Fibrinogen-associated plasma metabolites and implications for coagulation, inflammation, and vascular diseases

Background Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation. Objectives Here, we used fibrinogen as a representative quantitative measure of procoagulant risk and evaluated metabolites associated with fibrinogen levels using nontargeted plasma metabolomics profiling (Broad and Metabolon platforms). Methods Our analysis included 10 533 individuals across 6 United States-based cohorts representing diverse population groups. The cross-sectional relationship between each of the 789 metabolites tested and plasma fibrinogen concentration was assessed after adjustment for relevant covariates, including age, cohort-reported sex, body mass index, and circulating lipoprotein levels. Results Meta-analysis of per-cohort results revealed 270 metabolites significantly associated with fibrinogen levels (false discovery rate-adjusted P value < .05). Lipid species, such as glycerophospholipids, sphingolipids, and fatty acyls, were among the most significantly associated metabolites; some of these may capture effects of inflammation, as supported by sensitivity analyses adjusted for C-reactive protein. Significant associations between fibrinogen levels and serotonin, thyroxine, and sex hormone derivatives may capture endogenous influences on fibrinogen levels. Exogenous compounds and microbial cometabolites were significantly associated with fibrinogen, also implicating lifestyle and microbiome risk factors. Only a portion of fibrinogen-associated metabolites (30%) has been associated with cardiovascular disease outcomes in a prior study, suggesting that the associations discovered here may provide insights into vascular biology that case-control studies may not yet be powered to detect. Conclusion These findings contribute to the growing list of metabolite biomarkers that may influence coagulation and inflammation pathways and, thereby, vascular risk.