended. The diagnosis of typical PV is based on demonstration of the V617F mutation of the JAK2 gene along with a significant increase of red cell parameters. If these are close to borderline, the demonstration of increased total red cell mass (RCM) is required. In atypical cases lacking polyglobulia or elevated RCM, the HP picture of PV (in accordance with WHO description) plus JAK2 V617F mutation is satisfactory for diagnosis, or, in cases lacking JAK2 V617F mutation, the HP picture of PV along with polyglobulia (or increased RCM) is sufficient. The treatment principles of ET and other MPDs with thrombocythemia (MPD-T; i.e. the early stages of PMF and PV) are identical. The patients are stratified by their thrombotic risk (preceding thrombosis, another thrombophilic state, JAK2 mutation), presence of disease symptoms (mainly microcirculatory), platelet count and age. Only patients up to 65 years lacking the above mentioned risks with a platelet count < 1 000 × 10⁹/ l are considered as low-risk and do not demand cytoreducing therapy. The others are high-risk ones and have an indication for thromboreduction. In patients older than 65 years, the potentially leukemogenic drug hydroxyurea (HU) may be used. In the younger ones, the choice is between anagrelide (ANG) or interferon-α (IFN). In high-risk patients, the treatment goal is to maintain platelet counts below 400, and in low-risk ones, below 600 × 10⁹/ l. In PV, polycythemia itself is another thrombotic risk factor. The condition is treated by bloodletting or erythrocytaphereses. If hematocrit levels ≤ 45 are not achieved, cytoreductive therapy using HU in patients over 65 years, or IFN in younger individuals is required. All patients with thrombocythemia in PV are high-risk and have an indication for cytoreduction. Acetylsalicylic acid is given to all patients with MPD-T with platelets < 1 000 × 10⁹/ l (at higher counts, hemorrhage is imminent), and to all individuals with PV, unless contraindication is present. In case of platelet count normalization, it may be withdrawn in cases of low-risk ET or PMF, not in JAK2+ PV. The treatment of advanced stages of PMF is symptomatic, with substitution of blood derivatives being the basis. The only curative treatment is allogeneic stem cell transplantation, which should not be indicated too early seeing to its risks, but also not too late – we must not allow transition into acute leukemia, which is heralded by blasts in the blood picture. The indication is the presence of any of the following criteria: values of hemoglobin < 10 g/ dl, WBC < 4 × 10⁹/ l and platelets < 100 × 10⁹/ l, any percentage of blasts or ≥ 10% immature granulocytes in the differential picture, > 1 erythroblast per 100 cells – all at repeated examinations within at least a 2-month interval, and in addition, rapid progression of hepato-/splenomegaly, presence of general symptoms of the disease, portal hypertension and extensive swellings.

Key words:
Ph- myeloproliferative disease – essential thrombocythemia – polycythaemia vera – primary myelofibrosis – diagnosis – risk factors – treatment algorithm – hydroxyurea – anagrelide – interferon-α – acetylsalicylic acid – hematopoietic stem cell transplantation

Sources

1. Tefferi A, Thiele J, Orazi A et al. 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; 110: 1092–1097.

2. Jacobson RJ, Salo A, Fialkow PJ. Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis. Blood 1978; 51: 189–194.

3. Fialkow PJ, Faguet GB, Jacobson RJ et al. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood 1981; 58: 916–919.

4. Adamson JW, Fialkow PJ, Murphy S et al. Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med 1976; 295: 913–916.

5. Dameshek W. Some speculation on the myeloproliferative syndromes. Blood 1951; 6: 372–375.

6. Baxter EJ, Scott LM, Campbell PJ et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

7. James C, Ugo V, Le Couédic JP et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

8. Kralovics R, Passamonti F, Buser AS et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

9. Olcaydu D, Harutyunyan A, Jäger R et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 2009; 41: 450–454.

10. Jones AV, Chase A, Silver RT et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 2009; 41: 446–449.

11. Pardanani A, Lasho TL, Finke CM et al. The JAK2 46/1 haplotype confers susceptibility to essential thrombocythemia regardless of JAK2V617F mutational status – clinical correlates in a study of 226 consecutive patients. Leukemia 2010; 24: 110–114.

12. Kralovics R, Teo SS, Li S et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006; 108: 1377–1380.

13. Nussenzveig RH, Swierczek SI, Jelinek J et al. Polycythemia vera is not initiated by JAK2-V617F mutation. Exp Hematol 2007; 35: 32–38.

14. Schaub FX, Jäger R, Looser R et al. Clonal analysis of deletions on chromosome 20q and JAK2-V617F in MPD suggests that del20q acts independently and is not one of the predisposing mutations for JAK2-V617F. Blood 2009; 113: 2022–2027.

15. Delhommeau F, Dupont S, Della Valle V et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.

16. Michiels JJ, Kvasnicka HM, Thiele J. Myeloproliferative disorders. Current perspectives on diagnostic criteria, histopathology and treatment in essential therombocythemia, polycythemia rubra vera and chronic idiopathic myelofibrosis. Much (Germany): Verlag ME 2005.

17. Schwarz J, Pytlík R, Doubek M et al. Analysis of risk factors: the rationale of the guidelines of the Czech Hematological Society for diagnosis and treatment of chronic myeloproliferative disorders with thrombocythemia. Semin Thromb Hemost 2006; 32: 231–245.

