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APL Coagulopathy

  • Anna Falanga
  • Laura Russo
  • Pau Montesinos
Chapter

Abstract

Acute promyelocytic leukemia (APL) typically presents with a life-threatening hemorrhagic diathesis. New treatment regimens for remission induction including all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) have significantly improved the mortality due to lethal bleeding, which however remains one of the major barriers to the cure of APL. Simultaneous to bleeding manifestations is often the occurrence of thrombosis, which constitutes an integral part of the thrombo-hemorrhagic syndrome (THS) accompanying the clinical presentation of the disease. The laboratory abnormalities of blood coagulation in these patients are consistent with the diagnosis of disseminated intravascular coagulation (DIC) with excess hyperfibrinolysis.

Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium and secrete inflammatory cytokines, which in turn stimulate the prothrombotic activities of endothelial cells and leukocytes.

This chapter will summarize our current knowledge on the epidemiology and pathogenesis of the APL-associated THS and will overview the therapeutic approaches for the management of bleeding and thrombotic complications.

Keywords

Acute promyelocytic leukemia Thrombo-hemorrhagic syndrome (THS) Disseminated intravascular coagulation (DIC) Tissue factor Cancer procoagulant Cytokines Fibrinolysis All-trans-retinoic acid (ATRA) Arsenic trioxide 

