Abstract 12420: Reversal of Low Molecular Weight Heparin and Fondaparinux by a Recombinant Antidote (r-Antidote, PRT064445)
Anticoagulants, including indirect factor Xa (fXa) inhibitors low molecular weight heparin (LMWH) and fondaparinux, are widely used for the treatment and prevention of thrombosis but have the liability of clinically relevant bleeding. Protamine sulfate is unable to completely reverse LMWHs and does not reverse fondaparinux mediated anticoagulation. We have previously demonstrated the ability of r-Antidote, a recombinant fXa derivative which is catalytically inactive and lacks the Gla-domain, to reverse the anticoagulant effects of direct fXa inhibitors such as rivaroxaban. We now report the potential of r-Antidote to reverse the anticoagulant effects of enoxaparin and fondaparinux. With enoxaparin, r-Antidote dose-dependently reversed 1) anti-fXa activity in rat and human plasma; 2) inhibition of thrombin generation in human plasma; 3) the increase in anti-fXa units and clotting times in enoxaparin-treated rats. In addition to correcting PD parameters, r-Antidote was further tested in a rat tail transection blood loss model for restoration of hemostasis. Intravenous infusion of r-Antidote dose-dependently and completely corrected blood loss due to enoxaparin (4.5mg/kg, IV bolus) anticoagulation. Decreased blood loss correlated with both r-Antidote plasma concentrations (r2=0.80) and reduction of anti-fXa units (r2=0.89). In the same model, r-Antidote also completely corrected blood loss due to fondaparinux (25 mg/kg, IV bolus) administration whereas protamine failed to do so. These results demonstrate that r-Antidote neutralizes both direct and indirect fXa inhibitors and has the potential to reverse anticoagulant activity and restore hemostasis in patients treated with current and novel agents in this class of drugs.
- © 2010 by American Heart Association, Inc.