title: 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.
authors.affiliation: Department of Hematology, Children's Hospital of Orange County, Orange, California, USA. gyoung@chla.usc.edu
authors.forename: Guy
authors.initials: G
authors.lastname: Young
authors.forename: Karyn E
authors.initials: KE
authors.lastname: Yonekawa
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Nakagawa
authors.forename: Rachelle C
authors.initials: RC
authors.lastname: Blain
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovejoy
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Nugent
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D015942:Factor VIIa / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology*; D013916:Thrombelastography / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D011994:Recombinant Proteins; D015942:Factor VIIa