Download PDF
Semin Thromb Hemost 2006; 32(4): 381-398
DOI: 10.1055/s-2006-942759
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Role of JAK2 V617F Mutation, Spontaneous Erythropoiesis and Megakaryocytopoiesis, Hypersensitive Platelets, Activated Leukocytes, and Endothelial Cells in the Etiology of Thrombotic Manifestations in Polycythemia Vera and Essential Thrombocythemia

Sylvia Bellucci1 , Jan J. Michiels2
  • 1AP-HP, Service d'Hematologie Biologique, Hôpital Lariboisière; Denis Diderot, Faculté de Médecine, Paris, France
  • 2Department of Hematology, University Hospital Antwerp, Antwerp, Belgium; Hemostasis Thrombosis and Vascular Research, Goodheart Institute Rotterdam, MPD Center Europe, Rottterdam, The Netherlands
Further Information

Publication History

Publication Date:
29 June 2006 (online)

    Permissions and Reprints

ABSTRACT

Exaggerated erythropoiesis and megakaryocytopoiesis are present at a variable extent in polycythemia vera (PV) and essential thrombocythemia (ET). With the recent discovery of the V617F mutation in the Janus kinase 2 (JAK2) tyrosine kinase in almost all cases of PV and in a subset of patients with ET, studies are now pending to assess the role of this mutation in the hematopoietic cell activation process and/or in the occurrence of thromboses in ET and PV. The JAK2 V617F point mutation makes the normal hematopoietic progenitor cells hypersensitive to thrombopoietin, erythropoietin, and myeloid progenitor cells, leading to trilinear hematopoietic myeloproliferation. This will have three main clinical consequences during long-term follow-up. First, spontaneous growth of enlarged mature megakaryocytes in ET/PV with overproduction of hypersensitive platelets results in a broad spectrum of platelet-mediated microvascular circulatory disturbances, which are very sensitive to low-dose aspirin. Second, spontaneous growth of erythropoiesis with the overproduction of erythrocytes leads to classic PV with increased hemoglobin, hematocrit, and red cell mass. This is associated with a high frequency of major arterial and venous thrombotic complications in addition to platelet-mediated microvascular circulatory disturbances of thrombocythemia. Third, the slowly progressive myeloid (granulocytic) metaplasia in bone marrow and spleen is complicated by secondary myelofibrosis caused by a megakaryocytic/granulocytic cytokine storm in about one fourth to one third of JAK2 V617F-positive PV patients after long-term follow-up, with no tendency of leukemic transformation as long as they are not treated with myelosuppressive agents. Randomized clinical trials directly comparing phlebotomy versus hydroxyurea or interferon α versus hydroxyurea in PV with progressive disease are lacking. Heterozygous V617F mutation is enough to produce the clinical picture of ET with a slight tendency to increased hemoglobin and hematocrit (early PV mimicking ET). Homozygous V617F mutation is associated with the clinical picture of classic PV and with a higher tendency to secondary myelofibrosis, but with no increased leukemia unless other biological or genetic factors come into play, such as myelosuppressive agents or the acquisition of additional biologic or genetic defects. Depending on the biological background of individual patients, heterozygous and homozygous JAK2 V617F ET/PV may preferentially induce myeloid metaplasia with myelofibrosis with a relative suppression of megakaryocytic and erythropoietic myeloproliferation leading to clinical pictures of fibrotic chronic idiopathic myelofibrosis (CIMF) or agnogenic myeloid metaplasia. The main conclusion is that JAK2 V617F is a 100% specific clue to a new distinct clonal myeloproliferative disorder. JAK2 V617F-positive ET/PV and CIMF should be distinguished from wild-type JAK2 ET, rare cases of PV, and CIMF, and should be evaluated during life-long follow-up.

