Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography

Abstract

Bleeding is the major adverse reaction to anticoagulants, leading to significant morbidity and even mortality. Protamine is a specific antidote for heparin yet is only partially effective for enoxaparin, and the activated factor X inhibitor fondaparinux and the direct thrombin inhibitors argatroban and bivalirudin lack specific antidotes. We evaluated the ability of recombinant activated factor VII (rFVIIa), a general hemostatic agent, to reverse the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, as measured by thromboelastography. Whole-blood samples containing each test anticoagulant, with or without rFVIIa 1.5-4.5 microg/ml, were prepared ex vivo (n >or= 48, each anticoagulant) and analyzed by thromboelastography. The thromboelastography parameters of clot initiation, propagation, rigidity and elasticity were compared for the ex-vivo samples for each anticoagulant. The reversal ability of rFVIIa was also assessed using the standard clinical assay used to monitor each anticoagulant. Thromboelastography was performed on blood from eight stably anticoagulated patients, with and without exogenous rFVIIa. For each anticoagulant, rFVIIa significantly improved and, in some cases, completely normalized all thromboelastography parameters (P < 0.001). rFVIIa significantly (P < 0.01) decreased the activated partial thromboplastin time for argatroban-containing, bivalirudin-containing, or heparin-containing blood yet did not affect the anti-activated factor X levels for enoxaparin-containing or fondaparinux-containing blood. By thromboelastography, rFVIIa exerted generally similar reversal effects on the anticoagulated patient samples as on the ex-vivo samples. In conclusion, rFVIIa effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, and should be considered for patients with excessive bleeding associated with these anticoagulants.

Case files of the medical toxicology fellowship at banner good samaritan medical center in Phoenix, AZ: A non-warfarin anticoagulant overdose

“…Animal models, however, have demonstrated incomplete reversal of antifactor Xa levels following the administration of protamine sulfate [50][51]. In vitro studies have demonstrated effective reversal of LMWH following the administration of recombinant factor VIIa [52]. Following an overdose of LMWH, we would recommend protamine be administered only in the setting of clinicallysignificant bleeding.…”

Continuous Renal Replacement Therapy and Anticoagulation:

“…1,27,28 If bleeding occurs during anticoagulation with argatroban, the infusion can be turned off. In an ex vivo study, 29 the effects of argatroban could be reversed by using recombinant activated factor VII. In patients with hepatic failure or with multiple organ dysfunction syndrome and sepsis, the clearance of argatroban may be markedly reduced.…”

Management of antithrombotic agents in patients undergoing flexible bronchoscopy

“…Unlike heparin, fondaparinux does not interact with protamine sulfate. In cases where uncontrolled bleeding occurs, PCCs or rFVIIa can be used in an attempt to reverse its anticoagulant effect [109,110].…”