18. Thiele J, Kvasnicka HM. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 2003; 82: 148–152.

19. Berlin NI. Diagnosis and classification of the polycythemias. Semin Hematol 1975; 12: 339–351.

20. Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol 1999; 36 (1 Suppl 2): 9–13.

21. Georgii A, Buhr T, Buesche G et al. Classification and staging of Ph- negative myeloproliferative disorders by histopathology from bone marrow biopsies. Leuk Lymphoma 1996; 22 (Suppl 1): 15–29.

22. Michiels JJ, De Raeve H, Hebeda K et al. WHO bone marrow features and European clinical, molecular, and pathological (ECMP) criteria for the diagnosis of myeloproliferative disorders. Leuk Res 2007; 31: 1031–1038.

23. 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.

24. Michiels JJ, Thiele J. Clinical and pathological criteria for the diagnosis of essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis (agnogenic myeloid metaplasia). Int J Hematol 2002; 76: 133–145.

25. Imbert M, Pierre R, Thiele J et al. Essential thrombocythemia. In: Jaffe E, Harris N, Stein H et al (eds). WHO Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press 2001: 39–41.

26. Pierre R, Imbert M, Thiele J et al. Polycythemia vera. In: Jaffe E, Harris N, Stein H et al (eds). WHO Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press 2001: 32–34.

27. Thiele J, Pierre R, Imbert M et al. Chronic idiopathic myelofibrosis. In: Jaffe E, Harris N, Stein H et al (eds). WHO Classification of Tumours: Pathology & Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press 2001: 35–38.

28. Schwarz J, Penka M, Indrák K et al. The WHO 2008 classification of Ph-myeloproliferative disorders: statement of the Czech MPD Working Group. Leukemia 2008; 22: 2118–2119.

29. Penka M, Schwarz J, Pytlík R et al. Doporučený postup diagnostiky a terapie esenciální trombocytemie a trombocytemie provázející jiné myeloproliferativní choroby. Vnitř Lék 2005; 51: 741–751.

30. Schwarz J, Penka M. Trombocytózy a trombocytemie. Vnitř Lék 2005; 51: 861–871.

31. Samuelson SJ, Parker CJ, Prchal JT. Revised criteria for the myeloproliferative disorders: too much too soon? Blood 2008; 111: 1741–1742.

32. Spivak JL, Silver RT. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood 2008; 112: 231–239.

33. Teofili L, Giona F, Martini M et al. The revised WHO diagnostic criteria for Ph-negative myeloproliferative diseases are not appropriate for the diagnostic screening of childhood polycythemia vera and essential thrombocythemia. Blood 2007; 110: 3384–3386.

34. Campbell PJ, Scott LM, Buck G et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366: 1945–1953.

35. Thiele J, Kvasnicka HM, Facchetti F et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 2005; 90: 1128–1132.

36. Kvasnicka HM, Thiele J. Classification of Ph-negative chronic myeloproliferative disorders – morphology as the yardstick of classification. Pathobiology 2007; 74: 63–71.

37. Wilkins BS, Erber WN, Bareford D et al. Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Blood 2008; 111: 60–70.

38. Gisslinger H, Gotic M, Holowiecki J et al. Final results of the ANAHYDRET-study: non-inferiority of anagrelide compared to hydroxyurea in newly diagnosed WHO-essential thrombocythemia patients. Blood 2008: 112. Abstract 661.

39. De Stefano V, Teofili L, Leone G et al. Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis. Semin Thromb Hemost 1997; 23: 411–418.

40. Lengfelder E, Hochhaus A, Kronawitter U et al. Should a platelet limit of 600 × 10(9)/ l be used as a diagnostic criterion in essential thrombocythaemia? An analysis of the natural course including early stages. Br J Haematol 1998; 100: 15–23.

41. Chait Y, Condat B, Cazals-Hatem D et al. Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol 2005; 129: 553–560.

42. Boissinot M, Lippert E, Girodon F et al. Latent myeloproliferative disorder revealed by the JAK2-V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis. Blood 2006; 108: 3223–3224.

43. Brière JB. Budd-Chiari syndrome and portal vein thrombosis associated with myeloproliferative disorders: diagnosis and management. Semin Thromb Hemost 2006; 32: 208–218.

44. Marková J, Průková D, Volková Z et al. A new allelic discrimination assay using locked nucleic acid-modified nucleotides (LNA) probes for detection of JAK2 V617F mutation. Leuk Lymphoma 2007; 48: 636–639.

45. Pardanani AD, Levine RL, Lasho T et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.

46. Schnittger S, Haferlach C, Beelen DW et al. Detection of three different MPLW515 mutations in 10.1% of all JAK2 V617 unmutated ET and 9.3% of all JAK2 V617F unmutated OMF: a study of 387 patients. Blood 2007: 110. Abstr. 2546.

47. Beer PA, Campbell PJ, Scott LM et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008; 112: 141–149.

48. Hussein K, Bock O, Theophile K et al. JAK2V(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis. Exp Hematol 2009; 37: 1186–1193.

49. Beer PA, Jones AV, Bench AJ et al. Clonal diversity in the myeloproliferative neoplasms: independent origins of genetically distinct clones. Br J Haematol 2009; 144: 904–908.

50. Ding J, Komatsu H, Wakita A et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198–4200.

51. Tefferi A, Skoda R, Vardiman JW. Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. Nat Rev Clin Oncol 2009; 6: 627–637.

52. Goerttler PS, Steimle C, März E et al. The Jak2V617F mutation, PRV-1 overexpression and EEC formation define a similar cohort of MPD patients. Blood 2005; 106: 2862–2864.

