Best Practice & Research Clinical Haematology
Volume 22, Issue 1 , Pages 103-114 , March 2009

Thrombosis in childhood acute lymphoblastic leukaemia: epidemiology, aetiology, diagnosis, prevention and treatment

  • Ulrike Nowak-Göttl, MD (Professor, Doctor)

      Affiliations

    • Paediatric Haematology and Oncology, University Hospital Münster, Albert-Schweitzer-Str. 33, D-48149 Münster, Germany
    • Corresponding Author InformationCorresponding author. Tel.: + 49 251 8347783; Fax: +49 251 8347828.
    • ,
  • Gili Kenet, MD (Professor, Doctor)

      Affiliations

    • Israel National Haemophilia Centre, Sheba Medical Centre, Tel-Hashomer, Israel
    • ,
  • Lesley G. Mitchell, MSc (Professor)

      Affiliations

    • Stollery Children's Hospital, Edmonton, Alberta, Canada

References 

  1. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83:1251–1257
  2. Van Ommen CH, Heijboer H, Büller HR, et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr. 2001;139:676–681
  3. Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med. 2004;351:1081–1088
  4. Kuhle S, Koloshuk B, Marzinotto V, et al. A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res. 2003;111:227–233
  5. Monagle P, Adams M, Mahoney M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res. 2000;47:763–766
  6. Kuhle S, Massicotte P, Chan A, et al. Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service. Thromb Haemost. 2004;92:722–728
  7. Athale U, Siciliano S, Thabane L, et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer. 2008;51:792–797
  8. Bajzar L, Chan AK, Massicotte MP, et al. Thrombosis in children with malignancy. Curr Opin Pediatr. 2006;18:1–9
  9. Caruso V, Iacoviello L, Di CA, et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. 2006;108:2216–2222
  10. Payne JH, Vora AJ. Thrombosis and acute lymphoblastic leukaemia. Br J Haematol. 2007;138:430–445
  11. Appel IM, Hop WC, Pieters R. Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases. Blood Coagul Fibrinolysis. 2006;17:139–146
  12. Carlsson H, Stockelberg D, Tengborn L, et al. Effects of Erwinia-asparaginase on the coagulation system. Eur J Haematol. 1995;55:289–293
  13. Castaman G, Rodeghiero F, Dini E. Thrombotic complications during L-asparaginase treatment for acute lymphocytic leukemia. Haematologica. 1990;75:567–569
  14. Eckhof-Donovan S, Schwamborn D, Körholz D, et al. Thrombosis in children with acute lymphoblastic leukemia treated with the COALL protocol, Klin Padiatr. 1994;206:327–330
  15. Eden OB, Shaw MP, Lilleyman JS, et al. Non-randomised study comparing toxicity of Escherichia coli and Erwinia asparaginase in children with leukaemia. Med Pediatr Oncol. 1990;18:497–502
  16. Farinasso L, Bertorello N, Garbarini L, et al. Risk factors of central venous lines-related thrombosis in children with acute lymphoblastic leukemia during induction therapy: a prospective study. Leukemia. 2007;21:552–556
  17. Hongo T, Okada S, Ohzeki T, et al. Low plasma levels of hemostatic proteins during the induction phase in children with acute lymphoblastic leukemia: a retrospective study by the JACLS. Japan Association of Childhood Leukemia Study. Pediatr Int. 2002;44:293–299
  18. Jaime-Perez JC, Gomez-Almaguer D. The complex nature of the prothrombotic state in acute lymphoblastic leukemia of childhood. Haematologica. 2003;88:ELT25
  19. Kirschke R, Nürnberger W, Eckhof-Donovan S, et al. Coagulation and fibrinolysis in children with acute lymphoblastic leukaemia treated according to the COALL-05-92-protocol. Klin Padiatr. 1998;210:285–290
  20. Korte W, Feldges A, Baumgartner C, et al. Increased thrombin generation during fibrinogen and platelet recovery as an explanation for hypercoagulability in children with L-asparaginase therapy for ALL or NHL: a preliminary report. Klin Padiatr. 1994;206:331–333
  21. Kucuk O, Kwaan HC, Gunnar W, et al. Thromboembolic complications associated with L-asparaginase therapy. Etiologic role of low antithrombin III and plasminogen levels and therapeutic correction by fresh frozen plasma. Cancer. 1985;55:702–706
