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

The reported incidence of thromboembolism in children with acute lymphoblas tic 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 lipoprote in (a) concentrations in leukemic children treated according to the ALL-Ber lin-Frankfurt-Muenster (BFM) 90/95 study protocols with respect to the onse t of vascular events. Three hundred and one consecutive leukemic children w ere enrolled in this study. Fifty-five of these 301 subjects investigated h ad one established single prothrombotic risk factor: 20 children showed the TT677 MTHFR genotype; 5 showed the heterozygous prothrombin G20210A varian t; 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 antithr ombin type I deficiency; 9 patients were suffering from familially increase d lipoprotein (a) [Lp(a)] concentrations (>30 mg/dL). In addition, combined prothrombotic defects were found in a further 10 patients: the n! 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 MTHF R 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 30 1 patients were available for thrombosis-free survival analysis. In 32 (11% ) of these 289 patients venous thromboembolism occurred. The overall thromb osis-free survival in patients with at least one prothrombotic defect was s ignificantly 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 centra l 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 r isk factors, ALL treatment, and further environmental factors is likely to cause thrombotic manifestations. (C) 1999 by The American Society of Hemato logy.