Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase

GM Galstyan, OA Polevodova, AV Bazhenov, VV Troitskaya, OA Gavrilina, DG Gitel’zon, AE Vasil’ev, EN Parovichnikova

National Medical Hematology Research Center, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Gennadii Martinovich Galstyan, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(916)488-50-73; e-mail:

For citation: Galstyan GM, Polevodova OA, Bazhenov AV, et al. Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase. Clinical oncohematology. 2018;11(1):89-99.

DOI: 10.21320/2500-2139-2018-11-1-89-99


The article provides a literature review on the use of the L-asparaginase (ASP) in acute lymphoblastic leukemia (ALL) and describes two clinical cases. During the treatment with ASP as part of remission induction therapy thrombotic and hemorrhagic complications in the central nervous system were registered. In both cases these complications were associated with reduced plasma levels of antithrombin III (АТ), hypofibrinogenemia and thrombocytopenia. The risk factors for thrombohemorrhagic complications in ALL patients during ASP treatment are reviewed including combined ASP + anthracycline therapy, oral contraceptives, glucocorticosteroids, thrombophilia and the presence of central venous catheter (CVC). Possible mechanisms of thrombosis as well as the timing of its occurrence and possible localisation are discussed. The article considers different strategies for prevention and treatment of thrombotic and hemorrhagic complications in ALL patients receiving ASP. In all ALL patients receiving ASP plasma levels of fibrinogen and AT should be assessed before treatment initiation, on day 3 after the injection and further every 5 to 7 days within a period of 3 weeks after the injection. Novel oral anticoagulants are not dependent on blood AT levels and may be used for prevention and treatment of thrombotic and hemorrhagic complications associated with ASP intake. Finally, recommendations for the correction of AT levels and hypofibrinogenemia are given.

Keywords: L-asparaginase, thrombosis, thromboelastography, antithrombin III, hypofibrinogenemia, thrombocytopenia, novel oral anticoagulants.

