REVERSAL OF ANTICOAGULANTS IN VIVO

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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.