Effect of clot composition on thrombus resolution

描述(申请人提供)：深静脉血栓形成(DVT)和随后的血栓形成后综合征(PTS)是每年影响无数美国人的严重健康问题。“开放静脉假说”假设快速清除静脉血栓对降低PTS风险很重要。因此，了解血栓消退的过程对于改善深静脉血栓患者的临床治疗至关重要。纤维蛋白--为血栓提供支持和稳定的不溶性网络--位于导致血栓形成的危险因素的结合点。我的实验室最近的研究表明，高纤维蛋白原血症是急性血栓形成的原因。重要的是，高纤维蛋白原血症也增加了体内对血栓溶解的抵抗力。这些发现支持我的全球假设，即血栓成分(纤维蛋白含量)影响血栓溶解的自然过程。在小鼠下腔静脉血栓分解的创新模型中的初步数据表明，血栓纤维蛋白含量调节血栓的稳定性和溶解。这些发现支持调查的两个目标。首先，使用体内和体外模型，我将通过测试两个问题来确定血栓成分(纤维蛋白含量)如何决定血栓溶解的过程：1)纤维蛋白含量增加是否延迟体内恢复通畅？2)纤维蛋白含量增加是否增加血栓体积并减少血小板凝块回缩？其次，再次使用体内和体外模型，我将确定血栓成分在血栓溶解过程中如何影响白细胞功能。我将测试以下三个问题：1)纤维蛋白含量增加是否会改变白细胞在血栓中的聚集？2)纤维蛋白含量增加是否会改变白细胞功能(细胞因子或纤溶介质的分泌)？3)纤维蛋白含量增加是否会改变白细胞在血栓中的迁移？这些实验的结果将阐明有助于静脉血栓稳定的机制。这些发现将通过提供血栓成分在血栓解决中的作用的信息来推动这一领域的发展，并确定加速血栓解决的靶点。 公共卫生相关性：不适当的血液凝块形成(血栓形成)是西方世界死亡和残疾的主要原因。“开放静脉假说”认为，快速清除静脉血栓可降低血栓形成后综合征的风险。了解调节血栓溶解的自然过程的机制对于开发预防和管理这种毁灭性疾病的方法至关重要。

DESCRIPTION (provided by applicant): Deep vein thrombosis (DVT) and subsequent post-thrombotic syndrome (PTS) are serious health concerns affecting numerous Americans each year. The "open vein hypothesis" postulates that rapid removal of venous thrombi is important for reducing PTS risk. Understanding the course of thrombus resolution is therefore critical for improved clinical management of individuals with DVT. Fibrin-the insoluble meshwork that provides support and stability to a clot-lies at the nexus of risk factors contributing to thromboss. Recent work by my lab has shown that hyperfibrinogenemia is causative in acute thrombosis. Importantly, hyperfibrinogenemia also increased resistance to thrombolysis in vivo. These findings support my global hypothesis that thrombus composition (fibrin content) influences the natural course of thrombus resolution. Preliminary data in an innovative model of thrombus resolution in the murine inferior vena cava suggest thrombus fibrin content modulates thrombus stability and lysis. These findings support two aims of investigation. First, using in vivo and in vitro models, I will determine how thrombus composition (fibrin content) dictates the course of thrombus resolution by testing two questions: 1) Does increased fibrin content delay return to patency in vivo? 2) Does increased fibrin content increase clot volume and decrease platelet clot retraction? Second, again using in vivo and in vitro models, I will determine how thrombus composition influences leukocyte function during thrombus resolution. I will test the following three questions: 1) Does increased fibrin content alter leukocyte recruitment to the clot? 2) Does increased fibrin content alter leukocyte function (secretion of cytokines or fibrinolytic mediators? 3) Does increased fibrin content alter leukocyte migration through the clot? Results from these experiments will elucidate mechanisms contributing to venous thrombus stability. These findings will advance the field by providing information on the role of thrombus composition in thrombus resolution, and identify targets for accelerating thrombus resolution. PUBLIC HEALTH RELEVANCE: Inappropriate blood clot formation (thrombosis) is the leading cause of death and disability in the Western world. The "open vein hypothesis" postulates that rapid removal of venous thrombi reduces the risk of post-thrombotic syndrome. Understanding the mechanisms that regulate the natural course of thrombus resolution is critical to develop approaches for preventing and managing this devastating disease.