Blood tissue factor activity, risk factors and CAD

描述(申请人摘要)有不断发展的证据表明，循环血液中含有活性组织因子(TF)，这可能会导致血液血栓形成能力增强。动脉粥样硬化性疾病的危险因素，如高胆固醇血症、吸烟和2型糖尿病，可能在一定程度上是血液血栓形成增强的触发因素。在大约三分之一的急性冠状动脉综合征(ACS)中，通常不会出现富含脂质的小斑块的破裂，而只是狭窄和纤维化斑块的表面侵蚀(图1)。因此，这类病例中的复杂血栓很可能是由上述系统性危险因素引发的血液凝血活性-转铁蛋白依赖性增加的结果。我们将检验这一假设，即在高胆固醇血症、2型糖尿病和吸烟者(AIM 1a)中，血液凝血活性和循环组织因子(TF)活性将被发现增强；通过危险因素修改方法(AIM 1b)，将获得血栓形成能力和循环TF活性正常化的降低。在两组动脉粥样硬化性疾病和高胆固醇血症患者中，循环TF活性的变化将与高胆固醇血症的改善相关，并与主要疗效相关，主要疗效通过一组患者颈动脉、胸主动脉和冠状动脉的无创性磁共振成像(MRI)(AIM 2a)和另一组患者的有创冠状动脉内超声(IVUS)(AIM 2b)来衡量。最后，在正在进行的女性健康研究中，将探讨循环TF活性与心血管事件之间的关系(AIM 3a)，以及这两个参数与高胆固醇血症、2型糖尿病或吸烟的存在之间的关系(AIM 3b)。作为不同目标的一部分，还将测量血液中的血小板-白细胞聚集和激活以及血浆中的C反应蛋白(CRP)。

DESCRIPTION (Applicant's Abstract) There is evolving evidence that circulating blood contains active tissue factor (TF) and that this may lead to enhanced blood thrombogenicity. Risk factors for atherosclerotic disease, such as hypercholesterolemia, cigarette smoking, and diabetes type 2 may in part act as triggers of enhanced blood thrombogenicity. In about a third of acute coronary syndromes (ACS) there is not the usual disruption of a small lipid-rich plaque but just a superficial erosion of a stenotic and fibrotic plaque (Fig 1). Thus, complicated thrombi in such cases may well be the result of an increased blood thrombogenicity- TF dependent, triggered by systemic risk factors such as those mentioned above. We will test the hypothesis that enhanced blood thrombogenicity and circulating tissue factor (TF) activity will be found in individuals with hypercholesterolemia, with diabetes type 2 and in cigarette smokers (AIM 1a); decreased thrombogenicity and normalization of circulating TF activity will be obtained with risk factor modifying approaches (AIM 1b). In two cohorts of patients with atherosclerotic disease and hypercholesterolemia, changes in circulating TF activity will be correlated with modification of hypercholesterolemia and with primary efficacy as measured by the rate of plaque regression/stabilization/progression by noninvasive magnetic resonance imaging (MRI) of the carotid arteries, thoracic aorta and coronary arteries in one cohort (AIM 2a) and by invasive coronary intravascular ultrasound (IVUS)in the other cohort (AIM 2b). Finally, in the ongoing women's Health Study, the relationship between circulating TF activity and cardiovascular events will be approached (AIM 3a), as well as the relationship between these two parameters and the presence of hypercholesterolemia, diabetes type 2 or cigarette smoking (AIM 3b). Platelet - leukocyte aggregates and activation in blood and C-reactive protein (CRP) in plasma will also be measured as part of the various aims.