H. B. Moore1,2, E. Gonzalez1,2, A. P. Morton1,2, M. P. Chapman1, A. L. Slaughter1,2, C. C. Silliman1,3, K. C. Hansen1, E. E. Moore1,2 1University Of Colorado Denver,Surgery,Aurora, CO, USA 2Denver Health Medical Center,Surgery,Denver, CO, USA 3Bonfils Blood Center,Hematology,Denver, C), USA
Introduction: Plasminogen (PLG) is a complex multi-domain protein with diverse functions. PLG is cleaved by tissue plasminogen activator (tPA)and yields plasmin, which degrages fibrin. Neutrophil proteases, such as elastase, can also modify PLG and produce angiostatin, which retains the fibrin-binding site of plasmin without the proteolytic domain. Previous animal work has demonstrated that hemorrhagic shock increases fibrinolytic activity while tissue injury reduces fibrinolytic activity while both causing a depletion of PLG. We hypothesize trauma patients with hyperfibrinolysis and fibrinolysis shutdown will have decreased PLG compared to trauma patients with normal fibrinolytic activity and healthy controls, and that angiostatin is a potent inhibitor of fibrinolysis.
Methods: 150 trauma activations were screened and, patients(n=10) with the lowest fibrinolytic activity(shutdown) were contrasted patients with the highest fibrinlytic activity(hyperfibrinolysis n=10), normal fibrinolytic activity(physiologic n=10) and healthy controls(n=10). PLG levels and firbrinolytic regulator proteins were measured in each of these cohorts. Exogenous angiostatin and elastase were mixed ex vivo in healthy volunteer blood (n=6) and challenged with tPA to promote fibrinolysis. Fibrinolysis was quantified by the LY30 variable using thrombelastography (TEG).
Results:PLG levels were decreased in shutdown and hyperfibrinolytic patients compared to trauma patients with physiologic activity and healthy controls (p<0.001). Fibriolytic regulator protein were also depleted in these phenotypes (figure1). Exogenous angiostatin reduced LY30 by 62% (p=0.046) in tPA challenged blood of healthy volunteers. Elastase also reduced LY30 by 96% (p=0.046). Additional clotting parameters were not effected by the addition of angiostatin in whole blood with and without tPA. However, elastase reduced R time by 30% (p=0.028) with and without tPA (-34% p=0.028) and increased angle by 33% with tPA (p=0.075).
Conclusion: Depletion of plasminogen post injury is associated with the hyperfibrinolytic and fibrinolysis shutdown phenotype. The breakdown of PLG may be the result of different mechanisms. Exogenous elastase promotes a hypercoaguable clot that is resistant to fibrinolysis, which is a common hemostatic derangement of patients in the surgical intensive care unit. These data support inflammation initiates an alternative utilization of PLG promoting post injury fibrinolysis resistance despite depletion of other fibrinolytic regulatory proteins.
