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.