Shock releases bile acidinducing platelet inhibition and fibrinolysis

Abstract

Introduction Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. Methods TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM to 750 μM was utilized due to biologic relevance. Whole blood mixtures were assayed using thrombelastography (TEG) for clot strength (MA) and fibrinolysis (LY30) quantification. Tranexamic acid (TXA) was used to block plasmin mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Results Fibrinolysis increased, when 750 μM TUCA was added to whole blood (median LY30 0.08 to 5.7, p=0.010), and clot strength decreased (median MA of 53.3 to 43.8, p=0.010). The addition of TXA, to a 750 μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 vs. with 2.7) and the decrease in clot strength (MA: without 48.2 vs. with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100 μM TUCA. Rats had a median 52-fold increase in TUCA, following a shock state that stayed elevated following resuscitation. Conclusion TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.

Red blood cells in hemorrhagic shock: a critical role for glutaminolysis in fueling alanine transamination in rats

“…This is relevant in the light of the role of succinate as a marker of mortality in critically ill patients in the military 21 and civilian population 22 , and the increasingly appreciated role succinate plays in (postshock) inflammatory responses 3 and trauma-induced coagulopathy. 8 Appreciation of the limited contribution of glutaminolysis to hemorrhagic RBC succinate in this model suggests that, analogously to previous observations in ischemic rodents, 16 other substrates may fuel hemorrhagic succinate accumulation. For example, increased proteolysis results in increased availability of circulating free amino acids that can be metabolized to succinate through alternative reactions, such as glutamate, isoleucine, valine, methionine, threonine.…”

“…3 Deregulation of metabolism following HS is a long-established concept. 4 Metabolic aberrations following hemorrhage can indeed predispose the body to inflammatory [5][6][7] and coagulopathic 8 complications. Understanding these mechanisms may soon provide actionable targets to improve short-and long-term outcomes in severely hemorrhaged patients in the civilian and military settings, for example, by determining whether early administration of plasma rather than normal saline can improve survival and metabolic recovery in humans, in like fashion to observations in a rodent model of profound HS.…”

Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine

“…At the same time, metabolic approaches are key in defining effective resuscitation strategies to meet the increased physiologic demands of critically injured patients by providing specific metabolic substrates such as glutamine 12,25–27 and arginine 28–32 , either alone or in combination with omega-3 fatty acids and nucleotides 33 . Recently, we applied metabolomics technologies to delineate the metabolic derangements in hemorrhaged rodents and critically ill patients to identify shared perturbations of the post-shock metabolic pathways observed in the animal model and the clinical setting 4,6,10,13 . After confirming the potential clinical relevance of the rodent model, we moved to defining the time course development of metabolic derangements in plasma after early mild hemorrhage and late severe HS 10 .…”

“…These observations from our and other groups suggest the potential significance of TCA cycle intermediates accumulating in post-shock plasma with respect to metabolic acidosis 10,13,34–36 . Recent observations indicate a role for ischemic hypoxia-derived succinate in inflammation 3,16 , and for post-shock plasma succinate levels in fibrinolysis in rodents and humans 6 . Consequently, we performed stable isotope tracing experiments with heavy glucose and glutamine in vivo in rodents to determine the metabolic origin of these TCA cycle compounds 5,12 .…”

“…Inflammatory responses encompass a broad variety of disease including infectious complications, acute respiratory distress and multiple organ failure 2 and have been recently related to mechanisms involving small molecule metabolites 3 . Early metabolic changes predispose the body for inflammatory 4,5 and coagulopathic 6 complications, but the mechanisms remain poorly understood. Despite advances in damage control surgery and resuscitation, patients continue to have substantial delayed morbidity 7,8 .…”