Plasma proteomics improves thrombosis prediction in cancer and implicates a targetable IL-17-driven endothelial activation pathway
Thrombosis remains a major cause of morbidity and mortality in cancer patients. Existing risk models fail to reliably predict venous thromboembolism (VTE), underscoring the need for more accurate predictive models. In this study, we conducted a high-throughput proteomic analysis of 1,105 plasma proteins from newly diagnosed lung and gastric cancer patients prospectively monitored for VTE development. Utilizing a Bayesian probabilistic machine learning approach, we developed a predictive model incorporating 11 protein biomarkers and five clinical parameters (age, sex, history of VTE, body mass index, and hemoglobin), which significantly outperformed the Khorana prediction model. Orthogonal validation in an external placebo cohort from a phase III trial confirmed the model's predictive power. Further investigation into the mechanistic role of CD200R1, a checkpoint receptor limiting leukocyte inflammatory response that contributed strongly to the model, showed that reduced levels in plasma correlated with higher D-dimer and thrombosis risk. In CD200R1-deficient mice, elevated thrombin-antithrombin complexes confirmed a prothrombotic state characterized by increased IL-17A and endothelial inflammation. Administration of anti-IL-17A antibodies to CD200R1 deficient mice normalized thrombin generation in vivo, and a meta-analysis of human clinical IL-17A inhibitory antibody studies confirmed antithrombotic activity. These findings improve the prediction of thrombosis in cancer and highlight the utility of plasma proteomics to identify unanticipated mechanistic insights and therapeutic targets in thrombo-inflammatory disease. Overall design: To investigate transcriptional difference in gene expression in whole liver between wildtype and Cd200r1 knockout mice.