Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet, University Hospital, Stockholm, Sweden.
Curr Opin Hematol. 2011 Sep;18(5):349-55. doi: 10.1097/MOH.0b013e3283497e61.
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.
动脉和静脉血栓形成是发病率和死亡率的主要原因，随着人口老龄化，血栓栓塞性疾病的发病率增加。血栓由激活的血小板和纤维蛋白形成。后者是血浆凝血系统的产物。目前可用的抗凝剂，如肝素、维生素 K 拮抗剂和凝血酶或因子 Xa 抑制剂，针对的是凝血级联反应中的关键酶，这些酶对纤维蛋白形成至关重要。然而，纤维蛋白对于在血管损伤部位止血也是必要的。因此，目前临床使用的抗凝剂增加了出血的风险，部分抵消了减少血栓形成的益处。本文综述了与最小或无治疗相关出血增加相关的抗凝新靶点。
使用小鼠的实验模型和遗传性凝血因子 XI 或 XII 缺乏症患者的临床研究数据表明，这两种凝血因子都与血栓形成有关，而在止血（止血）过程中几乎没有明显作用。
凝血因子 XII（Hageman 因子）或因子 XI 的遗传性缺乏，即启动凝血内在途径的血浆蛋白酶，会损害血栓形成并提供对血管闭塞事件的保护，而对止血的影响最小。由于因子 XII-因子 XI 途径对血栓形成的贡献大于对正常止血的贡献，因此这些凝血因子的药理学抑制可能为抗凝治疗提供令人兴奋的可能性，具有最小或无出血风险。
