Does Venous Thrombosis Chemoprophylaxis (VTC) Adversely Affect the Hemorrhagic Lesion In a Preclinical Model of Penetrating Traumatic Brain Injury?

Excessive blood clotting often occurs in severe traumatic brain injury (TBI) patients. It leads to the formation of blood clots (a pathological condition known as venous thromboembolism; VTE) in the deep veins, usually in the leg (deep vein thrombosis; DVT) with potential for the clot to travel to the lungs (pulmonary embolism; PE), a serious and potentially fatal complication. Immobilization is a risk factor for DVT, and military casualties, with a combination of initial injury severity plus the immobilization associated with prolonged aeromedical transportation to definitive care, present a unique challenge for military physicians. One of the preventive interventions against DVT in surgical and immobilized patients is the use of medication such as heparinoids (also known as blood thinners) to reduce the clotting ability of the blood. Neurosurgeons, however, have traditionally been reticent to use this approach in the setting of a condition where the use of blood thinners might increase bleeding in the brain. Previous clinical studies demonstrated that early use of heparinoids in severe penetrating TBI patients was able to reduce the incidence of DVT but did not exacerbate bleeding in the brain. Despite these findings, there is no consensus among neurosurgeons regarding its use in the presence of TBI. To address this issue, we propose to use a rat model of penetrating TBI to investigate the safety of heparinoids with regard to adversely affecting bleeding in the brain.

In the proposed study, we will first examine the relationship between the amount of heparinoids administered and the bleeding in the brain following penetrating TBI. Heparinoids will be injected every 24 hours for up to 7 days with the first dose administered at 24 hours post-injury. Imaging and blood work will be performed to assess bleeding within the brain. At the end of the study, brain tissue will be analyzed for the presence of micro-bleeding and clot formation. Next, we will define the appropriate time window for heparinoids use by varying the administration time while using the best dosage based on the results from the first experiment. The first dose will be administered at 6 hours post-injury with the subsequent dose being injected at 24-hour intervals for up to 7 days. If 6-hour administration adversely affects the brain injury, the administration time of the first dose will be postponed to 12 hours post-injury. If the 6-hour or 12-hour regimen is proven to be safe (i.e., no exacerbation of bleeding within the brain), different doses of heparinoids will be evaluated. This proposed study will be completed in 2 years. 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.