Homocysteine as a risk factor for thrombosis and when to ask for testing

Abstract

Homocysteine (Hcy) is a sulfur-containing amino acid that is produced from methionine through the removal of a methyl group. It can be recycled into methionine, an essential amino acid found in food, through two primary pathways: remethylation and transsulfuration. The remethylation process involves vitamins B6, B9, and B12, as well as 5-methyltetrahydrofolate, while transsulfuration converts Hcy into cysteine; this is facilitated by pyridoxal-5’-phosphate (vitamin B6) and the enzyme cystathionine β-synthase. Hcy has long been regarded as a risk factor for both venous and arterial thrombosis. However, clinical trials using folate have not demonstrated a significant effect in reducing the recurrence of venous thromboembolism or cardiovascular disease, except for a slight reduction in the incidence of ischemic stroke. We aimed to clarify the best course of action for managing hyperhomocysteinemia (HHcy) levels over 15 μmol/L. Moreover, we focused on severe HHcy, which may lead to a misdiagnosis of either homocystinuria or a remethylation defect. This condition is associated with a heightened risk of both venous and arterial thrombosis. In fact, a thrombotic episode can often be the first clinical manifestation of the disease, as well as a serious complication during its progression. Finally, we discuss the opportunity for including Hcy testing in thrombophilia screening.  We conclude that this is not an appropriate approach to adopt, but Hcy testing should be requested for a young or adolescent patient with an unproven, unexplained thrombotic event.