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Semin Thromb Hemost 2008; 34(2): 204-210
DOI: 10.1055/s-2008-1079262
© Thieme Medical Publishers

Hypercoagulability and Tissue Factor Gene Upregulation in Hematologic Malignancies

Anna Falanga1 , Tiziano Barbui1 , Frederick R. Rickles2
  • 1Department Hematology/Oncology, Ospedali Riuniti di Bergamo, Bergamo, Italy
  • 2The George Washington University, Washington, D.C.
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Publication History

Publication Date:
21 July 2008 (online)

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ABSTRACT

Thrombotic complications in patients with hematologic malignancies are as frequent as in those with solid tumors and significantly affect morbidity and mortality. In acute leukemia, thrombosis and bleeding manifestations may occur concomitantly as a part of the same thrombo-hemorrhagic syndrome. In patients with Philadelphia chromosome–negative chronic myeloproliferative disorders (i.e., essential thrombocythemia [ET] and polycythemia vera [PV]), a thrombosis rate as high as 40% has been recorded. A hypercoagulable state is present in virtually all of these patients, even without clinical manifestations. In this review, we focus on the pathogenic mechanisms underlying the hypercoagulable state of these two hematologic malignancies. Although the pathogenesis of hypercoagulability is complex, a central role is played by the fundamental molecular changes of both the leukemic cells and of the progeny arising from the hematopoietic progenitor cells that have undergone clonal rearrangement. These cells overexpress procoagulant factors, as well as adhesion molecules and cytokines capable of inducing procoagulant changes in the vascular wall and stimulating increased cellular interactions. Recent molecular studies in experimental models of human tumors have demonstrated for the first time that oncogene- and repressor gene–mediated neoplastic transformation induces activation of blood coagulation. Similarly, in cells from patients with acute promyelocytic leukemia, the t15–17 translocation induces hyperexpression of tissue factor (TF) and renders the patient hypercoagulable. Furthermore, in blood cells from patients with PV or ET, the presence of the JAK2V617F mutation translates into activation of hemostasis, with increased expression of platelet-associated TF microparticles and the formation of increased platelet/neutrophil aggregates. Understanding the pathophysiology of hypercoagulability is critical to the design of appropriate measures for intervention in these hematologic disorders to prevent thromboembolic complications.

KEYWORDS

Hypercoagulable state - tissue factor - acute promyelocytic leukemia - essential thrombocythemia - polycythemia vera

