The Therapeutic Potential of Cold Stored Platelets in Regulating Vascular Instability in Trauma

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PROJECT SUMMARY/ABSTRACT Administrative Supplement The Therapeutic Potential of Cold Stored Platelets in Regulating Vascular Stability in Trauma Trauma is the leading cause of death world-wide in individuals between the ages of 1-44, with traumatic brain injury (TBI) being the number one cause of death after trauma. Platelet transfusion and balanced ratios of blood products have been shown to increase survival in severely injured bleeding trauma patients. In the current US blood-banking practice, platelets (Plts) are stored in incubators at 22°C for up to 5 days. Storage of Plts at 22°C for 5 days is associated with a storage lesion, increased infectious risk, and an overall decline in hemostatic function. 4°C storage of Plts has been proposed as an equivalent and in some cases superior alternative to 22 °C storage. Therapeutically, in addition to their critical role in hemostasis, Plts are known to safeguard the integrity of the vascular endothelium. Vascular instability is a hallmark effect of traumatic injury leading to vascular permeability, inflammation, coagulation disturbances and end organ failure. In TBI, intracranial hemorrhage (ICH) and cerebral edema are the leading causes of mortality, which are potentially addressable by Plt transfusion. Our previous data demonstrate that 4°C Plts regulate vascular stability and inhibit endothelial cell (EC) permeability similar to 22°C Plts. In our original RO1 we investigated the use of 4°C Plts as a first line therapeutic intervention in TBI to decrease cerebral edema, ICH, neuroinflammation and improve outcomes in TBI utilizing a murine model of injury. In these studies, we found that 4°C Plts could attenuate ICH, cerebral edema and neuroinflammation induced by TBI. We also found that 4°C Plts had equivalent clot forming potential to 22°C Plts in injured vasculature. In this administrative supplement, we aim to also investigate the therapeutic effects of 4°C Plts on long- term neurocognitive endpoints. Patients who survive moderate to severe TBI will often present with learning and memory dysfunction weeks to years later after the TBI. We hypothesize that the beneficial effects we have found of platelet treatment on the brain’s vasculature, will lead to benefits in neurocognitive function in TBI. In Aim 1 we will test the efficacy of 4°C cold stored platelets in improving neurocognitive function after TBI. We will utilize two main tests: the contextual fear conditioning test and the Morris Water Maze to test context discrimination and learning and memory in TBI mice treated with 4°C Plts. In addition, we will conduct tracking experiments of where the platelets go long term to answer the question of whether they are still in circulation or in the tissue 4-6 weeks post injury. Histopathological analysis has also been added to this administrative supplement to evaluate the chronic effects of platelet treatment on TBI induced gliosis and neuroinflammation, two pathological conditions that can linger for months after injury. Taken together, this administrative supplement will add to our existing fund of knowledge which explores the therapeutic benefit of 4°C Plts in TBI, supporting translation of this product from Bench to Bedside.