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

Abstract

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.

Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana‐Farber Cancer Institute protocols: effect of age and risk stratification of disease

“…This lesser exposure to ASP may explain the infrequent occurrence of symptomatic TE during the induction phase of treatment despite freshly inserted CVLs prior to the start of chemotherapy and the administration of steroids for 4 weeks. Symptomatic TE complicated intensification therapy in 9% of our patients; this rate is comparable with the rate of TE in children receiving concomitant ASP and steroids on contemporary ALL protocols (Nowak-Gottl et al, 1999;Kishi et al, 2003;Mathew et al, 2003).…”

“…The thrombogenic potential of steroids is well described in the literature (Isacson, 1970;Jorgenson et al, 1982;Zanon et al, 1982;van Giezen & Jansen, 1992;Patrassi et al, 1992;Ozturk et al, 1994;Patrassi et al, 1995;Nowak-Gottl et al, 1999, 2001aSartori et al, 1999;Athale & Chan, 2003b). Several investigators have shown that steroid therapy leads to elevation of factors VIII, von Willebrand factor (VWF), prothrombin and antithrombin, and decreases the levels of fibrinogen and plasminogen (Ozsoylu et al, 1962;Isacson, 1970;Jorgenson et al, 1982;Zanon et al, 1982;van Giezen & Jansen, 1992;Halton et al, 1992;Ozturk et al, 1994;Patrassi et al, 1995;Sartori et al, 1999).…”

“…The majority of the events of symptomatic TE in the present study occurred during the intensification phase of therapy in which patients received weekly ASP in combination with pulses of steroids (for 5 d in each 21-d cycle). Other investigators have documented that occurrence of TE in children with ALL is most frequent at the time of adminis-tration of ASP (Andrew et al, 1994;Mitchell et al, 1994aMitchell et al, , 1995Nowak-Gottl et al, 1999;Athale & Chan, 2003b). Although DFCI-ALL protocols 95-01 and 2000-01 also used ASP during the induction phase, it was given as a single dose only (Fig 1).…”

“…Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute protocols: effect of age and risk stratification of disease Thromboembolism (TE) is an important complication in children undergoing therapy for acute lymphoblastic leukaemia (ALL) as it has the potential to impact adversely on both their survival and quality of life (Andrew et al, 1994;Mitchell et al, 1994aMitchell et al, , 1995Nowak-Gottl et al, 1999;Athale & Chan, 2003a). TE is largely preventable with the use of effective prophylactic anticoagulant therapy (Nowak-Gottl et al, 1999;Elhasid et al, 2001). Ideally, thromboprophylaxis would be administered to only those patients whose risk of thrombosis is high, and whose risk of bleeding is acceptable.…”

“…The association between ASP therapy and thrombosis is well known (Andrew et al, 1994;Mitchell et al, 1994a;Athale & Chan, 2003a). More recently, comparative analysis of two contemporary German ALL study protocols identified concomitant administration of ASP and steroids as the most important risk factor for the development of TE in children (Nowak-Gottl et al, 1999, 2001aMauz-Korholz et al, 2000). However, despite the evidence for prothrombotic effects of steroids, the thrombogenic potential of steroid therapy in the context of childhood ALL has been recognised only recently (Nowak-Gottl et al, 2001a.…”