Mechanism of sickle cell disease-specific venous thromboembolism

项目总监/主要研究者（最后一名、第一名、中间名）Pawlinski、Rafal和Key、奈杰尔 摘要 静脉血栓栓塞（VTE）是仅次于心肌梗死的第三种最常见的心血管疾病。 梗死和缺血性中风，在美国每年约有900，000例。VTE可能存在 临床上称为深静脉血栓形成（DVT）和/或肺栓塞（PE）。然而，不知道为什么有些人 患者表现为有症状的DVT，而其他患者表现为PE。近年来， 患有镰状细胞病（SCD）的人，以及SCD的携带者--他们被认为具有镰状细胞特征， 患静脉血栓栓塞的风险增加。有趣而不同寻常的是，在镰状细胞病和性状中， 观察到DVT和PE患者比例的分布（有利于PE）。我们称之为 镰状细胞悖论（Sickle Cell Paradox）SCD是由于血红蛋白的遗传突变， 仅存在于红细胞（RBC）中。因此，在本提案中，我们假定， SCD中静脉血栓栓塞的机制，以及镰状细胞悖论的解释，将由一个 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 实验诱导静脉血栓，同时研究血凝块的定性方面， 由SCD患者的血液离体形成。为达致这个目标，我们会处理以下的具体问题： 目的：在目的1中，我们将确定红细胞对SCD小鼠模型中静脉血栓栓塞的影响。 我们预计部分红细胞交换将导致更小，更稳定的DVT和PE的发生率降低。在 目的2，我们将研究镰状红细胞如何增强SCD中凝血酶的产生。在第三个目标中，我们将 确定降低镰状凝块对纤维蛋白溶解敏感性的细胞和分子机制。我们 预期这种效应是由SCD RBC中的遗传缺陷介导的，而且事实上， 患有SCD的患者过度活跃。最后，在目标4中，我们将确定血小板数量的减少是否 减少VTE并恢复镰状小鼠和SCD患者对纤维蛋白溶解的正常敏感性， RBC交换每年全球SCD出生率超过30万（估计有2.5亿人 因此，对镰状细胞疾病中VTE的机制性理解是一个高度优先事项。 OMB编号0925-0001/0002（2016年3月修订版，批准至2018年10月31日）

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