Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency

Abstract

Pediatric patients with acute lymphoblastic leukemia (ALL) are at an increased risk of thromboembolic events. Potential responsible mechanisms include the disease process itself, treatment with chemotherapeutic agents (particularly L-Asparaginase [ASP]), or a combination of the disease and treatment. We studied thrombin regulation in 26 consecutive children with ALL and 14 healthy age- matched controls by: (1) plasma concentrations of prothrombin; (2) plasma inhibition of 125I-alpha-thrombin; and (3) four biochemical markers of in vivo thrombin activation (thrombin complexed to its inhibitor antithrombin III [ATIII; TAT], prothrombin fragment 1.2 (F1.2), activated protein C complexed to the inhibitors alpha 1 antitrypsin [APCAT]), and protein C inhibitor (APC-PCI). Measurements were made at presentation before treatment, after treatment with ASP alone, and during combination chemotherapy with and without ASP. At presentation, the capacity to generate thrombin (reflected by plasma prothrombin concentrations) and the capacity to inhibit thrombin (125I- alpha-thrombin--inhibitor complex formation) were similar in children with ALL compared with that for healthy children. After ASP alone or as part of combination chemotherapy, prothrombin levels were preserved, whereas plasma inhibition of 125I-alpha-thrombin decreased significantly because of a decrease in plasma concentrations of inhibitors, most importantly ATIII. After combination chemotherapy without ASP, plasma concentrations of ATIII and the capacity to inhibit 125I-alpha-thrombin returned to normal values, whereas prothrombin levels increased above control values. Thrombin generation in vivo also differed from healthy controls. At presentation, plasma concentrations of three of four markers of in vivo thrombin activity (TAT, F1.2, APCAT, but not APC-PCI) were increased in children with ALL. Neither ASP alone nor combination chemotherapy with or without ASP significantly altered values of these three markers. In summary, although the in vitro capacity to generate thrombin was preserved, the in vitro capacity to inhibit 125I-alpha-thrombin decreased after ASP therapy. Evidence for increased endogenous thrombin generation was documented in children with ALL at presentation and throughout treatment. We speculate that poor regulation of this thrombin may contribute to thrombotic complications in children with ALL.

Changes in coagulation and fibrinolysis in childhood ALL: a two‐step dose reduction of one E. coli asparaginase preparation

“…Results of this dose-reduction study show a down-regulation of coagulation and fibrinolytic proteins with improvement in children treated with 2500 IU/m 2 Medac ASP. Confirming literature data (Homans et al, 1987;Mitchell et al, 1994;Nowak-Göttl et al, 1994, 1996bSemeraro et al, 1990), a marked decrease in fibrinogen, plasminogen and 2-antiplasmin during the course of Medac ASP administration was recorded. Compared with a previous randomized trial (Nowak-Göttl et al, 1994), changes were less pronounced in the second-step dose reduction: 2-antiplasmin and fibrinolytic activation normalized and were similar to those documented for children treated with 10 000 IU/m 2 Bayer ASP.…”

“…Alterations in haemostasis have been frequently observed in patients with leukaemia, and thrombotic events are well documented in children receiving L-asparaginase (ASP) as a single agent or in combination with vincristine or prednisone, sometimes complemented by an anthracycline (Homans et al, 1987;Kucuk et al, 1985;Mitchell et al, 1994;Nowak-Göttl et al, 1994, 1996bPui et al, 1987;Semeraro et al, 1990).…”

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

“…Enhanced thrombin generation during induction therapy in ALL has been identified in several reports, 1,[17][18][19][20] Our data were derived using a plasma-based global assay in the absence of Plts. Satisfactory Plt counts were largely observed at the later stages of induction (T2 and T3), and these tended to coincide with an improvement in the relationship between T-EP and P-Peak ratios.…”

“…The study population included consecutive newly diagnosed patients with ALL enrolled from August 2014 to March 2018 at four core hospitals for pediatric hematology and oncology in Japan. All patients received induction chemotherapy following the guidelines of either the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol, consisting of a total of six doses of Escherichia coli L-Asp (Leunase R , Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan) 6000 U/m 2 (JACLS group, Day 15,17,19,22,24,and 26) or the Berlin-Frankfurt-Münster (BFM) 95 oriented protocol consisting of a total of eight doses of E. coli L-Asp (Leunase R ) 5000 U/m 2 (BFM group, Days 12,15,18,21,24,27,30, and 33) ( Figure 1). 14,15 Thromboprophylaxis including FFP transfusion, usually without cryoprecipitate because of it being an uncommon product in Japan, for low fibrinogen (Fbg) levels (≤50 mg/dL), AT supplementation for low AT levels (≤70% of control), and administration of Dana for anticoagulation was included in these protocols, if required, ultimately based on the decision of each clinician.…”

DNA- and Plasma-based Screening for Risk Factors in Infants and Children with Symptomatic Thromboembolism/DNA- und plasmabasiertes Screening von Risikofaktoren bei Säuglingen und Kindern mit symptomatischen thromboembolischen Ereignissen

“…Thus, to estimate the individual patient risk in pediatric patients suffering thromboembolism, it is recommended that symptomatic patients should be investigated in comparison with age-and gender-matched healthy controls from the same geographic catchment areas. Since there are only sparse data available to date with respect to the presence of inherited prothrombotic risk factors in pediatric populations others than Jews [39,64] or Caucasians [7,19,34,36,43,47,56,61], the following recommendations are restricted to Caucasian German and Austrian children with venous thrombosis or stroke [7,18,19,27,34,35,36,43,47,56,61]. In the latter cohort, screening for the inherited prothrombotic risk factors listed in Table 4, including the measurement of Lp(a) concentrations, is recommended along with evaluation of underlying clinical conditions ( Table 1).…”