Deranged Coagulation and Fibrinolytic Cascades in Idiopathic Pulmonary Fibrosis

描述（申请人提供）：特发性肺纤维化（IPF）是一种肺部瘢痕性疾病，尽管采用了最佳治疗，中位生存期仍为3年。许多机制性和小规模的观察性研究表明，凝血-纤溶系统的异常是人类和实验性肺纤维化的原因。总的来说，他们证明了组织因子依赖性促凝血活性被诱导，并且在纤维化肺的肺泡隔室中正常的纤溶活性被抑制。尽管有这些概念性知识，但关于凝血/纤溶途径中的因素是否可预测IPF的预后或抗凝治疗反应，仍有许多需要了解的内容。为了支持进一步研究凝血/纤溶系统的重要性，IPF患者发生动脉粥样硬化血栓形成相关临床事件的风险增加，一项小型试验首次证明了IPF抗凝治疗的生存获益。在这里，我们显示了IPF患者血浆中凝血激活（组织因子抗原增加）和纤溶抑制（派-1抗原增加）的初步数据。值得注意的是，组织因子抗原作为肺生理损害的函数而变化，这与预后可能反映在凝血激活程度上的可能性一致。 此外，血浆纤维蛋白D二聚体水平从一个小的抗凝剂试验中增加，在急性加重，和那些血浆D二聚体水平升高，尽管抗凝治疗，不太可能生存。我们的早期结果表明，利用基因表达谱来鉴定IPF进展相关基因是可行的。基于收集的数据，我们假设凝血/纤溶系统的异常是IPF发病机制的基础。我们建议通过与NHLBI IPFnet临床研究网络Warfarin试验（ACE; IPF中的抗凝剂有效性）相关联来检验这一假设。ACE是一项随机化、双盲、安慰剂对照、多中心美国试验，旨在评价沃替康对IPF患者结局的疗效。这项母试验将严格确定Warcantine是否对IPF有改善作用。重要的是，它还提供了一个独特的机会，在仔细和全面表征的IPF患者队列中，在进展和抗凝治疗反应的背景下评估我们的假设。拟定研究具有时间敏感性，因为它们将在基线和之后的时间点使用具有时间敏感性的处理/加工程序采集和分析入组正在进行的IPFnet试验的患者的血浆样本。IPFnet指导委员会认识到这些机制研究的价值，并完全支持这一应用。完成后，我们将确定分子链，并确定 凝血/纤溶对IPF发病机制的预后意义。此外，结果将提供抗凝生物学反应数据，以支持相关ACE母临床结局试验，并告知试验Warcantine的作用机制。这些途径中关键分子的鉴定也将支持未来开发更具针对性的抗凝剂。公共卫生相关性：特发性肺纤维化（IPF）是一种肺部瘢痕性疾病，尽管有最佳治疗，但预后不良。因此，IPF患者将大大受益于新方法，从而更好地了解其病因。我们建议研究IPF患者血液中的凝血和凝块溶解系统，方法是将其与正在进行的NIH申办的试验联系起来，在该试验中IPF患者接受抗凝剂或安慰剂治疗。希望我们的研究结果将有助于确定IPF的病因，并提供诊断和治疗有用的信息。这些知识将有望导致有效治疗剂的开发。(End摘要）

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a scarring disorder of the lungs with a 3-yr median survival despite the best available treatment. Many mechanistic and small observational studies in humans implicate abnormalities in the coagulation-fibrinolytic systems in the causation of human and experimental pulmonary fibrosis. Collectively, they demonstrate that tissue factor-dependent pro-coagulant activity is induced, and that the normal fibrinolytic activity is suppressed in the alveolar compartment of the fibrotic lung. Despite this conceptual knowledge, there is much to be learned regarding whether factors in the coagulation/fibrinolysis pathways predict prognosis, or anticoagulant treatment response in IPF. In support of the importance of further study of the blood coagulation/fibrinolysis system, patients with IPF have an increased risk of atherothrombosis-related clinical events, and one small trial demonstrates, for the first time, a survival benefit of anticoagulant treatment in IPF. Here, we show preliminary data that there is activation of coagulation (increased tissue factor antigen), and inhibition of fibrinolysis (increased PAI-1 antigen) in plasma from patients with IPF. Strikingly, tissue factor antigen varied as a function of the pulmonary physiologic impairment, consistent with the possibility that prognosis may be reflected in the extent of coagulation activation. Furthermore, plasma fibrin D dimer levels from a small anti-coagulant trial were increased during an acute exacerbation, and those with elevated plasma D dimer levels, despite anticoagulant treatment, were less likely to survive. Our early results indicate that it is feasible to utilize gene expression profiling to identify progression related genes in IPF. Based on the collective data, we hypothesize that abnormalities in the coagulation/fibrinolytic system underlie the pathogenesis of IPF. We propose to test this hypothesis by linking to the NHLBI IPFnet clinical research network Warfarin trial (ACE; Anticoagulant Effectiveness in IPF). ACE is a randomized, double-blind placebo-controlled, multi-center US trial to evaluate the efficacy of Warfarin on outcome in patients with IPF. This parent trial will rigorously determine if Warfarin has an ameliorative effect on IPF. Importantly, it also provides a unique opportunity to evaluate our hypothesis in the context of progression, and response to anticoagulant treatment, in a carefully and thoroughly characterized cohort of IPF patients. The proposed studies are time-sensitive in that they would collect and analyze plasma samples from patients enrolled in ongoing IPFnet trials, at baseline and at timed points thereafter, using handling/processing procedures that are time-sensitive. The IPFnet steering committee recognizes the value of these mechanistic studies and fully supports this application. When completed, we will identify the molecular links, and determine the prognostic significance, of blood coagulation/fibrinolysis to the pathogenesis of IPF. Furthermore, the results will provide the anti-coagulant biological response data to support the linked ACE parent clinical outcome trial, and inform the trial as to mechanism(s) of Warfarin's effect. Identification of the critical molecules in these pathways will also support the future development of more targeted anti-coagulant agents. Public Health Relevance: Idiopathic pulmonary fibrosis (IPF) is a scarring disorder of the lungs with a poor prognosis despite the best available therapy. Thus, patients with IPF would greatly benefit from new approaches that lead to a better understanding of its cause. We propose to study the blood clotting and clot dissolving systems in blood from patients with IPF, by linking to an ongoing NIH-sponsored trial where IPF patients are treated with either an anticoagulant or placebo. It is hoped that our results will help to identify the cause of IPF, and provide prognostically and therapeutically useful information. Such knowledge will hopefully lead to the development of effective therapeutic agents. (End of Abstract)