Thrombocytosis and thrombocythemia

Czech version

Authors: J. Schwarz ¹; M. Penka ²
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
Published in: Vnitř Lék 2005; 91(7 a 8): 861-872
Category: 128th Internal Medicine Day - 21rd Vanysek's Day Brno 2005

Overview

In this review, we recommend the nosological classification of the Ph- myeloproliferative disorders with thrombocythemia (MPD-T) to be performed either according to the WHO or to the Rotterdam criteria, both of which are based on demonstration of specific histopathological features of the respective MPD-T. The most frequent of the primary MPD-Ts is the proliferative, prefibrotic or early fibrotic phase of idiopathic myelofibrosis, but reactive thrombocytoses are even more frequently seen. The differences between the primary MPD-Ts and secondary thrombocytoses are discussed along with the issue of clonality of these disorders and the methodology of its determination. The most serious complications of MPD-Ts are the following: 1. arterial and venous thromboses, 2. transformation of MPD-T into secondary acute myeloid leukemia, 3. microcirculation problems, 4. hemorrhage. The main risk factors of thrombosis are age, history of previous thrombosis, thrombocyte counts 350-2200 x 109/L and the presence of an additional thrombophilic risk factor (hereditary thrombophilia, malignancy, gravidity, hypercoagulable states, cardiovascular disease). The treatment of MPD-Ts, according to the prepared recommendations of the Czech multiinstitutional group, should be stratified with respect to the thrombotic and hemorrhagic risks. In high-risk patients, thromboreductive treatment is warranted. Seeing to the possible leukemogenicity of all the cytostatic drugs used, including hydroxyurea, they should not be administered over prolonged periods of time to individuals less than 60 years old. In these patients, interferon-α or anagrelide should be preferred. In low-risk patients, antiaggregation therapy is sufficient.

Key words:
myeloproliferative disease - thrombocythemia - secondary thrombocytosis - risk factors - diagnostics - clonality - leukemic transformation - thrombosis - treatment algorithm - hydroxyurea - interferon - anagrelide

Sources

1. Schafer AI. Thrombocytosis. N Engl J Med 2004; 350: 1211-1219.

2. Barbui T, Finazzi G. Treatment indications and choice of a platelet-lowering agent in essential thrombocythemia. Curr Hematol Rep 2003; 2: 248-256.

3. Randi ML, Fabris F, Rossi C et al. Sex and age as prognostic factors in essential thrombocythemia. Haematologica 1992; 77: 402-404.

4. Murphy S, Peterson P, Iland H et al. Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol 1997; 34: 29-39.

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

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

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

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

9. Murphy S, Iland H, Rosenthal D et al. Essential thrombocythemia: an interim report from the Polycythemia Vera Study Group. Semin Hematol 1986; 23: 177-182.

10. Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 1999; 17: 2954-2970.

11. Thiele J, Kvasnicka HM, Boeltken B et al. Initial (prefibrotic) stages of idiopathic (primary) myelofibrosis (IMF) - a clinicopathological study. Leukemia 1999; 13: 1741-1748.

12. 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.

13. Michiels JJ. Diagnostic criteria of the myeloproliferative disorders (MPD): essential thrombocythaemia, polycythaemia vera and chronic megakaryocytic granulocytic metaplasia. Neth J Med 1997; 51: 57-64.

14. 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.

15. Michiels JJ. Bone marrow histopathology and biological markers as specific clues to the differential diagnosis of essential thrombocythemia, polycythemia vera and prefibrotic or fibrotic agnogenic myeloid metaplasia. Hematol J 2004; 5: 93-102.

16. Lengfelder E, Hochhaus A, Kronawitter U et al. Should a platelet limit of 600 x 109/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.

17. 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.

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

19. Barbui T, Cortelazzo S, Viero P et al. Thrombohaemorrhagic complications in 101 cases of myeloproliferative disorders: relationship to platelet number and function. Eur J Cancer Clin Oncol 1983; 19: 1593-1599.

20. 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.

