The methylenetetrahydrofolate reductase polymorphism (MTHFR c.677C>T) and elevated plasma homocysteine levels in a U.S. pediatric population with incident thromboembolism.

OBJECTIVE: Elevated plasma homocysteine (tHcy) and the MTHFR c.677C>T variant have been postulated to increase the risk of venous thromboembolism (VTE), although mechanisms and implications to pediatrics remain incompletely understood. The objectives of this study were to determine the prevalences of elevated tHcy and MTHFR variant in a pediatric population with VTE or arterial ischemic stroke (AIS), and to determine associations with thrombus outcomes.

STUDY DESIGN: Subjects were enrolled in an institution-based prospective cohort of children with VTE or AIS. Inclusion criteria consisted of objectively confirmed thrombus, ≤21years at diagnosis, tHcy measured and MTHFR c.677C>T mutation analysis. Clinical and laboratory data were collected. Frequencies for elevated tHcy and MTHFR variant were compared with NHANES values for healthy US children and also between study groups (VTE vs AIS, provoked vs idiopathic) and by age.

RESULTS: The prevalences of hyperhomocysteinemia or MTHFR variant were not increased in comparison to NHANES. tHcy did not differ between those with wild-type MTHFR versus either c.677C>T heterozygotes or homozygotes. There was no association between tHcy or MTHFR variant and thrombus outcomes.

CONCLUSION: In this cohort of US children with VTE or AIS, neither the prevalence of hyperhomocysteinemia nor that of MTHFR variant was increased relative to reference values, and adverse thrombus outcomes were not definitively associated with either. While it is important to consider that milder forms of pyridoxine-responsive classical homocystinuria will be detected only by tHcy, we suggest that routine testing of MTHFR c.677C>T genotype as part of a thrombophilia evaluation in children with incident thromboembolism is not warranted until larger studies have been performed in order to establish or refute a link between MTHFR and adverse outcomes.