Yes, it matters: in contrast to blood plasma, serum metabolomics is confounded by platelets

Metabolomics is an emerging and powerful molecular profiling method supporting clinical investigations. For clinical metabolomics studies, serum is commonly used. Serum is collected after blood coagulation, a complex biochemical process involving active platelet metabolism. This may proof relevant as platelet counts and function may vary substantially in individuals. Applying a multi-omics analysis strategy comprising proteins and metabolites with a focus on lipid mediators, we systematically investigated serum and plasma obtained from the same healthy donors. While Biocrates MxP Quant 500 results correlated well (n=461, R2=0.991), lipid mediators (n=77, R2=0.906) and proteins (n=322, R2=0.860) differed substantially between serum and plasma. Actually, secretome analysis of activated platelets identified all proteins and most lipid mediators significantly enriched in serum when compared to plasma. Furthermore, a prospective, randomized, controlled parallel group metabolomics trial was performed, monitored by serum and plasma analyses. Healthy individuals received either acetylsalicylic acid, affecting platelets, or omega-3 fatty acids, hardly affecting platelets, for a period of seven days. In the acetylsalicylic acid group, serum analysis apparently demonstrated a significant drug-induced downregulation of the lipid mediators TXB2 and 12-HETE. The absence of these observation in plasma analyses suggested that these drug effects took place only during blood coagulation. Other effects of acetylsalicylic acid on alpha-linolenic acid and the fatty acid composition of triglycerides were detected both in serum and plasma. In the omega-3 fatty acid group, serum and plasma analysis results did not differ. These data strongly support the hypothesis that the serum metabolome is substantially confounded by platelets. Key pointsO_LISerum metabolomics data are confounded by platelets C_LIO_LIClinical evaluation of drug effects should be based on plasma metabolomics C_LI