References

  1. 1.
    Falanga A, Rickles FR. Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003;16(3):463–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Falanga A. Predicting APL lethal bleeding in the ATRA era. Blood. 2017;129(13):1739–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Levi M. Cancer-related coagulopathies. Thromb Res. 2014;133(Suppl 2):S70–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Falanga A, Russo L, Tartari CJ. Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia. Mediterr J Hematol Infect Dis. 2011;3(1):e2011068.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies. J Clin Oncol. 2009;27(29):4848–57.PubMedCrossRefGoogle Scholar
  6. 6.
    Libourel EJ, et al. Disseminated intravascular coagulation at diagnosis is a strong predictor for both arterial and venous thrombosis in newly diagnosed acute myeloid leukemia. Blood. 2016.Google Scholar
  7. 7.
    Tallman MS, Abutalib SA, Altman JK. The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia. Semin Thromb Hemost. 2007;33(4):330–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Lo-Coco F, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–21.CrossRefPubMedGoogle Scholar
  9. 9.
    Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood. 1992;79(3):543–53.PubMedGoogle Scholar
  10. 10.
    Fenaux P. Management of acute promyelocytic leukemia. Eur J Haematol. 1993;50(2):65–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood. 1998;91(9):3093–102.PubMedGoogle Scholar
  12. 12.
    Castaigne S, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990;76(9):1704–9.PubMedGoogle Scholar
  13. 13.
    Lehmann S, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25(7):1128–34.CrossRefPubMedGoogle Scholar
  14. 14.
    Breccia M, Lo Coco F. Thrombo-hemorrhagic deaths in acute promyelocytic leukemia. Thromb Res. 2014;133(Suppl 2):S112–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Altman JK, et al. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res. 2013;37(9):1004–9.PubMedCrossRefGoogle Scholar
  16. 16.
    de la Serna J, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111(7):3395–402.PubMedCrossRefGoogle Scholar
  17. 17.
    Breccia M, et al. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features. Leukemia. 2007;21(1):79–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Chang H, et al. Acute promyelocytic leukemia-associated thrombosis. Acta Haematol. 2013;130(1):1–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Rashidi A, et al. Thrombosis in acute promyelocytic leukemia. Thromb Res. 2013;131(4):281–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Montesinos P, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113(4):775–83.PubMedCrossRefGoogle Scholar
  21. 21.
    Mitrovic M, et al. Thrombotic events in acute promyelocytic leukemia. Thromb Res. 2015;135(4):588–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Montesinos P, de la Serna J, Vellenga E, Rayon C, Bergua J, Parody R, Esteve J, Gonzalez M, Brunet S, Sanz M. Incidence and Risk Factors for Thrombosis in Patients with Acute Promyelocytic Leukemia. Experience of the PETHEMA LPA96 and LPA99 Protocols. Blood. 2006;108:1503.Google Scholar
  23. 23.
    De Stefano V, et al. The risk of thrombosis in patients with acute leukemia: occurrence of thrombosis at diagnosis and during treatment. J Thromb Haemost. 2005;3(9):1985–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Falanga A. Mechanisms of hypercoagulation in malignancy and during chemotherapy. Haemostasis. 1998;28(Suppl 3):50–60.PubMedGoogle Scholar
  25. 25.
    Falanga A, et al. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid. Blood. 1995;86(3):1072–81.PubMedGoogle Scholar
  26. 26.
    Tallman MS, 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(8):1341–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Booth NA, Bennett B. Plasmin-alpha 2-antiplasmin complexes in bleeding disorders characterized by primary or secondary fibrinolysis. Br J Haematol. 1984;56(4):545–56.PubMedCrossRefGoogle Scholar
  28. 28.
    Reddy VB, et al. Global and molecular hemostatic markers in acute myeloid leukemia. Am J Clin Pathol. 1990;94(4):397–403.PubMedCrossRefGoogle Scholar
  29. 29.
    Speiser W, et al. Hemostatic and fibrinolytic parameters in patients with acute myeloid leukemia: activation of blood coagulation, fibrinolysis and unspecific proteolysis. Blut. 1990;61(5):298–302.PubMedCrossRefGoogle Scholar
  30. 30.
    Dombret H, et al. Coagulation disorders associated with acute promyelocytic leukemia: corrective effect of all-trans retinoic acid treatment. Leukemia. 1993;7(1):2–9.PubMedGoogle Scholar
  31. 31.
    Dombret H, 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(1):19–24.PubMedGoogle Scholar
  32. 32.
