Mechanism of sickle cell disease-specific venous thromboembolism

项目主任/首席调查员(最后、第一、中间)Pawlinski，Rafal和Key，Nigel 摘要 静脉血栓栓塞症(VTE)是仅次于心肌梗塞的第三种常见的心血管疾病 脑梗塞和缺血性中风，在美国每年约有90万例。VTE可能会出现 临床表现为深静脉血栓形成(DVT)和/或肺栓塞(PE)。然而，尚不清楚为什么有些人 患者出现症状性DVT，而其他患者出现PE。近年来，它已经成立了 患有镰状细胞病(SCD)的人，以及SCD的携带者--据说具有镰状细胞特征 --患VTE的风险增加。有趣和不同寻常的是，在镰状细胞疾病和特征中，一个倾斜的 观察DVT和PE(偏向PE)患者的比例分布。我们已将其命名为 “镰刀细胞悖论”现象。SCD是由于表达的血红蛋白中的一种遗传突变 仅限于红细胞(RBC)。因此，在这项提案中，我们假设更好地理解 SCD中VTE的机制，以及对镰状细胞悖论的解释，将通过一个 详细研究镰状红细胞在VTE中的作用。为了解决这个问题，我们将利用SCD的动物模型 实验诱导的静脉血栓，同时研究血栓的定性方面 由SCD患者的血液在体外形成。为了实现这一目标，我们将解决以下具体问题 目的：在目标1中，我们将确定红细胞对SCD小鼠模型静脉血栓形成的影响。 我们预计部分RBC交换将导致更小、更稳定的DVT，并减少PE的发生率。在……里面 目的研究镰状红细胞在SCD中促进凝血酶生成的作用。在第三个目标中，我们将 确定降低镰状凝块对纤溶的敏感性的细胞和分子机制。我们 预计这一效应既是由SCD红细胞的遗传缺陷所介导的，也是由血小板在 SCD患者过度活跃。最后，在目标4中，我们将确定血小板数量的减少 减少VTE并恢复镰状小鼠和慢性SCD患者对纤溶的正常敏感性 RBC兑换。每年全球SCD出生率超过30万(估计为2.5亿 对于有镰刀特征的人)，对镰状细胞疾病中的VTE有更好的机制理解是一个高度优先的问题。 OMB编号0925-0001/0002(03/16修订版批准至2018年10月31日)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle) Pawlinski, Rafal and Key, Nigel Abstract Venous thromboembolism (VTE) is the third most common form of cardiovascular disease after myocardial infarction and ischemic stroke, with approximately 900,000 cases annually in the United States. VTE may present clinically as deep vein thrombosis (DVT) and/or pulmonary embolism (PE). However, it is unknown why some patients present with symptomatic DVT, while others present with PE. In recent years, it has been established that individuals with sickle cell disease (SCD), as well as carriers for SCD -- who are said to have sickle cell trait -- are at increased risk of VTE. Interestingly and unusually, in both sickle cell disease and trait, a skewed distribution in the proportions of patients with DVT and PE (in favor of PE) is observed. We have termed this phenomenon “the sickle cell paradox”. SCD is due to an inherited mutation in hemoglobin that is expressed exclusively in red blood cells (RBCs). Therefore, in this proposal, we postulate that a greater understanding of the mechanism of VTE in SCD, as well as an explanation for the sickle cell paradox, will be explained by a detailed study of the role of sickle RBCs in VTE. To address this question, we will utilize animal models of SCD with experimentally induced venous thrombi, while concurrently studying the qualitative aspects of blood clots formed from the blood of patients with SCD ex vivo. Towards this goal, we will address the following specific aims: in Aim 1, we will determine the effect of RBCs on venous thromboembolism in a mouse model of SCD. We expect that partial RBC exchange will result in smaller, more stable DVTs and a reduced incidence of PE. In Aim 2, we will investigate how sickle RBCs enhance thrombin generation in SCD. In the third Aim, we will determine the cellular and molecular mechanisms that attenuate sensitivity of sickle clots to fibrinolysis. We anticipate this effect is mediated both by the inherited defect in SCD RBCs, but also the fact that platelets in patients with SCD are over-activated. Finally, in Aim 4, we will determine whether reduction of platelet numbers reduces VTE and restores normal susceptibility to fibrinolysis in sickle mice and SCD patients undergoing chronic RBC exchange. With an annual worldwide SCD birth rate of more than 300,000 (and an estimated 250 million individuals with sickle trait), a greater mechanistic understanding of VTE in sickle cell disorders is a high priority. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page