Download PDF
Thromb Haemost 2013; 109(04): 633-642
DOI: 10.1160/TH12-11-0845
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation

Mandy N. Lauw
1   Department of Haematology, Academic Medical Center, Amsterdam, The Netherlands
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Bronno van der Holt
3   HOVON Data Centre, Erasmus MC-Daniel den Hoed, Rotterdam, The Netherlands
,
Saskia Middeldorp
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Joost C. M. Meijers
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Jan J. Cornelissen
4   Department of Haematology, Erasmus MC-Daniel den Hoed, Rotterdam, The Netherlands
,
Mariateresa Bajetta
1   Department of Haematology, Academic Medical Center, Amsterdam, The Netherlands
,
Bart J. Biemond
1   Department of Haematology, Academic Medical Center, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received: 20 November 2012

Accepted after minor revision: 11 January 2013

Publication Date:
22 November 2017 (online)

    Permissions and Reprints

Summary

Treatment of acute lymphoblastic leukaemia (ALL) is frequently complicated by venous thromboembolism (VTE). The efficacy and optimal approach of VTE prevention are unclear, particularly in adult patients. We assessed the effect of thromboprophylaxis on symptomatic VTE incidence in cycle 1 of ALL treatment in adult patients. Secondly, we explored potential etiologic factors for VTE and the clinical impact of VTE on ALL outcome. We retrospectively assessed symptomatic VTE incidence and use of thromboprophylaxis in 240 adults treated for newly diagnosed ALL in the Dutch-Belgian HOVON-37 multicentre study (1999–2005). Potential etiologic factors were explored by analysis of patient and disease characteristics, impact of VTE on ALL outcome by analysis of complete remission and overall survival rates. Symptomatic VTE was observed in 24 of 240 patients (10%). Thromboprophylaxis differed by centre (prophylactic fresh frozen plasma (FFP) supplementation or no thromboprophylaxis) and was applied only during L-asparaginase in cycle 1. VTE incidence was significantly lower with FFP supplementation than without FFP (6% vs. 19%; adjusted odds ratio [OR] 0.28; 95% confidence interval [CI] 0.10–0.73). FFP did not influence antithrombin or fibrinogen plasma levels. Patients with VTE in cycle 1 had a significantly poorer complete remission rate (adjusted OR 0.18; 95% CI 0.07–0.50), particularly patients with cerebral venous thrombosis (adjusted OR 0.17; 95% CI 0.04–0.65). Our study suggests that prophylactic FFP supplementation effectively reduces symptomatic VTE incidence during ALL treatment in adults. This should be confirmed in a randomised controlled trial.

Keywords

Acute lymphoblastic leukaemia - fresh frozen plasma - L-asparaginase - thromboprophylaxis - venous thrombosis
 

