Download PDF
Semin Thromb Hemost 2006; 32(3): 231-245
DOI: 10.1055/s-2006-939434
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Analysis of Risk Factors: The Rationale of the Guidelines of the Czech Hematological Society for Diagnosis and Treatment of Chronic Myeloproliferative Disorders with Thrombocythemia

Jiří Schwarz1 , Robert Pytlík2 , Michael Doubek3 , Yvona Brychtová3 , Petr Dulíček4 , Vít Campr1 , 5 , Leoš Křen6 , Miroslav Penka7
  • 1Clinical Section, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
  • 21st Department of Internal Medicine, 1st Medical Faculty, Charles University, Prague, Czech Republic
  • 3Internal Hematooncological Department, Faculty Hospital Brno-Bohunice, Masaryk University, Brno, Czech Republic
  • 41st Department of Internal Medicine, Faculty Hospital Hradec Králové, Charles University, Hradec Králové, Prague, Czech Republic
  • 5Institute of Pathological Anatomy, 2nd Medical Faculty, Charles University, Faculty Hospital Motol, Prague, Czech Republic
  • 6Department of Pathology, Faculty Hospital Brno-Bohunice, Masaryk University, Brno, Czech Republic;
  • 7Department of Clinical Hematology, Faculty Hospital Brno-Bohunice, Masaryk University, Brno, Czech Republic
Further Information

Publication History

Publication Date:
02 May 2006 (online)

    Permissions and Reprints

ABSTRACT

The rationale of the Czech Hematological Society guidelines for diagnosis and treatment of Philadelphia chromosome-negative myeloproliferative disorders with thrombocythemia (MPD-T) is reviewed. For diagnosis of MPD-T, the classification according to the World Health Organization or to the Rotterdam criteria is preferred because they distinguish true essential thrombocythemia from prefibrotic or early fibrotic idiopathic myelofibrosis and prepolycythemic polycythemia vera. The histopathology-based nosological distinction provided by these classifications yields valuable information on prognosis (including the risks of transition into secondary acute myeloid leukemia and myelofibrosis). Another serious complication in MPD-T is thrombosis (arterial or venous), the main risk factors of which are age, previous thrombosis, platelet counts 350 to 2200 × 109/L (peak at ~900 × 109/L) and the presence of additional thrombophilic risk factors (hereditary thrombophilia, any hypercoagulable state, cardiovascular disease). The hemorrhagic risk starts increasing progressively at platelet counts > 1000 × 109/L. Treatment should be stratified with respect to the thrombotic and hemorrhagic risks. In high-risk patients, thromboreductive therapy is warranted. All of the cytostatic drugs, including hydroxyurea, may be leukemogenic and should be given only to patients > 60 years old, whereas anagrelide or interferon α are preferred in younger individuals. In low-risk patients, antiaggregation therapy is sufficient, unless the platelet count exceeds 1000 × 109/L, which is another indication for thromboreduction. Thrombopheresis is indicated in thrombocythemia > 2000 × 109/L.

KEYWORDS

Myeloproliferative disease - essential thrombocythemia - polycythemia vera - idiopathic myelofibrosis - risk factors - thrombosis - treatment algorithm

