Hyperhomocysteinemia in cancer patients with thrombosis is not associated with methylene tetrahydrofolate reductase (MTHFR) gene mutations is down regulated by low molecular weight heparin (LMWHs) treatment

Abstract

2056 Background: MTHFR gene mutations, nutritional factors (folic acid/ B12) and anticancer drugs are primarily responsible for the observed hyper-homocysteinemia in cancer patients. In addition, it is well known that cancer patients exhibit increased prevalence of thrombotic events which may be due to the effects of homocysteine on endothelial function. The aim of this study was to demonstrate that an upregulation of homocysteine is multifactorial in cancer associated thrombosis. Methods: In three groups of 210 patients who were diagnosed with cancer and thrombosis and in a group of medical patients (cancer free) with thrombosis who were enrolled in a treatment study with LMWH, (Reviparin, n=90), blood levels of homocysteine were measured using an ELISA method (Diazyme Laboratories, San Diego, CA). In addition, molecular methods utilizing PCR were used to measure the MTHFR (677 and 1298) variants. Results: On a cumulative basis the cancer patients with thrombosis exhibited a relatively higher level of homocysteine (12.8± 4.9; range 2.2–39.4 uM/L) in comparison to normal (n=140, 4.8± 3.9; range 2.8=6.9 uM/L) and medical patients with thrombosis (5.3± 3.1; range 2.1–9.8 uM/L). Of the 210 cancer patients profiled for the molecular analysis 42/210 (20%) were positive for the 677 variant and 24/210 (11%) were positive for the 1298 variant. Similar results were obtained in the medical patients and normal volunteers. In one group of cancer patients (n=72) who were treated with a LMWH for 4–6 weeks, a down-regulation of homocysteine levels (4.8±2.5 uM/L) was noted. Conclusions: These results clearly suggest that, cancer patients with thrombosis exhibited a relatively higher homocysteine levels independent of MTHFR mutations. Medical (cancer free) patients with thrombosis do not exhibit this increase in circulating homocysteine levels. Thus, other relevant factors such as the chemotherapeutic agents contribute to this acquired upregulation of homocysteine. These observations also suggest that LMWHs are capable of reducing the homocysteine levels which may contribute to the observed effects of these agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis