Recombinant Factor VIIa Reverses the Anticoagulant Effects of Argatroban, Bivalirudin, Fondaparinux, Enoxaparin, and Heparin as Assessed Ex Vivo by Thromboelastography.

Abstract

BACKGROUND: The novel anticoagulants fondaparinux (Fond), argatroban (Arg), and bivalirudin (Biv) are being used increasingly for a variety of indications, even replacing heparin and warfarin in certain settings. While heparin and warfarin have antidotes (protamine and vitamin K, respectively), the newer agents lack known antidotes. Recombinant factor VIIa (rFVIIa) has reversed the effects of some novel anticoagulants in in vitro and animal studies. We evaluated the ability of rFVIIa to reverse the anticoagulant effects of Fond, Arg, Biv, unfractionated heparin (Hep), and enoxaparin (Enox) in whole blood using thromboelastography (TEG). METHODS: TEG was performed using dilute tissue factor as an activator on native whole blood from healthy adults within 4 minutes of atraumatic venipuncture and the following parameters measured: time to clot initiation (R, in mins), rate of clot propagation (K, in mins and angle in degrees), clot rigidity (MA, in mm), and clot strength (G, in dynes/cm2). For each experiment the blood was split 4 ways before analysis and the following was added: nothing (baseline), anticoagulant, anticoagulant plus rFVIIa, and anticoagulant plus rFVIIa placebo (control). Multiple experiments using 9 volunteers were done for each anticoagulant at a therapeutic concentration and rFVIIa at a final concentration of 1.5, 3, 4.5, and 9 mcg/mL (1.5–3 mcg/mL is a therapeutic concentration in hemophilia). Protamine reversal served as a positive control for heparin. RESULTS: Each anticoagulant delayed clot initiation and propagation. The direct thrombin inhibitors (Arg, Biv) exerted lesser effects than the antithrombin-dependent agents (Hep, Enox, Fond) on clot rigidity and strength. rFVIIa at each test concentration reversed the anticoagulant effect of each agent as measured by TEG (placebo had no effect). A dose response was noted for the 9 mcg/mL rFVIIa concentration but not for the 3 lower concentrations. We thus grouped the results for the 3 lower concentrations. The data for the 9 mcg/mL rFVIIa concentration (not shown) was in line with the grouped data yet with values closer to baseline. The reversal effect was statistically significant for each parameter with the antithrombin-dependent agents and for clot initiation and propagation for the direct thrombin inhibitors. See tables for details. Protamine successfully reversed heparin’s effect (data not shown). CONCLUSIONS: rFVIIa successfully reversed the anticoagulant effects in whole blood of therapeutic concentrations of Arg, Biv, and Fond, which lack known antidotes, Enox, for which protamine reversal is only partially effective, and heparin. These findings support rFVIIa as a potential non-specific antidote for newer anticoagulants. TEG parameters: Antithrombin-dependent agents with and without addition of rFVIIa Baseline Hep Hep+rFVIIa Enox Enox+rFVIIa Fond Fond+rFVIIa Mean values; changes in parameters between anticoagulant and anticoagulant + rFVIIa are all statistically significant (p<0.05). R 8.6 23 14 20.5 7.5 29.6 9.2 K 3.1 11.3 4.9 9.7 3 17 4.8 Angle 50.9 18.8 38 20.7 43.6 12.5 41.6 MA 60.5 44.3 54.6 39 54.2 31.1 58.3 G 7.3 4 6.1 3.3 6 2.6 7.1 TEG parameters: Direct thrombin inhibitors with and without addition of rFVIIa Baseline Arg Arg+rFVIIa Biv Biv+rFVIIa Mean values; changes in parameters R, K and angle between anticoagulant and anticoagulant + rFVIIa are statistically significant (p<0.05). R 8.6 14.8 10.8 26.2 21.2 K 3.1 4.6 3 7.4 4 Angle 50.9 40.9 53.2 31.5 43.1 MA 60.5 57.1 59.6 49 53.4 G 7.3 6.7 7.4 5.3 5.6