The applicant will test in this grant the hypothesis that acute traumatic coagulopahty is primarily caused by tissue hypoperfusion resulting in a complement mediated activation and subsequent depletion of the protein C pathway (AIMS 1 and 2). While the in vitro and in vivo approaches detailed in AIMS 1 and 2 will provide important mechanistic information regarding acute traumatic coagulopathy, the coagulation system is of such complexity to be completely visualized using the traditional cascade. The applicant will test the hypothesis that new techniques in network topology and dynamic modeling will allow for superior visualization and predict changes in the structure and function of the protein C system after trauma (AIM 3). Specifically he will first use a mouse model of trauma/shock to determine the timing and mechanism of perturbations in protein C after trauma and hypoperfusion. Secondly, he will use both the in vivo mouse model as well as an in vitro model of endothelial cell ischemia reperfusion to test the role of complement in activation of protein C after trauma and shock. Third, he will utilize a network representation of the protein C pathway as well as a newly constructed dynamic model of protein C to model in silico the protein C pathway after trauma and shock. The information obtained in these experiments will have important therapeutic significance in humans. The preliminary data from trauma patients that form the rationale for this grant application indicates that coagulation and complement abnormalities begin early after trauma, and are associated with significant morbidity and increased mortality. Thus understanding the molecular and systems level mechanisms associated with post traumatic coagulation and complement abnormalities may provide new avenues for therapy in trauma patients. The concerns here are that the model does replicate elements of what patients present with clinically. The typical trauma patient has not suffered only a loss on intravascular volume but has associated tissue injury. Damaged tissue represents an important part of the injury burden and contributes to the post injury dyshomeostasis. How this will impact the interpretation of the experimental model output needs to be directly considered by the applicant.
Aim 3 entails dynamic modeling based on the results of Aim 1 and 2 data and as such is an interesting approach. The question is how will it be validated as reflective of what occurs in trauma patients?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM085689-05
Application #
8318769
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2008-09-18
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$118,800
Indirect Cost
$8,800
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Kutcher, Matthew E; Kornblith, Lucy Z; Vilardi, Ryan F et al. (2014) The natural history and effect of resuscitation ratio on coagulation after trauma: a prospective cohort study. Ann Surg 260:1103-11
Kornblith, Lucy Z; Cohen, Mitchell Jay (2014) Response: the whole is greater than the sum of its parts: hemostatic profiles of whole-blood variants. J Trauma Acute Care Surg 77:1003-4
Grossman, Adam D; Cohen, Mitchell J; Manley, Geoffrey T et al. (2013) Altering physiological networks using drugs: steps towards personalized physiology. BMC Med Genomics 6 Suppl 2:S7
Kornblith, Lucy Z; Kutcher, Matthew E; Evans, Abigail E et al. (2013) The "found down" patient: a diagnostic dilemma. J Trauma Acute Care Surg 74:1548-52
Kutcher, Matthew E; Ferguson, Adam R; Cohen, Mitchell J (2013) A principal component analysis of coagulation after trauma. J Trauma Acute Care Surg 74:1223-9; discussion 1229-30
Kutcher, Matthew E; Kornblith, Lucy Z; Narayan, Raja et al. (2013) A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices. JAMA Surg 148:834-40
Howard, Benjamin M; Daley, Aaron T; Cohen, Mitchell Jay (2012) Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions. Semin Thromb Hemost 38:250-8
Laroche, Mathieu; Kutcher, Matthew E; Huang, Michael C et al. (2012) Coagulopathy after traumatic brain injury. Neurosurgery 70:1334-45
Cohen, Mitchell Jay; Call, Mariah; Nelson, Mary et al. (2012) Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 255:379-85

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