Multiomics alterations associated with tolerance and response to simulated progressive hemorrhage in healthy adult humans

Hemorrhagic shock is a leading cause of preventable death among military and civilian trauma patients. Although caused by severe hypovolemia, the threshold of blood volume reduction that triggers recruitment of compensatory mechanisms varies markedly. Individuals have been classified as having low tolerance (LT) or high tolerance (HT) to hypovolemia; however, molecular features contributing to tolerance remain unclear. Here we investigate multiomics correlates of hypovolemia tolerance and molecular responses underlying physiological compensating mechanisms of blood loss. Healthy adult human subjects (<i>n</i> = 133) recruited from two sites underwent lower body negative pressure (LBNP) to simulate progressive hemorrhage. The primary outcome variable was hemodynamic instability accompanied by onset of decompensated shock defined by systolic blood pressure <80 mmHg. Participants were classified into HT (<i>n</i> = 90) and LT (<i>n</i> = 43) subjects using a cumulative stress index quantifying maximal LBNP tolerance. Genome-wide messenger ribonucleic acid (mRNA), microRNA, whole exome sequencing, and select protein abundances were assayed using blood samples collected immediately before and after LBNP procedure. LBNP produced extensive transcriptomic response at post- compared with pre-LBNP, including natural killer cell-mediated immunity activation and gas transport processes inhibition. Differentially expressed microRNAs (miRNAs) also regulated these enriched processes. Tolerance group-specific signals include alpha-beta T cell activation and major histocompatibility complex (MHC) class II protein complex assembly inhibition in HT group. Integrated analysis of multiple molecular layers demonstrated a role of cytokines and epigenetic regulators in molecular mechanisms of compensating for progressive hemorrhage. Overall, our results indicate that individual tolerances to central hypovolemia are associated with specific genomic mechanisms underlying the capacity to compensate for severe blood loss.<b>NEW & NOTEWORTHY</b> This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals' tolerance levels for progressive blood loss.