The Double Hazard of Thrombophilia and Bleeding in Acute Promyelocytic Leukemia

 

 Buy Article Permissions and Reprints

ABSTRACT

Acute promyelocytic leukemia (APL), once highly fatal, has emerged as the most curable subtype of acute myeloid leukemia in adults. Cure is now expected in ~70 to 90% of patients when treatment includes all-trans retinoic acid (ATRA) combined with anthracycline-based chemotherapy. Early mortality most often is due to a severe and often catastrophic bleeding, often intracerebral in location, and remains a major cause of treatment failure. Thrombosis, either at diagnosis or during the course of treatment, may be unrecognized and reflects the complexity of the coagulopathy. The dual phenomenon of bleeding and thrombosis is attributable to at least three processes: disseminated intravascular coagulation; fibrinolysis (generated in part by expression of annexin-II on the APL cell surface); and direct proteolysis of several proteins including fibrinogen and von Willebrand factor. Both ATRA and arsenic trioxide are associated with rapid resolution of the coagulopathy. The use of heparin, once a mainstay of therapy for patients with APL, has been all but abandoned. Preliminary studies suggest no role for the routine use of antifibrinolytic agents. The most important therapeutic strategy is early institution of ATRA at the first suspicion of the diagnosis (without waiting for genetic confirmation) and aggressive blood product support during induction.