KEYWORDS

Essential thrombocythemia - polycythemia vera - myeloproliferative disorders - platelet activation - thrombosis - leukocyte/platelet activation

REFERENCES

  • 1 Vaquez M H. Sur une forme speciale de cyanose accompagnée d'hyperglobulie excessive et persitante.  Comptes Rendues des Seances de la Societé de Biologie. 1892;  44 384-388
    PubMedGoogle Scholar
  • 2 Osler W. Chronic cyanosis with polycythaemia and enlarged spleen. A new clinical entity.  Am J Med Sci. 1903;  126 187-201
    PubMedGoogle Scholar
  • 3 Moschowitz E. Biology of Disease. New York; Grune and Stratton 1948: 48-60
    Google Scholar
  • 4 Rosenthal M C. Extramedullary hematopoiesis: myeloid metaplasia.  Bull New Engl Med Cent. 1950;  12 154-160
    PubMedGoogle Scholar
  • 5 Dameshek W. Physiopathology and course of polycythemia vera as related to therapy.  JAMA. 1950;  18 790-797
    PubMedGoogle Scholar
  • 6 James C, Ugo V, Le Couedic P F et al.. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera.  Nature. 2005;  434 1144-1148
    CrossrefPubMedGoogle Scholar
  • 7 James C, Ugo V, Casadevall N, Constantinescu S N, Vainchenker W A. JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.  Trends Mol Med. 2005;  11 546-554
    CrossrefPubMedGoogle Scholar
  • 8 Vainchenker W, Constantinescu S N. A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases.  Hematology (Am Soc Hematol Educ Program). 2005;  195-200
    CrossrefPubMedGoogle Scholar
  • 9 Pearson T C, Messinezy M. The diagnosis criteria of polycythemia rubra vera.  Leuk Lymphoma. 1996;  22(suppl 1) 87-93
    PubMedGoogle Scholar
  • 10 Berlin N I. Diagnosis and classification of the polycythemias.  Semin Hematol. 1975;  12 339-351
    PubMedGoogle Scholar
  • 11 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
    PubMedGoogle Scholar
  • 12 Baxter E J, Scott L M, Campbell P J et al.. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.  Lancet. 2005;  365 1054-1061
    CrossrefPubMedGoogle Scholar
  • 13 Levine R L, Wadleigh M, Cools J et al.. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.  Cancer Cell. 2005;  7 387-397
    CrossrefPubMedGoogle Scholar
  • 14 Kralovics R, Passamonti F, Buser A S et al.. A gain-of-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
    CrossrefPubMedGoogle Scholar
  • 15 Zhao R, Xing S, Li Z et al.. Identification of an acquired JAK2 mutation in polycythemia vera.  J Biol Chem. 2005;  280 22788-22792
    CrossrefPubMedGoogle Scholar
  • 16 Staerk J, Kallin A, Demoulin J B, Vainchenker W, Constantinescu S N. JAK1 and TYK2 activation by homologous polycythemia vera JAK2 V617F mutation: cross talk with IGF1 receptor.  J Biol Chem. 2005;  280 41893-41899
    CrossrefPubMedGoogle Scholar
  • 17 Kaushansky K. On the origin of the chronic myeloproliferative disorders: it makes all sense.  Blood. 2005;  105 4187-4190
    CrossrefPubMedGoogle Scholar
  • 18 Goldman J M. A unifying mutation in chronic myeloproliferative disorders.  N Engl J Med. 2005;  352 1744-1745
    CrossrefPubMedGoogle Scholar
  • 19 Cazzola M, Skoda R. Gain of function, loss of control. A molecular basis for chronic myeloproliferative disorders.  Haematologica. 2005;  90 871-874
    PubMedGoogle Scholar
  • 20 Lu X, Levine R, Wernig G, Pikman Y, Zarnegar S, Gilliland D G. Expression of a homodimeric type I cytokine receptor is required for JAK2 V617F-mediated transformation.  Proc Natl Acad Sci USA. 2005;  102 18962-18967
    CrossrefPubMedGoogle Scholar
  • 21 Michiels J J, Berneman Z, Van Bockstaele D, van der Planken M, De Raeve H, Schroyens W. Clinical and laboratory features, pathobiology of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera.  Semin Thromb Hemost. 2006;  32 174-207
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Ellis J T, Silver R T, Coleman M, Geller S A. The bone marrow in polycythemia vera.  Semin Hematol. 1975;  12 433-444
