Otto Thielen (Aurora, CO / US), Benjamin W Stocker (Aurora, CO / US), William Hallas (Aurora, CO / US), Lauren T Gallagher (Aurora, CO / US), Benjamin J Ramser (Aurora, CO / US), Sanchayita Mitra (Aurora, CO / US), Christopher Silliman (Aurora, CO / US), Ernest E. Moore (Aurora, CO / US; Denver, CO / US), Kirk Hansen (Aurora, CO / US), Angelo D'Alessandro (Aurora, CO / US), Mitchell J Cohen (Aurora, CO / US)
Introduction: Activated Protein C (APC) has been shown to play dual roles after injury driving both trauma-induced coagulopathy (TIC) by cleaving, and thus inactivating, factors Va and VIIIa and re-depressing fibrinolysis while also mediating an inflammomodulatory milieu through PAR-1 cytoprotective signaling. Because of this dual role it represents an ideal target for study and therapeutics after trauma. Importantly, Protein C (PC) is inversely related to APC as it becomes activated.
Objectives: Our aim is to uncover other important metabolic pathways associated with PC levels after trauma.
Materials & Methods: Serum samples from 105 trauma patients were collected as part of the Control of Major Bleeding After Trauma (COMBAT) randomized control trial. Analyses of large-scale metabolite expression using LC-MS/MS mass spectrometry were performed. Empirical Bayesian Analysis of Microarray (EBAM) was performed on samples collected at the emergency department (ED) to identify the metabolites most positively and negatively associated with total PC, followed by pathway analyses of these top correlated metabolites.
Results: A total of 15 metabolites were statistically significant (P<0.05) based on EBAM (Figure 1). These metabolites enriched most highly for vitamin B6 metabolism, as well as biosynthesis of unsaturated fatty acids, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, the tricarboxylic acid (TCA) cycle, and metabolism of glutathione, arachidonic acid, tryptophan, and purines (P<0.0001) (Figure 2).
Conclusion: These dual roles of PC, specifically in the antagonism of thrombosis and inflammation, make it an ideal therapeutic target. Our data shows not only PC"s associations beyond cleavage of coagulation factors Va and VIIIa, but also its variety of metabolic roles such as the generation and mobilization of cellular energy stores, for example. By uncovering these pathways, we pave the way to further define APC"s cytoprotective use in trauma.
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