Uncontrolled hemorrhage is the major cause of death in adults exposed to severe trauma. Trauma induced coagulopathy (TIC) occurs after injury and shock, accompanied by a "storm" of inflammatory and coagulation events leading to incapacitation of the hemostatic process. TICs compromise the hemostatic system because of dysregulated processes occurring on a systemic basis in which proteolytic systems destroy essential coagulation components. Previous studies have identified activated protein C-mediated destruction of the cofactor factor Va and implicated systemic fibrinolytic activity in which unregulated proteolysis destroys fibrinogen and parts of the plasma coagulation system. These terminal events observed in phlebotomy blood of TIC patients are caused by in vivo processes involving the proteins, cells and cytokines in blood and vascular tissues and tissue damage material entering the blood. The causes and breadth of TICs are not understood. This TACTIC proposal provides a comprehensive evaluation of the contributions of plasma proteins, blood cells, the vascular endothelium, the blood vessel, and extravascular tissue to TIC, making use of a unique infrastructure that includes already-funded DoD sites involved in trauma trials and Systems Biology. A comprehensive team approach by leading investigators in coagulation and inflammation research addresses the problem using a composite of in vitro and in vivo approaches to identify candidates responsible for TICs. Early translation of laboratory results into useful technology will be enabled by a set of 5 TACTIC trauma centers. Simultaneous with these studies, interactions with clinical centers engaged in DoD clinical trials will be developed in which research personnel at each center will be responsible for point-of-care studies and processing of blood samples. Collection techniques will utilize inhibitory cocktails to block ex vivo, post phlebotomy artifacts. Blood/plasma samples will be shipped to a secure repository and analyzed utilizing new technology to identify the natural history of TIC events. Continuation of TACTIC research projects will be dependent upon their potential utility for diagnosis and selection of therapy for trauma patients. Although uncontrolled bleeding is the major cause of death in people with severe traumatic injuries, the reasons for this bleeding are not completely understood. We plan to comprehensively describe the causes of trauma-related clotting and bleeding, and propose methods to diagnose the different causes and ultimately therapeutic interventions to prevent morbidity and mortality in traumatic settings.

Public Health Relevance

Although uncontrolled bleeding is the major cause of death in people with severe traumatic injuries, the reasons for this bleeding are not completely understood. We plan to comprehensively describe the causes of trauma-related clotting and bleeding, and propose methods to diagnose the different causes and ultimately therapeutic interventions to prevent morbidity and mortality in traumatic settings.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
1UM1HL120877-01
Application #
8616454
Study Section
Special Emphasis Panel (ZHL1-CSR-C (S1))
Program Officer
Kindzelski, Andrei L
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$4,569,600
Indirect Cost
$548,054
Name
University of Vermont & St Agric College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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