REFERENCES

  • 1 Murphy S, Peterson P, Iland H, Laszlo J. 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
    PubMedSearch in Google Scholar
  • 2 Michiels J J. Diagnostic criteria of the myeloproliferative disorders (MPD): essential thrombocythaemia, polycythaemia vera and chronic megakaryocytic granulocytic metaplasia.  Neth J Med. 1997;  51 57-64
    PubMedSearch in Google Scholar
  • 3 Michiels J J, 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
    PubMedSearch in Google Scholar
  • 4 Imbert M, Pierre R, Thiele J, Vardiman J, Brunning R, Flandrin G. Essential thrombocythemia. In: Jaffe E, Harris N, Stein H, Vardiman J WHO Classification of Tumours: Pathology & Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France; IARC Press 2001: 39-41
    Search in Google Scholar
  • 5 Pierre R, Imbert M, Thiele J, Vardiman J, Brunning R, Flandrin G. Polycythemia vera. In: Jaffe E, Harris N, Stein H, Vardiman J WHO Classification of Tumours: Pathology & Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France; IARC Press 2001: 32-34
    Search in Google Scholar
  • 6 Thiele J, Pierre R, Imbert M, Vardiman J, Brunning R, Flandrin G. Chronic idiopathic myelofibrosis. In: Jaffe E, Harris N, Stein H, Vardiman J WHO Classification of Tumours: Pathology & Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France; IARC Press 2001: 35-38
    Search in Google Scholar
  • 7 Michiels J J, 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
    PubMedSearch in Google Scholar
  • 8 Michiels J J. 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
    CrossrefPubMedSearch in Google Scholar
  • 9 Michiels J J, Kvasnicka H M, Thiele J. Myeloproliferative disorders. Current Perspectives on Diagnostic Criteria, Histopathology and Treatment in Essential Thrombocythemia, Polycythemia Rubra Vera and Chronic Idiopathic Myelofibrosis. Much Germany; 2005
    Search in Google Scholar
  • 10 Thiele J, Kvasnicka H M, Werden C, Zankovich R, Diehl V, Fischer R. Idiopathic primary osteo-myelofibrosis: a clinico-pathological study on 208 patients with special emphasis on evolution of disease features, differentiation from essential thrombocythemia and variables of prognostic impact.  Leuk Lymphoma. 1996;  22 303-317
    PubMedSearch in Google Scholar
  • 11 Thiele J, Kvasnicka H M, Diehl V, Fischer R, Michiels J J. Clinicopathological diagnosis and differential criteria of thrombocythemias in various myeloproliferative disorders by histopathology, histochemistry and immunostaining from bone marrow biopsies.  Leuk Lymphoma. 1999;  33 207-218
    PubMedSearch in Google Scholar
  • 12 Thiele J, Kvasnicka H M. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients.  Ann Hematol. 2003;  82 148-152
    PubMedSearch in Google Scholar
  • 13 Schwarz J. Essential thrombocythemia: the experience with anagrelide and its place in the treatment algorithm. [In Czech] (abst). In: XIIIth Czech and Slovak Hematological and Transfusiological Congress. Prague, Czech Republic; 2002: P/154
    Search in Google Scholar
  • 14 Penka M, Buliková A, Matýšková M, Zavřelová J, Doubek M. Efficacy of anagrelide in the treatment of essential thrombocythemia [In Czech]. (abst). In: XIIIth Czech and Slovak Hematological and Transfusiological Congress. Prague, Czech Republic; 2002: P/155
    Search in Google Scholar
  • 15 Penka M, Schwarz J, Pytlík R, Doubek M, Brychtová Y, Dulíček P. Practice guidelines for diagnosis and therapy of essential thrombocythemia and thrombocythemia associated with other myeloproliferative diseases [In Czech].  Vnitr Lek. 2005;  51 741-751
    PubMedSearch in Google Scholar
  • 16 Schwarz J, Penka M. Thrombocytosis and thrombocythemia.  , [In Czech] Vnitr Lek. 2005;  51 861-871
    PubMedSearch in Google Scholar
  • 17 Berlin N I. Diagnosis and classification of the polycythemias.  Semin Hematol. 1975;  12 339-351
    PubMedSearch in Google Scholar