  • References

  • 1 Nowak-Gottl U, Kenet G, Mitchell LG. Thrombosis in childhood acute lymphoblastic leukaemia: epidemiology, aetiology, diagnosis, prevention and treatment. Best Pract Res Clin Haematol 2009; 22: 103-114.
    CrossrefPubMedGoogle Scholar
  • 2 Payne JH, Vora AJ. Thrombosis and acute lymphoblastic leukaemia. Br J Haematol 2007; 138: 430-445.
    CrossrefPubMedGoogle Scholar
  • 3 Athale UH, Chan AK. Thrombosis in children with acute lymphoblastic leukemia. Part I. Epidemiology of thrombosis in children with acute lymphoblastic leukemia. Thromb Res 2003; 111: 125-131.
    CrossrefPubMedGoogle Scholar
  • 4 Caruso V, Iacoviello L, Di Castelnuovo A. et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a metaanalysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108: 2216-2222.
    CrossrefPubMedGoogle Scholar
  • 5 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.
    CrossrefPubMedGoogle Scholar
  • 6 Gugliotta L, Mazzucconi MG, Leone G. et al. Incidence of thrombotic complications in adult patients with acute lymphoblastic leukaemia receiving L-asparaginase during induction therapy: a retrospective study. The GIMEMA Group. Eur J Haematol 1992; 49: 63-66.
    PubMedGoogle Scholar
  • 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; 05: 621-623.
    CrossrefPubMedGoogle Scholar
  • 8 Elliott MA, Wolf RC, Hook CC. et al. Thromboembolism in adults with acute lymphoblastic leukemia during induction with L-asparaginase-containing multi-agent regimens: incidence, risk factors, and possible role of antithrombin. Leuk Lymphoma 2004; 45: 1545-1549.
    CrossrefPubMedGoogle Scholar
  • 9 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: 452-459.
    CrossrefPubMedGoogle Scholar
  • 10 Kuhle S, Spavor M, Massicotte P. et al. Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost 2008; 06: 589-594.
    CrossrefPubMedGoogle Scholar
  • 11 Athale UH, Chan III AK. Thrombosis in children with acute lymphoblastic leukemia Part. Pathogenesis of thrombosis in children with acute lymphoblastic leukemia: effects of host environment. Thromb Res 2003; 111: 321-327.
    CrossrefPubMedGoogle Scholar
  • 12 Athale UH, Chan II AK. Thrombosis in children with acute lymphoblastic leukemia. Part. Pathogenesis of thrombosis in children with acute lymphoblastic leukemia: effects of the disease and therapy. Thromb Res 2003; 111: 199-212.
    CrossrefPubMedGoogle Scholar
  • 13 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: 325-330.
    PubMedGoogle Scholar
  • 14 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.
    PubMedGoogle Scholar
  • 15 Schneider P, Van DP, Rousseau A. et al. Increased levels of tissue factor activity and procoagulant phospholipids during treatment of children with acute lymphoblastic leukaemia. Br J Haematol 2010; 148: 582-592.
    CrossrefPubMedGoogle Scholar
  • 16 Astwood E, Vora A. Personal practice: how we manage the risk of bleeding and thrombosis in children and young adults with acute lymphoblastic leukaemia. Br J Haematol 2011; 152: 505-511.
    CrossrefPubMedGoogle Scholar
  • 17 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.
    CrossrefPubMedGoogle Scholar
  • 18 Nowak-Gottl 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.
    PubMedGoogle Scholar
  • 19 Hunault-Berger M, Chevallier P, Delain M. et al. Changes in antithrombin 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: 1488-1494.
    CrossrefPubMedGoogle Scholar
  • 20 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: 5146-5151.
    CrossrefPubMedGoogle Scholar
  • 21 Gugliotta L, D’Angelo A, Mattioli BM. et al. Hypercoagulability during L-asparaginase treatment: the effect of antithrombin III supplementation in vivo. Br J Haematol 1990; 74: 465-470.
    CrossrefPubMedGoogle Scholar
  • 22 Mitchell L, Andrew M, Hanna K. et al. Trend to efficacy safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PARKAA study. Thromb Haemost 2003; 90: 235-244.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Nowak-Gottl U, Kuhn N, Wolff JE. et al. Inhibition of hypercoagulation by antithrombin substitution in E. coli L-asparaginasetreated children. Eur J Haematol 1996; 56: 35-38.
    PubMedGoogle Scholar
  • 24 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.
    CrossrefPubMedGoogle Scholar
  • 25 Harlev D, Zaidman I, Sarig G. et al. Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treatment. Thromb Res 2010; 126: 93-97.
    CrossrefPubMedGoogle Scholar
  • 26 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.
    CrossrefPubMedGoogle Scholar
  • 27 Cornelissen JJ, van der Holt B, Verhoef GE. et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood 2009; 113: 1375-1382.
    CrossrefPubMedGoogle Scholar
  • 28 Monchi M, Berghmans D, Ledoux D, Citrate vs. et al. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Intensive Care Med 2004; 30: 260-265.
    CrossrefPubMedGoogle Scholar
  • 29 Nohe B, Kiefer RT, Ploppa A. et al. The effects of fresh frozen plasma on neutrophil-endothelial interactions. Anesth Analg 2003; 97: 216-221.
    PubMedGoogle Scholar
  • 30 Steiner M, Attarbaschi A, Haas OA. et al. Fresh frozen plasma contains free asparagine and may replace the plasma asparagine pool during L-asparaginase therapy. Leukemia 2008; 22: 1290.
    CrossrefPubMedGoogle Scholar
  • 31 Kamps WA, van der Palde Bruin KM, Veerman AJ. et al. Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004. Leukemia 2010; 24: 309-319.
    CrossrefPubMedGoogle Scholar
  • 32 Silverman LB, Gelber RD, Dalton VK. et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97: 1211-1218.
    CrossrefPubMedGoogle Scholar