Patients with cancer who have a diet high in tryptophan, or protein-rich foods, have an increased risk for developing cancer-associated venous thromboembolism, according to preclinical findings published in Blood Advances.
This increased risk could potentially be mitigated by treatment with an IDO1 inhibitor, suggested the study authors, led by Saran Lotfollahzadeh, MD, MSc, Instructor at Boston University Chobanian & Avedisian School of Medicine.
Study Methods and Key Findings
Venous thromboembolism is the second most common cause of death among cancer survivors, so researchers continue to try to understand the underlying mechanisms of cancer-associated venous thromboembolism to improve outcomes.
The study authors looked at a mouse model of colon cancer and venous thromboembolism to determine how diet-derived metabolites impact venous thromboembolism and how these effects could potentially be overcome.
They found that diets imbalanced by protein-rich foods increased the risk for venous thrombogenicity in tumor-bearing mice. The tryptophan in the diet led to a procoagulant venous wall that demonstrated upregulation of tissue factor, plasminogen activator inhibitor-1, and von Willebrand Factor, as well as downregulation of thrombomodulin.
An examination of targeted metabolomics of sera from the tumor-bearing mice showed a pattern of increased biogenesis of kynurenine and catabolism, which are correlated with venous clots.
“Nutrition management is an integral component of cancer patient care. Patients with cancer are often advised to increase their dietary protein intake to compensate for cancer cachexia ... and chemotherapy side effects. At times, these patients receive parenteral nutrition..., including approximately five to eight times more [tryptophan] than dietary recommendation,” explained co-corresponding author Vipul Chitalia, MD, PhD, Professor of Medicine at Boston University Chobanian & Avedisian School of Medicine.
As IDO1 is an enzyme that can convert tryptophan to kynurenine, and because the tumor-bearing mice had increased IDO1 activity in the sera and of protein levels in the inferior vena cava, the researchers explored the use of an IDO1 inhibitor to overcome the risks of venous thromboembolism.
The IDO1 inhibitor reduced serum levels of kynurenine, restored the balance of both procoagulant and anti-coagulant factors in the venous endothelium, as well as suppressing venous thrombogenicity in the mice.
“Although our new findings are based on experimental models, we believe that knowledge gained from this study could prompt interest in further testing relevance to the human condition,” stated co-corresponding author Katya Ravid, DSc, the Barbara E. Corkey Professor of Medicine at the Boston University Chobanian & Avedisian School of Medicine.
Disclosure: Research funding was provided by a grant from the AHA Cardio-oncology SFRN CATHD Center, the Center of Cross Organ Vascular Pathology, and by the Thrombosis and Hemostasis Affinity Research Collaborative at Boston University Chobanian and Avedesian School of Medicine. For full disclosures of the study authors, visit ashpublications.org.