    Kawai Y, et al. Rapid improvement of coagulopathy by all-trans retinoic acid in acute promyelocytic leukemia. Am J Hematol. 1994;46(3):184–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Watanabe R, et al. Long-term follow-up of hemostatic molecular markers during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia. Keio Hematology-Oncology Cooperative Study Group (KHOCS). Thromb Haemost. 1997;77(4):641–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Avvisati G, et al. Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia. Br J Haematol. 1988;70(1):43–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Schwartz BS, et al. Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency. Ann Intern Med. 1986;105(6):873–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Menell JS, et al. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340(13):994–1004.PubMedCrossRefGoogle Scholar
  37. 37.
    Kwaan HC. The unique hemostatic dysfunction in acute promyelocytic leukemia. Semin Thromb Hemost. 2014;40(3):332–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Avvisati G. Coagulopathy in APL: a step forward? Blood. 2012;120(1):4–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Rodeghiero F, et al. Liver dysfunction rather than intravascular coagulation as the main cause of low protein C and antithrombin III in acute leukemia. Blood. 1984;63(4):965–9.PubMedGoogle Scholar
  40. 40.
    Falanga A, Barbui T, Rickles FR. Hypercoagulability and tissue factor gene upregulation in hematologic malignancies. Semin Thromb Hemost. 2008;34(2):204–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Boccaccio C, et al. The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature. 2005;434(7031):396–400.PubMedCrossRefGoogle Scholar
  42. 42.
    Rong Y, et al. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res. 2005;65(4):1406–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Yu JL, et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood. 2005;105(4):1734–41.PubMedCrossRefGoogle Scholar
  44. 44.
    Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359(9):938–49.PubMedCrossRefGoogle Scholar
  45. 45.
    Andoh K, et al. Tissue factor activity in leukemia cells. Special reference to disseminated intravascular coagulation. Cancer. 1987;59(4):748–54.PubMedCrossRefGoogle Scholar
  46. 46.
    Gouault Heilmann M, et al. The procoagulant factor of leukaemic promyelocytes: demonstration of immunologic cross reactivity with human brain tissue factor. Br J Haematol. 1975;30(2):151–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Bauer KA, et al. Tissue factor gene expression in acute myeloblastic leukemia. Thromb Res. 1989;56(3):425–30.PubMedCrossRefGoogle Scholar
  48. 48.
    Hair GA, et al. Tissue factor expression in human leukemic cells. Leuk Res. 1996;20(1):1–11.PubMedCrossRefGoogle Scholar
  49. 49.
    Cheng GX, et al. Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. Proc Natl Acad Sci U S A. 1999;96(11):6318–23.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kwaan HC, Rego EM. Role of microparticles in the hemostatic dysfunction in acute promyelocytic leukemia. Semin Thromb Hemost. 2010;36(8):917–24.PubMedCrossRefGoogle Scholar
  51. 51.
    Ma G, et al. Increased promyelocytic-derived microparticles: a novel potential factor for coagulopathy in acute promyelocytic leukemia. Ann Hematol. 2013;92(5):645–52.PubMedCrossRefGoogle Scholar
  52. 52.
    Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant: a cysteine proteinase from malignant tissue. Biochemistry. 1985;24(20):5558–67.PubMedCrossRefGoogle Scholar
  53. 53.
    Donati MB, et al. Cancer procoagulant in human tumor cells: evidence from melanoma patients. Cancer Res. 1986;46(12 Pt 1):6471–4.PubMedGoogle Scholar
  54. 54.
    Mielicki W, et al. Procoagulant activity of human stomach and colon cancers. Oncology. 1990;47(4):299–302.PubMedCrossRefGoogle Scholar
  55. 55.
    Falanga A, et al. A new procoagulant in acute leukemia. Blood. 1988;71(4):870–5.PubMedGoogle Scholar
  56. 56.
    Donati MB, et al. Cancer procoagulant in acute non lymphoid leukemia: relationship of enzyme detection to disease activity. Thromb Haemost. 1990;64(1):11–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Hajjar KA. Cellular receptors in the regulation of plasmin generation. Thromb Haemost. 1995;74(1):294–301.PubMedGoogle Scholar
  58. 58.
    Bennett B, et al. The bleeding disorder in acute promyelocytic leukaemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol. 1989;71(4):511–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Francis RB Jr, Seyfert U. Tissue plasminogen activator antigen and activity in disseminated intravascular coagulation: clinicopathologic correlations. J Lab Clin Med. 1987;110(5):541–7.PubMedGoogle Scholar
  60. 60.
