Severe Trauma Provokes Pathologic Continuum of Plasmin Activation

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Project Summary: Severe trauma is a significant cause of death and disability. Early in convalescence, it causes bleeding, thrombosis and multi-organ dysfunction syndrome; later in convalescence, it instigates pathologic tissue repair and homeostasis, which prevents return to activities of daily living. Severe trauma related death and disability is directly correlated with the degree of activation of pathologic activation of coagulation (trauma- induce coagulopathy (TIC)) and inflammation (systemic inflammatory response syndrome (SIRS)) suggesting that mitigating TIC and/or SIRS would reduce complications caused by severe trauma. There is a key knowledge gap regarding the molecular instigators of TIC and SIRS following severe trauma. Our preliminary data support a transformative hypothesis that implicates inappropriate early activation of plasmin, the principle protease of the fibrinolytic system essential for tissue repair and homeostasis, as a key event that initiates TIC and SIRS, that also results in a prolonged loss of plasmin activity that disrupts tissue repair and homeostasis. Premise: Following an isolated trauma, plasminogen activation is tightly regulated and restricted to the wound site. However, following a severe trauma, plasmin is systemically activated (hyperfibrinolysis) followed by a prolonged deficit of plasmin activity (hypofibrinolysis), both of which are associated with poor outcomes. Our central hypothesis is that (i) early hyperfibrinolysis following severe trauma is a primary accelerant of TIC and SIRS, (ii) early hyperfibrinolysis causes hypofibrinolysis by exhausting plasminogen, and that (iii) the acquired plasminogen deficiency is a driver of pathologic tissue homeostasis and repair. Methods & Approach: Employing a murine burn injury as a representative model of severe trauma, we will determine in Aim 1 whether early hyperfibrinolysis accelerates TIC and SIRS and in Aim 2 whether early hyperfibrinolysis causes late sustained hypofibrinolysis. Plasmin activity will be pharmacologically inhibited/enhanced and measured using novel molecular tools. TIC and SIRS will be assessed with serial analysis of established biomarkers, platelet function, and organ specific NF-κB quantification as a surrogate measure of multiorgan dysfunction syndrome. The fibrinolytic system will be assessed by quantifying its individual elements, protease-inhibitor complexes, fibrin degradation products, and activity assays. Next, in Aim 3 we will combine the murine burn model with a femur fracture and skeletal muscle injury model to assess whether late hypofibrinolysis causes bone-related pathologies; specifically impaired fracture healing, heterotopic ossification in muscle, and trauma-induced osteoporosis. At the molecular level, we will determine if restoring plasmin activity prevents these bone complications and to what extent of the bone pathologic processes are due to fibrin, or fibrin mediated inflammation. Taken together, if true, these findings would provide support for 1) inhibition of plasminogen activation during the early convalescence to prevent, in part, TIC and SIRS and 2) resuscitation of plasminogen, or alternative means of promoting fibrinolysis, during late convalescence, to preserve bone health.