Plasma homocysteine levels are considered to be an important surrogate marker of vasculopathy in thrombotic disorders. Methylene tetrahydrofolate reductase (MTHFR) gene mutations, nutritional factors (folic acid/ B12) and anticancer drugs are primarily responsible for the observed increase in this surrogate marker. In addition, it is well known that cancer patients exhibit increased prevalence of thrombotic events. The aim of these studies was to demonstrate that an upregulation of homocysteine plays a role in cancer associated thrombosis. However, initial screening of cancer patients showed that the malignancy related thrombotic state was independent of molecular defects in Factor V Leiden, Prothrombin 20210 and MTHFR ( 677 and 1298) variants (

Hoppensteadt et al. Proceedings ASCO 2003. 22:346;861
). In a group of 102 patients who were diagnosed with cancer and thrombosis and in a group of medical patients (cancer free) with thrombosis enrolled in a treatment study with low molecular weight heparin (CORTES, n=50), blood levels of homocysteine were measured using a highly specific ELISA method (Diazyme Laboratories, San Diego, CA). In addition, molecular methods utilizing PCR were used to measure the MTHFR (677 and 1298) variants. On a cumulative basis the cancer patients with thrombosis exhibited a relatively higher level of homocysteine (11.8± 4.7 uM/L) in comparison to normal (n=140, 4.6± 2.9 uM/L) and medical patients with thrombosis (5.3± 3.1 uM/L). Of the 102 cancer patients profiled for the molecular analysis 18% were positive for the 677 variant and 12% were positive for the 1298 variant. Similar results were obtained in the medical patients and normal volunteers. These results clearly suggest that, cancer patients with thrombosis exhibited a relatively higher level of circulating homocysteine levels which are unrelated to a molecular defect in MTHFR. Medical (cancer free) patients with thrombosis do not exhibit this increase in circulating homocysteine levels. Thus, other relevant factors such as the use of chemotherapeutic agents like methotrexate and purine analogs may contribute to this apparently acquired upregulation of homocysteine. This observation warrants periodic monitoring of homocysteine in patients with thrombosis and cancer. Nutritional supplementation of folic acid and B12 may be helpful in the overall management of these patients including those who are treated with methotrexate and purine analogues.

Topics:
cancer, hyperhomocysteinemia, methylenetetrahydrofolate reductase (nadph2), mutation, thrombosis, homocysteine, antineoplastic agents, methotrexate, purine nucleosides, surrogate markers

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2005, The American Society of Hematology
2004
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