Severe trauma is a significant cause of death and disability. Early in convalescence, it causes 2 bleeding, thrombosis and multi-organ dysfunction syndrome; later in convalescence, it instigates pathologic 3 tissue repair and homeostasis, which prevents return to activities of daily living. Severe trauma related death 4 and disability is directly correlated with the degree of activation of pathologic activation of coagulation (trauma- 5 induce coagulopathy (TIC)) and inflammation (systemic inflammatory response syndrome (SIRS)) suggesting 6 that mitigating TIC and/or SIRS would reduce complications caused by severe trauma. There is a key knowledge 7 gap regarding the molecular instigators of TIC and SIRS following severe trauma. Our preliminary data support 8 a transformative hypothesis that implicates inappropriate early activation of plasmin, the principle protease of 9 the fibrinolytic system essential for tissue repair and homeostasis, as a key event that initiates TIC and SIRS, 10 that also results in a prolonged loss of plasmin activity that disrupts tissue repair and homeostasis. Premise: 11 Following an isolated trauma, plasminogen activation is tightly regulated and restricted to the wound site. 12 However, following a severe trauma, plasmin is systemically activated (hyperfibrinolysis) followed by a prolonged 13 deficit of plasmin activity (hypofibrinolysis), both of which are associated with poor outcomes. Our central 14 hypothesis is that (i) early hyperfibrinolysis following severe trauma is a primary accelerant of TIC and SIRS, 15 (ii) early hyperfibrinolysis causes hypofibrinolysis by exhausting plasminogen, and that (iii) the acquired 16 plasminogen deficiency is a driver of pathologic tissue homeostasis and repair. Methods & Approach: 17 Employing a murine burn injury as a representative model of severe trauma, we will determine in Aim 1 whether 18 early hyperfibrinolysis accelerates TIC and SIRS and in Aim 2 whether early hyperfibrinolysis causes late 19 sustained hypofibrinolysis. Plasmin activity will be pharmacologically inhibited/enhanced and measured using 20 novel molecular tools. TIC and SIRS will be assessed with serial analysis of established biomarkers, platelet 21 function, and organ specific NF-?B quantification as a surrogate measure of multiorgan dysfunction syndrome. 22 The fibrinolytic system will be assessed by quantifying its individual elements, protease-inhibitor complexes, 23 fibrin degradation products, and activity assays. Next, in Aim 3 we will combine the murine burn model with a 24 femur fracture and skeletal muscle injury model to assess whether late hypofibrinolysis causes bone-related 25 pathologies; specifically impaired fracture healing, heterotopic ossification in muscle, and trauma-induced 26 osteoporosis. At the molecular level, we will determine if restoring plasmin activity prevents these bone 27 complications and to what extent of the bone pathologic processes are due to fibrin, or fibrin mediated 28 inflammation. Taken together, if true, these findings would provide support for 1) inhibition of plasminogen 29 activation during the early convalescence to prevent, in part, TIC and SIRS and 2) resuscitation of plasminogen, 30 or alternative means of promoting fibrinolysis, during late convalescence, to preserve bone health.

Public Health Relevance

Severe trauma is a significant cause of death and disability caused by pathologic activation of coagulation and inflammation and dysfunctional tissue repair and homeostasis. Previous studies in trauma patients suffering these complications indicate that they cluster together, suggesting common pathophysiology. The purpose of this proposal is to test our transformative hypothesis that implicates inappropriate early convalescent activation of plasmin, the principle protease of the fibrinolytic system, not only as a key event that initiates pathologic coagulation and inflammation, but also results in a prolonged loss of plasmin activity that is required for proper tissue homeostasis and repair in late convalescence.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Zhao, Xiaoli
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Vanderbilt University Medical Center
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