REVERSAL OF ANTICOAGULANTS IN VIVO

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目前的抗血栓药物抑制止血，这是它们普遍的不良副作用。大多数较老的抗血栓药物有多个分子靶点，包括参与血栓形成和止血的基本血液成分。正在开发的新药通常更具特异性，有些只针对一个分子(例如凝血酶、FXA、血小板GPIIbIIIa等)，但这些靶点仍然不是血栓形成的特异性靶点。因此，所有新的抗血栓药物都有严重的出血副作用。抗凝血患者的出血管理是一个主要的医学问题。目前解决这一问题的唯一合理方法是建议使用血浆来源的凝血酶原复合体浓缩物(Feiba、VT、免疫)来增强止血而不促进血栓形成。我们已经证明，当直接凝血酶抑制物(Dli)抗凝剂(Melagatran)不能抑制FVIIa时，NovoSeven或Feiba确实可以安全地逆转药物诱导的灵长类动物止血损害。我们现在已经确定，其他凝血因子的直接抑制剂，例如FXA抑制剂(利伐沙班)的出血效应也可以通过过量的FVIIa逆转。这是一个悬而未决的问题，因为FXA抑制剂预计会抑制Tenase(Tf/F VII aJFX)复合体的促凝血活性。进一步研究证实，飞霸还能逆转利伐沙班的止血作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Current antithrombotic agents inhibit hemostasis, which is their universal undesirable side effect. Most older antithrombotic agents have multiple molecular targets that include essential blood components that participate in both thrombosis and hemostasis. Newer drugs under development are typically more specific, some targeting exclusively one molecule only (e.g., thrombin, FXa, platelet GPIIbIIIa, etc.), but these targets are still not specific for thrombosis. Accordingly, all new antithrombotic drugs have serious bleeding side effects. Management of bleeding in anticoagulated patients is a major medical problem. The only existing rational approach to this problem is the proposed use of plasma-derived prithrombin complex concentrate (FEIBA, VT, Immuno) to enhance hemostasis without promoting thrombosis. We have demonstrated that when a direct thrombin inhibitor (Dli) anticoagulant drug (melagatran) does not inhibit FVIIa, NovoSeven or FEIBA could indeed be used to safely reverse the drug-induced hemostasis impairment in primates. We now have determined that the hemorrhagic effect of other direct inhibitors of coagulation factors, e.g., a FXa inhibitor (rivaroxaban) could also be reversed using excess FVIIa. This is an open question, since FXa inhibitors are expected to inhibit the procoagulant activity of the tenase (TF/F VII aJFX) complex. Further studies confirmed that FEIBA also reverses the antihemostatic effect of rivaroxaban.