    PubMedGoogle Scholar
  • 23 Lengfelder E, Hochhaus A, Kronawitter U et al.. Should a platelet limit of 600 × 10/L be used as a diagnostic criterion in essential thrombocythaemia?.  Br J Haematol. 1998;  100 15-23
    CrossrefPubMedGoogle Scholar
  • 24 Kiladjian J J, Elkassar N, Hetet G, Balitrand N et al.. Analysis of JAK2 mutation in essential thrombocythemia (ET) patients with monoclonal and polyclonal X-chromosome inactivation patterns (XCIPs).  Leukemia. 2006;  , In press
    PubMedGoogle Scholar
  • 25 Campbell P, Scott L M, Buck G et al.. Definition of essential thrombocythemia and relation of essential thrombocythemia to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.  Lancet. 2005;  366 1945-1953
    CrossrefPubMedGoogle Scholar
  • 26 Prchal J F, Axelrad A A. Bone-marrow responses in polycythemia vera.  N Engl J Med. 1974;  290 1382
    PubMedGoogle Scholar
  • 27 Weinberg R S. In vitro erythropoiesis in polycythemia vera and other myeloproliferative disorders.  Semin Hematol. 1997;  34 64-69
    PubMedGoogle Scholar
  • 28 Kralovics R, Prchal J T. Haematopoietic progenitors and signal transduction in polycythaemia vera and primary thrombocythaemia.  Baillieres Clin Haematol. 1998;  11 803-818
    PubMedGoogle Scholar
  • 29 Weinberg R S, Worsley A, Gilbert H S, Cuttner J, Berk P D, Alter B P. Comparison of erythroid progenitor cell growth in vitro in polycythemia vera and chronic myelogenous leukemia: only polycythemia vera has endogenous colonies.  Leuk Res. 1989;  13 331-338
    CrossrefPubMedGoogle Scholar
  • 30 Kralovics R, Buser A S, Teo S S et al.. Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders.  Blood. 2003;  102 1869-1871
    CrossrefPubMedGoogle Scholar
  • 31 Dobo I, Boiret N, Lippert E et al.. A standardized endogenous megakaryocytic erythroid colony assay for the diagnosis of essential thrombocythemia.  Haematologica. 2004;  89 1207-1212
    PubMedGoogle Scholar
  • 32 Correa P N, Eskenazi D, Axellrad A A. Circulating erythroid progenitors in polycythemia vera are hypersensitive to insulin-like grown factor-1 in vitro: studies in an improved serum-free medium.  Blood. 1994;  83 99-112
    PubMedGoogle Scholar
  • 33 Dai C H, Krantz S B, Dessypris E N, Means Jr R T, Horn S T, Gilbert H S. Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor.  Blood. 1992;  80 891-899
    PubMedGoogle Scholar
  • 34 Ugo V, Marzac C, Teyssandier I et al.. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera.  Exp Hematol. 2004;  32 179-187
    CrossrefPubMedGoogle Scholar
  • 35 Shih L Y, Lee C T. Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay.  Blood. 1994;  83 744-748
    PubMedGoogle Scholar
  • 36 Liu E, Jelinek J, Pastore Y D, Guan Y, Prchal J F, Prchal J T. Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin.  Blood. 2003;  101 3294-3301
    CrossrefPubMedGoogle Scholar
  • 37 Juvonen E, Ikkala E, Oksanen K, Ruutu T. Megakaryocyte and erythroid colony formation in essential thrombocythaemia and reactive thrombocytosis: diagnostic value and correlation to complications.  Br J Haematol. 1993;  83 192-197
    PubMedGoogle Scholar
  • 38 Spinelli O, Rota B, Finazzi G, Barbui T, Rambaldi A. Quantitative analysis of PRV-1 gene expression in chronic myeloproliferative disorders: positive correlation with polycythemia vera diagnosis and leukocyte alkaline phosphatase expression.  Blood. 2002;  100(suppl 1) 3145a
    PubMedGoogle Scholar
  • 39 Lippert E, Girodon F, Kralovics R et al.. Quantitative analysis of wild type and V617F JAK2 expression in neutrophils of Polycythemia Vera and Essential Thrombocythemia patients at diagnosis.  Blood. 2005;  106 78a-257 (abst)
    PubMedGoogle Scholar
  • 40 Battegay E J, Thomssen C, Nissen C, Gudat F, Speck B. Endogenous megakaryocyte colonies from peripheral blood in precursor cell cultures of patients with myeloproliferative disorders.  Eur J Haematol. 1989;  42 321-326