REFERENCES

• 1 Hillestad L K. Acute promyelocytic leukemia.  Acta Med Scand. 1957;  159 189-194
  CrossrefPubMedGoogle Scholar
• 2 Kantarjian H M, Keating M J, Walters R S et al.. Acute promyelocytic leukemia: MD Anderson Hospital experience.  Am J Med. 1986;  80 789-797
  CrossrefPubMedGoogle Scholar
• 3 Cordonnier C, Vernant J P, Brun B et al.. Acute promyelocytic leukemia in 57 previously untreated patients.  Cancer. 1985;  55 18-25
  CrossrefPubMedGoogle Scholar
• 4 Petti M C, Avvisati G, Amadori S et al.. Acute promyelocytic leukemia: Clinical aspects and results of treatment in 62 patients.  Haematologica. 1987;  72 151-155
  PubMedGoogle Scholar
• 5 Stone R M, Maguire M, Goldberg M A et al.. Complete remission in acute promyelocytic leukemia despite persistence of abnormal bone marrow promyelocytes during induction therapy: experience in 34 patients.  Blood. 1988;  71 690-696
  PubMedGoogle Scholar
• 6 Avvisati G, Petti M C, Lo Coco F et al.. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia; final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up.  Blood. 2002;  100 3141-3146
  CrossrefPubMedGoogle Scholar
• 7 Pittman G R, Senhauser D A, Lowney J F. Acute promyelocytic leukemia: a report of 3 autopsied cases.  Am J Clin Pathol. 1966;  46 214-220
  PubMedGoogle Scholar
• 8 Daly P A, Schiffer C A, Wiernik P H. Acute promyelocytic leukemia-clinical management in 15 patients.  Am J Hematol. 1980;  8 347-359
  CrossrefPubMedGoogle Scholar
• 9 Gralnick H R, Abrell E. Studies of the procoagulant activity of promyelocytes in acute promyelocytic leukemia.  Br J Haematol. 1973;  24 89-99
  CrossrefPubMedGoogle Scholar
• 10 Kim H, Lee J-H, Choi S-J et al.. Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients.  Haematologica. 2004;  89 622-624
  PubMedGoogle Scholar
• 11 Fenaux P, Le Deley M C, Castaigne S et al.. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL Group.  Blood. 1993;  82 3241-3249
  PubMedGoogle Scholar
• 12 Fenaux P, Chastang C, Chevret S et al.. A randomized comparison of all trans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia.  Blood. 1999;  94 1192-1200
  PubMedGoogle Scholar
• 13 Tallman M S, Andersen J W, Schiffer C A 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 4298-4302
  CrossrefPubMedGoogle Scholar
• 14 Sanz M A, Martin G, Gonzalez M et al.. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monotherapy: a multicenter study by the PETHEMA group.  Blood. 2004;  103 1237-1243
  CrossrefPubMedGoogle Scholar
• 15 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;  116 109-114
  CrossrefPubMedGoogle Scholar
• 16 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 treatment.  Leuk Lymphoma. 2000;  37 605-610
  CrossrefPubMedGoogle Scholar
• 17 Escudier S M, Kantarjian H M, Estey E H. Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid.  Leuk Lymphoma. 1996;  20 435-439
  CrossrefPubMedGoogle Scholar
• 18 Runde V, Aul C, Heyll A, 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;  79 534-535
  PubMedGoogle Scholar
• 19 Colovic M, Miljic O, Colovic M, Jankovic G, Stojkovic M. Reversible portal vein thrombosis complicating induction therapy of acute promyelocytic leukemia.  Thromb Res. 2001;  101 101-103
  CrossrefPubMedGoogle Scholar
• 20 Torromeo C, Latagliata R, Avvisati G, Petti M C, Mandelli F. Intraventricular thrombosis during all-trans retinoic acid treatment of acute promyelocytic leukemia.  Leukemia. 2001;  15 1311-1313
  CrossrefPubMedGoogle Scholar
• 21 Levin M D, Betjes M G, V d Kwast T H, Wenberg B L, Leebeek F W. Acute adrenal cortex necrosis caused by arterial thrombosis during treatment for acute promyelocytic leukemia.  Haematologica. 2003;  88 ECR21
  PubMedGoogle Scholar
• 22 Kalk E, Goede A, Rose P. Acute arterial thrombosis in acute promyelocytic leukemia.  Clin Lab Haematol. 2003;  25 267-270
  CrossrefPubMedGoogle Scholar
• 23 Goldschmidt N, Gural A, Ben-Yehuda D. Extensive splenic infarction, deep vein thrombosis and pulmonary emboli complicating induction therapy with all-trans retinoic acid (ATRA) for acute promyelocytic leukemia.  Leuk Lymphoma. 2003;  44 1433-1437
  CrossrefPubMedGoogle Scholar
• 24 De Stefano V, Sora F, Rossi E et al.. The risk of thrombosis with acute leukemia: occurrence of thrombosis at diagnosis and during treatment.  J Thromb Haemost. 2005;  3 1985-1992
  CrossrefPubMedGoogle Scholar
• 25 Breccia M, Avvisati G, Latagliata R et al.. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features.  Leukemia. 2007;  3 79-83
  PubMedGoogle Scholar
• 26 Lou Y, Mai W Y, Jin J. Simultaneous presentation of acute myocardial infarction and acute promyelocytic leukemia.  Ann Hematol. 2006;  85 409-410
