Hyperhomocysteinemia in cancer patients with thrombosis is independent of methylene tetrahydrofolate reductase gene mutation

Abstract

6152 Background: Methylene Tetrahydrofolate reductase (MTHFR) gene mutations and nutritional factors (folic acid/ B12) are primarily responsible for the observed increase in this surrogate marker. Since, cancer patients exhibit increased prevalence of thrombotic events, we hypothesized that upregulation of homocysteine may play a role in cancer associated thrombosis. However, initial screening of cancer patients in the ONCENOX study showed that the malignancy related thrombotic state was independent of molecular defects in Factor V Leiden, Prothrombin 20210 and MTHFR variants. (Hoppensteadt et al. Pathophysiology of Hemostasis and Thrombosis 2003; 33. S1. 03 A. 56). Methods: In the same group of 102 patients who were enrolled in a randomized open label, multidose, active comparator, parallel design study (ONCENOX) and in another group of cancer free patients 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). Results: On a cumulative basis ONCENOX patients exhibited a relatively higher level of homocysteine (11.8± 4.7 μM/L) in comparison to normal (n=140, 4.6± 2.9 μM/L) and in contrast to cancer patients exhibiting homocysteine levels (7.8± 3.1 μM/L). No difference in the MTHFR gene mutation profile was noted in the three groups. 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. Conclusions: 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. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Mitsubishi; Pfizer