53. Barosi G, Mesa RA, Thiele J et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 2008; 22: 437–438.

54. Thiele J, Kvasnicka HM, Orazi A. Bone marrow histopathology in myeloproliferative disorders-current diagnostic approach. Semin Hematol 2005; 42: 184–195.

55. Cortelazzo S, Viero P, Finazzi G et al. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990; 8: 556–562.

56. Besses C, Cervantes F, Pereira A et al. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia 1999; 13: 150–154.

57. Michiels JJ, Kutti J, Stark P et al. Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis. Neth J Med 1999; 54: 46–62.

58. Michiels JJ, Berneman ZN, Schroyens W et al. Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythaemia and polycythaemia vera. Platelets 2004; 15: 67–84.

59. Wolanskyj AP, Schwager SM, McClure RF et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006; 81: 159–166.

60. Carobbio A, Finazzi G, Guerini V et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007; 109: 2310–2313.

61. Carobbio A, Antonioli E, Guglielmelli P et al. Leukocytosis and risk stratification assessment in essential thrombocythemia. J Clin Oncol 2008; 26: 2732–2736.

62. Tefferi A. Leukocytosis as a risk factor for thrombosis in myeloproliferative neoplasms-biologically plausible but clinically uncertain. Am J Hematol 2010; 85: 93–94.

63. Schwarz J, Markova J, Volkova Z et al. Chronic myeloproliferative disorders with thrombocythemia: thrombosis associated with inherited thrombophilia or JAK2 V617F gene mutation. Haematologica 2007, 92 (Suppl 1): 385–386. Abstr. 1044.

64. Schwarz J, Penka M, Doubek M et al. JAK2 mutation and additional thrombophilic state are major prothrombotic risk factors in myeloproliferations with thrombocythemia – data from a registry of anagrelide-treated patients. Haematologica 2008; 93 (Suppl 1): 57–58. Abstr. 0144.

65. Penka M, Schwarz J, Pavlík T et al. Jak léčíme nemocné s esenciální trombocytémií a dalšími myeloproliferacemi provázenými trombocytemií a co může být prediktivní známkou rizika trombózy u těchto nemocných – zpráva z registru pacientů léčených Thromboreductinem. Vnitř Lék 2008; 54: 775–782.

66. Conlan MG, Haire WD. Low protein S in essential thrombocythemia with thrombosis. Am J Hematol 1989; 32: 88–93.

67. Bucalossi A, Marotta G, Bigazzi C et al. Reduction of antithrombin III, protein C, and protein S levels and activated protein C resistance in polycythemia vera and essential thrombocythemia patients with thrombosis. Am J Hematol 1996; 52: 14–20.

68. Ruggeri M, Gisslinger H, Tosetto A et al. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. Am J Hematol 2002; 71: 1–6.

69. Amitrano L, Guardascione MA, Ames PR et al. Thrombophilic genotypes, natural anticoagulants, and plasma homocysteine in myeloproliferative disorders: relationship with splanchnic vein thrombosis and arterial disease. Am J Hematol 2003; 72: 75–81.

70. Kessler CM. Propensity for hemorrhage and thrombosis in chronic myeloproliferative disorders. Semin Hematol 2004; 41 (2 Suppl 3): 10–14.

71. Schwarz J, Hrachovinova I, Vorlova Z et al. Thromboembolism in thrombocythemia patients with an additional thrombophilic state. Hematol J 2004; 5 (Suppl 2): S321. Abstr. 974.

72. Gisslinger H, Müllner M, Pabinger I et al. Mutation of the prothrombin gene and thrombotic events in patients with polycythemia vera or essential thrombocythemia: a cohort study. Haematologica 2005; 90: 408–410.

73. Falanga A. Thrombosis and malignancy: an underestimated problem. Haematologica 2003; 88: 607–610.

74. Griesshammer M, Grünewald M, Michiels JJ. Acquired thrombophilia in pregnancy: essential thrombocythemia. Semin Thromb Hemost 2003; 29: 205–212.

75. Schafer AI, Levine MN, Konkle BA et al. Thrombotic disorders: diagnosis and treatment. Hematology (Am Soc Hematol Educ Program) 2003: 520–539.

76. Tatewaki W, Shibata A. Acquired von Willebrand disease in patients with chronic myeloproliferative disorders. Leuk Lymphoma 1989; 1: 51–57.

77. van Genderen PJJ, Michiels JJ, van der Poel-van de Luytgaarde SCPAM et al. Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia: relationship with platelet count. Ann Hematol 1994; 69: 81–84.

78. van Genderen PJJ, Budde U, Michiels JJ et al. The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count. Br J Haematol 1996; 93: 962–965.

79. McMullin MF, Bareford D, Campbell P et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 2005; 130: 174–195.

80. Jones AV, Kreil S, Zoi K et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005; 106: 2162–2168.

81. Scott LM, Tong W, Levine RL et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459–468.

82. Schnittger S, Haferlach C, Geer T et al. Detection of JAK2 exon 12 mutations in 10 patients (10.1%) of V617F negative PV: a study of 211 cases with PV or suspected PV. Blood 2007: 110. Abstr. 2541.

83. Dawson AA, Ogston D. The influence of the platelet count on the incidence of thrombotic and haemorrhagic complications in polycythaemia vera. Postgrad Med J 1970; 46: 76–78.

84. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2: 1219–1222.

