Background Venous thromboembolism is a common complication in patients with colorectal cancer who exhibit high homocysteine and low folate levels. However, whether venous thrombosis is the result of a direct effect of folic acid or the presence of a homocysteine-mediated mediating effect cannot be determined. This study aimed to explore the association and mediating effects of serum folate and homocysteine on venous thromboembolism in patients with colorectal cancer. Methods This study included patients with colorectal cancer who were admitted to the First Hospital of Shanxi Medical University from May 2020 to May 2022. The patients’ medical records were reviewed to collect information on general demographic characteristics, the prevalence of venous thromboembolism on admission, laboratory blood indices, serum folate, and serum homocysteine. SPSS 26.0 software was used for data collation and statistical analysis; the χ 2 test was utilized for univariate analysis and unconditional logistic regression was applied for multivariate analysis. R 4.1.2 was used to perform the mediating effect test. Results A total of 236 colorectal cancer patients were investigated. The prevalence of colorectal cancer combined with venous thromboembolism was 15.3%; serum folate was <10.75 nmol/L in 25.4% of patients; and serum homocysteine was ≥22 µmol/L in 30.5% of patients. After controlling for confounding factors, the risk of venous thromboembolism was 2.48 times greater [95% confidence interval (CI): 1.04 to 5.94] in patients with low serum folate (<10.75 nmol/L) than in those with high serum folate (≥10.75 nmol/L). Also, the risk of venous thromboembolism was greater in those with high serum homocysteine (≥22 µmol/L) [odds ratio (OR) =2.99. 95% CI: 1.11 to 8.08]. The mediating effect test showed no direct effect of serum folate on venous thromboembolism combined with colorectal cancer, and a full mediating effect of serum homocysteine between serum folate and venous thromboembolism combined with colorectal cancer, with a mediating effect value of 0.002 and a total effect value of 0.0054. Conclusions Serum folate influences the formation of venous thromboembolism through serum homocysteine. It is recommended that the nutritional supplementation of patients be enhanced to control serum folate and serum homocysteine levels.
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