Deranged Coagulation and Fibrinolytic Cascades in Idiopathic Pulmonary Fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是一种肺部瘢痕性疾病，尽管有最好的治疗方法，但中位生存期为3年。许多机械性和小规模的人体观察性研究表明，凝血-纤溶系统的异常与人类和实验性肺纤维化的病因有关。总的来说，他们证明了组织因子依赖的促凝活性被诱导，并且在纤维化肺的肺泡室中正常的纤溶活性被抑制。尽管有这些概念性知识，关于凝血/纤溶途径中的因素是否能预测IPF的预后或抗凝治疗反应，还有很多需要了解的。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相关临床事件的风险增加，一项小型试验首次证明抗凝治疗对IPF患者的生存有好处。在这里，我们展示了IPF患者血浆中凝血激活（组织因子抗原增加）和纤维蛋白溶解抑制（PAI-1抗原增加）的初步数据。引人注目的是，组织因子抗原随肺生理性损伤的功能而变化，这与凝血激活程度反映预后的可能性一致。

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)