Semin Thromb Hemost 2010; 36(4): 388-403
DOI: 10.1055/s-0030-1254048
© Thieme Medical Publishers

Disseminated Intravascular Coagulation in Hematologic Malignancies

Massimo Franchini1 , Matteo Nicola Dario Di Minno2 , Antonio Coppola2
  • 1Department of Pathology and Laboratory Medicine, Immunohematology and Transfusion Center, University Hospital, Parma, Italy
  • 2Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Naples, Italy
Further Information

Publication History

Publication Date:
07 July 2010 (online)

ABSTRACT

Disseminated intravascular coagulation (DIC) significantly contributes to the bleeding and thrombotic complications in patients with hematologic malignancies. As shown in other cancer settings, an underlying condition of activation of the coagulation system leading to a prothrombotic state of chronic or subclinical DIC is detectable. A variety of disease- or treatment-related factors may affect this condition, enhancing the risk of thrombosis or of bleeding and further triggering mechanisms of DIC in this setting. An overt DIC is diagnosed in ~15% of patients with acute leukemia, and bleeding manifestations prevail over thrombosis, with the highest and most harmful clinical impact in acute promyelocytic leukemia (APL). Pathogenic mechanisms include a series of intrinsic properties of malignant cells, able to directly activate the coagulation system or to stimulate prothrombotic effects by the host cells. Moreover, chemotherapy or concomitant infections play an important concurrent role. In this review the coagulation abnormalities, clinical manifestations, and the presently known pathophysiologic mechanisms of DIC in patients with hematologic malignancies are discussed, focusing on the most extensively studied condition of APL. Current approaches and open issues for the management and treatment of these patients are also reviewed.