    PubMedGoogle Scholar
  • 41 Kimura H, Ishibashi T, Sato T, Matsuda S, Uchida T, Kariyone S. Megakaryocytic colony formation (CFU-Meg) in essential thrombocythemia: quantitative and qualitative abnormalities of bone marrow CFU-Meg.  Am J Hematol. 1987;  24 23-30
    PubMedGoogle Scholar
  • 42 Mazur E M, Cohen J L, Bogart L. Growth characteristics of circulating hematopoietic progenitor cells from patients with essential thrombocythemia.  Blood. 1988;  71 1544-1550
    PubMedGoogle Scholar
  • 43 Han Z C, Briere J, Nedellec G et al.. Characteristics of circulating megakaryocyte progenitors (CFU-MK) in patients with primary myelofibrosis.  Eur J Haematol. 1988;  40 130-135
    PubMedGoogle Scholar
  • 44 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
    PubMedGoogle Scholar
  • 45 Li Y, Hetet G, Maurer A M, Chait Y, Dhermy D, Briere J. Spontaneous megakaryocyte colony formation in myeloproliferative disorders is not neutralizable by antibodies against IL3, IL6 and GM-CSF.  Br J Haematol. 1994;  87 471-476
    PubMedGoogle Scholar
  • 46 Florensa L, Besses C, Almarcha J et al.. Circulating erythroid and megakaryocytic progenitors in polycythaemia vera and essential thrombocythaemia.  Eur J Haematol. 1989;  43 417-422
    PubMedGoogle Scholar
  • 47 Taksin A L, Couedic J P, Dusanter-Fourt I et al.. Autonomous megakaryocyte growth in essential thrombocythemia and idiopathic myelofibrosis is not related to a c-mpl mutation or to an autocrine stimulation by Mpl-L.  Blood. 1999;  93 125-139
    PubMedGoogle Scholar
  • 48 Kiladjian J J, Elkassar N, Hetet G, Briere J, Grandchamp B, Gardin C. Study of the thrombopoietin receptor in essential thrombocythemia.  Leukemia. 1997;  11 1821-1826
    CrossrefPubMedGoogle Scholar
  • 49 Li Y, Hetet G, Kiladjian J J, Gardin C, Grandchamp B, Briere J. Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders.  Br J Haematol. 1996;  92 60-66
    CrossrefPubMedGoogle Scholar
  • 50 Han Z C, Bellucci S, Tenza D, Caen J P. Negative regulation of human megakaryocytopoiesis by human platelet factor 4 and beta thromboglobulin: comparative analysis in bone marrow cultures from normal individuals and patients with essential thrombocythaemia and immune thrombocytopenic purpura.  Br J Haematol. 1990;  74 395-401
    PubMedGoogle Scholar
  • 51 Han Z C, Sensebe L, Abgrall J F, Briere J. Platelet factor 4 inhibits human megakaryocytopoiesis in vitro.  Blood. 1990;  75 1234-1239
    PubMedGoogle Scholar
  • 52 Han Z C, Maurer A M, Bellucci S et al.. Inhibitory effect of platelet factor 4 (PF4) on the growth of human erythroleukemia cells: proposed mechanism of action of PF4.  J Lab Clin Med. 1992;  120 645-660
    PubMedGoogle Scholar
  • 53 Kobayashi S, Teramura M, Hoshino S, Motoji T, Oshimi K, Mizoguchi H. Circulating megakaryocyte progenitors in myeloproliferative disorders are hypersensitive to interleukin-3.  Br J Haematol. 1993;  83 539-544
    PubMedGoogle Scholar
  • 54 Axelrad A A, Eskinazi D, Correa P N, Amato D. Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development factor (PEG-rHu MGDF) in essential thrombocythemia.  Blood. 2000;  96 3310-3321
    PubMedGoogle Scholar
  • 55 Li J, Yang C, Xia Y et al.. Thrombocytopenia caused by the development of antibodies to thrombopoietin.  Blood. 2001;  98 3241-3248
    CrossrefPubMedGoogle Scholar
  • 56 Horikawa Y, Matsumura I, Hashimoto K et al.. Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia.  Blood. 1997;  90 4031-4038
    PubMedGoogle Scholar
  • 57 von dem Borne A E, Folman C, Linthorst G E et al.. Thrombopoietin: its role in platelet disorders and as a new drug in clinical medicine.  Baillieres Clin Haematol. 1998;  11 427-445
    PubMedGoogle Scholar
