Very Low Prevalence of Hyperhomocysteinemia among US Children with Personal/Family History of Thrombosis. Towards Reconsideration of the Recommendation for Routine Testing.

Background: Comprehensive thrombophilia laboratory testing is recommended for the evaluation of children with thrombosis by the Perinatal and Pediatric Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH). The C677T thermolabile variant of the methylene tetrahydrofolate reductase (MTHFR) gene is highly prevalent in Caucasians, carried in heterozygous form in 45% and homozygously in 10%. The thrombogenicity of the MTHFR C667T mutation is mediated via elevation in plasma homocysteine concentration. However, in the U.S., folate fortification of food products may circumvent the impact of this mutation upon plasma homocysteine.

Objective: To determine the prevalence of hyperhomocysteinemia among U.S. children with a personal history of thrombosis (thrombosis group) or a first-degree family history of thrombosis or thrombophilia (familial risk group).

Methods: All children comprising the two study groups had been referred to the Thrombosis/Thrombophilia Program at The Children’s Hospital, Denver, and were consecutively recruited for participation in collection of laboratory and clinical data for this research. Plasma homocysteine, performed clinically as part of the ISTH recommended thrombophilia laboratory assessment, was determined by gas chromatograph mass spectroscopy.

Results: Homocysteine concentration was normally distributed within the study population, and did not vary with age or differ significantly between the two study groups. Table 1 displays the results relative to age and study group. In 100% of subjects, homocysteine level was either low or normal with respect to the previously-established reference range for healthy individuals.

Conclusions: Despite a high historical prevalence of the MTHFR C677T mutation in Caucasians, the prevalence of hyperhomocysteinemia among U.S. children with thrombosis or a familial risk of thrombosis is extremely low, being absent among nearly 200 children studied. Because other mutations that do result in hyperhomocysteinemia and thrombosis occur rarely, homocysteine testing as part of a comprehensive thrombophilia assessment in U.S. children should be targeted to those patients in whom metabolic disease is suspected clinically.