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

22. Regev A, Stark P, Blickstein D et al. Thrombotic complications in essential thrombocythemia with relatively low platelet counts. Am J Hematol 1997; 56: 168-172.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. Gisslinger H, Mannhalter C, Pabinger I et al. High risk of deep vein thrombosis in carriers of a prothrombin-gene mutation in patients with polycythemia vera and essential thrombocythemia. Abstr. 3144. Blood 2002; 100: 796a.

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

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

32. Gisslinger H, Rodeghiero F, Ruggeri M et al. Homocysteine levels in polycythaemia vera and essential thrombocythaemia. Br J Haematol 1999; 105: 551-555.

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

34. Harrison CN, Donohoe S, Carr P et al. Patients with essential thrombocythaemia have an increased prevalence of antiphospholipid antibodies which may be associated with thrombosis. Thromb Haemost 2002; 87: 802-807.

35. Musolino C, Alonci A, Bellomo G et al. Myeloproliferative disease: markers of endothelial and platelet status in patients with essential thrombocythemia and polycythemia vera. Hematology 2000; 4: 397-402.

36. Musolino C, Calabro L, Bellomo G et al. Soluble angiogenic factors: implications for chronic myeloproliferative disorders. Am J Hematol 2002; 69: 159-163.

37. Teofili L, Pierconti F, Di Febo A et al. The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia. Blood 2002; 100: 714-717.

38. Harrison CN, Gale RE, Machin SJ et al. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood 1999; 93: 417-424.

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

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

41. Nowak-Gottl U, Duering C, Kempf-Bielack B et al. Thromboembolic diseases in neonates and children. Pathophysiol Haemost Thromb 2003; 33: 269-274.

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

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

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

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

46. Yan L, Elkassar N, Gardin C et al. Clonality assays and megakaryocyte culture techniques in essential thrombocythemia. Leuk Lymphoma 1996; 22(Suppl 1): 31-40.

47. El-Kassar N, Hetet G, Briere J et al. Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. Blood 1997; 89: 128-134.

48. Zamora L, Espinet B, Florensa L et al. Clonality analysis by HUMARA assay in Spanish females with essential thrombocythemia and polycythemia vera. Haematologica/Hematol J 2005; 90: 259-261.

49. Skoda RC. Chronic myeloproliferative disorders: molecular markers and pathogenesis. Hematol J 2004; 5(Suppl. 3): S122-S125.

50. 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. Hematol J 2004; 5: 161-167.

51. Pettit JE. The non-leukaemic myeloproliferative disorders. In: Hoffbrand AV, Lewis SM. Postgraduate Haematology. 2nd ed. London: Heinemann 1981: 577-604.

52. Raposa T, Várkonyi J. The relationship between sister chromatid exchange induction and leukemogenicity of different cytostatics. Cancer Detect Prev 1987; 10: 141-151.

53. 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.

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

55. Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol 1992; 19(Suppl. 9): 1-10.

56. 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.

57. Marsteinstredet U, Brunborg G, Bjoras 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.

58. 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.

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

60. 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.

61. 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.

62. Randi ML, Fabris F, Girolami A. Leukemia and myelodysplasia effect of multiple cytotoxic therapy in essential thrombocythemia. Leuk Lymphoma 2000; 37: 379-385.

63. 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.

64. Sterkers Y, Preudhomme C, Lai 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.

65. Tothova E, Fricova M, Stecova N et al. Leukemic transformation of polycythemia vera after treatment with hydroxyurea with abnormalities of chromosome 17. Neoplasma 2001; 48: 389-392.

66. Finazzi G, Caruso V, Marchioli R et al. Acute leukemia in polycythemia vera. An analysis of 1,638 patients enrolled in a prospective observational study. Blood. 2005; 105(7): 2664-2670.

67. Bultas J, Karetová D. Nové trendy ve farmakoterapii kardiovaskulárních chorob. Vnitř Lék 2004; 50(Suppl 1): S37-58.

68. Griesshammer M, Bangerter M, Grünewald M. Current treatment practice for essential thrombocythaemia in adults. Expert Opin Pharmacother 2001; 2: 385-393.

69. 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.