  • 58 Hirayama Y, Sakamaki S, Matsunaga T et al.. Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cells.  Blood. 1998;  92 46-52
    PubMedGoogle Scholar
  • 59 Fielder P J, Gurney A L, Stefanich E et al.. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets.  Blood. 1996;  87 2154-2161
    PubMedGoogle Scholar
  • 60 Gurney A L, Wong S C, Henzel W J, de Sauvage F J. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation.  Proc Natl Acad Sci USA. 1995;  92 5292-5296
    PubMedGoogle Scholar
  • 61 Bellucci S, Michiels J J. Spontaneous proliferative megakaryocytopoiesis and platelet hyperreactivity in essential thrombocythemia: is thrombopoietin the link?.  Ann Hematol. 2000;  79 51-58
    CrossrefPubMedGoogle Scholar
  • 62 Preston F E, Martin J F, Stewart R M, Davies-Jones G A. Thrombocytosis, circulating platelet aggregates, and neurological dysfunction.  BMJ. 1979;  2 1561-1563
    PubMedGoogle Scholar
  • 63 Mehta P, Mehta J, Ross M, Ostrowski N, Player D. Decreased platelet aggregation but increased thromboxane A2 generation in polycythemia vera.  Arch Intern Med. 1985;  145 1225-1227
    CrossrefPubMedGoogle Scholar
  • 64 Vreeken J, van Aken W G. Spontaneous aggregation of blood platelets as a cause of idiopathic thrombosis and recurrent painful toes and fingers.  Lancet. 1971;  2 1395-1397
    PubMedGoogle Scholar
  • 65 Wu K K. Platelet hyperaggregability and thrombosis in patients with thrombocythemia.  Ann Intern Med. 1978;  88 7-11
    CrossrefPubMedGoogle Scholar
  • 66 Bellucci S, Janvier M, Tobelem G et al.. Essential thrombocythemias. Clinical evolutionary and biological data.  Cancer. 1986;  58 2440-2447
    PubMedGoogle Scholar
  • 67 van Genderen P J, Michiels J J, Zijlstra F J. Lipoxygenase deficiency in primary thrombocythemia is not a true deficiency.  Thromb Haemost. 1994;  71 803-804
    PubMedGoogle Scholar
  • 68 Bellucci S, Ignatova E, Jaillet N, Boffa M C. Platelet hyperactivation in patients with essential thrombocythemia is not associated with vascular endothelial cell damage as judged by the level of plasma thrombomodulin, protein S, PAI-1, t-PA and vWF.  Thromb Haemost. 1993;  70 736-742
    PubMedGoogle Scholar
  • 69 Boughton B J, Allington M J, King A. Platelet and plasma beta thromboglobulin in myeloproliferative syndromes and secondary thrombocytosis.  Br J Haematol. 1978;  40 125-132
    PubMedGoogle Scholar
  • 70 Grossi A, Vannucchi A M, Rafanelli D, Filimberti E, Rossi Ferrini P. Beta-thromboglobulin content in megakaryocytes of patients with myeloproliferative diseases.  Thromb Res. 1986;  43 367-374
    CrossrefPubMedGoogle Scholar
  • 71 Najean Y, Poirier O, Lokiec F. The clinical significance of beta-thromboglobulin and platelet factor-4 in polycythaemic patients.  Scand J Haematol. 1983;  31 298-304
    PubMedGoogle Scholar
  • 72 van Genderen P J, Lucas I S, van Strik R et al.. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.  Thromb Haemost. 1996;  76 333-338
    PubMedGoogle Scholar
  • 73 Griesshammer M, Beneke H, Nussbaumer B, Grunewald M, Bangerter M, Bergmann L. Increased platelet surface expression of P-selectin and thrombospondin as markers of platelet activation in essential thrombocythaemia.  Thromb Res. 1999;  96 191-196
    CrossrefPubMedGoogle Scholar
  • 74 Thibert V, Bellucci S, Cristofari M, Gluckman E, Legrand C. Increased platelet CD36 constitutes a common marker in myeloproliferative disorders.  Br J Haematol. 1995;  91 618-624
    PubMedGoogle Scholar
  • 75 Jensen M K, de Nully Brown P, Lund B V, Nielsen O J, Hasselbalch H C. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders.  Br J Haematol. 2000;  110 116-124
    CrossrefPubMedGoogle Scholar
  • 76 Rocca B, Ciabattoni G, Tartaglione R et al.. Increased thromboxane biosynthesis in essential thrombocythemia.  Thromb Haemost. 1995;  74 1225-1230
    PubMedGoogle Scholar
