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

描述(申请人提供)：凝血的组织因子(TF)途径的激活与血液凝血活性的增加有关，凝血水平标记物的增加可能在一定程度上解释了急性缺血性中风(AIS)患者严重的神经预后不良和中风复发。我们发现AIS后膜结合型组织因子促凝血活性(TF-PCA)和血浆激活因子VII(FVIIa)以及凝血酶生成的标志物凝血酶原片段1.2(F1.2)和凝血酶-抗凝血酶复合物(TAT)显著升高。虽然这些标记物在T2 DM和高血糖患者中最高，但血糖控制(BG)对凝血标志物水平的影响及其与中风预后的关系尚不清楚。因此，更好地了解这些指标与卒中后其他凝血指标和临床结果之间的关系，以及高血糖控制如何调节这些指标，对急性缺血性卒中的治疗具有很大的希望。卒中试验(I-SPOT)：对胰岛素使用的反应和血糖控制建议是为配合卒中高血糖胰岛素网络努力(SINE)临床试验而设计的，这是一项第三阶段的多中心、随机、对照试验计划，旨在确定中风患者血糖控制的有效性和安全性。SHARE选拔赛将招募1400名人工智能人员 2型糖尿病(T2 DM)合并高血糖的患者，分别接受静脉(IV)胰岛素治疗或皮下胰岛素(SQ)对照治疗3天的高血糖控制。分别于治疗前和治疗后48h检测凝血标志物[全血TF-PCA~血浆凝血因子VII、VIIa、VIII~血浆TAT~D-二聚体~组织因子途径抑制物(TFPI)~、纤溶酶原激活物抑制物-1(PAI-1)]水平。生物标志物水平的基线和时间变化将在不同的治疗组之间进行比较。I-SPOT研究的目的和假设是：1)比较严格的高血糖控制和标准的高血糖治疗对AIS后T2 DM患者膜结合型TF-PCA和凝血标志物的影响；2)确定SHET治疗和对照组患者循环TF-PCA与凝血标志物和神经功能预后的关系。我们预计：1)接受静脉注射的患者凝血标志物水平的下降幅度将更大 与以SQ Insulin作为标准方式治疗的患者相比，使用SQ Insulin治疗的患者更容易降低血糖；2)与预后不佳的患者相比，预后良好的患者的凝血标志物水平下降更大(定义为急性卒中后90天的基线中风严重程度调整后功能能力的测量)。此外，我们期望高血糖控制将调节T2 DM患者凝血水平和功能结局之间的关系，为进一步了解血糖调节对急性卒中凝血因子途径的影响提供进一步的见解。

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.