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Increased endogenous thrombin generation in children with acute
lymphoblastic leukemia: risk of thrombotic complications in
L'Asparaginase-induced antithrombin III deficiency
L Mitchell, H Hoogendoorn, AR Giles, P Vegh and M Andrew
Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada.
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.
Volume 83,
Issue 2,
pp. 386-391,
01/15/1994
Copyright © 1994 by The American Society of Hematology
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