Received: August 16, 2017

Accepted: October 27, 2017

Read in PDF 


  1. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. и др. Национальные клинические рекомендации по диагностике и лечению острых миелоидных лейкозов взрослых. Гематология и трансфузиология. 2014;59(1):1–32. [Savchenko VG, Parovichnikova EN, Afanas’ev BV, et al. National clinical recommendations for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i transfuziologiya. 2014;59(1):1–32. (In Russ)]
  2. Asselin BL. The three asparaginases. In: Kaspers GJL, Pieters R, Veerman AJP, eds. Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol. 457. Boston: Springer; 1999. pp. 621–9. doi: 10.1007/978-1-4615-4811-9_69.
  3. Попа А.В. Возможности адекватного выбора различных препаратов аспарагиназы. Онкогематология. 2007;1:52–6. [Popa AV. The abilities of adequate choice of different asparaginase products. Onkogematologiya. 2007;1:52–6. (In Russ)]
  4. 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(6):984–9. doi: 10.1016/s0022-3476(82)80535-0.
  5. Caruso V, Iacoviello L, Castelnuovo A Di, et al. Thrombotic complications in childhood acute lymphoblastic leukemia : a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood. 2006;108(7):2216–22. doi: 10.1182/blood-2006-04-015511.
  6. Rozen L, Noubouossie D, Dedeken L, et al. Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study. Pediatr Blood Cancer. 2017;26(2):294–301. doi: 10.1002/pbc.26228.
  7. Caruso V, Iacoviello L, Di Castelnuovo A, et al. Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis. J Thromb Haemost. 2007;5(3):621–3. doi: 10.1111/j.1538-7836.2007.02383.x.
  8. Ranta S, Heyman MM, Jahnukainen K, et al. Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinol.  2013;24(7):749–56. doi: 10.1097/mbc.0b013e328363b147.
  9. Abbott LS, Deevska M, Fernandez CV, et al. The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase. Blood. 2009;114(25):5146–51. doi: 10.1182/blood-2009-07-231084.
  10. Grace RF, Dahlberg SE, Neuberg D, et al. The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol. 2011;152(4):452–9. doi: 10.1111/j.1365-2141.2010.08524.x.
  11. Merlen C, Bonnefoy A, Wagner E, et al. L-Asparaginase Lowers Plasma Antithrombin and Mannan-Binding-Lectin Levels: Impact on Thrombotic and Infectious Events in Children With Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2015;62(8):1381–7. doi: 10.1002/pbc.25515.
  12. Mizrahi T, Leclerc J-M, David M, et al. ABO Group as a Thrombotic Risk Factor in Children With Acute Lymphoblastic Leukemia: A Retrospective Study of 523 Patients. J Pediatr Hematol Oncol. 2015;37(5):e328–32. doi: 10.1097/mph.0000000000000333.
  13. Lauw MN, Van der Holt B, Middeldorp S, et al. Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation. Thromb Haemost. 2013;109(4):633–42. doi: 10.1160/th12-11-0845.
  14. 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(2):508–16. doi: 10.1002/cncr.11042.
  15. Sibai H, Seki JT, Wang TQ, et al. Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia. Curr Oncol. 2016;23(4):e355–61. doi: 10.3747/co.23.3077.
  16. Goyal G, Bhatt VR. L-asparaginase and venous thromboembolism in acute lymphocytic leukemia. Fut Oncol. 2015;11(17):2459–70. doi: 10.2217/fon.15.114.
  17. Couturier M-A, Huguet F, Chevallier P, et al. Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience. Am J Hematol. 2015;90(11):986–91. doi: 10.1002/ajh.24130.
  18. Wani NA, Kosar T, Pala NA, Qureshi UA. Sagittal sinus thrombosis due to L-asparaginase. J Pediatr Neurosci. 2010;5(1):32–5. doi: 10.4103/1817-1745.66683.
  19. Guzman-Uribe P, Vargas-Ruiz AG. Thrombosis in Leukemia: Incidence, Causes, and Practical Management. Curr Oncol Rep. 2015;17(5):444. doi: 10.1007/s11912-015-0444-2.
  20. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with philadelphia chromosome-negative acute lymphoblastic leukemia: The GRAALL-2003 study. J Clin Oncol. 2009;27(6):911–8. doi: 10.1200/jco.2008.18.6916.
  21. Santoro N, Colombini A, Silvestri D, et al. Screening for coagulopathy and identification of children with acute lymphoblastic leukemia at a higher risk of symptomatic venous thrombosis: an AIEOP experience. J Pediatr Hematol Oncol. 2013;35(5):348–55. doi: 10.1097/mph.0b013e31828dc614.
  22. Pui C, Chesney CM, Bergum PW, et al. Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia. Br J Haematol. 1986;64(2):283–90. doi: 10.1111/j.1365-2141.1986.tb04121.x.
  23. Mauz-Korholz C, Junker R, Gobel U, Nowak-Gottl U. Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost. 2000;83(6):840–3.
  24. Risseeuw-Appel IM, Dekker I, Hop WC, Hahlen K. 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(4):335–43. doi: 10.1002/mpo.2950230404.
  25. Domenech C, Thomas X, Chabaud S, et al. L-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: Results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011;153(1):58–65. doi: 10.1111/j.1365-2141.2011.08588.x.
  26. Nowak-Gottl U, Ahlke E, Fleischhack G, et al. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood. 2003;101(7):2529–33. doi: 10.1182/blood-2002-06-1901.
  27. Hernandez-Espinosa D, Minano A, Ordonez A, et al. Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment. J Thromb Haemostasis. 2009;7(7):1128–33. doi: 10.1111/j.1538-7836.2009.03449.x.
  28. Hunault-Berger M, Chevallier P, Delain M, et al. Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: The CAPELAL study. Haematologica. 2008;93(10):1488–94. doi: 10.3324/haematol.12948.
  29. Ueno T, Ohtawa K, Mitsui K, et al. Cell cycle arrest and apoptosis of leukemia cells induced by L-asparaginase. Leukemia. 1997;11(11):1858–61. doi: 10.1038/sj.leu.2400834.
  30. Sugimoto K, Suzuki HI, Fujimura T, et al. A clinically attainable dose of L-asparaginase targets glutamine addiction in lymphoid cell lines. Cancer Sci. 2015;106(11):1534–43. doi: 10.1111/cas.12807.
  31. De Stefano V, Za T, Ciminello A, et al. Haemostatic alterations induced by treatment with asparaginases and clinical consequences. Thromb Haemost. 2015;113(2):247–61. doi: 10.1160/th14-04-0372.
  32. Giordano P, Molinari AC, Del Vecchio GC, et al. Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am J Hematol. 2010;85(5):325–30. doi: 10.1002/ajh.21665.
  33. Nowak-Gottl U, Boos J, Wolff J, et al. Asparaginase decreases clotting factors in vitro: a possible pitfall? Int J Clin Lab Res. 1995;25(3):146–8. doi: 10.1007/bf02592556.
  34. Bushman JE, Palmieri D, Whinna HC, Church FC. Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. Leuk Res. 2000;24(7):559–65. doi: 10.1016/s0145-2126(00)00017-5.
  35. Priest JR, Ramsay NKC, 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(6):990–5. doi: 10.1016/s0022-3476(82)80536-2.
  36. Mazzucconi MG, Gugliotta L, Leone G, et al. Antithrombin III infusion suppresses the hypercoagulable state in adult acute lymphoblastic leukaemia patients treated with a low dose of Escherichia coli L-asparaginase. A GIMEMA study. Blood Coagul Fibrinol. 1994;5(1):23–8. doi: 10.1097/00001721-199402000-00004.
  37. 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(2):235–44. doi: 10.1160/th02-11-0283.
  38. Farrell K, Fyfe A, Allan J, et al. An antithrombin replacement strategy during asparaginase therapy for acute lymphoblastic leukemia is associated with a reduction in thrombotic events. Leuk Lymphoma. 2016;57(11):2567–74. doi: 10.3109/10428194.2016.1165815.
  39. Elhasid R, Lanir N, Sharon R, et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinol. 2001;12(5):367–70. doi: 10.1097/00001721-200107000-00005.
  40. 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(2):298–303. doi: 10.1002/pbc.21222.
  41. Plander M, Szendrei T, Bodo I, Ivanyi JL. Successful treatment with rivaroxaban of an extended superficial vein thrombosis in a patient with acquired antithrombin deficiency due to Peg-asparaginase treatment. Ann Hematol. 2015;94(7):1257–8. doi: 10.1007/s00277-015-2368-1.