85. Berk PD, Goldberg JD, Donovan PB et al. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986; 23: 132–143.

86. Pikman Y, Lee BH, Mercher T et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3: e270.

87. Vannucchi AM, Antonioli E, Guglielmelli P et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood 2008; 112: 844–847.

88. Dupriez B, Morel P, Demory JL et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996; 88: 1013–1018.

89. Dingli D, Schwager SM, Mesa RA et al. Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer 2006; 106: 623–630.

90. Kvasnicka HM, Thiele J, Werden C et al. Prognostic factors in idiopathic (primary) osteomyelofibrosis. Cancer 1997; 80: 708–719.

91. Cervantes F, Dupriez B, Pereira A et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009; 113: 2895–2901.

92. U.S. Preventive Services Task Force Ratings: grade definitions. Guide to clinical preventive services, third edition: Periodic updates, 2000-2003. Available from: http://www.ahrq.gov/clinic/3rduspstf/ratings.htm.

93. Střední délka života ve věku 65 let – muži. Střední délka života ve věku 65 let – ženy. Praha: ÚZIS (Ústav zdravotnických informací a statistiky ČR) 2009. Dostupné z: http://www.uzis.cz/cz/dps/data/frame.html?T0=r2008+&T1=UKZ+0054+0064+&T2=REG+CZE+.

94. Nowak-Göttl U, Kosch A, Schlegel N et al. Thromboembolism in children. Curr Opin Hematol 2002; 9: 448–453.

95. Tripodi A. Levels of coagulation factors and venous thromboembolism. Haematologica 2003; 88: 705–711.

96. Antonioli E, Guglielmelli P, Poli G et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica 2008; 93: 41–48.

97. Larsen TS, Pallisgaard N, Møller MB et al. High prevalence of arterial thrombosis in JAK2 mutated essential thrombocythaemia: independence of the V617F allele burden. Hematology 2008; 13: 71–76.

98. Pemmaraju N, Moliterno AR, Williams DM et al. The quantitative JAK2 V617F neutrophil allele burden does not correlate with thrombotic risk in essential thrombocytosis. Leukemia 2007; 21: 2210–2212.

99. Kittur J, Knudson RA, Lasho TL et al. Clinical correlates of JAK2V617F allele burden in essential thrombocythemia. Cancer 2007; 109: 2279–2284.

100. Mitus AJ, Schafer AI. Thrombocytosis and thrombocythemia. Hematol Oncol Clin North Am 1990; 4: 157–178.

101. Falanga A, Marchetti M, Barbui T et al. Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils. Semin Hematol 2005; 42: 239–247.

102. Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC et al. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica 2006; 91: 169–175.

103. Maugeri N, Giordano G, Petrilli MP et al. Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug? J Thromb Haemost 2006; 4: 2593–2598.

104. Schwarz J, Penka M. The Czech Collaborative Group for Ph- MPD. Thromboreductin patient registry, a Czech success story. Turracher Höhe (Rakousko): AOP Orphan 2008.

105. Cortelazzo S, Finazzi G, Ruggeri M et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 332: 1132–1136.

106. Laguna MS, Kornblihtt LI, Marta RF et al. Effectiveness of anagrelide in the treatment of symptomatic patients with essential thrombocythemia. Clin Appl Thromb Hemost 2000; 6: 157–161.

107. Michiels JJ. Aspirin and platelet-lowering agents for the prevention of vascular complications in essential thrombocythemia. Clin Appl Thromb Hemost 1999; 5: 247–251.

108. Landolfi R, Marchioli R, Kutti J et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114–124.

109. Colwell JA. Aspirin for the primary prevention of cardiovascular events. Timely Top Med Cardiovasc Dis 2006; 10: E25.

110. Michiels JJ. Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts. Pathol Biol (Paris) 2003; 51: 167–175.

111. Finazzi G, Barbui T. Efficacy and safety of hydroxyurea in patients with essential thrombocythemia. Pathol Biol (Paris) 2001; 49: 167–169.

112. Barbui T, Barosi G, Grossi A et al. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004; 89: 215–232.

113. Harrison CN. Essential thrombocythaemia: challenges and evidence-based management. Br J Haematol 2005; 130: 153–165.

114. Barbui T. The leukemia controversy in myeloproliferative disorders: is it a natural progression of disease, a secondary sequela of therapy, or a combination of both? Semin Hematol 2004; 41 (2 Suppl 3): 15–17.

115. Briere J, Guilmin F. Management of patients with essential thrombocythemia: current concepts and perspectives. Pathol Biol (Paris) 2001; 49: 178–183.

116. Fruchtman SM. Treatment paradigms in the management of myeloproliferative disorders. Semin Hematol 2004; 41 (2 Suppl 3): 18–22.

117. Birgegård G. Long-term management of thrombocytosis in essential thrombocythaemia. Ann Hematol 2009; 88: 1–10.

118. Finazzi G, Caruso V, Marchioli R et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005; 105: 2664–2670.

119. Mazur EM, Rosmarin AG, Sohl PA et al. Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans. Blood 1992; 79: 1931–1937.

120. Spencer CM, Brogden RN. Anagrelide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia. Drugs 1994; 47: 809–822.

121. Solberg LA Jr, Tefferi A, Oles KJ et al. The effects of anagrelide on human megakaryocytopoiesis. Br J Haematol 1997; 99: 174–180.

122. Pescatore SL, Lindley C. Anagrelide: a novel agent for the treatment of myeloproliferative disorders. Expert Opin Pharmacother 2000; 1: 537–546.