REFERENCES

  • 1 Risak E. Die Fibrinopenie.  Z Klin Med. 1935;  128 605-609
  • 2 Croizat P, Favre-Gilly J. Les aspects du syndrome hémorragique des leucémies.  Sang. 1949;  20 417-421
  • 3 Hillestad L K. Acute promyelocytic leukemia.  Acta Med Scand. 1957;  159(3) 189-194
  • 4 Rand J J, Moloney W D, Sise H S. Coagulation defects in acute promyelocytic leukemia.  Arch Intern Med. 1969;  123(1) 39-47
  • 5 Gralnick H R, Marchesi S, Givelber H. Intravascular coagulation in acute leukemia: clinical and subclinical abnormalities.  Blood. 1972;  40(5) 709-718
  • 6 Al-Mondhiry H. Hypofibrinogenemia associated with vincristine and prednisone therapy in lymphoblastic leukemia.  Cancer. 1975;  35(1) 144-147
  • 7 Champion L A, Luddy R E, Schwartz A D. Disseminated intravascular coagulation in childhood acute lymphocytic leukemia with poor prognostic features.  Cancer. 1978;  41(4) 1642-1646
  • 8 Daly P, Brito-Babapulle V, Lawlor E, Blaney C, Parreira A, Catovsky D. Variant translocation t(8;22) and abnormalities of chromosome 15(q22) and 17(q12-21) in a Burkitt's lymphoma/leukaemia with disseminated intravascular coagulation.  Br J Haematol. 1986;  64(3) 561-569
  • 9 Ribeiro R C, Pui C H. The clinical and biological correlates of coagulopathy in children with acute leukemia.  J Clin Oncol. 1986;  4(8) 1212-1218
  • 10 Sarris A, Cortes J, Kantarjian H et al.. Disseminated intravascular coagulation in adult acute lymphoblastic leukemia: frequent complications with fibrinogen levels less than 100 mg/dl.  Leuk Lymphoma. 1996;  21(1-2) 85-92
  • 11 Green D. Management of bleeding complications of hematologic malignancies.  Semin Thromb Hemost. 2007;  33(4) 427-434
  • 12 Levi M. Disseminated intravascular coagulation in cancer patients.  Best Pract Res Clin Haematol. 2009;  22(1) 129-136
  • 13 Tallman M S, Abutalib S A, Altman J K. The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia.  Semin Thromb Hemost. 2007;  33(4) 330-338
  • 14 Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia.  Semin Thromb Hemost. 2001;  27(6) 593-604
  • 15 Gugliotta L, Mazzucconi M G, Leone G et al.. Incidence of thrombotic complications in adult patients with acute lymphoblastic leukemia receiving L-asparaginase during induction therapy: a retrospective study. The GIMEMA Group.  Eur J Haematol. 1992;  49 63-66
  • 16 Ottinger H, Belka C, Kozole G et al.. Deep venous thrombosis and pulmonary artery embolism in high-grade non Hodgkin's lymphoma: incidence, causes and prognostic relevance.  Eur J Haematol. 1995;  54(3) 186-194
  • 17 Zangari M, Anaissie E, Barlogie B et al.. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.  Blood. 2001;  98(5) 1614-1615
  • 18 Dally N, Hoffman R, Haddad N, Sarig G, Rowe J M, Brenner B. Predictive factors of bleeding and thrombosis during induction therapy in acute promyelocytic leukemia—a single center experience in 34 patients.  Thromb Res. 2005;  116(2) 109-114
  • 19 De Stefano V, Sorà 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(9) 1985-1992
  • 20 Falanga A, Barbui T, Rickles F R, Levine M N. Guidelines for clotting studies in cancer patients. For the Scientific and Standardization Committee of the Subcommittee on Haemostasis and Malignancy International Society of Thrombosis and Haemostasis.  Thromb Haemost. 1993;  70 540-542
  • 21 Falanga A, Ofosu F A, Delaini F et al.. The hypercoagulable state in cancer patients: evidence for impaired thrombin inhibitions.  Blood Coagul Fibrinolysis. 1994;  5(5 suppl 1) S19-S23 discussion 59-64
  • 22 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient.  Semin Thromb Hemost. 1999;  25(2) 173-182
  • 23 Chong B H, Lee S-H. Management of thromboembolism in hematologic malignancies.  Semin Thromb Hemost. 2007;  33(4) 435-448
  • 24 Arbuthnot C, Wilde J T. Haemostatic problems in acute promyelocytic leukaemia.  Blood Rev. 2006;  20(6) 289-297
  • 25 Stein E, McMahon B, Kwaan H, Altman J K, Frankfurt O, Tallman M S. The coagulopathy of acute promyelocytic leukaemia revisited.  Best Pract Res Clin Haematol. 2009;  22(1) 153-163
  • 26 Nur S, Anwar M, Saleem M, Ahmad P A. Disseminated intravascular coagulation in acute leukaemias at first diagnosis.  Eur J Haematol. 1995;  55(2) 78-82