  • 77 van Genderen P J, Prins F J, Michiels J J, Schror K. Thromboxane-dependent platelet activation in vivo precedes arterial thrombosis in thrombocythaemia: a rationale for the use of low-dose aspirin as an antithrombotic agent.  Br J Haematol. 1999;  104 438-441
    CrossrefPubMedGoogle Scholar
  • 78 Landolfi R, Ciabattoni G, Patrignani P et al.. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo.  Blood. 1992;  80 1965-1971
    CrossrefPubMedGoogle Scholar
  • 79 Van Genderen P JJ, Michiels J J, van Strik R, Lindemans J, van Vliet H HDM. Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.  Thromb Haemost. 1995;  73 210-214
    PubMedGoogle Scholar
  • 80 Michiels J J. Erythromelalgia and thrombocythemia: a disease of platelet prostaglandin metabolism. Thesis 1981, Rotterdam.  Semin Thromb Hemost. 1997;  23 335-338
    PubMedGoogle Scholar
  • 81 Michiels J J, Abels J, Steketee J, van Vliet H HDM, Vuzevski V D. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.  Ann Intern Med. 1985;  102 466-471
    PubMedGoogle Scholar
  • 82 Michiels J J, Koudstaal P, Mulder A H, van Vliet H HDM. Transient neurologic and ocular manifestations in primary thombocythemia.  Neurology. 1993;  43 1107-1110
    PubMedGoogle Scholar
  • 83 Michiels J J, Van Genderen P JJ, Janssen P HP, Koudstaal P. Atypical transient ischemic attacks in thrombocythemia of various myeloproliferative disorders.  Leuk Lymphoma. 1996;  22(suppl 1) 65-70
    PubMedGoogle Scholar
  • 84 Michiels J J, Berneman Z, Schroyens W, Koudstaal P J, Lindemans J, van Vliet H HDM. Platelet-mediated thrombotic complications in patients with ET: reversal by aspirin, platelet reduction but not by coumadin.  Blood Cells Mol Dis. 2006;  36 199-205
    CrossrefPubMedGoogle Scholar
  • 85 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
    PubMedGoogle Scholar
  • 86 Chen J, Herceg-Harjacek L, Groopman J E, Grabarek J. Regulation of platelet activation in vitro by the c-Mpl ligand, thrombopoietin.  Blood. 1995;  86 4054-4062
    PubMedGoogle Scholar
  • 87 Usuki K, Iki S, Endo M et al.. Influence of thrombopoietin on platelet activation in myeloproliferative disorders.  Br J Haematol. 1997;  97 530-537
    CrossrefPubMedGoogle Scholar
  • 88 Finazzi G, Budde U, Michiels J J. Bleeding time and platelet function in essential thrombocythemia and other myeloproliferative disorders.  Leuk Lymphoma. 1996;  22(suppl 1) 71-78
    PubMedGoogle Scholar
  • 89 Petrides P E, Siegel F. Thrombotic complications in essential thrombocythemia (ET): clinical facts and biochemical riddles.  Blood Cells Mol Dis. 2006;  , In press
    PubMedGoogle Scholar
  • 90 Cesar J M, de Miguel D, Garcia Avello A, Burgaleta C. Platelet dysfunction in primary thrombocythemia using the platelet function analyzer, PFA-100.  Am J Clin Pathol. 2005;  123 772-777
    CrossrefPubMedGoogle Scholar
  • 91 Michiels J J. Acquired von Willebrand Disease due to increasing platelet count can readily explain the paradox of thrombosis and bleeding in thrombocythemia.  Clin Appl Thromb Hemost. 1999;  5 147-151
    PubMedGoogle Scholar
  • 92 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 thrombocythemia is related to the platelet count.  Br J Haematol. 1996;  93 962-965
    CrossrefPubMedGoogle Scholar
  • 93 Van Genderen P JJ. Pathophysiological Aspects of Platelet-Mediated Thrombosis and Bleeding in Essential Thrombocythemia [thesis]. Rotterdam, The Netherlands; Erasmus University 1998
    Google Scholar
  • 94 Troost M M, van Genderen P JJ. Excessive prolongation of the Ivy bleeding time after aspirin in essential thrombocythemia is also demonstrable in vitro in the high shear stress system PFA-100.  Ann Hematol. 2002;  81 352-353
    CrossrefPubMedGoogle Scholar
  • 95 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
    PubMedGoogle Scholar