  22. Legnani C, Palareti G, Pession A, et al. Intravascular coagulation phenomena associated with prevalent fall in fibrinogen and plasminogen during L-asparaginase treatment in leukemic children. Haemostasis. 1988;18:179–186
  23. Mauz-Körholz C, Junker R, Göbel U, et al. Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost. 2000;83:840–843
  24. Miniero R, Pastore G, Saracco P, et al. Hemostatic changes in children with acute lymphoblastic leukemia treated according to two different L-asparaginase schedules. Am J Pediatr Hematol Oncol. 1986;8:116–120
  25. Mitchell LG, Halton JM, Vegh PA, et al. Effect of disease and chemotherapy on hemostasis in children with acute lymphoid leukemia. Am J Pediatr Hematol Oncol. 1994;16:120–126
  26. Mitchell LG, Andrew M, Hanna K, et al. A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer. 2003;97:508–516
  27. Nowak-Göttl U, Funk M, Mosch G, et al. Univariate tolerance regions for fibrinogen, antithrombin III, protein C, protein S, plasminogen and alpha 2-antiplasmin in children using the new Automated Coagulation Laboratory (ACL) method. Klin Padiatr. 1994;206:437–439
  28. Nowak-Göttl U, Boos J, Wolff E. Influence of two different asparaginase preparations on coagulation and fibrinolysis: a randomised trial. Fibrinolysis. 1994;8:S66–S68
  29. Nowak-Göttl U, Strater R, Dübbers A, et al. Ischaemic stroke in infancy and childhood: role of the Arg506 to Gln mutation in the factor V gene. Blood Coagul Fibrinolysis. 1996;7:684–688
  30. Nowak-Göttl U, Ahlke E, Schulze-Westhoff P, et al. Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E. coli asparaginase preparation. Br J Haematol. 1996;95:123–126
  31. Nowak-Göttl U, Werber G, Ziemann D, et al. Influence of two different Escherichia coli asparaginase preparations on fibrinolytic proteins in childhood ALL. Haematologica. 1996;81:127–131
  32. Nowak-Göttl U, Ahlke E, Klösel K, et al. Changes in coagulation and fibrinolysis in childhood acute lymphoblastic leukaemia re-induction therapy using three different asparaginase preparations. Eur J Pediatr. 1997;156:848–850
  33. Nowak-Göttl U, Sträter R, Heinecke A, et al. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood. 1999;94:3678–3682
  34. Nowak-Göttl U, Wermes C, Junker R, et al. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood. 1999;93:1595–1599
  35. Nowak-Göttl U, Kotthoff S, Hagemeyer E, et al. Interaction of fibrinolysis and prothrombotic risk factors in neonates, infants and children with and without thromboembolism and underlying cardiac disease. a prospective study. Thromb Res. 2001;103:93–101
  36. Pastore G, Miniero R, Saracco P, et al. Thrombosis and hemorrhage during L-asparaginase therapy. J Pediatr. 1983;102:639–640
  37. Priest JR, Ramsay NK, Latchaw RE, et al. Thrombotic and hemorrhagic strokes complicating early therapy for childhood acute lymphoblastic leukemia. Cancer. 1980;46:1548–1554
  38. Priest JR, Ramsay NK, Bennett AJ, et al. The effect of L-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia. J Pediatr. 1982;100:990–995
  39. Priest JR, Ramsay NK, Steinherz PG, et al. A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J Pediatr. 1982;100:984–989
  40. Pui CH, Jackson CW, Chesney CM, et al. Involvement of von Willebrand factor in thrombosis following asparaginase-prednisone-vincristine therapy for leukemia. Am J Hematol. 1987;25:291–298
  41. Risseeuw-Appel IM, Dekker I, Hop WC, et al. Minimal effects of E. coli and Erwinia asparaginase on the coagulation system in childhood acute lymphoblastic leukemia: a randomized study. Med Pediatr Oncol. 1994;23:335–343
  42. Semeraro N, Montemurro P, Giordano P, et al. Unbalanced coagulation-fibrinolysis potential during L-asparaginase therapy in children with acute lymphoblastic leukaemia. Thromb Haemost. 1990;64:38–40
  43. Shapiro AD, Clarke SL, Christian JM, et al. Thrombosis in children receiving L-asparaginase. Determining patients at risk. Am J Pediatr Hematol Oncol. 1993;15:400–405
  44. Sutor AH, Mall V, Thomas KB. Bleeding and thrombosis in children with acute lymphoblastic leukaemia, treated according to the ALL-BFM-90 protocol. Klin Padiatr. 1999;211:201–204