    Stephens R, et al. Production of an active urokinase by leukemia cells: a novel distinction from cell lines of solid tumors. Leuk Res. 1988;12(5):419–22.PubMedCrossRefGoogle Scholar
  61. 61.
    Liu Y, et al. The expression of annexin II and its role in the fibrinolytic activity in acute promyelocytic leukemia. Leuk Res. 2011;35(7):879–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Kwaan HC, Wang J, Weiss I. Expression of receptors for plasminogen activators on endothelial cell surface depends on their origin. J Thromb Haemost. 2004;2(2):306–12.PubMedCrossRefGoogle Scholar
  63. 63.
    Stein E, et al. The coagulopathy of acute promyelocytic leukaemia revisited. Best Pract Res Clin Haematol. 2009;22(1):153–63.PubMedCrossRefGoogle Scholar
  64. 64.
    Graf M, et al. High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis. Am J Hematol. 2005;79(1):26–35.PubMedCrossRefGoogle Scholar
  65. 65.
    Egbring R, et al. Demonstration of granulocytic proteases in plasma of patients with acute leukemia and septicemia with coagulation defects. Blood. 1977;49(2):219–31.PubMedGoogle Scholar
  66. 66.
    Nevo S, et al. Acute bleeding after bone marrow transplantation (BMT)- incidence and effect on survival. A quantitative analysis in 1,402 patients. Blood. 1998;91(4):1469–77.PubMedGoogle Scholar
  67. 67.
    Brower MS, Harpel PC. Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase. J Biol Chem. 1982;257(16):9849–54.PubMedGoogle Scholar
  68. 68.
    Sterrenberg L, et al. Anticoagulant properties of purified X-like fragments of human fibrinogen produced by degradation with leukocyte elastase. Thromb Haemost. 1984;51(3):398–402.PubMedCrossRefGoogle Scholar
  69. 69.
    Sterrenberg L, Nieuwenhuizen W, Hermans J. Purification and partial characterization of a D-like fragment from human fibrinogen, produced by human leukocyte elastase. Biochim Biophys Acta. 1983;755(2):300–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Griffin JD, et al. Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors. Blood. 1987;70(4):1218–21.PubMedGoogle Scholar
  71. 71.
    Khan MM, et al. Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNF-alpha and IL-1beta. Am J Physiol Heart Circ Physiol. 2010;298(2):H652–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Cozzolino F, et al. Potential role of interleukin-1 as the trigger for diffuse intravascular coagulation in acute nonlymphoblastic leukemia. Am J Med. 1988;84(2):240–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Raica M, Cimpean AM, Ribatti D. The role of podoplanin in tumor progression and metastasis. Anticancer Res. 2008;28(5B):2997–3006.PubMedGoogle Scholar
  74. 74.
    Lavallée VP, Marquis M, Bordeleau ME, Chagraoui J, MacRae T, Boivin I, Boucher G, Gendron P, Lemieux S, Bonnefoy A, Rivard GE, Hébert J, Sauvageau G. Transcriptional landscape of APL identifies aberrant podoplanin expression as a defining feature and missing link for the bleeding disorder of this disease. Blood. 2016;128:1075.Google Scholar
  75. 75.
    Federici AB, et al. Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukaemia by treatment with all-trans-retinoic acid. Br J Haematol. 1996;92(3):733–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Tallman MS, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100(13):4298–302.PubMedCrossRefGoogle Scholar
  77. 77.
    Falanga A, et al. Cancer procoagulant in the human promyelocytic cell line NB4 and its modulation by all-trans-retinoic acid. Leukemia. 1994;8(1):156–9.PubMedGoogle Scholar
  78. 78.
    Koyama T, et al. All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells. Blood. 1994;84(9):3001–9.PubMedGoogle Scholar
  79. 79.
    De Stefano V, et al. Effect of all-trans retinoic acid on procoagulant and fibrinolytic activities of cultured blast cells from patients with acute promyelocytic leukemia. Blood. 1995;86(9):3535–41.PubMedGoogle Scholar
  80. 80.
    Falanga A, et al. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells. Blood. 1998;92(1):143–51.PubMedGoogle Scholar
  81. 81.
    Saito T, et al. Anticoagulant effects of retinoic acids on leukemia cells. Blood. 1996;87(2):657–65.PubMedGoogle Scholar
  82. 82.
    Ishii H, et al. Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor. Blood. 1992;80(10):2556–62.PubMedGoogle Scholar
  83. 83.
    Falanga A, et al. All-trans-retinoic acid counteracts endothelial cell procoagulant activity induced by a human promyelocytic leukemia-derived cell line (NB4). Blood. 1996;87(2):613–7.PubMedGoogle Scholar
  84. 84.
    Oeth P, et al. Retinoic acid selectively inhibits lipopolysaccharide induction of tissue factor gene expression in human monocytes. Blood. 1998;91(8):2857–65.PubMedGoogle Scholar
  85. 85.
    Zhu J, et al. Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents. Leukemia. 1999;13(7):1062–70.PubMedCrossRefGoogle Scholar
  86. 86.