  • 18 Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia.  Semin Hematol. 1999;  36 9-13
    PubMedSearch in Google Scholar
  • 19 Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines.  J Clin Oncol. 1999;  17 2954-2970
    PubMedSearch in Google Scholar
  • 20 Thiele J, Kvasnicka H M, Zankovich R, Diehl V. The value of bone marrow histology in differentiating between early stage polycythemia vera and secondary (reactive) polycythemias.  Haematologica. 2001;  86 368-374
    PubMedSearch in Google Scholar
  • 21 Thiele J, Kvasnicka H M, Orazi A. Bone marrow histopathology in myeloproliferative disorders-current diagnostic approach.  Semin Hematol. 2005;  42 184-195
    CrossrefPubMedSearch in Google Scholar
  • 22 Georgii A, Buhr T, Buesche G, Kreft A, Choritz H. Classification and staging of Ph-negative myeloproliferative disorders by histopathology from bone marrow biopsies.  Leuk Lymphoma. 1996;  22(suppl 1) 15-29
    PubMedSearch in Google Scholar
  • 23 Harrison C N. Essential thrombocythaemia: challenges and evidence-based management.  Br J Haematol. 2005;  130 153-165
    CrossrefPubMedSearch in Google Scholar
  • 24 Thiele J, Kvasnicka H M, Zankovich R, Diehl V. Early-stage idiopathic (primary) myelofibrosis-current issues of diagnostic features.  Leuk Lymphoma. 2002;  43 1035-1041
    PubMedSearch in Google Scholar
  • 25 Buhr T, Georgii A, Choritz H. Myelofibrosis in chronic myeloproliferative disorders. Incidence among subtypes according to the Hannover Classification.  Pathol Res Pract. 1993;  189 121-132
    PubMedSearch in Google Scholar
  • 26 Thiele J, Kvasnicka H M, Zankovich R, Diehl V. Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis.  Haematologica. 2000;  85 1126-1134
    PubMedSearch in Google Scholar
  • 27 Thiele J, Kvasnicka H M, Schmitt-Graeff A, Diehl V. Dynamics of fibrosis in chronic idiopathic (primary) myelofibrosis during therapy: a follow-up study on 309 patients.  Leuk Lymphoma. 2003;  44 949-953
    CrossrefPubMedSearch in Google Scholar
  • 28 Thiele J, Kvasnicka H M, Schmitt-Graeff A, Zankovich R, Diehl V. Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): a retrospective clinicopathological study of 120 patients.  Am J Hematol. 2002;  70 283-291
    CrossrefPubMedSearch in Google Scholar
  • 29 Bellucci S, Janvier M, Tobelem G et al.. Essential thrombocythemias. Clinical evolutionary and biological data.  Cancer. 1986;  58 2440-2447
    PubMedSearch in Google Scholar
  • 30 Hehlmann R, Jahn M, Baumann B, Köpcke W. Essential thrombocythemia. Clinical characteristics and course of 61 cases.  Cancer. 1988;  61 2487-2496
    PubMedSearch in Google Scholar
  • 31 Fenaux P, Simon M, Caulier M T, Lai J L, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases.  Cancer. 1990;  66 549-556
    PubMedSearch in Google Scholar
  • 32 van Genderen P JJ, Mulder P GH, Waleboer M, van de Moesdijk D, Michiels J J. Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin.  Br J Haematol. 1997;  97 179-184
    CrossrefPubMedSearch in Google Scholar
  • 33 Michiels J J. Normal life expectancy and thrombosis-free survival in aspirin treated essential thrombocythemia.  Clin Appl Thromb Hemost. 1999;  5 30-36
    PubMedSearch in Google Scholar
  • 34 Bazzan M, Tamponi G, Schinco P et al.. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia.  Ann Hematol. 1999;  78 539-543
    CrossrefPubMedSearch in Google Scholar
  • 35 Passamonti F, Rumi E, Pungolino E et al.. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.  Am J Med. 2004;  117 755-761
    CrossrefPubMedSearch in Google Scholar
  • 36 Michiels J J, 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
    PubMedSearch in Google Scholar
  • 37 Thiele J, Kvasnicka H M, Schmitt-Graeff A, Diehl V. Bone marrow histopathology following cytoreductive therapy in chronic idiopathic myelofibrosis.  Histopathology. 2003;  43 470-479
    CrossrefPubMedSearch in Google Scholar