  • 96 Burgaleta C, Gonzalez N, Cesar J. Increased CD11/CD18 expression and altered metabolic activity on polymorphonuclear leukocytes from patients with polycythemia vera and essential thrombocythemia.  Acta Haematol. 2002;  108 23-28
    CrossrefPubMedGoogle Scholar
  • 97 Maugeri N, Evangelista V, Celardo A et al.. Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis.  Thromb Haemost. 1994;  72 450-456
    PubMedGoogle Scholar
  • 98 Jensen M K, de Nully Brown P, Lund B V, Nielsen O J, Hasselbalch H C. Increased circulating platelet-leukocyte aggregates in myeloproliferative disorders is correlated to previous thrombosis, platelet activation and platelet count.  Eur J Haematol. 2001;  66 143-151
    CrossrefPubMedGoogle Scholar
  • 99 Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera.  Exp Hematol. 2005;  33 523-530
    CrossrefPubMedGoogle Scholar
  • 100 Evangelista V, Celardo A, Dell'Elba G et al.. Platelet contribution to leukotriene production in inflammation: in vivo evidence in the rabbit.  Thromb Haemost. 1999;  81 442-448
    PubMedGoogle Scholar
  • 101 Maugeri N, Evangelista V, Piccardoni P et al.. Transcellular metabolism of arachidonic acid: increased platelet thromboxane generation in the presence of activated polymorphonuclear leukocytes.  Blood. 1992;  80 447-451
    PubMedGoogle Scholar
  • 102 Chlopicki S, Lomnicka M, Gryglewski R J. Obligatory role of lipid mediators in platelet-neutrophil adhesion.  Thromb Res. 2003;  110 287-292
    CrossrefPubMedGoogle Scholar
  • 103 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
    CrossrefPubMedGoogle Scholar
  • 104 Falanga A, Marchetti M, Balducci D et al.. Distinct hemostatic profile of leucocytes in essential thrombocythemia (ET) carrying the JAK2 V617F mutation.  Blood. 2005;  106 114a (378 abst)
    PubMedGoogle Scholar
  • 105 Arellano-Rodrigo E, Alvarez-Larran A, Reverter J C, Villamor N, Colomer D, Cervantes F. 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
    PubMedGoogle Scholar
  • 106 Blann A, Caine G, Bareford D. Abnormal vascular, platelet and coagulation markers in primary thrombocythaemia are not reversed by treatments that reduce the platelet count.  Platelets. 2004;  15 447-449
    CrossrefPubMedGoogle Scholar
  • 107 Karakantza M, Giannakoulas N C, Zikos P et al.. Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia vera.  Int J Hematol. 2004;  79 253-259
    CrossrefPubMedGoogle Scholar
  • 108 Juvonen E, Ikkala E, Fyhrquist F, Ruutu T. Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin.  Blood. 1991;  78 3066-3069
    PubMedGoogle Scholar
  • 109 De La Chapelle A, Traskelin A L, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.  Proc Natl Acad Sci USA. 1993;  90 4495-4499
    CrossrefPubMedGoogle Scholar
  • 110 Barbui T, Finazzi G, de Gaetano  et al.. Polycythemia vera: the natural history of 1213 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
    PubMedGoogle Scholar
  • 111 Fruchtman S M, Mack K, Kaplan M E, Peterson P, Berk P D, Wasserman L R. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera.  Semin Hematol. 1997;  34 17-23
    PubMedGoogle Scholar
  • 112 Berk P, Wasserman L R, Fruchtman S M, Goldberg J D. Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia Vera study Group. In.: Wasserman LR, Berk PD, Berlin NI Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia, PA; WB Saunders 1995
    Google Scholar
  • 113 Pearson T C, Wetherley-Mein G. Vascular occlusive episodes and venous hematocrit in primary proliferative polycythaemia.  Lancet. 1978;  2 1219-1222
    PubMedGoogle Scholar
  • 114 Thomas D J, Marshall J, Russell R WR et al.. Cerebral blood-flow in polycythemia.  Lancet. 1977;  2 161-163
    PubMedGoogle Scholar
  • 115 Thomas D J, du Boullat G H, Marshall J et al.. Effect of haematocrit on cerebral blood flow in man.  Lancet. 1977;  2 941-943
    PubMedGoogle Scholar