  • 27 Higuchi T, Toyama D, Hirota Y et al.. Disseminated intravascular coagulation complicating acute lymphoblastic leukemia: a study of childhood and adult cases.  Leuk Lymphoma. 2005;  46(8) 1169-1176
  • 28 Dixit A, Chatterjee T, Mishra P et al.. Disseminated intravascular coagulation in acute leukemia at presentation and during induction therapy.  Clin Appl Thromb Hemost. 2007;  13(3) 292-298
  • 29 Goldschmidt N, Linetsky E, Shalom E, Varon D, Siegal T. High incidence of thromboembolism in patients with central nervous system lymphoma.  Cancer. 2003;  98(6) 1239-1242
  • 30 Sase T, Wada H, Yamaguchi M et al.. Haemostatic abnormalities and thrombotic disorders in malignant lymphoma.  Thromb Haemost. 2005;  93(1) 153-159
  • 31 Wada H, Sase T, Yamaguchi M. Hypercoagulant states in malignant lymphoma.  Exp Oncol. 2005;  27(3) 179-185
  • 32 Avvisati G, ten Cate J W, Sturk A, Lamping R, Petti M G, Mandelli F. Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia.  Br J Haematol. 1988;  70(1) 43-48
  • 33 Cordonnier C, Vernant J P, Brun B et al.. Acute promyelocytic leukemia in 57 previously untreated patients.  Cancer. 1985;  55(1) 18-25
  • 34 Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients.  Blood. 1990;  75(11) 2112-2117
  • 35 Sanz M A, Martín G, González M et al.. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group.  Blood. 2004;  103(4) 1237-1243
  • 36 Tallman M S, Lefèbvre 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(8) 1341-1350
  • 37 Di Bona E, Avvisati G, Castaman G et al.. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia.  Br J Haematol. 2000;  108(4) 689-695
  • 38 Kim H, Lee J-H, Choi S-J, Kim W K, Lee J S, Lee K H. Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients.  Haematologica. 2004;  89(5) 622-624
  • 39 Raanani P, Segal E, Levi I et al.. Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA—a manifestation of the basic disease or the treatment.  Leuk Lymphoma. 2000;  37(5–6) 605-610
  • 40 Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia.  Blood. 1998;  91(9) 3093-3102
  • 41 Rovelli A, Biondi A, Cantù Rajnoldi A et al.. Microgranular variant of acute promyelocytic leukemia in children.  J Clin Oncol. 1992;  10(9) 1413-1418
  • 42 Bauer K A, Rosenberg R D. Thrombin generation in acute promyelocytic leukemia.  Blood. 1984;  64(4) 791-796
  • 43 Noguera N I, Breccia M, Divona M et al.. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol.  Leukemia. 2002;  16(11) 2185-2189
  • 44 Kiyoi H, Naoe T, Yokota S Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho) et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia.  Leukemia. 1997;  11(9) 1447-1452
  • 45 Rodeghiero F, Castaman G. The pathophysiology and treatment of hemorrhagic syndrome of acute promyelocytic leukemia.  Leukemia. 1994;  8(suppl 2) S20-S26
  • 46 Watanabe R, Murata M, Takayama N Keio Hematology-Oncology Cooperative Study Group (KHOCS) et al. Long-term follow-up of hemostatic molecular markers during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia.  Thromb Haemost. 1997;  77(4) 641-645
  • 47 Falanga A, Consonni R, Marchetti M et al.. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells.  Blood. 1998;  92(1) 143-151
  • 48 Wang J, Weiss I, Svoboda K, Kwaan H C. Thrombogenic role of cells undergoing apoptosis.  Br J Haematol. 2001;  115(2) 382-391
  • 49 Gordon S G, Franks J J, Lewis B. Cancer procoagulant A: a factor X activating procoagulant from malignant tissue.  Thromb Res. 1975;  6(2) 127-137
  • 50 Falanga A, Alessio M G, Donati M B, Barbui T. A new procoagulant in acute leukemia.  Blood. 1988;  71(4) 870-875
  • 51 Alessio M G, Falanga A, Consonni R et al.. Cancer procoagulant in acute lymphoblastic leukemia.  Eur J Haematol. 1990;  45(2) 78-81
  • 52 Falanga A, Consonni R, Marchetti M et al.. Cancer procoagulant in the human promyelocytic cell line NB4 and its modulation by all-trans-retinoic acid.  Leukemia. 1994;  8(1) 156-159
  • 53 De Stefano V, Teofili L, Sica S 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) 3535-3541
  • 54 Cozzolino F, Torcia M, Miliani A et al.. Potential role of interleukin-1 as the trigger for diffuse intravascular coagulation in acute nonlymphoblastic leukemia.  Am J Med. 1988;  84(2) 240-250
  • 55 Griffin J D, Rambaldi A, Vellenga E, Young D C, Ostapovicz D, Cannistra S A. Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors.  Blood. 1987;  70(4) 1218-1221
