Thromb Haemost 2024; 124(10): 973-985
DOI: 10.1055/a-2316-4547
Stroke, Systemic or Venous Thromboembolism

Thrombin Generation Profile Using ST-Genesia after PEG-asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia

Anna Ruiz-Llobet
1   Pediatric Hematology Department, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Universitat de Barcelona, Barcelona, Spain
2   Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain
,
Susanna Gassiot
3   Laboratory of Hematology, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Universitat de Barcelona, Barcelona, Spain
,
Edurne Sarrate
3   Laboratory of Hematology, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Universitat de Barcelona, Barcelona, Spain
,
Josune Zubicaray
4   Servicio de Hematología y Hemoterapia, Hematología y Oncología Pediátricas, Hospital Infantil Universitario Niño Jesús, Fundación para la Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain
,
Susana Rives
2   Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain
5   Hematology and Oncology, Leukemia and Lymphoma Department, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu de Barcelona, Esplugues de Llobregat, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain
,
Warda Suleman
3   Laboratory of Hematology, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Universitat de Barcelona, Barcelona, Spain
,
Rubén Berrueco
1   Pediatric Hematology Department, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Universitat de Barcelona, Barcelona, Spain
2   Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain
› Author Affiliations
Funding This study was funded by projects PI17/00356, integrated into Plan Nacional de I + D + I, and co-funded by ISCIII – Subdirección General de Evaluación y Fomento de la Investigación Sanitaria – and Fondo Europeo de Desarrollo Regional (FEDER), CIBERER.


Abstract

Background Venous thromboembolism (VTE) etiology in children with acute lymphoblastic leukemia (ALL) is multifactorial. The use of global assays of hemostasis as a thrombin generation test (TGT) is useful to individualize VTE risk in adult patients. This prospective cohort study aimed to evaluate the usefulness of an automated TGT to evaluate VTE risk during ALL treatment in children.

Methods TGT (automated analyzer ST Genesia; ThromboScreen) and pro- and anticoagulant plasma proteins were analyzed during ALL treatment in pediatric patients following LAL-SEHOP-PETHEMA-2013 guidelines. Results were compared with a series of pediatric normal controls and evaluated according to pegylated asparaginase PEG-ASP administration and to VTE risk factors.

Results The study included 67 patients: males n = 35, B-ALL (n = 60). None had a VTE during the evaluated period. Compared to healthy controls, the normalized endogenous thrombin potential (N-ETP) ratio in patients was higher and ETP inhibition (ETP-inh) was lower, especially after PEG-ASP administration. Plasmatic protein C and protein S levels decreased after PEG-ASP administration, but antithrombin mean level did not. A bivariant analysis showed that ETP-inh was lower in patients >10 years old (p = 0.05) and in those with non-O blood type (p = 0.005). A linear mixed model also showed a higher TGT prothrombotic profile in patients with inherited thrombophilia.

Conclusion TGT could be a biomarker of a high VTE risk in ALL pediatric patients. Non-O blood group and inherited thrombophilia were associated with a significantly higher thrombotic profile, and an increased profile was also observed after administration of PEG-ASP.