  • 116 Landolfi R, Marchioli R, Kutti J et al.. Efficacy and safety of low-dose aspirin in polycythemia vera: results of the ECLAP trial.  N Engl J Med. 2004;  350 114-124
    CrossrefPubMedGoogle Scholar
  • 117 Michiels J J, Barbui T, Finazzi G et al.. Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG.  Leuk Lymphoma. 2000;  36 239-253
    PubMedGoogle Scholar
  • 118 van Genderen P J, Mulder P G, 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
    CrossrefPubMedGoogle Scholar
  • 119 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
    CrossrefPubMedGoogle Scholar
  • 120 Jantunen R, Juvonen E, Ikkala E, Oksanen K, Anttila P, Ruutu T. The predictive value of vascular risk factors and gender for the development of thrombotic complications in essential thrombocythemia.  Ann Hematol. 2001;  80 74-78
    CrossrefPubMedGoogle Scholar
  • 121 Watson K V, Key N. Vascular complications of essential thrombocythaemia: a link to cardiovascular risk factors.  Br J Haematol. 1993;  83 198-203
    PubMedGoogle Scholar
  • 122 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
    CrossrefPubMedGoogle Scholar
  • 123 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
    CrossrefPubMedGoogle Scholar
  • 124 Griesshammer M, Klippel S, Strunck E et al.. PRV-1 mRNA expression discriminates two types of essential thrombocythemia.  Ann Hematol. 2004;  83 364-370
    CrossrefPubMedGoogle Scholar
  • 125 Johansson P, Ricksten A, Wennström L, Palmqvist L, Kutti J, Andreasson B. Increased risk for vascular complication in PRV-1 positive patients with essential thrombocythemia.  Br J Haematol. 2003;  123 513-516
    CrossrefPubMedGoogle Scholar
  • 126 Goerttler P S, Steimle C, Marz E et al.. The Jak2V617F mutation, PRV-1 overexpression, and EEC formation define a similar cohort of MPD patients.  Blood. 2005;  106 2862-2864
    CrossrefPubMedGoogle Scholar
  • 127 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
    CrossrefPubMedGoogle Scholar
  • 128 Cheung B Y, Radia D H, Pantelidis P. The presence of the V617F mutation is associated with higher haemoglobin, older age and increased risk of thrombosis in essential thrombocythemia.  Blood. 2005;  106 985a-3531 (abst)
    PubMedGoogle Scholar
  • 129 Finazzi G, Guerini V, Rambaldi A, Barbui T. JAK2 Val 617 Phe mutation correlates with the risk of thrombosis in patients with essential thrombocythemia.  Blood. 2005;  106 725a-2580 (abst)
    CrossrefPubMedGoogle Scholar
  • 130 Fiorini A, Reddiconto G, Farina G et al.. Clonality assay (X-CIP) and JAK2 V617F mutation: clustering patients with essential thrombocythemia at high risk for thrombosis.  Blood. 2005;  106 730a-2597 (abst)
    PubMedGoogle Scholar
  • 131 Bellucci S, Legrand C, Boval B, Drouet L, Caen J. Studies of platelet volume, chemistry and function in patients with essential thrombocythaemia treated with anagrelide.  Br J Haematol. 1999;  104 886-892
    CrossrefPubMedGoogle Scholar
  • 132 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
    CrossrefPubMedGoogle Scholar
  • 133 Fruchtman S M, Petitt R M, Gilbert H S, Fiddler G, Lyne A. Anagrelide Study Group . Anagrelide: analysis of long-term efficacy, safety and leukemogenic potential in myeloproliferative disorders.  Leuk Res. 2005;  29 481-491
    CrossrefPubMedGoogle Scholar
  • 134 Maugeri N, Giordano G, Petrilli M P, de Gaetano G, et al.. Leucocyte activation in myeloproliferative disease. J Thromb Haemost. ISTH, Sydney. 2005: 1594 (abst)-0
    Google Scholar
  • 135 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
    CrossrefPubMedGoogle Scholar
  • 136 Patrono C, Coller B, FitzGerald G A, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 234S-264S
    CrossrefPubMedGoogle Scholar

Sylvia BellucciM.D. Ph.D. 

Service d'Hematologie Biologique, Hôpital Lariboisière

2 rue Ambroise Paré, 75010 Paris, France

Email: sylvia.bellucci@lrb.ap-hop-paris.fr

      >