# Severe Trauma Provokes Pathologic Continuum of Plasmin Activation > **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $357,000 ## Abstract 1 Project Summary: 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-κB 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 d... ## Key facts - **NIH application ID:** 9904730 - **Project number:** 5R01GM126062-02 - **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER - **Principal Investigator:** Jonathan Schoenecker - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $357,000 - **Award type:** 5 - **Project period:** 2019-04-01 → 2023-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9904730 ## Citation > US National Institutes of Health, RePORTER application 9904730, Severe Trauma Provokes Pathologic Continuum of Plasmin Activation (5R01GM126062-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904730. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*