COAGULATION, PLATELET AND THROMBOSIS IN SICKLE DISEASE

镰状病中的凝血、血小板和血栓形成

• 批准号: 2233736
• 负责人: Robert D Rosenberg
• 金额: $ 38.77万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-28 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2233736
• 关键词: anticoagulants; antithrombins; blood coagulation; blood disorder chemotherapy; disease /disorder model; fibrinolysis; genetic manipulation; hemostasis; heparin; hirudins; laboratory mouse; linkage mapping; medical complication; nonhuman therapy evaluation; pathology; platelets; sickle cell anemia; thrombomodulin; thrombosis; warfarin

This grant application is devoted to determining whether the blood coagulation system is involved in the pathogenesis of the underlying organ damage caused by sickle cell disease and to evaluating whether therapeutic approaches directed at the coagulation system suppress these complications. In our view, these issues can be most effectively resolved at the present time in murine models of sickle cell disease where detailed investigations of thrombosis and sophisticated manipulations of genes can be carried out. We will initially characterize mice exhibiting moderate intensity sickle cell disease with regard to the extent of coagulation system activity, the severity of thrombotic events, and the magnitude of organ dysfunction. The above studies will be carried out in a wild type background as well as in backgrounds with fibrinolytic pathway defects of increasing severity. The correlation of time dependent changes in the extent of coagulation system activity, the severity of thrombotic events and the magnitude of organ dysfunction may establish a linkage between the hemostatic mechanism and organ damage. We will then investigate the proposed linkage in mice with mild intensity or severe intensity sickle cell disease. We may observe strong correlations between the above three variables at all intensities of sickle cell disease or at a particular intensity of sickle cell disease or note the absence of correlations at any intensity of sickle cell disease. These data should allow us to ascertain whether the coagulation system plays a major role or is of little importance in the development of thrombotic events and organ dysfunction. We will then alter coagulation system activity by genetically modifying thrombomodulin function. We expect that these manipulations will lead to an augmented or suppressed development of thrombotic events and organ damage. This effect might occur in the presence of a strong correlation between the three variables outlined above at all intensities of sickle cell disease or in the absence of a strong correlation between the three variables at any intensity of sickle cell disease. Thus, these results could reinforce our view that the coagulation mechanism plays a major role in the development of thrombotic events and organ damage or suggest that a genetic abnormality of the coagulation system could act in concert with sickle cell disease to produce a dramatic acceleration in organ dysfunction. We will then ascertain whether administration of anticoagulants to mice with sickle cell disease suppresses thrombotic events and organ damage. The amounts of anticoagulants employed will be determined with sophisticated assays of the coagulation system in order to minimize drug dosage and maximize therapeutic effect. The murine models utilized will be critically dependent upon previously establishing conditions under which the coagulation system plays a major role in the development of organ damage. The test systems may include mice with various intensities of sickle cell disease or a particular intensity of sickle disease in a wild type backgrounds or in backgrounds with specific defects of the coagulation system.

该赠款申请致力于确定是否血液 凝血系统参与了基础器官的发病机理 镰状细胞疾病造成的损害并评估是否治疗 针对凝血系统的方法抑制了这些 并发症。我们认为，这些问题可以最有效地解决 目前，在镰状细胞疾病的鼠模型中 对基因的血栓形成和复杂操纵的调查可以 被执行。 我们最初将表征表现出中等强度镰刀的小鼠 关于凝血系统活性程度的细胞疾病， 血栓性事件的严重程度和器官功能障碍的大小。这 上述研究将在野生型背景以及 严重程度增加的纤维蛋白水解途径缺陷的背景。这 凝血系统程度的时间依赖性变化的相关性 活性，血小板事件的严重程度和器官的大小 功能障碍可能在止血机制和 器官损坏。 然后，我们将研究轻度强度的小鼠中提出的连锁 或严重的强度镰状细胞疾病。我们可能会观察到很强 上述三个变量之间的相关性在所有强度 镰状细胞疾病或特定的镰状细胞疾病或 请注意，在任何强度的镰状细胞疾病中都没有相关性。 这些数据应该使我们能够确定是否凝结系统 扮演的主要角色或在发展中很重要 血小板事件和器官功能障碍。然后，我们将改变凝血 通过基因修饰血小板调节蛋白功能的系统活性。我们 预计这些操作将导致增强或压制 发展血栓事件和器官损伤。这种效果可能发生 在三个变量之间存在很强的相关性的情况下 在镰状细胞疾病的所有强度上概述了上面的概述 以任何强度的强度 镰状细胞性贫血症。因此，这些结果可以加强我们的观点 凝血机制在血栓形成的发展中起着重要作用 事件和器官损害或表明该遗传异常 凝血系统可以与镰状细胞疾病一起起作用 在器官功能障碍中产生戏剧性的加速度。 然后，我们将确定是否给小鼠施用抗凝剂 镰状细胞疾病抑制血栓性事件和器官损伤。 使用的抗凝剂的量将由 为了最大程度地减少药物的凝结系统的复杂测定 剂量和最大化治疗作用。使用的鼠模型将是 严格依赖于以前建立的条件 凝血系统在器官的发展中起着重要作用 损害。测试系统可能包括具有各种强度的小鼠 镰状细胞疾病或野性镰状疾病的特定强度 类型背景或背景，具有特定缺陷 凝血系统。