    Raelson JV, et al. The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood. 1996;88(8):2826–32.PubMedGoogle Scholar
  87. 87.
    Brand K, et al. Tissue factor mRNA in THP-1 monocytic cells is regulated at both transcriptional and posttranscriptional levels in response to lipopolysaccharide. Mol Cell Biol. 1991;11(9):4732–8.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Fang Y, et al. PML-RARa modulates the vascular signature of extracellular vesicles released by acute promyelocytic leukemia cells. Angiogenesis. 2016;19(1):25–38.PubMedCrossRefGoogle Scholar
  89. 89.
    Tapiovaara H, et al. Induction of differentiation of promyelocytic NB4 cells by retinoic acid is associated with rapid increase in urokinase activity subsequently downregulated by production of inhibitors. Blood. 1994;83(7):1883–91.PubMedGoogle Scholar
  90. 90.
    Marchetti M, et al. All-trans-retinoic acid increases adhesion to endothelium of the human promyelocytic leukaemia cell line NB4. Br J Haematol. 1996;93(2):360–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Vahdat L, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 1994;84(11):3843–9.PubMedGoogle Scholar
  92. 92.
    Di Noto R, et al. All-trans retinoic acid promotes a differential regulation of adhesion molecules on acute myeloid leukaemia blast cells. Br J Haematol. 1994;88(2):247–55.PubMedCrossRefGoogle Scholar
  93. 93.
    Larson RS, Brown DC, Sklar LA. Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2. Blood. 1997;90(7):2747–56.PubMedGoogle Scholar
  94. 94.
    Dubois C, et al. Modulation of IL-8, IL-1 beta, and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia. Leukemia. 1994;8(10):1750–7.PubMedGoogle Scholar
  95. 95.
    Marchetti M, et al. All-trans retinoic acid modulates microvascular endothelial cell hemostatic properties. Haematologica. 2003;88(8):895–905.PubMedGoogle Scholar
  96. 96.
    Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999;93(10):3167–215.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Emadi A, Gore SD. Arsenic trioxide—an old drug rediscovered. Blood Rev. 2010;24(4–5):191–9.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zhou J, et al. Phosphatidylserine exposure and procoagulant activity in acute promyelocytic leukemia. J Thromb Haemost. 2010;8(4):773–82.PubMedCrossRefGoogle Scholar
  99. 99.
    Zhang X, et al. [The impact of arsenic trioxide or all-trans retinoic acid treatment on coagulopathy in acute promyelocytic leukemia]. Zhonghua Nei Ke Za Zhi. 2001;40(12):829–33.Google Scholar
  100. 100.
    Watts JM, Tallman MS. Acute promyelocytic leukemia: what is the new standard of care? Blood Rev. 2014;28(5):205–12.PubMedCrossRefGoogle Scholar
  101. 101.
    Squizzato A, et al. Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost. 2016;115(5):896–904.PubMedCrossRefGoogle Scholar
  102. 102.
    Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011;29(5):495–503.PubMedCrossRefGoogle Scholar
  103. 103.
    Sanz MA, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood. 2008;112(8):3130–4.PubMedCrossRefGoogle Scholar
  104. 104.
    Rickles FR, et al. Bleeding and thrombosis in acute leukemia: what does the future of therapy look like? Thromb Res. 2007;120(Suppl 2):S99–106.PubMedCrossRefGoogle Scholar
  105. 105.
    Sanz MA, Montesinos P. Open issues on bleeding and thrombosis in acute promyelocytic leukemia. Thromb Res. 2010;125(Suppl 2):S51–4.PubMedCrossRefGoogle Scholar
  106. 106.
    Sanz MA, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–91.CrossRefPubMedGoogle Scholar
  107. 107.
    Rodeghiero F, et al. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood. 1990;75(11):2112–7.PubMedGoogle Scholar
  108. 108.
    Bassan R, et al. Short-term treatment for adult hypergranular and microgranular acute promyelocytic leukemia. Leukemia. 1995;9(2):238–43.PubMedGoogle Scholar
  109. 109.
    Arbuthnot C, Wilde JT. Haemostatic problems in acute promyelocytic leukaemia. Blood Rev. 2006;20(6):289–97.PubMedCrossRefGoogle Scholar
  110. 110.
    Zver S, Andoljsek D, Cernelc P. Effective treatment of life-threatening bleeding with recombinant activated factor VII in a patient with acute promyelocytic leukaemia. Eur J Haematol. 2004;72(6):455–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Alimoghaddam K, Ghavamzadeh A, Jahani M. Use of Novoseven for arsenic trioxide-induced bleeding in PML. Am J Hematol. 2006;81(9):720.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Immunohematology and Transfusion Medicine and the Hemostasis and Thrombosis CenterHospital Papa Giovanni XXIIIBergamoItaly
  2. 2.Department of HematologyHospital Universitari i Politecnic La FeValenciaSpain
  3. 3.Centro de Investigación Biomédica en Red de CáncerInstituto Carlos IIIMadridSpain

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