Deep Vein Thrombosis and Chronic Thrombotic Venous Disease

深静脉血栓形成和慢性血栓性静脉病

• 批准号: 8307476
• 负责人: TIMOTHY A MORRIS
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307476
• 关键词: Acute; Address; Affect; Amino Acid Sequence; Applications Grants; Biological Assay; Blood Clot; Blood Vessels; Blood coagulation; Blood flow; Case-Control Studies; Cells; Characteristics; Chronic; Chronic Disease; Cicatrix; Clinical; Coagulation Process; Cohort Studies; Complication; Cytolysis; Deep Vein Thrombosis; Development; Diagnosis; Disease; Elements; Embolism; Endothelial Cells; Epitopes; Etiology; Fiber; Fibrin; Fibrinogen; Fibrinolysis; Gene Mutation; Genetic Polymorphism; Goals; In Vitro; Institution; Investigation; Laboratories; Lead; Left; Leg; Location; Lung; Mass Spectrum Analysis; Measures; Mediating; Mutation; Obstruction; Pain in lower limb; Patients; Pattern; Pharmacogenetics; Phase; Pilot Projects; Plasmin; Plasminogen; Post-Translational Protein Processing; Postphlebitic Syndrome; Predisposition; Prevention; Probability; Process; Pulmonary Embolism; Pulmonary Hypertension; Pulmonary artery structure; Recovery; Recurrence; Relative (related person); Reporting; Resistance; Resolution; Risk; Signal Transduction; Structure; Thrombus; Tissues; Ultrasonography; Variant; Veins; Venous; base; deep vein; genetic analysis; genetic variant; improved; insight; prevent; prospective; public health relevance; repaired; research study

DESCRIPTION (provided by applicant): One of the principle long-term complications after acute deep vein thrombosis (DVT) is chronic thrombotic venous disease (CTVD), which increases the chance of recurrence and post-phlebitic syndrome. CTVD is characterized by remodeling of thrombotic material within the deep veins into intravascular scars that obstruct blood flow. Why some patients suffer this complication, while others lyse their thrombi is unknown. We have, however, discovered fibrinolytic abnormalities in a similar disease, chronic thrombo-embolic pulmonary hypertension (CTEPH), in which acute pulmonary thrombo-emboli are remodeled into scars within the pulmonary arteries. Our previous studies disclosed that fibrinogen purified from CTEPH patients is somewhat resistant to lysis by exogenous plasmin. Furthermore, we have identified specific fibrinogen mutations among CTEPH patients that may affect the structure of clots. Specifically, their fibrin tends to form less turbid clots, composed of thinner fibers that may enhance the accessibility of epitopes that are stimulatory to endothelial cells and other repair cells. We aim to determine whether similar genetic variants or post-translational modifications of fibrinogen are present in CTVD patients, which could confer enhancement and/or persistence of fibrin epitopes that stimulate vascular scar formation within acute thrombi. To address this hypothesis, we aim to (1) identify clinical and laboratory variables that may be associated with CTVD after an acute DVT; (2) characterize the fibrin-clot turbidity and the fibrinolytic resistance in a large group of patients with CTVD; (3) characterize structural variants in fibrinogen from patients with CTVD; and (4) determine if resistance to fibrinolysis or variant fibrinogen structure is an important determinant of incomplete recovery after acute DVT. Public Health Relevance: Chronic thrombotic venous disease (CTVD) occurs when blood clots in the leg vein (deep vein thrombi) do not dissolve entirely, and are remodeled into scars that obstruct blood flow. If left untreated, this condition can cause chronic leg pain and disfigurement. Our goal is to understand the mechanisms responsible for the development of CTVD in some patients after acute deep vein thrombosis.

描述（由申请人提供）： 急性深静脉血栓形成（DVT）后的主要并发症之一是慢性血栓性静脉疾病（CTVD），这增加了复发的机会和短肢综合征。 CTVD的特征是将深静脉内的血栓形成材料重塑为阻碍血液流动的血管内疤痕。为什么有些患者遭受这种并发症，而另一些患者则非是他们的血栓尚不清楚。但是，我们发现了类似疾病，慢性血栓栓塞性肺动脉高压（CTEPH）中的纤维蛋白水解异常，其中将急性肺动脉菌 - 栓塞重塑为肺动脉内的疤痕。我们先前的研究揭示了从CTEPH患者纯化的纤维蛋白原对外源性纤溶酶裂解具有抗性。此外，我们已经确定了可能影响凝块结构的CTEPH患者中的特定纤维蛋白原突变。具体而言，它们的纤维蛋白倾向于形成较少的浊度，由较薄的纤维组成，这些纤维可能会增强内皮细胞和其他修复细胞刺激性表位的可及性。我们旨在确定CTVD患者中是否存在类似的纤维蛋白原遗传变异或翻译后修饰，这可能会赋予纤维蛋白表位的增强和/或持续性，从而刺激急性血栓形成血管疤痕形成的纤维蛋白表位。为了解决这一假设，我们的目标是（1）确定急性DVT后可能与CTVD相关的临床和实验室变量； （2）表征了大量CTVD患者的纤维蛋白 - 凝集浊度和纤维蛋白耐药性； （3）表征来自CTVD患者的纤维蛋白原中的结构变异； （4）确定对纤维蛋白溶解或变异纤维蛋白原结构的抗性是急性DVT后不完全恢复的重要决定因素。公共卫生相关性：慢性血栓性静脉疾病（CTVD）发生时，当腿部静脉（深静脉血栓）中的血块不完全溶解，并且被重塑为阻碍血液流动的疤痕。如果未经治疗，这种情况可能会导致慢性腿部疼痛和毁容。我们的目标是了解急性深静脉血栓形成后某些患者中CTVD发展的机制。

项目成果

New synthetic antithrombotic agents for venous thromboembolism: pentasaccharides, direct thrombin inhibitors, direct Xa inhibitors.

用于静脉血栓栓塞的新型合成抗血栓药物：五糖、直接凝血酶抑制剂、直接 Xa 抑制剂。

• DOI: 10.1016/j.ccm.2010.06.006
• 发表时间: 2010
• 期刊: Clinics in chest medicine
• 影响因子: 5.7
• 作者: Morris,TimothyA

Structural insights into fibrinogen dynamics using amide hydrogen/deuterium exchange mass spectrometry.

• DOI: 10.1021/bi4007995
• 发表时间: 2013-08-13
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Marsh, James J.;Guan, Henry S.;Li, Sheng;Chiles, Peter G.;Danny Tran;Morris, Timothy A.
• 通讯作者: Morris, Timothy A.