Project Details


Background: Severe penetrating traumatic brain injury (TBI) patients represent the highest risk for complication associated with thromboembolism formation and hematoma expansion. Previous clinical studies demonstrated that the early use of venous thromboembolism chemoprophylaxis (VTC) in these patients did not exacerbate intracerebral hematoma while reducing the risk of thromboembolism. Despite these findings, there is no consensus among neurosurgeons regarding its use in the presence of TBI, the appropriate timing, or the dosing regimen. To address these issues, we propose to investigate the safety of VTC with regard to adversely affecting intracerebral hemorrhage in a rat model of penetrating TBI. The results of this study will potentially provide the scientific basis for modifying the clinical practice guidelines regarding the use of heparinoids for severe TBI in both civilian and military populations.Hypothesis: Prophylactic doses of heparin will not exacerbate cerebral contusion or hemorrhage in a rat model of penetrating ballistic-like brain injury (PBBI). Specific Aims: (1) Establish the dose-response relationship between heparinoid administration at 24h post-injury and intracerebral hemorrhage. (2) Define the time window for administration of heparinoid following PBBI.Study Design: All experiments will be conducted using a rat model of PBBI, which was designed to replicate the pathology of the permanent injury tract and temporary cavity created by a ballistic. (1) Three doses of enoxaparin (Lovenox®; LVX) were chosen based on available toxicology data and previous studies. At 24 hours following PBBI or sham procedures (craniotomy only), animals will receive either vehicle (water) or LVX subcutaneously at a 24-hour intervals over a 7-day period. Intracerebral hemorrhage will be assessed using computed tomography (CT) imaging at specified time points. Blood will be collected for coagulation tests. The animals will be euthanized on day 7 post-injury, and brains will be harvested for histological analyses including quantification of the lesion volume, intravascular microthrombi, and fibrin deposits. (2) Based on the emerging results in Specific Aim 1, an optimal dose of LVX will be identified and the initial dose will be administrated at 6 hours post-PBBI, followed by subsequent doses at a 24-hour intervals over a 7-day period. The outcome metrics will be the same as those in Specific Aim 1. If administration at 6 hours is proven to be safe, the dose-response profile will be determined. Alternatively, if administration at 6 hours results in high mortality and exacerbated intracerebral hemorrhage, the optimal dose will be evaluated with an initial dose given at 12 hours post-injury. If 12-hour administration is proven to be safe, the dose-response profile will be established.Relevance: Combat casualties are at risk of venous thromboembolism due to their initial injury severity followed by multiple, long distance air evacuation (intubated, sedated, lying flat at altitude) to hospitals where definitive care can be rendered. The use of heparinoids as prophylaxis for venous thromboembolism in the presence of TBI remains controversial among neurosurgeons and may exacerbate intracerebral hemorrhage. The proposed study aims at answering this important question: Does VTC adversely affect the hemorrhagic lesion in a preclinical model of penetrating TBI? The answers to this question, whether for or against the use of heparinoids, is of critical importance to the injured active duty Warfighter and is directly translatable from the benchtop to the bedside. Most certainly, the data will be used to further improve the military clinical practice guidelines for the management of severe TBI.

Effective start/end date30/09/1829/09/20


  • Congressionally Directed Medical Research Programs: $739,042.00


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