  • 56 Bevilacqua M P, Pober J S, Majeau G R, Fiers W, Cotran R S, Gimbrone Jr M A. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1.  Proc Natl Acad Sci U S A. 1986;  83(12) 4533-4537
  • 57 Moore K L, Esmon C T, Esmon N L. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture.  Blood. 1989;  73(1) 159-165
  • 58 Nachman R L, Hajjar K A, Silverstein R L, Dinarello C A. Interleukin 1 induces endothelial cell synthesis of plasminogen activator inhibitor.  J Exp Med. 1986;  163(6) 1595-1600
  • 59 Degos L, Dombret H, Chomienne C et al.. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia.  Blood. 1995;  85(10) 2643-2653
  • 60 Greeno E W, Bach R R, Moldow C F. Apoptosis is associated with increased cell surface tissue factor procoagulant activity.  Lab Invest. 1996;  75(2) 281-289
  • 61 Flynn P D, Byrne C D, Baglin T P, Weissberg P L, Bennett M R. Thrombin generation by apoptotic vascular smooth muscle cells.  Blood. 1997;  89(12) 4378-4384
  • 62 Casciola-Rosen L, Rosen A, Petri M, Schlissel M. Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus.  Proc Natl Acad Sci U S A. 1996;  93(4) 1624-1629
  • 63 Kwaan H C, Parmar S, Wang J. Pathogenesis of increased risk of thrombosis in cancer.  Semin Thromb Hemost. 2003;  29(3) 283-290
  • 64 Falanga A, Marchetti M, Giovanelli S, Barbui T. All-trans-retinoic acid counteracts endothelial cell procoagulant activity induced by a human promyelocytic leukemia-derived cell line (NB4).  Blood. 1996;  87(2) 613-617
  • 65 Koyama T, Hirosawa S, Kawamata N, Tohda S, Aoki N. 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) 3001-3009
  • 66 Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function.  FASEB J. 1992;  6(8) 2591-2599
  • 67 Marchetti M, Vignoli A, Bani M R, Balducci D, Barbui T, Falanga A. All-trans retinoic acid modulates microvascular endothelial cell hemostatic properties.  Haematologica. 2003;  88(8) 895-905
  • 68 Egbring R, Schmidt W, Fuchs G, Havemann K. Demonstration of granulocytic proteases in plasma of patients with acute leukemia and septicemia with coagulation defects.  Blood. 1977;  49(2) 219-231
  • 69 Plow E F, Edgington T S. An alternative pathway for fibrinolysis. I. The cleavage of fibrinogen by leukocyte proteases at physiologic pH.  J Clin Invest. 1975;  56(1) 30-38
  • 70 Nossel H L, Hurlet-Jensen A, Liu C Y, Koehn J A, Canfield R E. Fibrinopeptide release from fibrinogen.  Ann N Y Acad Sci. 1983;  408 269-278
  • 71 Schmidt W, Egbring R, Havemann K. Effect of elastase-like and chymotrypsin-like neutral proteases from human granulocytes on isolated clotting factors.  Thromb Res. 1975;  6(4) 315-329
  • 72 Brower M S, Harpel P C. Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase.  J Biol Chem. 1982;  257(16) 9849-9854
  • 73 Sterrenberg L, van Liempt G J, Nieuwenhuizen W, Hermans J. Anticoagulant properties of purified X-like fragments of human fibrinogen produced by degradation with leukocyte elastase.  Thromb Haemost. 1984;  51(3) 398-402
  • 74 Dombret H, Scrobohaci M L, Ghorra P et al.. Coagulation disorders associated with acute promyelocytic leukemia: corrective effect of all-trans retinoic acid treatment.  Leukemia. 1993;  7(1) 2-9
  • 75 Federici A B, Berkowitz S D, Lattuada A, Mannucci P M. Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis.  Blood. 1993;  81(3) 720-725
  • 76 Federici A B, Falanga A, Lattuada A, Di Rocco N, Barbui T, Mannucci P M. Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukaemia by treatment with all-trans-retinoic acid.  Br J Haematol. 1996;  92(3) 733-739
  • 77 Simak J, Gelderman M P. Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers.  Transfus Med Rev. 2006;  20(1) 1-26
  • 78 Horstman L L, Jy W, Jimenez J J, Bidot C, Ahn Y S. New horizons in the analysis of circulating cell-derived microparticles.  Keio J Med. 2004;  53(4) 210-230
  • 79 Tesselaar M E, Romijn F P, Van Der Linden I K, Prins F A, Bertina R M, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?.  J Thromb Haemost. 2007;  5(3) 520-527
  • 80 Gralnick H R, Abrell E. Studies of the procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukaemia.  Br J Haematol. 1973;  24(1) 89-99
  • 81 Bennett B, Booth N A, Croll A, Dawson A A. The bleeding disorder in acute promyelocytic leukaemia: fibrinolysis due to u-PA rather than defibrination.  Br J Haematol. 1989;  71(4) 511-517
