Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH
Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia
Results of the PARKAA study
Lesley Mitchell
1
Hospital for Sick Children, Toronto, Canada
,
Maureen Andrew
1
Hospital for Sick Children, Toronto, Canada
,
Kim Hanna
2
Bayer Inc., Toronto, Canada
,
Thomas Abshire
3
Emory University School of Medicine, Atlanta, USA
,
Jacqueline Halton
4
Children’s Hospital of Eastern Ontario, Ottawa, Canada
,
John Wu
5
B.C. Children’s Hospital, Vancouver, Canada
,
Ron Anderson
6
Alberta Children’s Hospital, Calgary, Canada
,
Irene Cherrick
7
University Hospital, Syracuse, USA
,
Sunil Desai
8
W Mackenzie Health Sciences Centre, Edmonton, Canada
,
Donald Mahoney
9
Baylor College of Medicine, Houston, USA
,
Patricia McCusker
1
Hospital for Sick Children, Toronto, Canada
,
Peter Chait
1
Hospital for Sick Children, Toronto, Canada
,
Mohamed Abdolell
1
Hospital for Sick Children, Toronto, Canada
,
Gabrielle de Veber
1
Hospital for Sick Children, Toronto, Canada
,
David Mikulis
1
Hospital for Sick Children, Toronto, Canada
› Author AffiliationsFinancial support: This work was supported by a grant from the Canadian Institutes of Health Research (Grant number: PA 14283) and Bayer Inc. L. M. is a scholar of the Canadian Institutes of Health Research. M. A. is a career scientist with the Heart and Stroke Foundation of Ontario
An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP.
Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.
1
Bjork I,
Danielsson A,
Fenton JW.
et al. The site in human antithrombin for functional proteolytic cleavage by human thrombin. FEBS Lett 1981; 126: 257-60.
4
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: 1251-7.
5
van Ommen CH,
Heijboer H,
Buller HR.
et al. Venous thromboembolism in childhood: A prospective two-year registry in The Nether-lands. J Pediatr 2001; 139: 676-81.
8
Heijboer H,
Brandjes DP,
Buller HR.
et al. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323: 1512-6.
9
Bauer K.
Rare hereditary coagulation factor abnormalities, in Nathan DG, Oski FA (eds): Hematology of Infancy and Childhood. Philadelphia, W.B: Saunders; 1998: 1660-75.
12
Mitchell LG,
Halton JM,
Vegh PA.
et al. Effect of disease and chemotherapy on hemo-stasis in children with acute lymphoid leukemia. Am J Pediatr Hematol. Oncol 1994; 16: 120-6.
13
Sutor A,
Ritter J.
Thrombosis in children with acute lymphoblastic leukemia with special regard to asparaginase treatment. Hemostaseologie 1992; 12: 35-43.
14
Pui CH,
Jackson CW,
Chesney CM.
et al. Involvement of von Willebrand factor in thrombosis following asparaginase-predni-sone-vincristine therapy for leukemia. Am J Hematol 1987; 25: 291-8.
15
Ott N,
Ramsay NK,
Priest JR.
et al. Sequelae of thrombotic or hemorrhagic complications following L- asparaginase therapy for childhood lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1988; 10: 191-5.
16
Pui CH,
Chesney CM,
Bergum PW.
et al. Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginaseprednisone-vincristine therapy for leukaemia. Br J Haematol 1986; 64: 283-90.
17
Priest J,
Ramsay K,
Steinherz P.
et al. A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J Pediatr 1982; 100: 984-9.
18
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: 386-91.
19
Mitchell L,
Sutor A,
Andrew M.
Hemostasis in childhood acute lymphoblastic leukemia: Co-agulopathy induced by disease and treatment. Semin Thromb Hemost 1995; 21 (04) 390-401.
20
Nowak-Gottl U,
Aschka I,
Koch HG.
et al. Resistance to activated protein C (APCR) in children with acute lymphoblastic leukaemia – the need for a prospective multicentre study. Blood Coagul Fibrinolysis 1995; 6: 761-4.
21
Nowak-Gottl 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 pro-thrombotic risk factors. Blood 1999; 93: 1595-9.
22
Mauz-Korholz C,
Junker R,
Gobel 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: 840-3.
24
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: 702-6.
25
Mitchell LG.
the PAARKA Investigators. 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. Cancer 2003; 97: 508-16.
26
Abshire TC,
Gold SH,
Odom LF.
et al. The coagulopathy of childhood leukemia. Throm-bin activation or primary fibrinolysis?. Cancer 1990; 66: 716-21.
27
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: 465-70.
28
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.
30
Sutor AH,
Niemeyer C,
Sauter S.
et al. Changes in blood coagulation in treatment with ALL-BFM-90 and NHL-BFM- 90 protocols. Klin Padiatr 1992; 204: 264-73.
31
Nowak-gottl U,
Ahlke E,
Klosel 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: 848-50.
32
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: 157-61.
33
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: 451-3.
34
Bauer KA,
Teitel JM,
Rosenberg RD.
L-asparaginase induced antithrombin III deficiency: evidence against the production of a hypercoagulable state. Thromb Res 1983; 29: 437-42.
35
Nowak-Gottl U,
Kuhn N,
Wolff JEA.
et al. Inhibition of hypercoagulation by antithrombin substitution in E coli L-asparaginase treated children. Eur J Haematol 1996; 56: 35-8.
36
Pogliani EM,
Parma M,
Baragetti I.
et al. L-asparaginase in acute lymphoblastic leukemia treatment: The role of human anti-thrombin III concentrates in regulating the prothrombotic state induced by therapy. Acta Haematol 1995; 93: 5-8.
37
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 Fibrinolysis 1994; 5: 23-8.
38
Cohn E,
Strong L,
Hughes Jr. W..
et al. Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946; 68: 459-65.
41
Brandt JT,
Triplett DA,
Alving B.
et al. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74: 1185-90.
43
Poort SR,
Rosendaal FR,
Reitsma PH.
et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
44
Schmidt B,
Gillie P,
Mitchell L.
et al. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158: 470-6.
