Mechanisms of coagulation-dependent pathologies in sickle cell disease

摘要 镰状细胞病（SCD）是一种血液系统疾病引起的点突变，在珠蛋白 基因慢性高凝状态是SCD的标志之一。临床研究 证明SCD患者发生静脉血栓栓塞的风险增加， 与死亡率增加有关。我们小组和其他人最近的研究表明， 表明高凝状态有助于慢性血管炎症， SCD小鼠模型中的终末器官损伤。这些研究有力地表明， SCD中的高凝状态有助于疾病病理学，而不是继发性 活动越来越多的证据表明，针对内在途径， 血栓形成风险而不影响止血。我们的初步结果表明，FXII 缺乏/抑制降低了镰状细胞小鼠在稳态和稳态期间的血栓前状态 和血管闭塞性危象仅在以下情况下需要FXI的FXIIa依赖性激活： 在血管闭塞危象期间观察到凝血酶生成增加。相反，凝血酶 稳态期间的生成不需要FXI，而是由高分子介导。 重量激肽原、Mac-1整合素和组织因子。使用小鼠模型，体外实验 和临床样本，我们建议进一步研究FXIIa依赖性的机制， 在SCD中的凝血酶生成，并评估FXII缺乏/抑制对SCD的长期影响。 镰状小鼠的血栓前状态、血管炎症和终末器官损伤。更好的 了解FXIIa对SCD病理学的贡献可能会导致 新的，基于抗凝剂的治疗，不会增加出血风险，可能是一部分， 预防SCD患者累积器官损伤的多模式方法。

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.