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.

项目概要/摘要行政补充 冷保存血小板对创伤后血管稳定性的调节作用 创伤是世界范围内1-44岁人群死亡的主要原因， 创伤性脑损伤（TBI）是创伤后死亡的头号原因。血小板输注与血液比例平衡 产品已被证明可提高严重受伤出血创伤患者的存活率。现行美国 在血库实践中，将血小板（Plt）在22°C下在培养箱中储存长达5天。Plt在22°C下的储存 持续5天与储存性病变、感染风险增加和止血能力总体下降相关。 功能4°C储存Plts已被提议作为22 ° C的等效替代品，在某些情况下更好上级。 °C储存。在治疗上，除了在止血中的关键作用外，已知Plt还可保护患者的免疫功能。 血管内皮的完整性。血管不稳定是创伤性损伤的标志性影响， 血管通透性、炎症、凝血障碍和终末器官衰竭。在TBI中，颅内 脑出血（ICH）和脑水肿是死亡的主要原因， 血小板输注。我们以前的数据表明，4°C Plts调节血管稳定性并抑制内皮细胞生长。 细胞（EC）渗透性类似于22°C Plts.在我们最初的RO 1中，我们研究了使用4°C Plts作为第一线 TBI中的治疗性干预，以减少脑水肿、ICH、神经炎症并改善结局 在TBI中使用损伤的鼠模型。在这些研究中，我们发现4°C Plts可以减轻ICH，脑出血， TBI引起的水肿和神经炎症。我们还发现，4°C Plts具有相同的凝块形成潜力， 至22°C Plts。 在这份行政补充中，我们的目标是还研究4°C Plts对长- 术语神经认知终点。中度至重度TBI存活的患者通常会表现出学习和 创伤性脑损伤后数周至数年后出现记忆障碍。我们假设我们的有益效果 在脑血管系统中发现血小板治疗，将导致TBI神经认知功能的益处。在 目的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的测试：情境恐惧条件反射测试和莫里斯水迷宫测试的背景 在用4°C Plts处理的TBI小鼠中的辨别力和学习和记忆力。此外，我们会进行追踪， 血小板长期去哪里的实验，以回答他们是否仍然在循环中， 在损伤后4-6周的组织中。在本行政报告中还增加了组织学分析。 补充以评估血小板治疗对TBI诱导的神经胶质增生和神经炎症的慢性作用， 这两种病理状态会在受伤后持续数月。总的来说，这一行政补充 将增加我们现有的知识基金，探索4°C Plts在TBI中的治疗益处，支持 将本产品从台架转移到床边。