  • 38 Thiele J, Kvasnicka H M, Fuchs N, Brunnbauer K, Volkwein N, Schmitt-Graeff A. Anagrelide-induced bone marrow changes during therapy of chronic myeloproliferative disorders with thrombocytosis. An immunohistochemical and morphometric study of sequential trephine biopsies.  Haematologica. 2003;  88 1130-1138
    PubMedSearch in Google Scholar
  • 39 Mitus A J, Schafer A I. Thrombocytosis and thrombocythemia.  Hematol Oncol Clin North Am. 1990;  4 157-178
    PubMedSearch in Google Scholar
  • 40 Dawson A A, 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
    PubMedSearch in Google Scholar
  • 41 Barbui T, Cortelazzo S, Viero P, Bassan R, Dini E, Semeraro N. Thrombohaemorrhagic complications in 101 cases of myeloproliferative disorders: relationship to platelet number and function.  Eur J Cancer Clin Oncol. 1983;  19 1593-1599
    CrossrefPubMedSearch in Google Scholar
  • 42 Griesshammer M, Bangerter M, van Vliet H HDM, Michiels J J. Aspirin in essential thrombocythemia: status quo and quo vadis.  Semin Thromb Hemost. 1997;  23 371-377
    PubMedSearch in Google Scholar
  • 43 Michiels J J. 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
    CrossrefPubMedSearch in Google Scholar
  • 44 Michiels J J, Berneman Z N, Schroyens W, Van Vliet H HDM. Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythaemia and polycythaemia vera.  Platelets. 2004;  15 67-84
    CrossrefPubMedSearch in Google Scholar
  • 45 Schwarz J, Hrachovinova I, Vorlova Z, Salaj P. Thromboembolism in thrombocythemia patients with an additional thrombophilic state. (abst 974).  Hematol J. 2004;  5(suppl 2) S321
    PubMedSearch in Google Scholar
  • 46 Regev A, Stark P, Blickstein D, Lahav M. Thrombotic complications in essential thrombocythemia with relatively low platelet counts.  Am J Hematol. 1997;  56 168-172
    CrossrefPubMedSearch in Google Scholar
  • 47 Storen E C, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia.  Blood. 2001;  97 863-866
    CrossrefPubMedSearch in Google Scholar
  • 48 Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia.  J Clin Oncol. 1990;  8 556-562
    PubMedSearch in Google Scholar
  • 49 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
    CrossrefPubMedSearch in Google Scholar
  • 50 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
    CrossrefPubMedSearch in Google Scholar
  • 51 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
    PubMedSearch in Google Scholar
  • 52 Rao A K. Molecular and biochemical basis for the platelet dysfunction in myeloproliferative disorders.  Semin Hematol. 2004;  41(suppl 3) 6-9
    PubMedSearch in Google Scholar
  • 53 Tatewaki W, Shibata A. Acquired von Willebrand disease in patients with chronic myeloproliferative disorders.  Leuk Lymphoma. 1989;  1 51-57
    PubMedSearch in Google Scholar
  • 54 van Genderen P JJ, Michiels J J, van der Poel-van de Luytgaarde S CPAM, van Vliet H HDM. Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia: relationship with platelet count.  Ann Hematol. 1994;  69 81-84
    CrossrefPubMedSearch in Google Scholar
  • 55 van Genderen P JJ, Budde U, Michiels J J, van Strik R, van Vliet H HDM. 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
    CrossrefPubMedSearch in Google Scholar
  • 56 Michiels J J. Aspirin and platelet-lowering agents for the prevention of vascular complications in essential thrombocythemia.  Clin Appl Thromb Hemost. 1999;  5 247-251
    PubMedSearch in Google Scholar
  • 57 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
    CrossrefPubMedSearch in Google Scholar
  • 58 Randi M L, Fabris F, Rossi C, Tison T, Barbone E, Girolami A. Sex and age as prognostic factors in essential thrombocythemia.  Haematologica. 1992;  77 402-404
    PubMedSearch in Google Scholar
  • 59 Conlan M G, Haire W D. Low protein S in essential thrombocythemia with thrombosis.  Am J Hematol. 1989;  32 88-93
    PubMedSearch in Google Scholar