REFERENCES

  • 1 Barbui T, Finazzi G, Falanga A. The management of bleeding and thrombosis in acute leukemia and chronic myeloproliferative disorders. In: Henderson ES, Lister TA, Greaves MF Leukemia, 7th ed. Philadelphia, PA; Saunders 2001: 363-382
    Google Scholar
  • 2 Falanga A, Rickles F R. Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia.  Best Pract Res Clin Haematol. 2003;  16 463-482
    CrossrefPubMedGoogle Scholar
  • 3 Falanga A, Marchetti M. Thromboembolism in hematologic malignancies. In: Khorana AA, Francis CW Cancer-Associated Thrombosis. New York, NY; Informa Healthcare 2008: 131-149
    Google Scholar
  • 4 Ziegler S, Sperr W R, Knobl P et al.. Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis.  Thromb Res. 2005;  115 59-64
    CrossrefPubMedGoogle Scholar
  • 5 De Stefano V, Sora F, Rossi E et al.. The risk of thrombosis in patients with acute leukemia: occurrence of thrombosis at diagnosis and during treatment.  J Thromb Haemost. 2005;  3 1985-1992
    CrossrefPubMedGoogle Scholar
  • 6 Barbui T, Finazzi G. Therapy for polycythemia vera and essential thrombocythemia is driven by the cardiovascular risk.  Semin Thromb Hemost. 2007;  33 321-329
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Schafer A I. Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia.  Blood. 2006;  107 4214-4222
    CrossrefPubMedGoogle Scholar
  • 8 Michiels J J, Berneman Z, Bockstaele D V, van der Planken M, De Raeve H, Schroyens W. Clinical and laboratory features, pathology of platelet-mediated thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications.  Semin Thromb Hemost. 2006;  32 174-207
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Dvorak H F, Rickles F R. Malignancy and hemostasis. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ Hemostasis and Thrombosis, Basic Principles and Clinical Practice. Philadelphia, PA; Lippincott Williams & Wilkins 2006: 851-873
    Google Scholar
  • 10 Rickles F R, Falanga A. Molecular basis for the relationship between thrombosis and cancer.  Thromb Res. 2001;  102 V215-V224
    CrossrefPubMedGoogle Scholar
  • 11 Boccaccio C, Sabatino G, Medico E et al.. The MET oncogene drives a genetic programme linking cancer to haemostasis.  Nature. 2005;  434 396-400
    CrossrefPubMedGoogle Scholar
  • 12 Rong Y, Post D E, Pieper R O et al.. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma.  Cancer Res. 2005;  65 1406-1413
    CrossrefPubMedGoogle Scholar
  • 13 Yu J L, May L, Lhotak V et al.. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.  Blood. 2005;  105 1734-1741
    CrossrefPubMedGoogle Scholar
  • 14 Falanga A, Marchetti M, Vignoli A et al.. V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte and plasma hemostatic and inflammatory molecules.  Exp Hematol. 2007;  35 702-711
    CrossrefPubMedGoogle Scholar
  • 15 Tallman M S, Lefebvre P, Baine R M et al.. Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia.  J Thromb Haemost. 2004;  2 1341-1350
    CrossrefPubMedGoogle Scholar
  • 16 Falanga A, Iacoviello L, Evangelista V et al.. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocitic leukemia given all-trans-retinoic acid.  Blood. 1995;  86 1072-1084
    PubMedGoogle Scholar
  • 17 Dombret H, Scrobohaci M L, Daniel M T et al.. In vivo thrombin and plasmin activities in patients with acute promyelocytic leukemia (APL): effect of all-trans retinoic acid (ATRA) therapy.  Leukemia. 1995;  9 19-24
    PubMedGoogle Scholar
  • 18 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
  • 19 Friedenberg W R, Roberts R C, David D E. Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders.  Am J Hematol. 1992;  40 283-289
    CrossrefPubMedGoogle Scholar
  • 20 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, tPA and vWF.  Thromb Haemost. 1993;  70 736-742
    PubMedGoogle Scholar
  • 21 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
  • 22 Elliott M A, Tefferi A. Thrombosis and haemorrage in polycythemia vera and essential thrombocythemia.  Br J Haematol. 2005;  128 275-290
    CrossrefPubMedGoogle Scholar
  • 23 Burgaleta C, Gonzalez N, Cesar J. Increased CD11/18 expression and altered metabolic activity in polymorphonuclear leukocytes from patients with polycythemia vera and essential thrombocythemia.  Acta Haematol. 2002;  108 23-28
    CrossrefPubMedGoogle Scholar
  • 24 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
  • 25 Kwaan H C, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities.  Semin Thromb Hemost. 2003;  29 451-458
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Yedgar S, Koshkaryev A, Barshtein G. The red blood cell in vascular occlusion.  Pathophysiol Haemost Thromb. 2002;  32 263-268
    CrossrefPubMedGoogle Scholar
  • 27 Valles J, Santos M T, Aznar J et al.. Platelet-erythrocyte interactions enhance alpha (IIb)beta(3) integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo.  Blood. 2002;  99 3978-3984
    CrossrefPubMedGoogle Scholar
  • 28 Pearson M J, Lipowsky H H. Influence of erythrocyte aggregation on leukocyte margination in postcapillary venules of rat mesentery.  Am J Physiol Heart Circ Physiol. 2000;  279 M1460-1471
    PubMedGoogle Scholar
  • 29 Jensen M K, de Nully Brown P, Lund B V, Nielsen O, 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
  • 30 Li N, Goodall A H, Hjemdahl P. A sensitive flow cytometric assay for circulating platelet-leukocyte aggregates.  Br J Haematol. 1997;  99 808-816
    CrossrefPubMedGoogle Scholar
  • 31 Villmow T, Kemkes-Matthes B, Matzdorff A C. Markers of platelet activation and platelet-leukocyte interaction in patients with myeloproliferative syndromes.  Thromb Res. 2002;  108 139-145
    CrossrefPubMedGoogle Scholar
  • 32 Alvarez-Larràn A, Garcìa-Pagàn J C, Abraldes J G et al.. Increased CD11b neuthrophil expression in Budd-Chiari syndrome or portal vein thrombosis secondary to polycythaemia vera.  Br J Haematol. 2004;  124 329-335
    CrossrefPubMedGoogle Scholar
  • 33 Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocytemia and polycythemia vera.  Exp Hematol. 2005;  33 523-530
    CrossrefPubMedGoogle Scholar
  • 34 Celi A, Pellegrini G, Lorenzet R et al.. P-selectin induces the expression of tissue factor on monocytes.  Proc Natl Acad Sci U S A. 1994;  91 8767-8771
    CrossrefPubMedGoogle Scholar
  • 35 Kralovics R, Passamonti F, Buser A S, Teo S S, Tiedt R, Passweg J R. A gain-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
    CrossrefPubMedGoogle Scholar
  • 36 Wolanskyj A P, Schwager S M, McClure R F, Larson D R, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors.  Mayo Clin Proc. 2006;  81 159-166
    CrossrefPubMedGoogle Scholar
  • 37 Campbell P J, Scott L M, 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
    CrossrefPubMedGoogle Scholar
  • 38 Muller I, Klocke A, Alex M et al.. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets.  FASEB J. 2003;  17 476-478
    PubMedGoogle Scholar
  • 39 Falati S, Liu Q, Gross P et al.. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin.  J Exp Med. 2003;  197 1585-1598
    CrossrefPubMedGoogle Scholar
  • 40 Myers D D, Hawley A E, Farris D M et al.. P-selectin and leukocyte microparticles are associated with venous thrombogenesis.  J Vasc Surg. 2003;  38 1075-1089
    CrossrefPubMedGoogle Scholar
  • 41 Maugeri N, Giordano G, Petrilli M P et al.. Inibition 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
    CrossrefPubMedGoogle Scholar
  • 42 Shoji M, Hancock W W, Abe K et al.. Activation of coagulation and angiogenesis in cancer. Immunohistochemical localization in situ of clotting proteins and VEGF in human cancers.  Am J Pathol. 1998;  152 399-411
    PubMedGoogle Scholar
  • 43 Lyman G H, Khorana A A, Falanga A et al.. American society of clinical oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer.  J Clin Oncol. 2007;  25 5490-5505
    CrossrefPubMedGoogle Scholar
  • 44 Kuderer N M, Khorana A, Lyman G H, Francis C W. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications.  Cancer. 2007;  110 1149-1161
    CrossrefPubMedGoogle Scholar

Anna FalangaM.D. 

Thrombosis and Hemostasis Center, Department Hematology/Oncology

Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24128 Bergamo, Italy

Email: annafalanga@yahoo.com