  45. Uszynski M, Osinska M, Zekanowska E, et al. Children with acute lymphoblastic leukemia: is there any subgroup of children without elevated thrombin generation? A preliminary study utilizing measurements of thrombin-antithrombin III complexes. Med Sci Monit. 2000;6:108–111
  46. (a)Zaunschirm A, Muntean W. Correction of hemostatic imbalances induced by L-asparaginase therapy in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1986;3:19–25(b)O'Meara A, Daly M, Hallinan FH. Increased antithrombin concentration in children with acute lymphoblastic leukemia receiving L-asparaginase therapy. Med Pediatr Oncol. 1988;16:169–174
  47. Nowak-Göttl U, Heinecke A, von Kries R, et al. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res. 2001;103:165–172
  48. Ruud E, Holmstrom H, de Lange C, et al. Thrombotic effects of asparaginase in two acute lymphoblastic leukemia protocols (NOPHO ALL-1992 versus NOPHO ALL-2000): a single-institution study. Pediatr Hematol Oncol. 2006;23:207–216
  49. Kaste SC, Gronemeyer SA, Hoffer FA, et al. Pilot study of noninvasive detection of venous occlusions from central venous access devices in children treated for acute lymphoblastic leukemia. Pediatr Radiol. 1999;29:570–574
  50. Kuhle S, Spavour M, Massicotte-Nolan P, et al. Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost. 2008;6:589–594
  51. Molloy W, English J, O'Dwyer R, et al. Clinical findings in the diagnosis of proximal deep vein thrombosis. Ir Med J. 1982;75:119–120
  52. Male C, Chait P, Ginsberg JS, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase. Thromb Haemost. 2002;87:593–598
  53. Male C, Kuhle S, Mitchell L. Diagnosis of venous thromboembolism in children. Semin Thromb Hemost. 2003;29:377–390
  54. Kenet G, Kirkham F, Niederstadt T, et al. Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet Neurol. 2007;6:595–603
  55. Kieslich M, Porto L, Lanfermann H, et al. Cerebrovascular complications of L-asparaginase in the therapy of acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2003;25:484–487
  56. Mitchell L, Hoogendoorn H, Giles AR, et al. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L-asparaginase-induced antithrombin III deficiency. Blood. 1994;83:386–391
  57. Mitchell L, Andrew M, Hanna K, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving L-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. 2003;90:235–244
  58. Santoro N, Giordano P, Del Vecchio GC, et al. Ischemic stroke in children treated for acute lymphoblastic leukemia: a retrospective study. J Pediatr Hematol Oncol. 2005;27:153–157
  59. Glaser DW, Medeiros D, Rollins N, et al. Catheter-related thrombosis in children with cancer. J Pediatr. 2001;138:255–259
  60. McLean TW, Fisher CJ, Snively BM, et al. Central venous lines in children with lesser risk acute lymphoblastic leukemia: optimal type and timing of placement. J Clin Oncol. 2005;23:3024–3029
  61. Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118:1373–1382
  62. Elhasid R, Lanir N, Sharon R, et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis. 2001;12:367–370
  63. Nowak-Göttl U, Ahlke E, Fleischhack G, et al. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood. 2003;101:2529–2533
  64. Sifontes MT, Nuss R, Hunger SP, et al. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol. 1997;96:484–489
  65. Wermes C, von Depka PM, Lichtinghagen R, et al. Clinical relevance of genetic risk factors for thrombosis in paediatric oncology patients with central venous catheters. Eur J Pediatr. 1999;158(Suppl. 3):S143–S146
  66. Arico M, Gamba G, Raiteri E, et al. Clotting abnormalities in children during maintenance chemotherapy for acute lymphoblastic leukemia. Haematologica. 1991;76:472–474
  67. de Stefano V, Gugliotta L, Mazzucconi MG, et al. Hypercoagulability during induction therapy of acute lymphoblastic leukemia is of scarce clinical relevance. Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto. Blood. 1993;81:2468–2469
  68. Homans AC, Rybak ME, Baglini RL, et al. Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia. J Clin Oncol. 1987;5:811–817