123. Hong Y, Erusalimsky JD. Comparison of the pharmacological mechanisms involved in the platelet lowering actions of anagrelide and hydroxyurea: a review. Platelets 2002; 13: 381–386.

124. Petrides PE. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opin Pharmacother 2004; 5: 1781–1798.

125. Pytlík R, Cmunt E, Kleibl Z et al. Úloha anagrelidu v léčbě esenciální trombocytemie. Transf Hematol Dnes 2004; 10: 154–160.

126. Dingli D, Tefferi A. A critical review of anagrelide therapy in essential thrombocythemia and related disorders. Leuk Lymphoma 2005; 46: 641–650.

127. Emadi A, Spivak JL. Anagrelide: 20 years later. Expert Rev Anticancer Ther 2009; 9: 37–50.

128. Balduini CL, Bertolino G, Noris P et al. Effect of anagrelide on platelet count and function in patients with thrombocytosis and myeloproliferative disorders. Haematologica 1992; 77: 40–43.

129. Balduini CL. Primary thrombocythemia: new drugs for an evolving disease. Haematologica 1992; 77: 297–301.

130. Doubek M, Brychtova Y, Doubek R et al. Anagrelide therapy in pregnancy: report of a case of essential thrombocythemia. Ann Hematol 2004; 83: 726–727.

131. Silverstein MN, Petitt RM, Solberg LA Jr et al. Anagrelide: a new drug for treating thrombocytosis. N Engl J Med 1988; 318: 1292–1294.

132. Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992; 92: 69–76.

133. Petrides PE, Beykirch MK, Trapp OM. Anagrelide, a novel platelet lowering option in essential thrombocythaemia: treatment experience in 48 patients in Germany. Eur J Haematol 1998; 61: 71–76.

134. Petrides PE, Gisslinger H, Steurer M et al. Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation. Clin Ther 2009; 31: 386–398.

135. Steurer M, Gastl G, Jedrzejczak WW et al. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer 2004; 101: 2239–2246.

136. Birgegård G, Björkholm M, Kutti J et al. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004; 89: 520–527.

137. Penka M, Schwarz J, Pavlík T et al. Esenciální trombocytemie a další myeloproliferace s trombocytemií v údajích registru pacientů léčených Thromboreductinem® do konce roku 2006. Vnitř Lék 2007; 53: 653–661.

138. Penka M, Schwarz J, Pavlík T et al. Výsledky léčby nemocných s esenciální trombocytemií a dalšími myeloproliferacemi provázenými trombocytemií – zpráva z registru pacientů léčených Thromboreductinem®. Vnitř Lék 2009; 55: I–XII.

139. Schwarz J, Penka M. The Czech Ph- MPD study group (CZEMP). Patient registry in the Czech Republic – updated results. Turracher Höhe (Rakousko): AOP Orphan 2010.

140. Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 2001; 97: 863–866.

141. Harrison CN, Campbell PJ, Buck G et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 33–45.

142. Petrides PE. Anagrelide: what was new in 2004 and 2005? Semin Thromb Hemost 2006; 32: 399–408.

143. Penka M, Doubek M, Schwarz J et al. Anagrelid v léčbě esenciální trombocytemie a dalších myeloproliferací s trombocytemií sledovaných v registru pacientů v ČR. Vnitř Lék 2006; 52: 498–503.

144. Wadenvik H, Kutti J, Ridell B et al. The effect of alpha-interferon on bone marrow megakaryocytes and platelet production rate in essential thrombocythemia. Blood 1991; 77: 2103–2108.

145. Lengfelder E, Griesshammer M, Hehlmann R. Interferon-alpha in the treatment of essential thrombocythemia. Leuk Lymphoma 1996; 22 (Suppl 1): 135–142.

146. Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-ABL-negative myeloproliferative neoplasms. Leukemia 2008; 22: 1990–1998.

147. Velu T, Delwiche F, Gangji D et al. Therapeutic effect of human recombinant interferon-alpha-2C in essential thrombocythaemia. Oncology 1985; 42 (Suppl 1): 10–14.

148. Giles FJ, Singer CR, Gray AG et al. Alpha-interferon therapy for essential thrombocythaemia. Lancet 1988; 2: 70–72.

149. Bellucci S, Harousseau JL, Brice P et al. Treatment of essential thrombocythaemia by alpha 2a interferon. Lancet 1988; 2: 960–961.

150. Melillo L, Tieghi A, Candoni A et al. Outcome of 122 pregnancies in essential thrombocythemia patients: a report from the Italian registry. Am J Hematol 2009; 84: 636–640.

151. Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol 1992; 19 (3 Suppl 9): 1–10.

152. Seino Y, Nagao M, Yahagi T et al. Mutagenicity of several classes of antitumor agents to Salmonella typhimurium TA98, TA100, and TA92. Cancer Res 1978; 38: 2148–2156.

153. Mehnert K, Vogel W, Benz R et al. Different effects of mutagens on sister chromatid exchange induction in three Chinese hamster cell lines. Environ Mutagen 1984; 6: 573–583.

154. Schroeder AL. Chromosome instability in mutagen sensitive mutants of Neurospora. Curr Genet 1986; 10: 381–387.

155. Marsteinstredet U, Brunborg G, Bjørås M et al. DNA damage induced by 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) in HL-60 cells and purified DNA in vitro. Mutat Res 1997; 390: 171–178.

