Resuscitation with blood products has been the mainstay of restoring oxygenation and pro-coagulant potential following major trauma/hemorrhagic shock (T/HS). With better overall survival due to the implementation of damage control surgery, the acute coagulopathy of trauma (ACoT) has emerged as a leading cause of mortality through the consumption of clotting factors and platelets and pro-inflammatory changes in the vascular endothelium (ECs) via activation of serine proteases. In sum, the physiologic mechanisms of T/HS and ACoT appear to deplete anti-proteases, while activating plasma proteases, changing the injured patients'phenotype to pro-inflammatory, mediated through stimulation of protease-activated receptors (PARS) on ECs and neutrophils (PMNs). These clinical events predispose patients to PMN-mediated post-injury multiple organ failure (MOF). Indiscriminate resuscitation with blood products may contribute to this bloody vicious cycle and the numbers of blood or plasma transfusions are leading predictors of mortality. Stored blood products contain bioactive lipids which activate ECs and prime PMNs in vitro and in vivo and are etiologic in acute lung injury (ALI), a part of MOF. Our global hypothesis is that standard resuscitation with stored blood components ignores ACoT and by further perturbing the patient's proteome and lipidome increases PIVIN-mediated patient morbidity. This hypothesis will be tested by completion of the following specific aims:
Aim 1 : Investigate the proteins that accumulate post-injury in patients: plasma or which are infused during resuscitation in transfused blood components, e.g.: proteases and metalloenzymes, anti-proteases, phospholipases, lipid carriers, and coagulation factors.
Aim 2 : Investigate the pro-inflammatory lipids, arachidonic acid (AA) and it metabolites infused during the resuscitation of injured patients that are present in the transfused blood components and in the injured patient: plasma.
Aim 3 : Employ these proteins and lipids in a two-event in vivo model of ALI as either the first event, if they activate HMVECs, or the second event, if they cause PMN priming.
Aim 4 : Measure the cytokines, chemokines, and growth factors in injured patients before, during, and after resuscitation by multiplex cytokine/chemokine/growth factor arrays or commercial ELISA to determine the role of injury and resuscitation on the concentrations of these pro-inflammatory mediators in vivo. Completion of these aims may discover improved methods of resuscitation and better ways to transfuse injured patients to make transfusions safer and to optimize survival for injured patients requiring massive transfusion.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM049222-19
Application #
8499329
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
19
Fiscal Year
2013
Total Cost
$329,435
Indirect Cost
$114,119
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Coleman, Julia R; Moore, Ernest E; Chapman, Michael P et al. (2018) Rapid TEG efficiently guides hemostatic resuscitation in trauma patients. Surgery 164:489-493
Banerjee, Anirban; Silliman, Christopher C; Moore, Ernest E et al. (2018) Systemic hyperfibrinolysis after trauma: a pilot study of targeted proteomic analysis of superposed mechanisms in patient plasma. J Trauma Acute Care Surg 84:929-938
Moore, Ernest E; Moore, Hunter B; Chapman, Michael P et al. (2018) Goal-directed hemostatic resuscitation for trauma induced coagulopathy: Maintaining homeostasis. J Trauma Acute Care Surg 84:S35-S40
Reisz, Julie A; Wither, Matthew J; Moore, Ernest E et al. (2018) All animals are equal but some animals are more equal than others: Plasma lactate and succinate in hemorrhagic shock-A comparison in rodents, swine, nonhuman primates, and injured patients. J Trauma Acute Care Surg 84:537-541
Stettler, Gregory R; Moore, Ernest E; Nunns, Geoffrey R et al. (2018) Rotational thromboelastometry thresholds for patients at risk for massive transfusion. J Surg Res 228:154-159
Nunns, Geoffrey R; Stringham, John R; Gamboni, Fabia et al. (2018) Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase-Activating protein in lung tissue. J Surg Res 229:262-270
Moore, Hunter B; Moore, Ernest E; Chapman, Michael P et al. (2018) Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet 392:283-291
Kuldanek, Susan; Silliman, Christopher C (2018) Mortality after red blood cell transfusions from previously pregnant donors: complexities in the interpretation of large data. J Thorac Dis 10:648-652
Nunns, Geoffrey R; Moore, Ernest E; Stettler, Gregory R et al. (2018) Empiric transfusion strategies during life-threatening hemorrhage. Surgery 164:306-311
Slaughter, Anne L; Nunns, Geoffrey R; D'Alessandro, Angelo et al. (2018) The Metabolopathy of Tissue Injury, Hemorrhagic Shock, and Resuscitation in a Rat Model. Shock 49:580-590

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