  • 60 Bucalossi A, Marotta G, Bigazzi C, Galieni P, Dispensa E. 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
    CrossrefPubMedSearch in Google Scholar
  • 61 Amitrano L, Guardascione M A, Ames P R 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
    CrossrefPubMedSearch in Google Scholar
  • 62 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
    CrossrefPubMedSearch in Google Scholar
  • 63 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. (abst 3144).  Blood. 2002;  100 796
    PubMedSearch in Google Scholar
  • 64 Kessler C M. Propensity for hemorrhage and thrombosis in chronic myeloproliferative disorders.  Semin Hematol. 2004;  41(suppl 3) 10-14
    CrossrefPubMedSearch in Google Scholar
  • 65 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
    PubMedSearch in Google Scholar
  • 66 Harrison C N, Donohoe S, Carr P, Dave M, Mackie I, Machin S J. Patients with essential thrombocythaemia have an increased prevalence of antiphospholipid antibodies which may be associated with thrombosis.  Thromb Haemost. 2002;  87 802-807
    PubMedSearch in Google Scholar
  • 67 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
    CrossrefPubMedSearch in Google Scholar
  • 68 Musolino C, Calabro L, Bellomo G et al.. Soluble angiogenic factors: implications for chronic myeloproliferative disorders.  Am J Hematol. 2002;  69 159-163
    CrossrefPubMedSearch in Google Scholar
  • 69 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
    CrossrefPubMedSearch in Google Scholar
  • 70 Harrison C N, Gale R E, Machin S J, Linch D C. 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
    PubMedSearch in Google Scholar
  • 71 Wolanskyj A P, Lasho T L, Schwager S M et al.. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance.  Br J Haematol. 2005;  131 208-213
    CrossrefPubMedSearch in Google Scholar
  • 72 Gisslinger H, Rodeghiero F, Ruggeri M et al.. Homocysteine levels in polycythaemia vera and essential thrombocythaemia.  Br J Haematol. 1999;  105 551-555
    PubMedSearch in Google Scholar
  • 73 Griesshammer M, Grünewald M, Michiels J J. Acquired thrombophilia in pregnancy: essential thrombocythemia.  Semin Thromb Hemost. 2003;  29 205-212
    Thieme ConnectPubMedSearch in Google Scholar
  • 74 Ruggeri Z, Cannata M L, Stella N C, Corrado F. Pregnancy in essential thrombocythemia during aspirin treatment.  Arch Gynecol Obstet. 2003;  268 209-210
    CrossrefPubMedSearch in Google Scholar
  • 75 Schafer A I, Levine M N, Konkle B A, Kearon C. Thrombotic disorders: diagnosis and treatment.  Hematology (Am Soc Hematol Educ Program). 2005;  520-539
    PubMedSearch in Google Scholar
  • 76 Falanga A. Thrombosis and malignancy: an underestimated problem.  Haematologica. 2003;  88 607-610
    PubMedSearch in Google Scholar
  • 77 Freytes C O. Thromboembolic complications related to indwelling central venous catheters in children: a neglected aspect of the study of vascular access devices.  Opin Top Supp Care Oncol. 2002;  42 7-8
    PubMedSearch in Google Scholar
  • 78 Tripodi A. Levels of coagulation factors and venous thromboembolism.  Haematologica. 2003;  88 705-711
    PubMedSearch in Google Scholar
  • 79 Nowak-Göttl U, Kosch A, Schlegel N, Salem M, Manco-Johnson M. Thromboembolism in children.  Curr Opin Hematol. 2002;  9 448-453
    CrossrefPubMedSearch in Google Scholar
  • 80 Harrison C N, Campbell P J, Buck G et al.. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.  N Engl J Med. 2005;  353 33-45
    CrossrefPubMedSearch in Google Scholar
  • 81 Chistolini A, Mazzucconi M G, Ferrari A et al.. Essential thrombocythemia: a retrospective study on the clinical course of 100 patients.  Haematologica. 1990;  75 537-540
    PubMedSearch in Google Scholar
  • 82 Balan K K, Critchley M. Outcome of 259 patients with primary proliferative polycythaemia (PPP) and idiopathic thrombocythaemia (IT) treated in a regional nuclear medicine department with phosphorus-32 - a 15 year review.  Br J Radiol. 1997;  70 1169-1173