Supplementary Material



Publication History

Received: 23 November 2023

Accepted: 28 April 2024

Accepted Manuscript online:
29 April 2024

Article published online:
17 May 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Kato M. Recent progress in pediatric lymphoblastic leukemia. Int J Hematol 2023; 117 (02) 155-161
  • 2 Nowak-Göttl U, Kenet G, Mitchell LG. Thrombosis in childhood acute lymphoblastic leukaemia: epidemiology, aetiology, diagnosis, prevention and treatment. Best Pract Res Clin Haematol 2009; 22 (01) 103-114
  • 3 Athale UH, Laverdiere C, Nayiager T. et al. Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study. BMC Cancer 2017; 17 (01) 313
  • 4 Levy-Mendelovich S, Barg AA, Kenet G. Thrombosis in pediatric patients with leukemia. Thromb Res 2018; 164 (Suppl. 01) S94-S97
  • 5 Pelland-Marcotte MC, Kulkarni K, Athale UH, Pole JD, Brandão LR, Sung L. Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: a report from CYP-C. Am J Hematol 2021; 96 (07) 796-804
  • 6 Sibson KR, Biss TT, Furness CL. et al; British Society for Haematology. BSH Guideline: management of thrombotic and haemostatic issues in paediatric malignancy. Br J Haematol 2018; 180 (04) 511-525
  • 7 Tullius BP, Athale U, van Ommen CH, Chan AKC, Palumbo JS, Balagtas JMS. Subcommittee on Hemostasis and Malignancy and the Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis. The identification of at-risk patients and prevention of venous thromboembolism in pediatric cancer: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (01) 175-180
  • 8 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 (05) 505-511
  • 9 Attard C, Ignjatovic V. Primary thromboprophylaxis in children with cancer: a road less travelled. Thromb Haemost 2019; 119 (12) 1894-1896
  • 10 Ruiz-Llobet A, Gassiot S, Sarrate E. et al. Venous thromboembolism in pediatric patients with acute lymphoblastic leukemia under chemotherapy treatment. Risk factors and usefulness of thromboprophylaxis. Results of LAL-SEHOP-PETHEMA-2013. J Thromb Haemost 2022; 20 (06) 1390-1399
  • 11 Caruso V, Iacoviello L, Di Castelnuovo A. et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108 (07) 2216-2222
  • 12 Athale UH, Mizrahi T, Laverdière C. et al. Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: a prospective evaluation. Pediatr Blood Cancer 2018; 65 (05) e26938
  • 13 Klaassen ILM, Lauw MN, Fiocco M. et al. Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia: risk factors and effect on prognosis. Res Pract Thromb Haemost 2019; 3 (02) 234-241
  • 14 Rühle F, Stoll M. Advances in predicting venous thromboembolism risk in children. Br J Haematol 2018; 180 (05) 654-665
  • 15 Mateos MK, Trahair TN, Mayoh C. et al. Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia. Thromb Res 2019; 178: 132-138
  • 16 Rodriguez V. Thrombosis complications in pediatric acute lymphoblastic leukemia: risk factors, management, and prevention: is there any role for pharmacologic prophylaxis?. Front Pediatr 2022; 10: 828702
  • 17 Athale UH, Flamand Y, Blonquist T. et al. Predictors of thrombosis in children receiving therapy for acute lymphoblastic leukemia: results from Dana-Farber Cancer Institute ALL Consortium trial 05-001. Pediatr Blood Cancer 2022; 69 (08) e29581
  • 18 Gidl A, Füreder A, Benesch M. et al; Austrian Berlin-Frankfurt-Münster (BFM) Study Group. Incidence and risk factors of venous thromboembolism in childhood acute lymphoblastic leukaemia - a population-based analysis of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group. Pediatr Hematol Oncol 2023; 40 (02) 181-191
  • 19 Rank CU, Toft N, Tuckuviene R. et al. Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years. Blood 2018; 131 (22) 2475-2484
  • 20 Barzilai-Birenboim S, Arad-Cohen N, Nirel R. et al. Thrombophilia screening and thromboprophylaxis may benefit specific ethnic subgroups with paediatric acute lymphoblastic leukaemia. Br J Haematol 2019; 184 (06) 994-998
  • 21 Lejhancova-Tousovska K, Zapletal O, Vytiskova S, Strbackova P, Sterba J. Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin-Frankfurt-Münster (BFM) protocols. Blood Coagul Fibrinolysis 2012; 23 (02) 144-154
  • 22 Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency. Blood 1994; 83 (02) 386-391
  • 23 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; 64 (02) 294-301
  • 24 Ishihara T, Nogami K, Ochi S. et al. Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L-asparaginase induction therapy in pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 2020; 67 (01) e28016
  • 25 Giordano P, Del Vecchio GC, Santoro N. et al. Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotypic subgroups. Pediatr Hematol Oncol 2000; 17 (08) 667-672
  • 26 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 (05) 325-330
  • 27 Lancé MD. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thromb J 2015; 13: 1
  • 28 Lim HY, Donnan G, Nandurkar H, Ho P. Global coagulation assays in hypercoagulable states. J Thromb Thrombolysis 2022; 54 (01) 132-144
  • 29 Depasse F, Binder NB, Mueller J. et al. Thrombin generation assays are versatile tools in blood coagulation analysis: a review of technical features, and applications from research to laboratory routine. J Thromb Haemost 2021; 19 (12) 2907-2917
  • 30 Binder NB, Depasse F, Mueller J. et al. Clinical use of thrombin generation assays. J Thromb Haemost 2021; 19 (12) 2918-2929
  • 31 Staddon JH, Smock KJ, Schiffman JD. et al. Pegasparaginase treatment alters thrombin generation by modulating the protein C and S system in acute lymphoblastic leukaemia/lymphoma. Blood Coagul Fibrinolysis 2015; 26 (07) 840-843
  • 32 Kumar R, Katare PB, Lentz SR, Modi AJ, Sharathkumar AA, Dayal S. Thrombotic potential during pediatric acute lymphoblastic leukemia induction: role of cell-free DNA. Res Pract Thromb Haemost 2021; 5 (05) e12557
  • 33 Gassiot S, Ruiz-Llobet A, Suleman W, Sarrate E, Berrueco R. Thrombin generation in children using ThromboScreen reagent kit with ST Genesia-a pilot study. Int J Lab Hematol 2021; 43 (06) 1612-1619
  • 34 Mesegué M, Alonso-Saladrigues A, Pérez-Jaume S. et al. Lower incidence of clinical allergy with PEG-asparaginase upfront versus the sequential use of native E. coli asparaginase followed by PEG-ASP in pediatric patients with acute lymphoblastic leukemia. Hematol Oncol 2021; 39 (05) 687-696
  • 35 Dargaud Y, Wolberg AS, Gray E, Negrier C, Hemker HC. Subcommittee on Factor VIII, Factor IX, and Rare Coagulation Disorders. Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (08) 1704-1707
  • 36 Athale U. Thrombosis in pediatric cancer: identifying the risk factors to improve care. Expert Rev Hematol 2013; 6 (05) 599-609
  • 37 Ismail MM, Hamed GM. Activity levels of natural anticoagulant proteins in childhood acute lymphoblastic leukemia: relation to thromboembolic complications and treatment. Blood Coagul Fibrinolysis 2017; 28 (01) 1-7
  • 38 Carmona R, Kizilocak H, Marquez-Casas E. et al. Markers of hypercoagulability in children with newly diagnosed acute lymphoblastic leukemia. Pediatr Blood Cancer 2022; 69 (03) e29522
  • 39 Albertsen BK, Grell K, Abrahamsson J. et al. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: a NOPHO ALL2008 randomized study. J Clin Oncol 2019; 37 (19) 1638-1646
  • 40 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 (02) 235-244
  • 41 Ay C, Dunkler D, Simanek R. et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011; 29 (15) 2099-2103
  • 42 Mitchell L, Lambers M, Flege S. et al. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study. Blood 2010; 115 (24) 4999-5004
  • 43 Sifontes MT, Nuss R, Hunger SP, Wilimas J, Jacobson LJ, Manco-Johnson MJ. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol 1997; 96 (03) 484-489
  • 44 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 (05) 348-355