  • 82 Tapiovaara H, Alitalo R, Stephens R, Myöhänen H, Ruutu T, Vaheri A. Abundant urokinase activity on the surface of mononuclear cells from blood and bone marrow of acute leukemia patients.  Blood. 1993;  82(3) 914-919
  • 83 Stephens R, Alitalo R, Tapiovaara H, Vaheri A. Production of an active urokinase by leukemia cells: a novel distinction from cell lines of solid tumors.  Leuk Res. 1988;  12(5) 419-422
  • 84 Reddy V B, Kowal-Vern A, Hoppensteadt D A et al.. Global and hemostatic markers in acute leukemia.  Am J Clin Pathol. 1990;  94 397-403
  • 85 Tapiovaara H, Matikainen S, Hurme M, Vaheri A. 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) 1883-1891
  • 86 Bennett M, Parker A C, Ludlam C A. Platelet and fibrinogen survival in acute promyelocytic leukaemia.  BMJ. 1976;  2(6035) 565
  • 87 Booth N A, Bennett B. Plasmin-alpha 2-antiplasmin complexes in bleeding disorders characterized by primary or secondary fibrinolysis.  Br J Haematol. 1984;  56(4) 545-556
  • 88 Menell J S, Cesarman G M, Jacovina A T, McLaughlin M A, Lev E A, Hajjar K A. Annexin II and bleeding in acute promyelocytic leukemia.  N Engl J Med. 1999;  340(13) 994-1004
  • 89 Hajjar K A, Jacovina A T, Chacko J. An endothelial cell receptor for plasminogen/tissue plasminogen activator. I. Identity with annexin II.  J Biol Chem. 1994;  269(33) 21191-21197
  • 90 Hajjar K A, Menell J S. Annexin II: a novel mediator of cell surface plasmin generation.  Ann N Y Acad Sci. 1997;  811 337-349
  • 91 Cesarman G M, Guevara C A, Hajjar K A. An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation.  J Biol Chem. 1994;  269(33) 21198-21203
  • 92 Kwaan H C, Wang J, Weiss I. Expression of receptors for plasminogen activators on endothelial cell surface depends on their origin.  J Thromb Haemost. 2004;  2(2) 306-312
  • 93 Lee A Y, Levine M N. The thrombophilic state induced by therapeutic agents in the cancer patient.  Semin Thromb Hemost. 1999;  25(2) 137-145
  • 94 Mitchell L G, Sutor A H, Andrew M. Hemostasis in childhood acute lymphoblastic leukemia: coagulopathy induced by disease and treatment.  Semin Thromb Hemost. 1995;  21(4) 390-401
  • 95 Sarris A H, Kempin S, Berman E et al.. High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia.  Blood. 1992;  79(5) 1305-1310
  • 96 Zangari M, Barlogie B, Anaissie E et al.. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.  Br J Haematol. 2004;  126(5) 715-721
  • 97 Anderlini P, Luna M, Kantarjian H M et al.. Causes of initial remission induction failure in patients with acute myeloid leukemia and myelodysplastic syndromes.  Leukemia. 1996;  10(4) 600-608
  • 98 Semeraro N, Colucci M. Changes in the coagulation-fibrinolysis balance of endothelial cells and mononuclear phagocytes: role in disseminated intravascular coagulation associated with infectious diseases.  Int J Clin Lab Res. 1992;  21(3) 214-220
  • 99 ten Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis.  Crit Care Med. 2000;  28(9, suppl) S9-S11
  • 100 Levi M, Toh C H, Thachil J, Watson H G. British Committee for Standards in Haematology . Guidelines for the diagnosis and management of disseminated intravascular coagulation.  Br J Haematol. 2009;  145(1) 24-33
  • 101 Taylor Jr F B, Toh C H, Hoots W K, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) . Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation.  Thromb Haemost. 2001;  86(5) 1327-1330
  • 102 Toh C H, Hoots W K. SSC on Disseminated Intravascular Coagulation of the ISTH . The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview.  J Thromb Haemost. 2007;  5(3) 604-606
  • 103 Dixit A, Kannan M, Mahapatra M, Choudhry V P, Saxena R. Roles of protein C, protein S, and antithrombin III in acute leukemia.  Am J Hematol. 2006;  81(3) 171-174
  • 104 Kantarjian H M, Keating M J, Walters R S et al.. Acute promyelocytic leukemia. M.D. Anderson Hospital experience.  Am J Med. 1986;  80 789-797
  • 105 Losada R, Espinosa E, Hernández C, Dorticos E, Hernández P. Thrombocytosis in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment.  Br J Haematol. 1996;  95(4) 704-705
  • 106 Degos L, Dombret H, Chomienne C et al.. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia.  Blood. 1995;  85(10) 2643-2653
