Disseminated Intravascular Coagulation in Hematologic Malignancies

Massimo Franchini; Matteo Nicola Dario Di Minno; Antonio Coppola

doi:10.1055/s-0030-1254048

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

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

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

Abstract

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.

KEYWORDS

Acute promyelocytic leukemia - bleeding - disseminated intravascular coagulation - hematologic malignancies - hypercoagulability - leukemia - thrombosis

Volltext

Referenzen

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