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Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or
Laurence Rozen1, Denis Noubouossie1, Laurence Dedeken2
1Laboratory of hematology, CHU Brugmann, LHUB-ULB, ULB Université libre de Bruxelles, Brussels, Belgium.
Insights
Asparaginase (Asp) and corticosteroid (CS) treatment for acute lymphoblastic leukemia (ALL) increases thrombosis risk. Native Asp significantly enhances thrombin generation (TG) more than PEG Asp, particularly during early treatment phases.
Area of Science:
- Hematology
- Pediatric Oncology
- Thrombosis Research
Background:
- Asparaginase (Asp) and corticosteroid (CS) therapy in acute lymphoblastic leukemia (ALL) is linked to increased thrombotic events.
- Understanding the hemostatic changes during Asp therapy is crucial for managing thrombosis risk in pediatric ALL patients.
Purpose of the Study:
- To characterize the global hemostatic phenotype of children with ALL during Asp therapy.
- To compare the impact of native Asp versus PEGylated Asp on thrombin generation and coagulation parameters.
Main Methods:
- Thrombin generation (TG) was assessed in platelet-poor plasma from 56 children with B-lineage ALL.
- Measurements included TG parameters (ETP, peak TG), Protein C (PC), free Protein S (PS), antithrombin (AT), and fibrinogen.
- TG was evaluated with and without thrombomodulin to assess the protein C pathway's function.
Main Results:
- Elevated TG (ETP, peak) was observed at diagnosis, during Induction, and Late Intensification phases.
- Native Asp caused significantly higher TG compared to PEG Asp (P < 0.001).
- Impaired thrombomodulin-mediated thrombin generation reduction suggested PS/PC pathway dysfunction in ALL patients.
Conclusions:
- Asp and CS treatment enhances TG in pediatric ALL, with native Asp having a more pronounced effect.
- This prothrombotic state, evident early and during specific treatment phases, correlates with the observed high incidence of thrombotic events.
- Further research is needed to elucidate the mechanisms behind the less pronounced effect of PEG Asp.
Background:
Asparaginase (Asp) and corticosteroid (CS) treatment in patients with acute lymphoblastic leukaemia (ALL) is associated with an increased risk of thrombotic events.
Objective:
Characterization of global haemostatic phenotypes of patients with ALL during Asp therapy.
Procedure:
Thrombin generation (TG) was monitored in platelet-poor plasma of 56 children treated for a B lineage ALL (36 with native, 20 with PEG Asp) using 1 pM tissue factor and 4 μM phospholipids, with and without thrombomodulin. Protein C activity (PC), free protein S (PS), antithrombin (AT) and fibrinogen levels were also measured.
Results:
Elevated endogenous thrombin potential (ETP) and peak of TG were noted at diagnosis, throughout the Induction phase and Late Intensification but was significantly less for PEG than for native Asp (P < 0.001), while age, sex, type of corticosteroid during Induction and molecular response had no significant effect. The reduction of ETP after addition of thrombomodulin was significantly lower in ALL children compared with that in controls, suggesting impairment in PS/PC pathway. Three patients experienced thrombosis: two treated with native and one with PEG Asp. The two patients with native Asp had, at the time of thrombosis, a prothrombotic profile.
Conclusions:
Treatment with Asp, in combination with CS, enhances TG in children with ALL, more significantly with native than PEG Asp, which is present early at diagnosis, persists during Induction and reappears during Late Intensification. This is consistent with the high incidence of thrombotic events described during these phases of therapy. The less pronounced effect of PEG Asp remains to be elucidated.
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