  • 107 Bassan R, Battista R, Viero P et al.. Short-term treatment for adult hypergranular and microgranular acute promyelocytic leukemia.  Leukemia. 1995;  9(2) 238-243
  • 108 British Committee for Standards in Haematology, Blood Transfusion Task Force . Guidelines for the use of platelet transfusions.  Br J Haematol. 2003;  122(1) 10-23
  • 109 Yanada M, Matsushita T, Asou N et al.. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome.  Eur J Haematol. 2007;  78(3) 213-219
  • 110 O'shaughnessy D F, Atterbury C, Bolton Maggs P British Committee for Standards in Haematology, Blood Transfusion Task Force et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant.  Br J Haematol. 2004;  126(1) 11-28
  • 111 Tallman M S, Kwaan H C. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia.  Blood. 1992;  79(3) 543-553
  • 112 Falanga A, Iacoviello L, Evangelista V 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) 1072-1081
  • 113 Tallman M S, Brenner B, de la Serna J et al.. Meeting report. Acute promyelocytic leukemia-associated coepulopathy; January 21, 2004, London, UK.  Leukemia Res. 2005;  29(3) 347-351
  • 114 Runde V, Aul C, Heyll A, Schneider W, Schneider W. All-trans retinoic acid: not only a differentiating agent, but also an inducer of thromboembolic events in patients with M3 leukemia.  Blood. 1992;  79(2) 534-535
  • 115 Forjaz De Lacenda J, Alves Do Carmo J, Lurdes Guerna M, Geraldes J, Forjaz De Lacerda J M. Multiple thrombosis in acute promyelocytic leukaemia after tretinoin.  Lancet. 1993;  342 114-115
  • 116 Hashimoto S, Koike T, Tatewaki W et al.. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid therapy combined with antifibrinolytic therapy for prophylaxis of hemorrhage.  Leukemia. 1994;  8(7) 1113-1115
  • 117 Schwartz B S, Williams E C, Conlan M G, Mosher D F. 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) 873-877
  • 118 Avvisati G, ten Cate J W, Büller H R, Mandelli F. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia.  Lancet. 1989;  2(8655) 122-124
  • 119 Sugawara T, Okuda M, Yamaguchi Y, Endo K, Yoshinaga K. Successful treatment with tranexamic acid for severe bleeding in acute promyelocytic leukemia.  Acta Haematol. 1992;  87(1–2) 109
  • 120 Warrell Jr R P, de Thé H, Wang Z-Y, Degos L. Acute promyelocytic leukemia.  N Engl J Med. 1993;  329(3) 177-189
  • 121 Franchini M, Manzato F, Salvagno G L, Lippi G. Potential role of recombinant activated factor VII for the treatment of severe bleeding associated with disseminated intravascular coagulation: a systematic review.  Blood Coagul Fibrinolysis. 2007;  18(7) 589-593
  • 122 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) 455-456
  • 123 Alimoghaddam K, Ghavamzadeh A, Jahani M. Use of Novoseven for arsenic trioxide-induced bleeding in PML.  Am J Hematol. 2006;  81(9) 720
  • 124 Warren B L, Eid A, Singer P KyberSept Trial Study Group et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.  JAMA. 2001;  286(15) 1869-1878
  • 125 Kienast J, Juers M, Wiedermann C J KyberSept investigators et al. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.  J Thromb Haemost. 2006;  4(1) 90-97
  • 126 Bernard G R, Vincent J L, Laterre P F Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group et al. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344(10) 699-709
  • 127 Dhainaut J F, Yan S B, Joyce D E et al.. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.  J Thromb Haemost. 2004;  2(11) 1924-1933
  • 128 Bernard G R, Macias W L, Joyce D E, Williams M D, Bailey J, Vincent J L. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis.  Crit Care. 2003;  7(2) 155-163
  • 129 Mechtcheriakova D, Wlachos A, Holzmüller H, Binder B R, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1.  Blood. 1999;  93(11) 3811-3823
  • 130 Kini A R, Peterson L A, Tallman M S, Lingen M W. Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid.  Blood. 2001;  97(12) 3919-3924
  • 131 Fenaux P, Chomienne C, Degos L. Treatment of acute promyelocytic leukaemia.  Best Pract Res Clin Haematol. 2001;  14(1) 153-174
  • 132 Soignet S L, Frankel S R, Douer D et al.. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia.  J Clin Oncol. 2001;  19(18) 3852-3860

Massimo FranchiniM.D. 

Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine

University Hospital, Via Gramsci, 14, 37124 Parma, Italy

Email: mfranchini@ao.pr.it

    >