Thrombin Generation in Pediatric Patients Treated with L-asparaginase.

Treatment with L-asparaginase is associated with an disturbance of coagulation cascade. Increased thrombin generation is the most frequently cited coagulation anomaly associated with L-asparaginase treatment. Until now, almost all studies aimed on estimation of thrombin generation, have used circulating procoagulant markers such are thrombin/antithrombin complexes(TAT),D dimers(DD),prothrombin fragments (F1,F2).Calibrated automated thrombogram (CAT) allows the precise estimation of the whole amount of thrombin generated in vivo at present time. We show the first data on thrombin generation measured by CAT among pediatric patients with acute lymphoblastic leukemia treated with L-asparaginase.

Thrombin generation was measured in platelet poor plasma of 18 patients (age 7-17years) by means of CAT. Samples were obtained at pre-defined time points during the induction and reinduction phase of protocol ALL-IC BFM 2000. We simultaneously checked the APTT,PT,AT III,fibrinogen and DD from each blood sample. Detailed patientsx data were collected prospectively.

We collected 22 series of CAT measurements from 18 patients. The average endogenous thrombin potential (ETP) value was 1237,64±334,49nM/min during protocol I(PI) and 892,31±405,03 during protocol II resp.III(PII/III) (p .000013). Maximum ETP was reached on day 24 in PI (1310,15±256,3nM/min) and on day 15 in PII/III (978,20±262,30 nM/ min). The average ETP value in 20 healthy controls was 1218,12±129,00 nM/min. Three patients developed deep venous thrombosis (DVT) during the study period, all of them on PI. Their average ETP value on the last measurement before thrombosis was 1510,54±78,6 nM/min. Four patient had an infection gr. III/IV, according WHO, during the study period. Their average ETP value after the infection was 1711,43±106,0 nM/min. Two of those four patient developed DVT within 5 resp.8 days after the first sign of infection. Fibrinogen level <1g/l was detected in 19 samples out of 104. From those 19 samples with fibrinogen < 1,0,the ETP value from the same sample was normal in 14 cases and low in 5 cases. There were no bleeding episodes in that time.

Thrombin generation is preserved in majority of patients treated with L-asparaginase in accordance with ALL-IC BFM 2000 protocol, despite the associated hypofibrinogenemia. Patients on induction treatment generate significantly more thrombin than patients on reinduction treatment. Our results show the sharp increase in ETP right after the infection with risk of DVT. Our data should be proved on larger group of patients.

No relevant conflicts of interest to declare.