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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1595-1599
Prospective Evaluation of the Thrombotic Risk in Children With Acute
Lymphoblastic Leukemia Carrying the MTHFR TT 677 Genotype, the
Prothrombin G20210A Variant, and Further Prothrombotic Risk Factors
Ulrike Nowak-Göttl,
Cornelia Wermes,
Ralf Junker,
Hans-Georg Koch,
Rosmarie Schobess,
Gudrun Fleischhack,
Dirk Schwabe, and
Silke Ehrenforth
From the Pediatric Hematology/ Oncology and Institute of Clinical and
Laboratory Medicine/Institute of Atherosclerosis Research, University
Hospitals Bonn, Frankfurt, Halle, Hanover, and
Münster, Germany.
The reported incidence of thromboembolism in children with acute
lymphoblastic leukemia (ALL) treated with L-asparaginase, vincristine,
and prednisone varies from 2.4% to 11.5%. The present study was
designed to prospectively evaluate the role of the TT677 methylenetetrahydrofolate reductase (MTHFR) genotype, the prothrombin G20210A mutation, the factor V G1691A mutation,
deficiencies of protein C, protein S, antithrombin, and increased
lipoprotein (a) concentrations in leukemic children treated according
to the ALL-Berlin-Frankfurt-Muenster (BFM) 90/95 study
protocols with respect to the onset of vascular events. Three hundred
and one consecutive leukemic children were enrolled in this study.
Fifty-five of these 301 subjects investigated had one established
single prothrombotic risk factor: 20 children showed the TT677 MTHFR genotype; 5 showed the heterozygous prothrombin G20210A variant; 11 were carriers of the factor V G1691A mutation (heterozygous, n = 10;
homozygous, n = 1); 4 showed familial protein C, 4 protein S, and 2 antithrombin type I deficiency; 9 patients were suffering from
familially increased lipoprotein (a) [Lp(a)] concentrations (>30
mg/dL). In addition, combined prothrombotic defects were found in a
further 10 patients: the FV mutation was combined with the prothrombin
G20210A variant (n = 1), increased Lp(a) (n = 3), protein
C deficiency (n = 1), and homozygosity for the C677T MTHFR
gene mutation (n = 1). Lp(a) was combined with protein C deficiency
(n = 2) and the MTHFR TT 677 genotype (n = 2). Two hundred
eighty-nine of the 301 patients were available for thrombosis-free survival analysis. In 32 (11%) of these 289 patients venous
thromboembolism occurred. The overall thrombosis-free survival in
patients with at least one prothrombotic defect was significantly
reduced compared with patients without a prothrombotic defect within
the hemostatic system (P < .0001). In addition, a clear-cut
positive correlation (P < .0001) was found between thrombosis
and the use of central lines. However, because the prothrombotic
defects diagnosed in the total childhood population studied were all
found within the prevalences reported for healthy Caucasian
individuals, the interaction between prothrombotic risk factors, ALL
treatment, and further environmental factors is likely to cause
thrombotic manifestations.
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