Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial (I-SPOT)

关于中风试验中选定的促凝标志物和结果的见解 (I-SPOT)

• 批准号: 8605239
• 负责人: NINA T GENTILE
• 金额: $ 47.94万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605239
• 关键词: Activities of Daily Living; Acute; Ancillary Study; Award; Binding; Biological Markers; Blood; Blood Coagulation Factor VII; Blood Glucose; Blood coagulation; Clinical; Clinical Pathways; Clinical Trials; Communities; Conduct Clinical Trials; Data; Disease; Emergency treatment; Factor VIIa; Fibrin fragment D; Funding; Generations; Glucose; Health Personnel; Hospitals; Hour; Hyperglycemia; Injury; Insulin; Intravenous; Ischemic Stroke; Measures; Membrane; National Institute of Neurological Disorders and Stroke; Neurologic; Neurological emergencies; Neurological outcome; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathway interactions; Patients; Phase; Plasma; Plasminogen Activator Inhibitor 1; Randomized Controlled Trials; Recruitment Activity; Recurrence; Research Design; Research Project Grants; Risk; Safety; Severities; Stroke; TFPI; Thrombin; Thromboplastin; United States National Institutes of Health; Whole Blood; acute stroke; antithrombin III-protease complex; blood glucose regulation; design; functional outcomes; glycemic control; insight; primary outcome; prothrombin fragment 1.2; public health relevance; research study; response; standard care; stroke therapy; subcutaneous; treatment duration; treatment trial

DESCRIPTION (provided by applicant): Activation of the tissue factor (TF) pathway of blood coagulation is associated with increased blood thrombogenicity and increases in markers of blood coagulation levels may in part explain the high degree of poor neurological outcome and recurrence of stroke in patients with acute ischemic stroke (AIS). We have shown that membrane-bound tissue factor procoagulant activity (TF-PCA) and plasma activated factor VII (FVIIa) and markers of thrombin generation, prothrombin fragment 1.2 (F1.2) and thrombin- antithrombin complexes (TAT), are markedly elevated after AIS. While these markers are highest in patients with T2DM and hyperglycemia, the effect of blood glucose (BG) control on levels of blood coagulation markers and their relationship with stroke outcome is unknown. Therefore, a better understanding of the relationhips between these and other markers of blood coagulation and clinical outcomes after stroke and how hyperglycemia control modulates these markers holds great promise for management of acute ischemic stroke. The Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial (I-SPOT): Response to Insulin Administration and Blood Glucose Control proposal is designed to accompany the Stroke Hyperglycemia Insulin Network Effort (SHINE) clinical trial, a Phase III multicenter, randomized, controlled trial planning to determine the efficacy an validate the safety of glycemic control in stroke patients. The SHINE trial will recruit 1,400 AIS patients with Type II diabetes mellitus (T2DM) and hyperglycemia, each receiving 3 days of hyperglycemia control with intravenous (IV) insulin therapy or control therapy with subcutaneous (SQ) insulin. Blood coagulation marker levels [whole blood TF-PCA~ plasma coagulation factors VII, VIIa, and VIII~ plasma TAT~ D-dimer~ tissue factor pathway inhibitor (TFPI)~ and plasminogen activator inhibitor-1 (PAI-1)] will be measured before and at 48 hours after the start of treatment. Baseline and temporal changes in biomarkers levels will be compared between treatment groups. The aims and hypotheses of the I-SPOT study are to 1) Compare the effects of strict hyperglycemia control with standard treatment of hyperglycemia on membrane- bound TF-PCA and markers of blood coagulation in T2DM patients after AIS and 2) Determine the relationship between circulating TF-PCA and markers of blood coagulation and functional neurological outcome in SHINE treatment and control patients. We anticipate that 1) the decrease in levels of markers of blood coagulation will be greater in patients treated with IV insulin to reduce BG than in patients treated with SQ Insulin as the standard fashion and 2) the decrease in levels of markers of blood coagulation will be greater in patients with than without favorable outcome (defined as the baseline stroke severity adjusted measure of functional ability at 90 days after acute stroke). Moreover, we expect that hyperglycemia control will modulate the relationship between blood coagulation levels and functional outcome in T2DM patients providing further insights on the effects of glucose regulation on the TF pathway of blood coagulation in acute stroke.

描述（由申请人提供）：血液凝固的组织因子（TF）途径的激活与血液血栓形成性增加有关，血液凝固水平标志物的增加可能部分解释了急性缺血性中风（AIS）患者神经系统预后不良和中风复发的严重程度。 我们已经表明，膜结合组织因子促凝血活性（TF-PCA）和血浆活化因子VII（FVIIa）和凝血酶生成标志物，凝血酶原片段1.2（F1.2）和凝血酶-抗凝血酶复合物（达特）在AIS后显著升高。虽然这些标志物在T2 DM和高血糖患者中最高，但血糖（BG）控制对凝血标志物水平的影响及其与卒中结局的关系尚不清楚。因此，更好地了解这些和其他凝血标志物与卒中后临床结局之间的关系，以及高血糖控制如何调节这些标志物，对急性缺血性卒中的管理具有很大的希望。 卒中试验（I-SPOT）中选择的促凝标志物和结局的见解：胰岛素给药反应和血糖控制建议旨在伴随卒中高血糖胰岛素网络努力（SHINE）临床试验，这是一项III期多中心、随机、对照试验，计划确定卒中患者血糖控制的疗效并验证其安全性。SHINE试验将招募1，400名AIS 患有II型糖尿病（T2 DM）和高血糖症的患者，每例患者均接受3天的静脉（IV）胰岛素治疗或皮下（SQ）胰岛素对照治疗控制高血糖症。将在治疗开始前和治疗开始后48小时测量凝血标志物水平[全血TF-PCA ~血浆凝血因子VII、VIIa和VIII~血浆达特~ D-二聚体~组织因子途径抑制物（TFPI）~和纤溶酶原激活物抑制物-1（派-1）]。将比较治疗组之间生物标志物水平的基线和时间变化。I-SPOT研究的目的和假设是：1）比较严格的高血糖控制与高血糖标准治疗对AIS后T2 DM患者的膜结合TF-PCA和凝血标志物的影响; 2）确定SHINE治疗和对照患者中循环TF-PCA与凝血标志物和功能性神经结局之间的关系。我们预期：1）静脉注射治疗的患者，凝血标志物水平的下降幅度更大， 与接受SQ胰岛素作为标准方式治疗的患者相比，胰岛素降低血糖的作用更大; 2）结局良好的患者的凝血标志物水平下降幅度大于无结局的患者（定义为基线中风严重程度调整后的功能能力指标）急性中风后90天）。此外，我们预计高血糖控制将调节2型糖尿病患者凝血水平和功能结局之间的关系，从而进一步了解葡萄糖调节对急性卒中凝血TF途径的影响。