Mechanisms of coagulation-dependent pathologies in sickle cell disease

摘要 镰状细胞病(SCD)是一种由珠蛋白点突变引起的血液疾病。 吉恩。慢性高凝状态是SCD的特征之一。临床研究 证明SCD患者静脉血栓栓塞症的风险增加，这是 与死亡率增加有关。我们小组和其他人最近的研究表明 证明高凝状态有助于慢性血管炎症和 SCD小鼠模型的终末器官损害。这些研究强烈表明， SCD的高凝状态有助于疾病的病理，而不是继发性的 事件。越来越多的证据表明，以内在途径为靶点会减少 在不影响止血的情况下有血栓风险。我们的初步结果表明，FXII 缺陷/抑制降低镰状细胞小鼠在两种稳定状态下的血栓前状态 以及血管闭塞危象。依赖于FXIIa的FXI激活仅适用于 在血管闭塞危象中观察到凝血酶生成增加。相比之下，凝血酶 稳定状态下的产生不需要FXI，而是由高分子介导的 体重激肽原、Mac-1整合素和组织因子。使用小鼠模型，进行体外实验 和临床样本，我们建议进一步研究FXIIa依赖的机制 SCD患者凝血酶生成及FXII缺乏/抑制的远期疗效 镰刀鼠血栓前状态、血管炎症和终末器官损伤。更好的 了解FXIIa在SCD病理中的作用可能会导致 新的基于抗凝剂的疗法不会增加出血风险，并可能成为 预防SCD患者累积性器官损害的多模式方法。

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.