Novel Metabolites Are Associated with Coagulation Markers in Children with Congenital Heart Disease: A Metabolomic Study

BackgroundChildren with congenital heart disease (CHD) have an increased risk of developing thrombosis. Coagulation markers are used to guide clinical anti-coagulation decisions. We aimed to identify circulating metabolites that are associated with coagulation markers in children with CHD. MethodsPlasma samples were separated from whole blood under consistent conditions (consistent timing of blood draws and the same processing procedures). Untargeted metabolomic data were measured by Metabolon in plasma from young patients (age range: 0 days-24 years) with CHD before cardiac surgery. Coagulation markers included activated partial thromboplastin time (aPTT), prothrombin time (PT), activated clotting time (ACT), and international normalized ratio. Associations of individual metabolites with four coagulation markers were assessed with multivariable regression models, with false discovery rate (FDR) correction for multiple comparison. ResultsOut of 1,115 metabolites measured in samples from 203 patients, 776 met the quality control criteria. In total, 418 metabolites were associated with at least one marker, with one (valine) associated with ACT, three (gamma-CEHC, retinol, and behenoyl sphingomyelin) with PT, and 415 with aPTT (FDR q value < 0.05); among these, behenoyl sphingomyelin was associated with both PT and aPTT. Among the metabolites associated with aPTT, the top three were ornithine, X-21364 (identity unknown), and androstenediol disulfate. Metabolic pathway analysis based on the 415 metabolites significantly associated with aPTT suggested three pathways with an FDR q value<0.05: valine, leucine and isoleucine biosynthesis; histidine metabolism; and arginine and proline metabolism. ConclusionWe have identified promising novel metabolites and metabolic pathways associated with coagulation markers in children with CHD. Future studies are warranted to confirm these findings and examine the implications of the links between these metabolites and coagulation markers. HIGHLIGHTSO_LIIn this metabolomic study, we identified 418 metabolites associated with coagulation markers in young patients with CHD; C_LIO_LIThese metabolites indicated three novel metabolic pathways in this patient population; C_LIO_LIPlasma metabolites clustered into eight modules that were also associated with coagulation markers. C_LI