REVERSAL OF ANTICOAGULANTS IN VIVO

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目前的抗血栓形成剂抑制止血，这是其普遍的不良副作用。大多数较老的抗血栓药物具有多个分子靶点，包括参与血栓形成和止血的基本血液成分。正在开发的较新药物通常更具特异性，一些仅针对一种分子（例如，凝血酶、FXa、血小板GPIIb IIIa等），但这些目标仍然不是血栓形成的特异性目标。因此，所有新的抗血栓药物都有严重的出血副作用。抗凝患者的出血管理是一个主要的医疗问题。解决该问题的唯一现有合理方法是建议使用重组FVIIa（NovoSeven）来增强止血而不促进血栓形成。我们已经证明，当直接凝血酶抑制剂（DTI）抗凝药物（melaglavin）不能抑制FVIIa时，诺和锐确实可以安全地逆转灵长类动物中药物诱导的止血功能障碍。我们现在已经开始研究，以确定其他凝血因子的直接抑制剂，FXA抑制剂（利伐沙班）也可以使用过量的FVIIa逆转。这是一个悬而未决的问题，因为预期FXa抑制剂抑制tenase（TF/FVIIa/FX）复合物的促凝血活性。

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 recombinant FVIIa (NovoSeven) to enhance hemostasis without promoting thrombosis. We have demonstrated that when a direct thrombin inhibitor (DTI) anticoagulant drug (melagatran) does not inhibit FVIIa, NovoSeven could indeed be used to safely reverse the drug-induced hemostasis impairment in primates. We now have initiated studies to determine whether 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/FVIIa/FX) complex.