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.

Cerebral Venous Sinus Thrombosis in Children with Acute Lymphoblastic Leukemia carrying the MTHFR TT677 Genotype and Further Prothrombotic Risk Factors

“…In the present prospective study clinical data of 17 out of 288 consecutively admitted leukemic children (5.9%) treated according to the ALL-BFM 90/95 study protocols, receiving E. coli ASP during induction therapy and suffering from cerebral venous sinus thrombosis are shown. As previously described [12], the rate of thrombotic events reported here was found to be within the range recently published in leukemic children during combined steroid and ASP administration. However, 3 out of 17 patients (17.6%) affected died directly associated with the thrombotic onset.…”

“…Thus, the findings presented here, especially the fact that the majority of thrombosis followed intrathecal methotrexate application in a median of three days, strengthen the hypothesis of recently published data that local intrathecal folate reduction due to methotrexate [23] may contribute not only to severe neurotoxicity but also to the onset of venous sinus thrombosis. In addition, the findings that symptomatic patients carrying the homozygous TT677 MTHFR variant have additionally increased fasting homocysteine serum concentrations [12] did support the laboratory results of Quinn et al [16], reporting elevated homocysteine in the cerebral fluid of children who received methotrexate for the treatment of cancer. of the remaining 14 patients (82.4%) showed prolonged clinical symptoms six weeks after the vascular accident.…”

“…E. coli ASP preparations of different sources [8, 14,19] and dosages [10] including Erwinia ASP [2] are involved in venous occlusion. However, the reported incidence ofvascular accidents in these patients varies from 2.4 to 11.5% [2,4,8,9,11,12,14,19].…”

“…As recently discussed, the homozygous MTHFR C677T gene mutation along with increased fasting homocysteine concentrations [3,12] was diagnosed in 5 children with sagittal venous sinus thrombosis alone or combined with further prothrombotic risk factors. Thus, the findings presented here, especially the fact that the majority of thrombosis followed intrathecal methotrexate application in a median of three days, strengthen the hypothesis of recently published data that local intrathecal folate reduction due to methotrexate [23] may contribute not only to severe neurotoxicity but also to the onset of venous sinus thrombosis.…”

Low plasma levels of hemostatic proteins during the induction phase in children with acute lymphoblastic leukemia: A retrospective study by the JACLS

“…Although ASP therapy has significantly contributed to the increased survival of children with ALL, it has a number of well‐documented, toxic side‐effects including thrombo­embolic events. Children with ALL are at risk for thrombo­embolism from the disease itself, 4,5 from the use of CV catheters, 6−8 from the acquired deficiency of AT III secondary to treatment with ASP, 4,5 , 9 and from carrying genetic prothrombotic risk factors 10 . Administration of E. coli ASP induces alterations in the plasma levels of several coagulation and fibrinolytic proteins including fibrinogen, plasminogen, AT III and protein C levels 11−14 .…”