156. Andersson M, Agurell E, Vaghef H et al. Extended-term cultures of human T-lymphocytes and the comet assay: a useful combination when testing for genotoxicity in vitro? Mutat Res 2003; 540: 43–55.

157. Ficsor G, Ginsberg LC. The effect of hydroxyurea and mitomycin C on sperm motility in mice. Mutat Res 1980; 70: 383–387.

158. Löfvenberg E, Nordenson I, Wahlin A. Cytogenetic abnormalities and leukemic transformation in hydroxyurea-treated patients with Philadelphia chromosome negative chronic myeloproliferative disease. Cancer Genet Cytogenet 1990; 49: 57–67.

159. Nand S, Messmore H, Fisher SG et al. Leukemic transformation in polycythemia vera: analysis of risk factors. Am J Hematol 1990; 34: 32–36.

160. Nand S, Stock W, Godwin J et al. Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Am J Hematol 1996; 52: 42–46.

161. Nielsen I, Hasselbalch HC. Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan. Am J Hematol 2003; 74: 26–31.

162. 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; 52: 134–139.

163. Najean Y, Rain JD. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997; 90: 3370–3377.

164. Kiladjian JJ, Rain JD, Bernard JF et al. Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost 2006; 32: 417–421.

165. Sterkers Y, Preudhomme C, Laï JL et al. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 1998; 91: 616–622.

166. Tóthová E, Fričová M, Štecová N et al. Leukemic transformation of polycythemia vera after treatment with hydroxyurea with abnormalities of chromosome 17. Neoplasma 2001; 48: 389–392.

167. Kiladjian JJ, Rain JD, Bernard JF et al. Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost 2006; 32: 417–421.

168. Papi M, Didona B, DePità O et al. Multiple skin tumors on light-exposed areas during long-term treatment with hydroxyurea. J Am Acad Dermatol 1993; 28: 485–486.

169. Best PJ, Petitt RM. Multiple skin cancers associated with hydroxyurea therapy. Mayo Clin Proc 1998; 73: 961–963.

170. Young HS, Khan AS, Kendra JR et al. The cutaneous side-effects of hydroxyurea. Clin Lab Haematol 2000; 22: 229–232.

171. Ravandi-Kashani F, Cortes J, Cohen P et al. Cutaneous ulcers associated with hydroxyurea therapy in myeloproliferative disorders. Leuk Lymphoma 1999; 35: 109–118.

172. Daoud MS, Gibson LE, Pittelkow MR. Hydroxyurea dermopathy: a unique lichenoid eruption complicating long-term therapy with hydroxyurea. J Am Acad Dermatol 1997; 36: 178–182.

173. Lannemyr O, Kutti J. Hydroxyurea as a cause of drug fever in essential thrombocythaemia. Eur J Haematol 1999; 62: 354–355.

174. Hallam MJ, Kolesar JM. Hydroxyurea induced acute elevations in liver function tests. J Oncol Pharm Pract 2008; 14: 61–63.

175. Finazzi G, Barbui T. Risk-adapted therapy in essential thrombocythemia and polycythemia vera. Blood Rev 2005; 19: 243–252.

176. Randi ML, Ruzzon E, Luzzatto G et al. Safety profile of hydroxyurea in the treatment of patients with Philadelphia-negative chronic myeloproliferative disorders. Haematologica 2005; 90: 261–262.

177. Wehmeier A, Südhoff T, Meierkord F. Relation of platelet abnormalities to thrombosis and hemorrhage in chronic myeloproliferative disorders. Semin Thromb Hemost 1997; 23: 391–402.

178. Rao AK. Molecular and biochemical basis for the platelet dysfunction in myeloproliferative disorders. Semin Hematol 2004; 41 (2 Suppl 3): 6–9.

179. van Genderen PJ, Mulder PG, Waleboer M et al. Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin. Br J Haematol 1997; 97: 179–184.

180. Griesshammer M, Bangerter M, van Vliet HH et al. Aspirin in essential thrombocythemia: status quo and quo vadis. Semin Thromb Hemost 1997; 23: 371–377.

181. Michiels JJ. Normal life expectancy and thrombosis-free survival in aspirin treated essential thrombocythemia. Clin Appl Thromb Hemost 1999; 5: 30–36.

182. Dzúrik R, Dzúriková V. Kyselina acetylsalicylová v antiagregačnej terapii. Slovakofarma Rev 1992; 2: 31–36.

183. Müller P, Dammann HG, Bergdolt H et al. Verbesserung der gastroduodenalen Verträglichkeit von Azetylsalizylsäure durch Ranitidin. Eine endoskopische kontrollierte Doppelblindstudie an gesunden Probanden. Arzneimittelforschung 1991; 41: 638–639.

184. Schnell O, Lang E, Bertholdt H. Untersuchungen zur thrombozytenaggregationshemmenden und analgetischen Wirkung der Acetylsalicylsäure. Arzneimittelforschung 1980; 30: 1917–1922.

185. Randi ML, Rossi C, Fabris F et al. Essential thrombocythemia in young adults: treatment and outcome of 16 pregnancies. J Intern Med 1999; 246: 517–518.

186. Ruggeri Z, Cannata ML, Stella NC et al. Pregnancy in essential thrombocythemia during aspirin treatment. Arch Gynecol Obstet 2003; 268: 209–210.

187. Niittyvuopio R, Juvonen E, Kaaja R et al. Pregnancy in essential thrombocythaemia: experience with 40 pregnancies. Eur J Haematol 2004; 73: 431–436.