    PubMedSearch in Google Scholar
  • 83 Cervantes F, Tassies D, Salgado C, Rovira M, Pereira A, Rozman C. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients.  Acta Haematol. 1991;  85 124-127
    CrossrefPubMedSearch in Google Scholar
  • 84 Okamura T, Kinukawa N, Niho Y, Mizoguchi H. Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients.  Int J Hematol. 2001;  73 194-198
    PubMedSearch in Google Scholar
  • 85 Pettit J E. The non-leukaemic myeloproliferative disorders. In: Hoffbrand AV, Lewis SM Postgraduate Haematology. 2nd ed. London; Heinemann 1981: 577-604
    Search in Google Scholar
  • 86 Najean Y, Rain J-D. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years.  Blood. 1997;  90 3370-3377
    PubMedSearch in Google Scholar
  • 87 Fruchtman S M. Treatment paradigms in the management of myeloproliferative disorders.  Semin Hematol. 2004;  41(suppl 3) 18-22
    CrossrefPubMedSearch in Google Scholar
  • 88 Briere J, Guilmin F. Management of patients with essential thrombocythemia: current concepts and perspectives.  Pathol Biol (Paris). 2001;  49 178-183
    CrossrefPubMedSearch in Google Scholar
  • 89 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(suppl 3) 15-17
    PubMedSearch in Google Scholar
  • 90 Yarbro J W. Mechanism of action of hydroxyurea.  Semin Oncol. 1992;  19(suppl 9) 1-10
    PubMedSearch in Google Scholar
  • 91 Hong Y, Erusalimsky J D. Comparison of the pharmacological mechanisms involved in the platelet lowering actions of anagrelide and hydroxyurea: a review.  Platelets. 2002;  13 381-386
    CrossrefPubMedSearch in Google Scholar
  • 92 Raposa T, Várkonyi J. The relationship between sister chromatid exchange induction and leukemogenicity of different cytostatics.  Cancer Detect Prev. 1987;  10 141-151
    PubMedSearch in Google Scholar
  • 93 Mehnert K, Vogel W, Benz R, Speit G. Different effects of mutagens on sister chromatid exchange induction in three Chinese hamster cell lines.  Environ Mutagen. 1984;  6 573-583
    PubMedSearch in Google Scholar
  • 94 Schroeder A L. Chromosome instability in mutagen sensitive mutants of Neurospora.  Curr Genet. 1986;  10 381-387
    CrossrefPubMedSearch in Google Scholar
  • 95 Seino Y, Nagao M, Yahagi T, Hoshi A, Kawachi T, Sugimura T. Mutagenicity of several classes of antitumor agents to Salmonella typhimurium TA98, TA100, and TA92.  Cancer Res. 1978;  38 2148-2156
    PubMedSearch in Google Scholar
  • 96 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
    PubMedSearch in Google Scholar
  • 97 Andersson M, Agurell E, Vaghef H, Bolcsfoldi G, Hellman B. 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
    PubMedSearch in Google Scholar
  • 98 Ficsor G, Ginsberg L C. The effect of hydroxyurea and mitomycin C on sperm motility in mice.  Mutat Res. 1980;  70 383-387
    PubMedSearch in Google Scholar
  • 99 Nand S, Messmore H, Fisher S G, Bird M L, Schulz W, Fisher R I. Leukemic transformation in polycythemia vera: analysis of risk factors.  Am J Hematol. 1990;  34 32-36
    PubMedSearch in Google Scholar
  • 100 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
    PubMedSearch in Google Scholar
  • 101 Randi M L, Fabris F, Girolami A. Leukemia and myelodysplasia effect of multiple cytotoxic therapy in essential thrombocythemia.  Leuk Lymphoma. 2000;  37 379-385
    PubMedSearch in Google Scholar
  • 102 Nielsen I, Hasselbalch H C. 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
    CrossrefPubMedSearch in Google Scholar
  • 103 Sterkers Y, Preudhomme C, Lai J L 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
    PubMedSearch in Google Scholar
  • 104 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
    PubMedSearch in Google Scholar
  • 105 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
    CrossrefPubMedSearch in Google Scholar