  CrossrefPubMedGoogle Scholar
• 27 Bauer K A, Rosenberg R D. Thrombin generation in acute promyelocytic leukemia.  Blood. 1984;  64 791-796
  CrossrefPubMedGoogle Scholar
• 28 Dombret H, Scrobohi M L, Ghorra P et al.. Coagulation disorders associated with acute promyelocytic leukemia: corrective effect of all-trans retinoic acid treatment.  Leukemia. 1993;  7 2-9
  PubMedGoogle Scholar
• 29 Watanabe R, Murata M, Takayama N 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;  77 641-645
  Article in Thieme ConnectPubMedGoogle Scholar
• 30 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
• 31 Tallman M S, Hakimian D, Kwaan H C, Rickles F R. New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia.  Leuk Lymphoma. 1993;  11 27-36
  CrossrefPubMedGoogle Scholar
• 32 Barbui T, Finazzi G, Falanga A. The impact of all-trans retinoic acid in the coagulopathy of acute promyelocytic leukemia.  Blood. 1998;  91 3093-3102
  PubMedGoogle Scholar
• 33 Rovelli A, Biondi A, Rajnoldi A C et al.. Microgranular variant of acute promyelocytic leukemia in children.  J Clin Oncol. 1992;  10 1413-1418
  PubMedGoogle Scholar
• 34 McKenna R W, Parkin J, Bloomfield C D, Dorothy S, Brunning R D. Acute promyelocytic leukemia: a study of 39 cases with identification of a hyperbasophilic microgranular variant.  Br J Haematol. 1982;  50 201-214
  PubMedGoogle Scholar
• 35 Kiyoi H, Naoe T, Yokota S et al.. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia.  Leukemia. 1997;  11 1447-1452
  CrossrefPubMedGoogle Scholar
• 36 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 2185-2189
  CrossrefPubMedGoogle Scholar
• 37 Gale R E, Hills R, Pizzey A R et al.. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia.  Blood. 2005;  106 3768-3776
  CrossrefPubMedGoogle Scholar
• 38 Falanga A, Alessio M G, Donati M B et al.. A new procoagulant in acute leukemia.  Blood. 1988;  71 870-875
  PubMedGoogle Scholar
• 39 Falanga A, Iacoviello L, Evangelista V et al.. Loss of blast cell procoagulant activity and improvement in hemostatic variables in patients with acute promyelocytic leukemia administered all-trans retinoic acid.  Blood. 1995;  86 1072-1081
  PubMedGoogle Scholar
• 40 Edwards R L, Brande W. Procoagulant activity of the VX2 carcinoma: tissue factor activity is expressed by tumor cells.  Clin Res. 1989;  37 466A
  PubMedGoogle Scholar
• 41 Andoh K, Sadakata H, Uchiyama T et al.. One-stage method for assay of tissue factor activity of leukemic cell with special reference to disseminated intravascular coagulation.  Am J Clin Pathol. 1990;  93 679-684
  PubMedGoogle Scholar
• 42 Nawroth P P, Handlet D, Esmon C T, Stern D. Interleukin-1 induces endothelial cell procoagulant while suppressing cell surface anticoagulant activity.  Proc Natl Acad Sci USA. 1986;  83 3460-3464
  PubMedGoogle Scholar
• 43 Bevilacqua M F, Pober J, Majeau G et al.. Recombinant human tissue necrosis factor induces procoagulant activity in cultures human vascular endothelium: characterization and comparison with interleukin-1.  Proc Natl Acad Sci USA. 1986;  83 4533-4537
  CrossrefPubMedGoogle Scholar
• 44 Nachman R L, Hajar K A, Silverstein R L, Dinarello C A. Interleukin-1 induces endothelial cell synthesis of plasminogen activator inhibitor.  J Exp Med. 1986;  163 1595-1599
  CrossrefPubMedGoogle Scholar
• 45 Losada R, Espinosa E, Hernandez C, Dorticos E, Hernandez P. Thrombocytosis in patients with acute promyelocytic leukemia during all-trans retinoic acid treatment.  Br J Haematol. 1996;  95 704-705
  CrossrefPubMedGoogle Scholar
• 46 Greeno E W, Bach R, Moldow C. Apoptosis is associated with increased cell surface tissue factor procoagulant activity.  Lab Invest. 1996;  75 281-289
  PubMedGoogle Scholar
• 47 Flynn P D, Byrne C, Baglin T, Weissberg P, Bennett M. Thrombin generation by apoptotic vascular smooth muscle cells.  Blood. 1997;  89 4378-4384
  PubMedGoogle Scholar
• 48 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 is systemic lupus erythematosus.  Proc Natl Acad Sci USA. 1996;  93 1624-1629
  CrossrefPubMedGoogle Scholar
• 49 Kwaan H, Parmar S, Wang J. Pathogenesis of increased risk of thrombosis in cancer.  Semin Thromb Hemost. 2003;  29 283-290
  Article in Thieme ConnectPubMedGoogle Scholar
• 50 Bennett B, Booth N A, Croll A, Dawson A A. The bleeding disorder in acute promyelocytic leukemia: fibrinolysis due to u-PA rather than defibrination.  Br J Haematol. 1989;  71 511-517
  CrossrefPubMedGoogle Scholar
• 51 Sakata Y, Murakami T, Noro A et al.. The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia.  Blood. 1991;  77 1949-1957
