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

冷藏血小板调节创伤血管不稳定的治疗潜力

• 批准号: 10909765
• 负责人: Shibani Pati
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10909765
• 关键词: Acute; Administrative Supplement; Age; Anesthesia procedures; Attenuated; Blinded; Blood Banks; Blood Platelets; Blood Vessels; Cause of Death; Cerebral Edema; Cerebrovascular system; Chronic; Cicatrix; Circulation; Coagulation Process; Control Animal; Data; Discrimination; Endothelial Cells; Female; Functional disorder; Funding; Gliosis; Goals; Hemorrhage; Hemostatic function; Hippocampus; Immune system; Incubators; Individual; Inflammation; Injury; Intracranial Hemorrhages; Knowledge; Learning; Lesion; Link; Long-Term Effects; Maze Learning; Memory; Memory impairment; Modeling; Mus; Neurocognition; Neurocognitive; Neuronal Injury; Organ failure; Outcome; Parietal Lobe; Pathologic; Patients; Permeability; Platelet Transfusion; Randomized; Research Personnel; Risk; Role; Temperature; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Translations; Trauma; Trauma patient; Traumatic Brain Injury; Traumatic injury; Vascular Endothelium; Vascular Permeabilities; behavioral study; bench to bedside; blood product; conditioned fear; efficacy testing; experience; experimental study; improved; improved outcome; injured; male; meter; morris water maze; mortality; mouse model; neurocognitive test; neuroinflammation; neuron loss; neuroprotection; novel therapeutics; platelet storage; severe injury

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.

项目摘要/摘要行政补充 冷藏血小板调节创伤血管稳定性的治疗潜力 外伤是全世界 1-44 岁人群死亡的主要原因，其中脑外伤 损伤（TBI）是创伤后死亡的第一大原因。血小板输注和血液平衡比例 产品已被证明可以提高严重受伤出血外伤患者的生存率。在当前的美国 在血库实践中，血小板 (Plts) 在 22°C 的培养箱中保存最多 5 天。 22°C 下保存 Plt 连续 5 天与储存损伤、感染风险增加以及止血效果总体下降有关。 功能。 4°C 的 Plt 储存已被提议作为 22 ℃ 的等效替代方案，在某些情况下甚至是更好的替代方案 °C 储存。在治疗上，除了止血方面的关键作用外，众所周知，Plt 还可以保护血液 血管内皮的完整性。血管不稳定是创伤性损伤导致的一个标志性效应 血管通透性、炎症、凝血障碍和终末器官衰竭。在 TBI 中，颅内 出血（ICH）和脑水肿是死亡的主要原因，可以通过以下方法解决： Plt输血。我们之前的数据表明 4°C Plts 调节血管稳定性并抑制内皮细胞 细胞 (EC) 渗透性与 22°C Plts 相似。在我们最初的 RO1 中，我们研究了 4°C Plts 作为一线的使用 对 TBI 进行治疗干预，以减少脑水肿、ICH、神经炎症并改善预后 利用小鼠损伤模型进行 TBI 治疗。在这些研究中，我们发现 4°C Plts 可以减轻 ICH、脑损伤 TBI 引起的水肿和神经炎症。我们还发现 4°C Plts 具有同等的凝块形成潜力 受损脉管系统中的温度降至 22°C。 在本行政补充中，我们的目标还在于研究 4°C Plts 对长期治疗的治疗效果。 术语神经认知终点。中度至重度 TBI 幸存下来的患者通常会表现出学习和 TBI 后数周至数年出现记忆功能障碍。我们假设我们所产生的有益影响 发现血小板治疗大脑血管系统将有益于 TBI 的神经认知功能。在 目标 1 我们将测试 4°C 冷藏血小板在改善 TBI 后神经认知功能方面的功效。 我们将利用两个主要测试：情境恐惧调节测试和莫里斯水迷宫来测试情境 用 4°C Plts 治疗的 TBI 小鼠的辨别力以及学习和记忆能力。此外，我们还会进行跟踪 血小板长期去往何处的实验可以回答它们是否仍在循环中或 损伤后 4-6 周在组织中。组织病理学分析也已添加到该管理中 补充评估血小板治疗对 TBI 诱导的神经胶质增生和神经炎症的慢性影响， 两种病理状况可能在受伤后持续数月。综上所述，本行政补充 将增加我们现有的知识库，探索 4°C Plts 在 TBI 中的治疗益处，支持 该产品从 Bench 翻译为 Bedside。