Interpaly of Thrombosis and Inflammation in Vasculitis

特发性炎性血管炎是一组多器官系统疾病， 常见的结果是不同大小的血管炎症，导致严重的，危及器官和生命的 疾病目前的治疗方法毒性很大，而且并不完全有效。 血栓形成在血管炎中的重要性日益被认识到。近日，默克尔博士与 他的同事已经证明，韦格纳肉芽肿病患者的 静脉血栓形成事件的发生率，这些事件与活动性血管炎相关。有 越来越多的证据强烈地将血栓形成的多个方面与血管炎症联系起来， 区域是本申请的重点。在这种结构中，“血栓形成”不仅限于大血管 临床上可见的血栓，但可能包括与损伤和修复周期相关的“微血栓”， 其中一些可能是病理性的。同样，传统上被称为 “炎症”会刺激“血栓形成”。我们认为，虽然炎症可能是导致糖尿病的最初原因， 血管炎损伤，血栓形成的每个止血成分，i）血小板依赖性因子; ii） 凝血级联;和iii）纤维蛋白溶解，也被触发，导致血栓形成的“二次打击”， 随后是炎症和血栓形成的恶性循环。 了解血栓形成的各个方面在血管炎中的作用， 深入了解这些疾病的病理生理学，但也将潜在地解决三个关键但未得到满足的问题。 血管炎的医疗需求：i）疾病活动的生物标志物的发展; ii） 疾病活动和结果的预测因子;和iii）测试新型治疗药物的基本原理 干预措施。 在本申请中，我们提出评估血栓形成标志物与血栓形成的相关性。 通过实现三个相关的具体目标，评估血管炎的事件、总体疾病活动和长期结局： 1.韦格纳病患者血栓形成选择性标志物与疾病活动性的相关性研究 肉芽肿病; 2.研究选择性血栓形成因子与存在或 韦格纳肉芽肿病患者无临床明显血栓形成; 3.研究 血栓形成标志物对韦格纳病患者治疗反应的预测价值 肉芽肿病我们将利用来自几个大型患者队列的临床数据和生物样本 与血管生物学和血栓形成的基础科学专家合作。 这项研究与公共卫生直接相关，因为它探讨了两种疾病之间的关系。 关键的生物过程：炎症和血栓形成（凝血）。这项工作可能会导致一个 更好地理解和治疗炎症性疾病。

The idiopathic inflammatory vasculitides are a group of multiorgan system diseases that have in common the findings of inflammation of vessels of varying sizes that results in serious, organ and lifethreatening disease. Current treatments are highly toxic and not fully effective. The importance of thrombosis in vasculitis is increasingly being recognized. Recently, Dr. Merkel and his colleagues have demonstrated that patients with Wegener's granulomatosis have a 20-fold increased incidence of venous thrombotic events and that these events are associated with active vasculitis. There is increasing evidence strongly linking multiple aspects of thrombosis with vascular inflammation and these areas are the focus of this application. In this construct, "thrombosis" is not limited to the large vessel thrombi seen clinically but may include "microthrombosis" associated with a cycle of damage and repair, some of which may be pathological. Similarly, aspects of what has traditionally been referred to as "inflammation" can stimulate "thrombosis". We propose that while inflammation may be the initial cause of damage in vasculitis, each hemostatic component of thrombosis, i) platelet-dependent factors; ii) the coagulation cascade; and iii) fibrinolysis, is also triggered, leading to a "second hit" of thrombosis and subsequently a vicious cycle of inflammation and thrombosis. Understanding the roles various aspects of thrombosis play in vasculitis will not only provide important insight into the pathophysiology of these diseases, but will also potentially address three critical but unmet medical needs in vasculitis: i) the development of biomarkers of disease activity; ii) the discovery of predictors of disease activity and outcome; and iii) a rationale for testing novel classes of therapeutic interventions. In this application we propose evaluating the association of markers of thrombosis with thrombotic events, overall disease activity, and long-term outcome in vasculitis by achieving three related specific aims: 1. Studying the association of selective markers of thrombosis with disease activity in Wegener's granulomatosis; 2. Studying the associations between selective thrombosis factors and the presence or absence of clinically evident thrombosis in patients with Wegener's granulomatosis; 3. Studying the predictive value of markers of thrombosis for response to therapy in patients with Wegener's granulomatosis. We will utilize clinical data and biological specimens from several large cohorts of patients with vasculitis and partner with experts in the basic science of vascular biology and thrombosis. This research is directly relevant to public health because it explores the relationship between two critical biological processes: inflammation and thrombosis (clotting). This work will potentially lead to a better understanding and better treatment of inflammatory diseases.