  • 106 Marchioli R, Finazzi G, Landolfi R et al.. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.  J Clin Oncol. 2005;  23 2224-2232
    CrossrefPubMedSearch in Google Scholar
  • 107 Finazzi G, Barbui T. Efficacy and safety of hydroxyurea in patients with essential thrombocythemia.  Pathol Biol (Paris). 2001;  49 167-169
    CrossrefPubMedSearch in Google Scholar
  • 108 Barbui T. Indications for lowering platelet numbers in essential thrombocythemia.  Semin Hematol. 2003;  40 22-25
    PubMedSearch in Google Scholar
  • 109 Falanga A, Marchetti M, Evangelista V et al.. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera.  Blood. 2000;  96 4261-4266
    PubMedSearch in Google Scholar
  • 110 Falanga A, Marchetti M, Barbui T, Smith C W. Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils.  Semin Hematol. 2005;  42 239-247
    CrossrefPubMedSearch in Google Scholar
  • 111 Lofvenberg 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
    CrossrefPubMedSearch in Google Scholar
  • 112 Lengfelder E, Griesshammer M, Hehlmann R. Interferon-alpha in the treatment of essential thrombocythemia.  Leuk Lymphoma. 1996;  22(suppl 1) 135-142
    PubMedSearch in Google Scholar
  • 113 Alvarado Y, Cortes J, Verstovsek S et al.. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia.  Cancer Chemother Pharmacol. 2003;  51 81-86
    CrossrefPubMedSearch in Google Scholar
  • 114 Anagrelide Study Group . Anagrelide, a therapy for thrombocythemic states: experience in 577 patients.  Am J Med. 1992;  92 69-76
    CrossrefPubMedSearch in Google Scholar
  • 115 Petrides P E. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia.  Expert Opin Pharmacother. 2004;  5 1781-1798
    CrossrefPubMedSearch in Google Scholar
  • 116 Petitt R M, Silverstein M N, Petrone M E. Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders.  Semin Hematol. 1997;  34 51-54
    PubMedSearch in Google Scholar
  • 117 Gisslinger H. Management of essential thrombocythemia.  Hematology (Am Soc Hematol Educ Program). 2005;  1 105-110
    PubMedSearch in Google Scholar
  • 118 Tefferi A, Barbui T. bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment.  Mayo Clin Proc. 2005;  80 1220-1232
    PubMedSearch in Google Scholar
  • 119 Finazzi G, Harrison C. Essential thrombocythemia.  Semin Hematol. 2005;  42 230-238
    CrossrefPubMedSearch in Google Scholar
  • 120 Barbui T, Finazzi G. When and how to treat essential thrombocythemia.  N Engl J Med. 2005;  353 85-86
    CrossrefPubMedSearch in Google Scholar
  • 121 Thiele J, Kvasnicka H M, Schmitt-Gräff A, Hülsemann R, Diehl V. Therapy-related changes of the bone marrow in chronic idiopathic myelofibrosis.  Histol Histopathol. 2004;  19 239-250
    PubMedSearch in Google Scholar
  • 122 Steurer M, Gastl G, Jedrzejczak W W et al.. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile.  Cancer. 2004;  101 2239-2246
    CrossrefPubMedSearch in Google Scholar
  • 123 Zweegman S, de Groot M R, Sonneveld P. The HOVON 58 study: pegylated interferon-2A or anagrelide in high risk essential thrombocythemia: a randomized phase II trial. Observational study of low and intermediate risk patients. Rotterdam, The Netherlands; European Working Group on Myeloproliferative Disorders 2004: 79-80
    Search in Google Scholar
  • 124 Gilbert H S. The role of anagrelide, hydroxyurea, and interferon-α in treating the thrombocythemia of myeloproliferative disease: a new approach for the millennium. Presented at: the XVth Meeting of the International Society of Haematology, African & European Division, Durban, South Africa September 18-23,1999: 141-143
    Search in Google Scholar
  • 125 Marchioli R, Finazzi G, Marfisi R M, Tognoni G, Barbui T. Clinical trials in myeloproliferative disorders: looking forward.  Semin Hematol. 2005;  42 259-265
    CrossrefPubMedSearch in Google Scholar

Jiři SchwarzM.D. 

Institute of Hematology and Blood Transfusion

U Nemocnice 1, 128 20, Prague 2, Czech Republic

Email: jiri.schwarz@uhkt.cz