Thrombolysis Profiles in tPA Response

tPA 反应中的溶栓曲线

• 批准号: 8956002
• 负责人: Eng H. Lo
• 金额: $ 38.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956002
• 关键词: Acute; Affect; Age; Albumins; Alteplase; Binding; Binding Proteins; Bioinformatics; Biological; Blood; Blood Circulation; Blood Coagulation Factor; Characteristics; Clinical; Coagulation Process; Comorbidity; Cytolysis; Data; Diabetes Mellitus; Disabled Persons; Dose; Enrollment; Equilibrium; Failure; Figs - dietary; Gender; Half-Life; Hospitals; Hour; Human; Individual; Institutional Review Boards; Intravenous; Ischemic Stroke; Laboratories; Mass Spectrum Analysis; Measurable; Measures; Methods; Monitor; Multicenter Studies; National Institute of Neurological Disorders and Stroke; Outcome; Outcome Measure; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Proteins; Proteomics; Publishing; Research Design; Role; Sensitivity and Specificity; Severities; Signal Transduction; Specificity; Stroke; Techniques; Time; VWF gene; Work; base; clinical effect; cohort; diabetic; diabetic patient; effective therapy; glycosylated serum albumin; improved; innovation; medical schools; meetings; non-diabetic; novel; novel marker; public health relevance; response; thrombolysis; transcriptomics

 DESCRIPTION (provided by applicant): Intravenous tissue plasminogen activator (tPA) is an effective treatment for acute ischemic stroke, but nearly two decades after FDA approval, its utilization remains low, and up to 80% of patients who receive tPA show no beneficial response. Currently, neither the mechanisms underlying tPA's effects in human blood nor the reasons for most patients' failure to respond are well understood. In order to develop clinical methods of monitoring tPA's activity in blood in real time, to guide treatment for individual patients, we aim to better understand tPA's clinical effects, especially with respect to its pleiotropic signaling within the blood. We hypothesize that tPA efficacy has a measurable and quantifiable signature in the circulation, and that perturbation of a delicate balance in coagulation and thrombolysis pathways is related to poor efficacy. Comparing tPA responders vs. non-responders, we employ a combined approach including conventional as well as innovative mass spectrometry (MS) techniques. As points of entry, we focus on two aspects that our preliminary data suggest are pivotal: the ADAMTS13/vWF pathway which plays a role in clot formation and lysis and is affected by tPA, and glycated albumin, which may sequester tPA leading to poorer outcomes for diabetic patients. Aim 1: Characterize tPA response by exploring the ADAMTS13/vWF axis/pathway, measuring levels of ADAMTS13 and vWF, and assessing ADAMTS13 activity by means of ADAMTS13-specific vWF substrate fragments, in responders vs. non-responders. We hypothesize that tPA responders will have elevated ADAMTS13 levels and activity, and decreased vWF. Aim 2: Investigate non-response in diabetic stroke patients by exploring the role of glycated albumin, high levels of which are characteristic of diabetes. We hypothesize that glycated albumin is higher in nonresponders, and that glycated albumin sequesters tPA, thereby diminishing tPA's efficacy in diabetic patients. We will use innovative proteomic techniques to examine the molecules "stuck" to albumin in individual patients' blood, and we hypothesize that glycated albumin sequesters more tPA than non-glycated albumin. With three collaborating US centers (MGH, BWH, UMass Medical School), and a fourth separate confirmation cohort (Vall d'Hebron Hospital, Barcelona) - we are able to enroll patients at a pace sufficient for our most conservative power calculation based on preliminary data. Our encouraging pilot data, IRB-approved published SOP and detailed analysis plan for longitudinal measures of outcome, adjusting for multiple co-morbidities, demonstrate the feasibility of recruitment and analysis, and directly support our hypotheses and approach.

 描述(申请人提供)：静脉注射组织型纤溶酶原激活剂(TPA)是治疗急性缺血性中风的有效药物，但在FDA批准近20年后，其利用率仍然很低，高达80%接受tPA的患者没有显示出有益的反应。目前，tPA在人体血液中的作用机制以及大多数患者无反应的原因都不是很清楚。为了发展临床上实时监测tPA活性的方法，以指导个别患者的治疗，我们的目标是 为了更好地了解tPA的临床效果，特别是关于其在血液中的多效性信号。我们假设tPA的疗效在循环中具有可测量和可量化的特征，并且凝血和溶栓途径中微妙平衡的扰动与不良疗效有关。比较tPA应答者和非应答者，我们采用了一种结合的方法，包括传统和创新的质谱学(MS)技术。作为切入点，我们关注两个方面，我们的初步数据表明是关键的：ADAMTS13/vWF通路，它在血栓形成和溶解中发挥作用，并受tPA的影响，以及糖化白蛋白，它可能隔离tPA，导致糖尿病患者预后较差。目的1：通过研究ADAMTS13/vWF轴/通路，检测ADAMTS13和vWF的水平，并通过ADAMTS13特异的vWF底物片段评估ADAMTS13的活性，在应答者和无应答者中表征tPA的反应。我们假设tPA应答者的ADAMTS13水平和活性升高，vWF降低。目的：通过探讨糖化白蛋白的作用来研究糖尿病卒中患者的无反应，糖化白蛋白是糖尿病的特征。我们假设糖化白蛋白在无反应者中更高，糖化白蛋白隔离tPA，从而降低tPA在糖尿病患者中的疗效。我们将使用创新的蛋白质组学技术来检测个体患者血液中“粘着”白蛋白的分子，我们假设糖化白蛋白比非糖化白蛋白能隔离更多的tPA。有了三个合作的美国中心(MGH、BWH、华盛顿大学马萨诸塞州医学院)和第四个独立的确认队列(巴塞罗那的Vall d‘Hebron医院)，我们能够以足以根据初步数据进行最保守的功率计算的速度招募患者。我们令人鼓舞的试点数据、IRB批准的发布的SOP和详细的纵向结果测量分析计划，根据多种并存情况进行调整，证明了招募和分析的可行性，以及 直接支持我们的假设和方法。