Intracranial hemorrhage (ICH) is a common sequel to traumatic brain injury (TBI) and a major cause of death and disability. For those who survive the initial insult, expansion of ICH within the first hours after trauma is a strong predictor of morbiity and mortality. However, current approaches to prevent progression of ICH have met with limited success. Injured brain is highly procoagulant and TBI releases abundant tissue factor (TF), which leads locally to the activation of platelets and coagulation proteins. This is followed by a systemic thrombin-mediated coagulopathy that constrains the efficacy of the unspecific anti-fibrinolytic tranexamic acid (TA) and may help explain the increased mortality that follows use of recombinant factor VIIa (rVIIa). We present a new hypothesis to explain the pathophysiology of ICH expansion and a new approach to its prevention. We postulate that marked release of the fibrinolysis initiators, tissue type plasminogen activator (tPA) and urokinase plasminogen activator, from the injured brain leads to both: 1) premature clot lysis and ICH expansion;and 2) neurotoxicity by excessive activation of N-methyl-D-aspartate receptors (NMDA-Rs) by tPA, which is not attenuated by TA or rVIIa. In support of this hypothesis, we show that a catalytically inactive tPA variant (tPAS481A) that specifically and in targeted fashion inhibits lysis of newly formed blood clots in the brain: a) attenuates expansion of ICH, b) reduces D-Dimers, c) lessens thrombocytopenia, d) decreases tPA mediated neurotoxicity, and e) improves neurological outcome post TBI. tPAS481A is significantly more effective than TA for all outcomes. We also developed tPA variants that selectively inhibit tPA-mediated neurotoxicity by blocking excessive NMDA-R mediated signal transduction, prevent fibrinolysis or block both pathways. We will test these tPA variants and use mice with genetic deletion of tPA to provide insight into the pathogenesis of progressive ICH post TBI and to develop novel therapeutic interventions.

Public Health Relevance

Development of intracerebral hemorrhage after traumatic brain injury is a strong predictor of morbidity and mortality for which no treatment is currently available. We hypothesize that hemorrhage expansion is caused by excessive release of tissue type and urokinase plasminogen activators (tPA and uPA) from the injured brain. We will study the ability of tPA variants to prevent hemorrhage and cell damage after traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS080014-02
Application #
8608015
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$180,000
Indirect Cost
$67,500
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104