  69. Oner AF, Gürgey A, Kirazli S, et al. Changes of hemostatic factors in children with acute lymphoblastic leukemia receiving combined chemotherapy including high dose methylprednisolone and L-asparaginase. Leuk Lymphoma. 1999;33:361–364
  70. Pitney WR, Phadke KP, Dean S. Antithrombin III deficiency during asparaginase therapy. Lancet. 1980;1:493–494
  71. Ramsay NK, Coccia PF, Krivit W, et al. The effect of L-asparaginase of plasma coagulation factors in acute lymphoblastic leukemia. Cancer. 1977;40:1398–1401
  72. Solano C, Lopez J, Gomez N, et al. Acute lymphoblastic leukemia: hypofibrinogenemia with a low incidence of clinical complications is often found during induction remission therapy. Blood. 1992;80:1366–1368
  73. Capizzi R, Holcenberg JS. L-asparaginase. In:  Holland J,  Frei E editor. Cancer Medicine. Philadelphia: Lea & Freibiger; 1992;p. 796–803
  74. Boos J, Nowak-Göttl U, Jurgens H, et al. Loss of activity of Erwinia asparaginase on repeat applications. J Clin Oncol. 1995;13:2474–2475
  75. Ohnuma T, Holland JF, Freeman A, et al. Biochemical and pharmacological studies with asparaginase in man. Cancer Res. 1970;30:2297–2305
  76. Boos J, Werber G, Ahlke E, et al. Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations. Eur J Cancer. 1996;32A:1544–1550
  77. Duval M, Suciu S, Ferster A, et al. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002;99:2734–2739
  78. Dentali F, Gianni M, Agnelli G, et al. Association between inherited thrombophilic abnormalities and central venous catheter thrombosis in patients with cancer: a meta-analysis. J Thromb Haemost. 2008;6:70–75
  79. Giordano P, Santoro N, Del Vecchio GC, et al. T-immunophenotype is associated with an increased prevalence of thrombosis in children with acute lymphoblastic leukemia. A retrospective study. Haematologica. 2003;88:1079–1080
  80. Goldenberg NA. Long-term outcomes of venous thrombosis in children. Curr Opin Hematol. 2005;12:370–376
  81. Journeycake JM, Eshelman D, Buchanan GR. Post-thrombotic syndrome is uncommon in childhood cancer survivors. J Pediatr. 2006;148:275–277
  82. Korte W, Greiner J. PARKAA paves the way. Thromb Haemost. 2003;90:163–164
  83. Randolph AG, Cook DJ, Gonzales CA, et al. Benefit of heparin in central venous and pulmonary artery catheters: a meta-analysis of randomized controlled trials. Chest. 1998;113:165–171
  84. Dillon PW, Jones GR, Bagnall-Reeb HA, et al. Prophylactic urokinase in the management of long-term venous access devices in children: a Children's Oncology Group study. J Clin Oncol. 2004;22:2718–2723
  85. Halton JM, Mitchell LG, Vegh P, et al. Fresh frozen plasma has no beneficial effect on the hemostatic system in children receiving L-asparaginase. Am J Hematol. 1994;47:157–161
  86. Nowak-Göttl U, Rath B, Binder M, et al. Inefficacy of fresh frozen plasma in the treatment of L-asparaginase-induced coagulation factor deficiencies during ALL induction therapy. Haematologica. 1995;80:451–453
  87. Nowak-Göttl U, Kuhn N, Wolff JE, et al. Inhibition of hypercoagulation by antithrombin substitution in E. coli L-asparaginase-treated children. Eur J Haematol. 1996;56:35–38
  88. Ruud E, Holmstrom H, De Lange C, et al. Low-dose warfarin for the prevention of central line-associated thromboses in children with malignancies – a randomized, controlled study. Acta Paediatr. 2006;95:1053–1059
  89. Meister B, Kropshofer G, Klein-Franke A, et al. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;50:298–303
  90. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(Suppl.):887S–968S
  91. Pui CH, Chesney CM, Weed J, et al. Altered von Willebrand factor molecule in children with thrombosis following asparaginase-prednisone-vincristine therapy for leukemia. J Clin Oncol. 1985;3:1266–1272
  92. Athale UH, Siciliano SA, Crowther M, et al. Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute protocols: effect of age and risk stratification of disease. Br J Haematol. 2005;129:803–810

PII: S1521-6926(09)00004-8

doi: 10.1016/j.beha.2009.01.003

Best Practice & Research Clinical Haematology
Volume 22, Issue 1 , Pages 103-114 , March 2009

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