Mechanisms of coagulation-dependent pathologies in sickle cell disease

镰状细胞病凝血依赖性病理机制

基本信息

批准号：
10178080
负责人：
RAFAL L PAWLINSKI
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10178080
关键词：
Accounting Affect Anticoagulant therapy Anticoagulants Anticoagulation Attenuated BDKRB2 gene Blood Vessels Bradykinin Cells Chronic Clinical Clinical Research Coagulation Process Complex Data Deep Vein Thrombosis Development Disease Event Factor XII Deficiency Factor Xa Frequencies GAG Gene Generations Genes Genetic Genetic Diseases Globin Glycosaminoglycans Hematological Disease Hemolytic Anemia Hemorrhage Hemostatic function High-Molecular-Weight Kininogen In Vitro Individual Inflammation Integrins Kininogens Lead Leukocytes Long-Term Effects Longevity Macrophage-1 Antigen Mediating Mediator of activation protein Mus Organ Outcome Pathology Pathway interactions Patients Pericytes Point Mutation Prekallikrein Principal Investigator Prothrombin Pulmonary Embolism Quality of life Risk Sampling Sickle Cell Sickle Cell Anemia System Testing Thrombin Thrombophilia Thromboplastin Thrombosis Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities attenuation base cell free DNA experimental study improved mast cell mortality mouse model multimodality neutrophil organ injury prevent programs receptor sickling thrombotic vascular inflammation vaso-occlusive crisis venous thromboembolism

项目摘要

Abstract Sickle cell disease (SCD) is a hematologic disorder caused by a point mutation in the globin gene. A chronic hypercoagulable state is one of the hallmarks of SCD. Clinical studies demonstrate that SCD patients are at an increased risk of venous thromboembolism, which is associated with increased mortality. Recent studies from our group and others have demonstrated that the hypercoagulable state contributes to chronic vascular inflammation and end-organ damage in mouse models of SCD. These studies strongly suggest that the hypercoagulable state in SCD contributes to disease pathology, rather than being a secondary event. A growing body of evidence indicates that targeting the intrinsic pathway reduces thrombotic risk without affecting hemostasis. Our preliminary results demonstrate that FXII deficiency/inhibition reduces the prothrombotic state in sickle cell mice during both steady state and vaso-occlusive crises. FXIIa-dependent activation of FXI was required only for the increased thrombin generation observed during vaso-occlusive crisis. In contrast, thrombin generation during steady state did not require FXI and instead was mediated by high molecular weight kininogen, Mac-1 integrin and tissue factor. Using mouse models, in vitro experiments and clinical samples, we propose to further investigate the mechanism of FXIIa-dependent thrombin generation in SCD and evaluate the long-term effects of FXII deficiency/inhibition on the prothrombotic state, vascular inflammation and end-organ damage in sickle mice. A better understanding of FXIIa contribution to the pathology of SCD may lead to the development of new, anticoagulant-based therapy that would not increase bleeding risk and could be a part of multimodal approach to prevent cumulative organ damage in patients with SCD.

抽象的镰状细胞疾病（SCD）是由球蛋白的点突变引起的血液学疾病基因。慢性高凝状态是SCD的标志之一。临床研究证明SCD患者患静脉血栓栓塞的风险增加，即与死亡率增加有关。我们小组和其他人的最新研究有证明了高加密状态有助于慢性血管炎症和 SCD鼠标模型中的最终器官损伤。这些研究强烈表明 SCD中的高凝状态有助于疾病病理学，而不是次要的事件。越来越多的证据表明，靶向内在途径会减少血小板风险而不会影响止血。我们的初步结果表明FXII 缺陷/抑制作用可在两个稳态下降低镰状细胞小鼠的促血栓性状态和血管熟悉的危机。 FXI依赖FXI的激活仅需要用于FXIIA 在血管结合性危机期间观察到的凝血酶产生增加。相反，凝血酶稳态期间的产生不需要FXI，而是由高分子介导重量激素，MAC-1整联蛋白和组织因子。使用鼠标模型，体外实验和临床样品，我们建议进一步研究FXIIA依赖性的机制 SCD中的凝血酶生成并评估FXII缺乏/抑制对镰状小鼠的促血栓性状态，血管炎症和末期损伤。更好了解FXIIA对SCD病理学的贡献可能会导致发展新的，基于抗凝剂的疗法不会增加出血风险，并且可能是防止SCD患者累积器官损伤的多模式方法。