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

描述（由申请人提供）：凝血组织因子（TF）途径的激活与血液血栓形成性增加有关，凝血水平标志物的增加可能部分解释了急性缺血性卒中（AIS）患者高度不良的神经预后和卒中复发。我们已经表明，AIS后，膜结合组织因子促凝活性（TF-PCA）和血浆活化因子VII （FVIIa）以及凝血酶生成标志物，凝血酶原片段1.2 （F1.2）和凝血酶-抗凝血酶复合物（TAT）显著升高。虽然这些指标在T2DM和高血糖患者中最高，但血糖（BG）控制对凝血指标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脑卒中后临床结果之间的关系，以及高血糖控制如何调节这些标志物，对急性缺血性脑卒中的治疗有很大的希望。卒中试验中选定的促凝标志物和结果的见解（I-SPOT）：胰岛素给药和血糖控制的反应提案是为了配合卒中高血糖胰岛素网络努力（SHINE）临床试验而设计的，这是一项多中心、随机、对照的III期试验计划，旨在确定卒中患者血糖控制的有效性和安全性。SHINE试验将招募1400名AIS

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.