  PubMedGoogle Scholar
• 52 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
• 53 Menell J S, Cesarman G M, Jacovina A T et al.. Annexin II and bleeding in acute promyelocytic leukemia.  N Engl J Med. 1999;  340 994-1004
  CrossrefPubMedGoogle Scholar
• 54 Kwaan H, Wang J, Weiss I. Expression of receptors for plasminogen activators on endothelial cell surface depends on their origin.  J Thromb Haemost. 2004;  2 306-312
  CrossrefPubMedGoogle Scholar
• 55 Brownstein C, Deora A B, Jacovina A T et al.. Annexin II mediates plasminogen-dependent matrix invasion by human monocytes: enhanced expression by macrophages.  Blood. 2004;  103 317-324
  CrossrefPubMedGoogle Scholar
• 56 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;  6 315-329
  CrossrefPubMedGoogle Scholar
• 57 Federici A B, Falanga A, Lattuada A et al.. Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukemia by treatment with all-trans retinoic acid.  Br J Haematol. 1996;  92 733-739
  CrossrefPubMedGoogle Scholar
• 58 Federici A B, D'amico E A. The role of von Willebrand factor in the hemostatic defect of acute promyelocytic leukemia.  Leuk Lymphoma. 1998;  31 491-499
  PubMedGoogle Scholar
• 59 Kini A R, Peterson L C, 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 3919-3924
  CrossrefPubMedGoogle Scholar
• 60 Alimoghaddam K, Shariftabrizi A, Tavangar M et al.. Anti-leukemic and anti-angiogenesis efficacy of arsenic trioxide in new cases of acute promyelocytic leukemia.  Leuk Lymphoma. 2006;  47 81-88
  CrossrefPubMedGoogle Scholar
• 61 Mechtcheriakova D, Wlachos A, Holzmuller 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 3811-3823
  PubMedGoogle Scholar
• 62 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 2643-2653
  PubMedGoogle Scholar
• 63 Chen G Q, Shi X G, Tang W et al.. Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells.  Blood. 1997;  89 3345-3353
  PubMedGoogle Scholar
• 64 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 3852-3860
  PubMedGoogle Scholar
• 65 Di Bona E, Avvisati G, Castaman G et al.. Early hemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukemia.  Br J Haematol. 2000;  108 689-695
  CrossrefPubMedGoogle Scholar
• 66 Tapiovara H, Matikainen S, Hurme M, Vaheri A. Induction of differentiating therapy of promyelocytic NB4 cells by retinoic acid is associated with rapid increase in urokinase activity subsequently downregulated by production of inhibitors.  Blood. 1994;  83 1883-1891
  CrossrefPubMedGoogle Scholar
• 67 Zhang X, Zhou H, Wang J et al.. Arsenic trioxide, retinoic acid and Ara-c regulated the expression of annexin-II on the surface of APL cells, a novel co-receptor for plasminogen/tissue plasminogen activator.  Thromb Res. 2002;  106 63-70
  CrossrefPubMedGoogle Scholar
• 68 Olwill S A, McGlynn H, Gilmore W S, Alexander H D. All-trans retinoic acid-induced downregulation of annexin-II expression in myeloid leukemia call lines is not confined to acute promyelocytic leukemia.  Br J Haematol. 2005;  131 258-264
  CrossrefPubMedGoogle Scholar
• 69 Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia.GIMEMA retrospective study in 268 consecutive patients.  Blood. 1990;  75 2112-2117
  PubMedGoogle Scholar
• 70 Keane T J, Gorman A M, O'Connell L G, Fennelly J J. Epsilon-amino-caproic acid in the management of acute promyelocytic leukemia.  Acta Haematol. 1976;  56 202-204
  PubMedGoogle Scholar
• 71 Schwartz B S, Williams E C, Conlan M G, Mosher D F. Epsilon-animocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency.  Ann Intern Med. 1986;  105 873-877
  PubMedGoogle Scholar
• 72 Tallman M S, Brenner B, de la Serna J et al.. Meeting report.  Leukemia Res. 2005;  29 347-351
  CrossrefPubMedGoogle Scholar
• 73 Hashimoto S, Koike T, Tatawaki W et al.. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid combined with antifibrinolytic therapy for prophylaxis of hemorrhage.  Leukemia. 1994;  8 1113-1115
  PubMedGoogle Scholar
• 74 Alimoghaddam K, Ghavamzadeh A, Jahani M. Use of NovoSeven for arsenic trioxide-induced bleeding in APL.  Am J Hematol. 2006;  81 720
  PubMedGoogle Scholar
• 75 Sanz M A, Tallman M S, LoCoco F et al.. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia.  Blood. 2005;  105 3019-3025
  CrossrefPubMedGoogle Scholar
• 76 Milligan D W, Grimwade D, Cullis J O et al.. Guidelines on the management of acute myeloid leukemia.  Br J Haematol. 2006;  135 450-474
  CrossrefPubMedGoogle Scholar

Martin S TallmanM.D. 

Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center

676 N. St. Clair Street Suite 850, Chicago, IL 60611

Email: m-tallman@northwestern.edu