COAGULATION ACTIVATION IN SICKLE CELL DISEASE

镰状细胞病中的凝血激活

• 批准号: 7736082
• 负责人: Kenneth I Ataga
• 金额: $ 40.74万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736082
• 关键词: Acute Pain; Anticoagulants; Anticoagulation; Arterial Disorder; Biochemical; Clinical; Clinical Research; Coagulation Process; Complication; Development; Disease; Elements; Erythrocytes; Exhibits; Functional disorder; Future; Generations; Goals; Hemostatic function; In Situ; Lead; Modality; Morbidity - disease rate; Pathogenesis; Patient Care; Patients; Plasma; Platelet Activation; Prevention; Proteins; Pulmonary Hypertension; Pulmonary vessels; Randomized Controlled Trials; Research; Role; Safety; Sickle Cell; Sickle Cell Anemia; Thrombin; Thrombophilia; Thrombosis; Vascular Endothelium; Walking; Warfarin; Work; design; improved; interest; mortality; patient population; postcapillary venule; prevent; programs

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.

由于存在大血管血栓形成并发症，以及持续凝血激活的生化证据，镰状细胞病（SED）通常被称为过度凝蛋白状态。但是，凝血激活对SCD发病机理的贡献尚不确定。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，但这些研究大多数都小且控制不佳。此外，由于急性疼痛发作似乎是由于红细胞和其他细胞元素与血管内皮细胞和下皮下皮基质蛋白的相互作用而抑制了后毛细血管静脉的，因此它可能不是评估SED患者抗癌作用的理想临床端点。 肺动脉高压（PHT）是一种与明显的发病率和死亡率相关的常见并发症，并且与组织病理学有关，发现涉及肺部血管的原位血栓形成，代表了一个临床终点，至少部分应部分归因于凝血酶的产生，因此可以用来评估凝结激活对pathosposyolysogy scd的贡献。 UNC综合 镰状细胞计划提供了一个大型且紧随其后的患者人群，我们将能够详细研究超凝性对SCD相关PHT的病理生理学的贡献。我们在SCD患者的护理方面以及止血和血栓形成的持续研究兴趣方面的专业知识使我们的中心成为回答这个基本问题的理想选择。我们假设增加的凝血酶产生以及血小板激活对于SCD的病理生理学至关重要，并有助于发生在内的几种SCDREAD并发症，包括PHI。结果，预计下调凝血酶生成的治疗方式将延迟PHT的进展，并改善SCD患者的生存率。 我们拟议的工作的长期目标是：1）评估抗凝SCD相关PHT的安全性和功效；和2）评估抗凝PHI患者SCD患者的凝血酶产生，血小板激活以及内皮激活的血浆标志物的影响。