188. Harrison C. Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br J Haematol 2005; 129: 293–306.

189. Tefferi A, Passamonti F. Essential thrombocythemia and pregnancy: Observations from recent studies and management recommendations. Am J Hematol 2009; 84: 629–630.

190. Gangat N, Wolanskyj AP, Schwager S et al. Predictors of pregnancy outcome in essential thrombocythemia: a single institution study of 63 pregnancies. Eur J Haematol 2009; 82: 350–353.

191. Patrono C, Rocca B. Aspirin, 110 years later. J Thromb Haemost 2009; 7 (Suppl 1): 258–261.

192. Taft EG, Babcock RB, Scharfman WB et al. Plateletpheresis in the management of thrombocytosis. Blood 1977; 50: 927–933.

193. Boughton BJ. Chronic myeloproliferative disorders: improved platelet aggregation following venesection. Br J Haematol 1978; 39: 589–598.

194. Panlilio AL, Reiss RF. Therapeutic plateletpheresis in thombocythemia. Transfusion 1979; 19: 147–152.

195. Beard ME, Blacklock HA, Varcoe AR. Control of thrombocytosis by plateletpheresis using a cell separator. N Z Med J 1980; 91: 136–138.

196. Orlin JB, Berkman EM. Improvement of platelet function following plateletpheresis in patients with myeloproliferative diseases. Transfusion 1980; 20: 540–545.

197. Fabris F, Belloni M, Casonato A et al. Improvement of platelet aggregation abnormalities in thrombocytosis after thrombocytopheresis. Folia Haematol Int Mag Klin Morphol Blutforsch 1981; 108: 853–862.

198. Baron BW, Mick R, Baron JM. Combined plateletpheresis and cytotoxic chemotherapy for symptomatic thrombocytosis in myeloproliferative disorders. Cancer 1993; 72: 1209–1218.

199. Greist A. The role of blood component removal in essential and reactive thrombocytosis. Ther Apher 2002; 6: 36–44.

200. Landolfi R, Di Gennaro L, Barbui T et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007; 109: 2446–2452.

201. Dameshek W. Physiopathology and course of polycythemia vera as related to therapy. J Am Med Assoc 1950; 142: 790–797.

202. Wasserman LR. Polycythemia vera: its course and treatment; relation to myeloid metaplasia and leukemia. Bull N Y Acad Med 1954; 30: 343–375.

203. Berk PD, Goldberg JD, Silverstein MN et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981; 304: 441–447.

204. Rosenthal N, Bassen F. Course of polycythaemia. Arch Intern Med 1938; 62: 903–907.

205. Stephens D.J, Kaltreider N. The therapeutic use of venesection in polycythemia. Ann Intern Med 1937; 10: 1565–1581.

206. Thomas DJ, du Boulay GH, Marshall J et al. Cerebral blood-flow in polycythaemia. Lancet 1977; 2: 161–163.

207. Thomas DJ, Marshall J, Russell RW et al. Effect of haematocrit on cerebral blood-flow in man. Lancet 1977; 2: 941–943.

208. Steensma DP. The chronic myeloproliferative disorders: an historical perspective. Curr Hematol Rep 2003; 2: 221–230.

209. Videbaek A. Polycythaemia vera. Course and prognosis. Acta Med Scand 1950; 138: 179–187.

210. Kaboth U, Rumpf KW, Liersch T et al. Advantages of isovolemic large-volume erythrocytapheresis as a rapidly effective and long-lasting treatment modality for red blood cell depletion in patients with polycythemia vera. Ther Apher 1997; 1: 131–134.

211. Kaboth U, Rumpf KW, Lipp T et al. Treatment of polycythemia vera by isovolemic large-volume erythrocytapheresis. Klin Wochenschr 1990; 68: 18–25.

212. Valbonesi M, Bruni R. Clinical application of therapeutic erythrocytapheresis (TEA). Transfus Sci 2000; 22: 183–194.

213. Fruchtman SM, Mack K, Kaplan ME et al. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997; 34: 17–23.

214. Koza V, Cetkovský P, Faber E et al. Indikace k alogenním a autologním transplantacím krvetvorných buněk. Doporučení České hematologické společnosti ČLS JEP a České onkologické společnosti ČLS JEP. Klin Onkol 2006; 19: 310–316.

215. Schwarz J, Marková M, Vítek A et al. Indikace k transplantaci hematopoetických kmenových buněk u Ph- myeloproliferativních onemocnění (MPO). (Abstr. H-O-032). Transf Hematol Dnes 2008; 14 (Suppl 2): 52–53.

216. Njoku OS, Lewis SM, Catovsky D et al. Anaemia in myelofibrosis: its value in prognosis. Br J Haematol 1983; 54: 79–89.

217. Barosi G, Berzuini C, Liberato LN et al. A prognostic classification of myelofibrosis with myeloid metaplasia. Br J Haematol 1988; 70: 397–401.

218. Visani G, Finelli C, Castelli U et al. Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol 1990; 75: 4–9.

219. Hasselbalch H, Jensen BA. Prognostic factors in idiopathic myelofibrosis: a simple scoring system with prognostic significance. Eur J Haematol 1990; 44: 172–178.

220. Cervantes F, Pereira A, Esteve J et al. Identification of “short-lived” and “long-lived” patients at presentation of idiopathic myelofibrosis. Br J Haematol 1997; 97: 635–640.

221. Reilly JT, Snowden JA, Spearing RL et al. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. Br J Haematol 1997; 98: 96–102.

