COAGULATION ACTIVATION IN SICKLE CELL DISEASE

镰状细胞病中的凝血激活

• 批准号: 7932119
• 负责人: Kenneth I Ataga
• 金额: $ 41.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932119
• 关键词: Acute Pain; Address; Anticoagulants; Anticoagulation; Arterial Disorder; Biochemical; Clinical; Clinical Research; Coagulation Process; Complication; Elements; Erythrocytes; Exhibits; Functional disorder; Generations; Goals; Hemostatic function; In Situ; Modality; Morbidity - disease rate; Pathogenesis; Patient Care; Patients; Plasma; Platelet Activation; Prevention; Proteins; Pulmonary Hypertension; Pulmonary vessels; Research; Safety; Sickle Cell; Sickle Cell Anemia; Thrombin; Thrombophilia; Thrombosis; Vascular Endothelium; Walking; Warfarin; Work; improved; interest; mortality; patient population; postcapillary venule; prevent; programs; public health relevance

As a result of the presence of macrovascular thrombotic complications, as well as the biochemical evidence of ongoing coagulation activation, sickle cell disease (SeD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. While the majority of clinical studies using anticoagulants have shown no convincing benefit in the prevention or treatment of acute pain episodes, most of these studies were small and poorly controlled. Furthermore, because the acute pain episode appears to result from the occlusion of postcapillary venules by the interaction of red blood cells and other cellular elements with the vascular endothelium and subendothelial matrix proteins, it may not be the ideal clinical endpoint for assessing the effect of anticoagulation in SeD patients. Pulmonary hypertension (PHT), a common complication associated with significant morbidity and mortality, and with histopathologic find ings of in situ thrombosis involving pulmonary vessels, represents a clinical endpoint that is likely due, at least in part, to increased thrombin generation, and may therefore be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. The UNC Comprehensive Sickle Cell Program offers a large and closely followed patient population in whom we will be able to study in detail the contribution of hypercoagulability to the pathophysiology of SCD-associated PHT. Our expertise in the care of patients with SCD, as well as ongoing research interests in hemostasis and thrombosis, makes our center an ideal one to answer this fundamental question. We hypothesize that increased thrombin generation, as well as platelet activation are central to the pathophysiology of SCD and contribute to the occurrence of several SCDrelated complications, including PHI. As a consequence, treatment modalities that down-regulate thrombin generation would be expected to delay the progression of PHT and result in improved survival in patients with SCD. The long-term goals of our proposed work are to: 1) evaluate the safety and efficacy of anticoagulation in SCD-associated PHT; and 2) evaluate the effect of anticoagulation on plasma markers of thrombin generation, platelet activation, as well as endothelial activation in SCD patients with PHI.

由于大血管血栓并发症的存在，以及持续凝血激活的生化证据，镰状细胞病(SED)通常被称为高凝状态。然而，凝血激活在SCD发病机制中的作用仍不确定。虽然大多数使用抗凝剂的临床研究表明，在预防或治疗急性疼痛发作方面没有令人信服的益处，但这些研究大多规模较小，控制不佳。此外，由于急性疼痛发作似乎是由于红细胞和其他细胞成分与血管内皮细胞和内皮下基质蛋白相互作用导致毛细血管后小静脉闭塞所致，因此它可能不是评估SED患者抗凝效果的理想临床终点。 肺动脉高压(PHT)是一种常见的并发症，与严重的发病率和死亡率以及组织病理学发现的肺血管原位血栓形成有关，它代表了一个临床终点，至少部分原因可能是凝血酶生成增加，因此可以用来评估凝血激活对SCD病理生理的贡献。北卡罗来纳大学综合 镰状细胞计划提供了大量密切关注的患者群体，在这些患者中，我们将能够详细研究高凝状态对SCD相关性PHT病理生理学的贡献。我们在SCD患者护理方面的专业知识，以及对止血和血栓形成的持续研究兴趣，使我们的中心成为回答这一根本问题的理想中心。我们推测，凝血酶生成增加和血小板激活是SCD的病理生理机制的核心，并导致包括PHI在内的几种SCD相关并发症的发生。因此，下调凝血酶生成的治疗方式有望延缓PHT的进展，并提高SCD患者的存活率。 我们提出的工作的长期目标是：1)评估抗凝治疗SCD相关性PHT的安全性和有效性；2)评估抗凝对SCD合并PHI患者凝血酶生成、血小板激活和内皮激活的影响。