Circulating Metabolites Associated with Prothrombin Time and Activated Clotting Time in Children with Congenital Heart Disease: An Untargeted Metabolomics Study

Background: Coagulation markers are used to guide clinical anticoagulation decisions. We aimed to identify circulating metabolites that are associated with coagulation markers in children with congenital heart disease (CHD). Methods: Plasma samples were separated from whole blood under consistent conditions. Untargeted metabolomic data were measured in plasma from up to 203 young patients (age range: 0 days-24 years) with CHD before cardiac surgery. Coagulation markers included activated partial thromboplastin time (aPTT), prothrombin time (PT), and activated clotting time (ACT). Weighted Gene Co-expression Network Analysis (WGCNA) was performed to explore metabolite modules (clusters). Associations of metabolites with the coagulation markers were assessed cross-sectionally with regression models, with false discovery rate (FDR) correction for multiple comparison. Associations between coagulation markers and "eigenmetabolites" from WGCNA modules were assessed by correlation analysis. Results: A total of 776 metabolites were included in the final analysis. Among these, 20 metabolites were associated with PT and one (valine) with ACT (FDR q value < 0.05). Among the metabolites associated with PT, the top three were retinol, 1-palmitoyl-GPI (16:0), and X-25371 (identity unknown). One module from WGCNA with metabolites from the lipid super pathway was correlated with PT (P = 0.004). Conclusion: In this first attempt to identify novel metabolites for coagulation markers, we report 21 metabolites associated with PT or ACT in children with CHD. Future studies are needed to replicate these findings in independent cohorts and to elucidate the biological mechanisms linking these metabolites to hemostatic regulation.