Factor XI and XII as antithrombotic targets.
Factor XI and XII as antithrombotic targets.
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DOI：
10.1097/moh.0b013e3283497e61
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发表时间：
2011-09
影响因子：
3.2
通讯作者：
Renné T
中科院分区：
文献类型：
--
作者：
Müller F;Gailani D;Renné T
动脉和静脉血栓形成是发病和死亡的主要原因，并且血栓栓塞性疾病的发病率随着人口老龄化而增加。血栓由活化的血小板和纤维蛋白形成。后者是血浆凝固系统的产物。目前可用的抗凝剂，如肝素、维生素 K 拮抗剂和凝血酶抑制剂或 Xa 因子抑制剂，针对凝血级联中对纤维蛋白形成至关重要的酶。然而，纤维蛋白对于终止血管损伤部位的失血也是必需的。因此，目前临床使用的抗凝剂会增加出血风险，部分抵消了减少血栓形成的好处。本综述重点关注与治疗相关的出血增加极少或无相关的抗凝新靶点。使用小鼠的实验模型和对凝血因子 XI 或 XII 遗传性缺陷患者的临床研究的数据表明，这两种凝血因子对于血栓形成都很重要，而在终止失血（止血）的过程中作用较小或没有明显作用。遗传性缺乏因子 XII（哈格曼因子）或因子 XI，这是一种血浆蛋白酶，可启动凝血的内在途径，损害血栓形成并提供针对血管闭塞事件的保护，同时对止血的影响最小。由于因子 XII-因子 XI 途径比正常止血在更大程度上促进血栓形成，因此对这些凝血因子的药理抑制可能会提供令人兴奋的抗凝治疗可能性，而出血风险最小或无出血风险。
Arterial and venous thrombosis are major causes of morbidity and mortality, and the incidence of thromboembolic diseases increases as a population ages. Thrombi are formed by activated platelets and fibrin. The latter is a product of the plasma coagulation system. Currently available anticoagulants such as heparins, vitamin K antagonists and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation. However, fibrin is also necessary for terminating blood loss at sites of vascular injury. As a result, anticoagulants currently in clinical use increase the risk of bleeding, partially offsetting the benefits of reduced thrombosis. This review focuses on new targets for anticoagulation that are associated with minimal or no therapy-associated increased bleeding. Data from experimental models using mice and clinical studies of patients with hereditary deficiencies of coagulation factors XI or XII have shown that both of these clotting factors are important for thrombosis, while having minor or no apparent roles in processes that terminate blood loss (hemostasis). Hereditary deficiency of factor XII (Hageman factor) or factor XI, plasma proteases that initiate the intrinsic pathway of coagulation, impairs thrombus formation and provides protection from vascular occlusive events, while having a minimal impact on hemostasis. As the factor XII–factor XI pathway contributes to thrombus formation to a greater extent than to normal hemostasis, pharmacological inhibition of these coagulation factors may offer the exciting possibility of anticoagulation therapies with minimal or no bleeding risk.