222. Kreft A, Weiss M, Wiese B et al. Chronic idiopathic myelofibrosis: prognostic impact of myelofibrosis and clinical parameters on event-free survival in 122 patients who presented in prefibrotic and fibrotic stages. A retrospective study identifying subgroups of different prognoses by using the RECPAM method. Ann Hematol 2003; 82: 605–611.

223. Strasser-Weippl K, Steurer M, Kees M et al. Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score. Leuk Lymphoma 2006; 47: 441–450.

224. Li Z, Deeg HJ. Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation. Leukemia 2001; 15: 465–467.

225. Hoffman R, Prchal JT, Samuelson S et al. Philadelphia chromosome-negative myeloproliferative disorders: biology and treatment. Biol Blood Marrow Transplant 2007; 13 (1 Suppl 1): 64–72.

226. Guardiola P, Anderson JE, Bandini G et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood 1999; 93: 2831–2838.

227. Deeg HJ, Gooley TA, Flowers ME et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102: 3912–3918.

228. Kröger N, Zabelina T, Schieder H et al. Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. Br J Haematol 2005; 128: 690–697.

229. Rondelli D, Barosi G, Bacigalupo A et al. Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 2005; 105: 4115–4119.

230. Kröger N, Holler E, Kobbe G et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114: 5264–5270.

231. Markova M, Schwarz J, Vitek A et al. Allogeneic transplantation for myelofibrosis in myeloproliferative disease-a single center experience. Haematologica 2008; 93 (Suppl 1): 134. Abstr. 0328.

232. Chanarin I. Folate deficiency in the myeloproliferative disorders. Am J Clin Nutr 1970; 23: 855–860.

233. Faurschou M, Nielsen OJ, Jensen MK et al. High prevalence of hyperhomocysteinemia due to marginal deficiency of cobalamin or folate in chronic myeloproliferative disorders. Am J Hematol 2000; 65: 136-140.

234. Jack FR, Smith SR, Saunders PW. Idiopathic myelofibrosis: anaemia may respond to low-dose dexamethasone. Br J Haematol 1994; 87: 877–878.

235. Arana-Yi C, Quintás-Cardama A, Giles F et al. Advances in the therapy of chronic idiopathic myelofibrosis. Oncologist 2006; 11: 929–943.

236. Cervantes F. Modern management of myelofibrosis. Br J Haematol 2005; 128: 583–592.

237. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC et al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 2004; 127: 399–403.

238. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol 2006; 134: 184–186.

239. Iki S, Yagisawa M, Ohbayashi Y et al. Adverse effect of erythropoietin in myeloproliferative disorders. Lancet 1991; 337: 187–188.

240. Berrebi A, Feldberg E, Spivak I et al. Mini-dose of thalidomide for treatment of primary myelofibrosis. Report of a case with complete reversal of bone marrow fibrosis and splenomegaly. Haematologica 2007; 92: e15–e16.

241. Tefferi A, Verstovsek S, Barosi G et al. Pomalidomide is active in the treatment of anémia associated with myelofibrosis. J Clin Oncol 2009; 27: 4563–4569.

242. Quintás-Cardama A, Kantarjian HM, Manshouri T et al. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol 2009; 27: 4760–4766.

243. Mesa RA, Steensma DP, Pardanani A et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003; 101: 2534–2541.

244. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 2009: 636–642.

245. Reilly JT. Idiopathic myelofibrosis: pathogenesis to treatment. Hematol Oncol 2006; 24: 56–63.

246. Barosi G, Ambrosetti A, Buratti A et al. Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction. Leukemia 1993; 7: 200–206.

247. Mesa RA. How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood 2009; 113: 5394–5400.

248. Tefferi A, Mesa RA, Nagorney DM et al. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000; 95: 2226–2233.

249. Abu-Hilal M, Tawaker J. Portal hypertension secondary to myelofibrosis with myeloid metaplasia: a study of 13 cases. World J Gastroenterol 2009; 15: 3128–3133.

250. Bělohlávek J, Schwarz J, Jirásek A et al. Idiopathic myelofibrosis complicated by portal hypertension treated with a transjugular intrahepatic portosystemic shunt (TIPS). Wien Klin Wochenschr 2001; 113: 208–211.

251. Doki N, Irisawa H, Takada S et al. Transjugular intrahepatic portosystemic shunt for the treatment of portal hypertension due to idiopathic myelofibrosis. Intern Med 2007; 46: 187–190.

252. Mishchenko E, Tefferi A. Treatment options for hydroxyurea-refractory disease complications in myeloproliferative neoplasms: JAK2 inhibitors, radiotherapy, splenectomy and transjugular intrahepatic portosystemic shunt. Eur J Haematol 2010; 85: 192–199.

253. Tefferi A, Barrett SM, Silverstein MN et al. Outcome of portal-systemic shunt surgery for portal hypertension associated with intrahepatic obstruction in patients with agnogenic myeloid metaplasia. Am J Hematol 1994; 46: 325–328.

254. Dulíček P, Malý J. Budd-Chiari syn-drom – úloha hematologa v multidisciplinárním přístupu. Vnitř Lék 2008; 54: 842–845.

255. Silverstein MN, ReMine WH. Splenectomy in myeloid metaplasia. Blood 1979; 53: 515–518.

256. Mach J. Profesní standardy, doporučené postupy a závazná stanoviska. Tempus medicorum 2010; 19: 6–8.