Project 1: Mechanisms of Dysregulated Fibrinolysis in Trauma-Induced Coagulopathy ABSTRACT With the incidence of multi-organ failure (MOF) after severe trauma falling below 10%, most mortality after trauma occurs early (<12hrs) and is attributable to coagulopathy. However, acute lung injury remains a common sequel and resource consumer in the ICU. In this project, we propose that the cause of acute mortality and late morbidity results from dysregulated clot stability due to over- or under-activation of the enzyme plasmin. We hypothesize that hemorrhagic shock predisposes towards systemic hyperfibrinolysis that leads to uncontrolled bleeding, whereas tissue injury provokes hypofibrinolysis (fibrinolysis shutdown), leading to organ dysfunction and venous thromboembolism. Unfortunately the coagulopathy seen in critically injured patients cannot be reproduced in animal models, thus this proposal relies predominantly on trauma patient assessment, employing animal experiments to address specific mechanistic questions.
Aims 1 and 2 dissect the role of the preeminent regulator of plasmin, tissue plasminogen activator (tPA), in the blood of injured patients and animals, while Aim 3 evaluates novel tPA/plasmin regulators proposed by the discovery program described in Project 2. Determining the regulation of plasmin and its upstream regulators requires measurements of dynamic and fragile protein complexes in fresh blood. By activating plasmin, tPA appears to be the key factor in humans initiating excessive clot degradation following severe blood loss. This could occur due to excess tPA activating proteins or a loss of inhibitors of t-PA or plasmin. Conversely, any increase of such inhibitors or clot stabilizing proteins would promote systemic inhibition of fibrinolysis. Therefore:
Specific Aim 1 : Determine if early systemic hyperfibrinolysis is due to unopposed tPA activity after hemorrhagic shock in severely injured patients. The hypothesis that tissue injury and blood loss lead to opposite regulation of clot breakdown cannot be determined unequivocally in patients, because severe trauma is often a combination of severe tissue injury and major blood loss. Hence, Specific Aim 2: Determine the mechanisms regulating systemic fibrinolysis, in animal models that dissociate shock from tissue injury. Major trauma releases abnormal proteins into the blood from disrupted cells, blood component transfusions, and reactive stress responses.
In Specific Aim 3 : Determine the role of novel proteins (Project 2) and metabolites (Project3) generated during shock or tissue injury that modulate the plasminogen interactome and regulate systemic fibrinolysis. Impact: Since patients can present with vastly different levels of fibrinolysis, and since the phenotype can change over time, each patient must be treated differently as conditions change. The methods and information gained will enable patient specific management to mitigate the consequences of dysregulated fibrinolysis.
|Stettler, Gregory R; Sumislawski, Joshua J; Moore, Ernest E et al. (2018) Citrated kaolin thrombelastography (TEG) thresholds for goal-directed therapy in injured patients receiving massive transfusion. J Trauma Acute Care Surg 85:734-740|
|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|
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