Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents

Abstract

The present invention relates to antidotes of anticoagulants targeting factor Xa which antidotes are used in combination with blood coagulating agents or other heparin antidotes to prevent or reduce bleeding in a subject. The antidotes described herein have reduced or no intrinsic coagulant activity. Disclosed herein are methods of stopping or preventing bleeding in a patient that is or will be undergoing anticoagulant therapy with a factor Xa inhibitor.

1 . (canceled) 
     
     
         2 . A method for preventing or reducing bleeding in a subject undergoing anticoagulant therapy with a fXa inhibitor, comprising administering to the subject an isolated polypeptide comprising the amino acid sequence of SEQ ID NO. 12, 13, or 15 or a polypeptide having at least 80% homology to SEQ ID NO. 12, 13, or 15 and a blood coagulating agent or a heparin antidote. 
     
     
         3 - 21 . (canceled) 
     
     
         22 . The method of  claim 2 , wherein the blood coagulating agent initiates or enhances blood coagulation or inhibits fibrinolysis or thrombosis. 
     
     
         23 . The method of  claim 2 , wherein the blood coagulating agent has procoagulant, anti-thrombolytic, and/or anti-fibrinolytic activity. 
     
     
         24 . The method of  claim 2 , wherein the blood coagulating agent is selected from the group consisting of a coagulation factor, a polypeptide related to the coagulation factor, a recombinant coagulation factor, and combinations thereof. 
     
     
         25 . The method of  claim 24 , wherein the coagulation factor is selected from the group consisting of plasma derived factors VII/VIIa, IX/IXa, X/Xa, II/IIa, VIII/VIIIa, V/Va and combinations thereof. 
     
     
         26 . The method of  claim 24 , wherein the recombinant coagulation factor is selected from the group consisting of recombinant factors VII/VIIa, IX/IXa, X/Xa, II/IIa, VIII/VIIIa, V/Va and combinations thereof. 
     
     
         27 . The method of  claim 26 , wherein the recombinant coagulation factor is recombinant factor VIIa. 
     
     
         28 . The method of  claim 23 , wherein the blood coagulating agent is a non-specific anti-bleeding agent. 
     
     
         29 . The method of  claim 28 , wherein the non-specific anti-bleeding agent is selected from the group consisting of an adsorbent chemical, a hemostatic agent, thrombin, fibrin glue, desmopressin, cryoprecipitate and fresh frozen plasma, coagulation factor concentrate, activated or non-activated prothrombin complex concentrate, Feiba Vh, platelet concentrates and combinations thereof. 
     
     
         30 . The method of  claim 2 , wherein the blood coagulating agent is selected from the group consisting of thrombin-activatable fibrinolysis inhibitor (TAFI), protein C inhibitor (PCI), protein S inhibitor (PSI), alpha-2-antiplasmin, tranexamic acid, aminocaproic acid, aprotinin and combinations thereof. 
     
     
         31 . The method of  claim 2 , wherein the heparin antidote is selected from the group consisting of protamie, PMX 60102, PMX 60126, PMX 60138, PMX 60100, PMX 60056, and combinations thereof. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 2 , wherein the isolated polypeptide is administered in a therapeutically effective or sub-therapeutically effective amount. 
     
     
         34 . The method of  claim 33 , wherein the blood coagulating agent or heparin antidote is administered in a therapeutically effective or sub-therapeutically effective amount. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The method of  claim 2 , wherein the fXa inhibitor is selected from the group consisting of fondaparinux, idraparinux, biotinylated idraparinux, enoxaparin, fragmin, NAP-5, rNAPc2, tissue factor pathway inhibitor, heparin, low molecular weight heparin, DX-9065a, YM-60828, YM-150, apixaban, rivaroxaban, betrixaban, PD-348292, otamixaban, DU-176b, LY517717, GSK913893 and combinations thereof. 
     
     
         38 . The method of  claim 2 , wherein the subject is experiencing a clinical major bleeding event selected from the group consisting of hemorrhage, bleeding into vital organs, bleeding requiring re-operation or a new therapeutic procedure and a bleeding index of equal to or greater than 2.0 with an associated overt bleeding. 
     
     
         39 . The method  claim 2 , wherein the subject is experiencing a bleeding event selected from the group consisting of persistent or recurrent epistaxis, rectal or urinary tract bleeding without the need for a therapeutic procedure, substantial injection site-hematomas, spontaneous hematomas at non-injection site, hematomas occurring with trivial trauma, substantial blood loss and bleeding requiring unplanned transfusion. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 2 , wherein the polypeptide is administered prior to a surgery. 
     
     
         42 . The method of  claim 2 , wherein the blood coagulating agent or heparin antidote is administered prior to or during a surgery. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 2 , wherein the polypeptide is administered before, after, or at the same time as the administration of the blood coagulating agent. 
     
     
         45 . The method of  claim 2 , wherein the subject is human. 
     
     
         46 - 56 . (canceled) 
     
     
         57 . A method for preventing or reducing bleeding in a subject undergoing anticoagulant therapy with a fXa inhibitor, comprising administering to the subject an effective amount of a composition comprising (i) an isolated polypeptide comprising the amino acid sequence of SEQ ID NO. 12, 13, or 15 or a polypeptide having at least 80% homology to SEQ ID NO. 12, 13, or 15 and (ii) a blood coagulating agent or a heparin antidote. 
     
     
         58 - 60 . (canceled)