Ability of Recombinant Factor VIIa to Reverse the Anticoagulant Effect of the Pentasaccharide Fondaparinux in Healthy Volunteers

Abstract

Background-The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. Methods and Results-In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 g/kg; nϭ8), fondaparinux and placebo (nϭ4), or placebo and rFVIIa (nϭ4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1ϩ2 (F 1ϩ2 ), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. Conclusions-rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment.The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Reversal of low-molecular-weight heparin-induced bleeding in patients with pre-existing hypercoagulable states with human recombinant activated factor VII concentrate

“…In contrast to some emerging data in the scenario of hemophilia alloantibody associated bleeding, there is no evidence of a dose-response relationship for RVIIa concentrate dosing and the ability to achieve hemostasis in otherwise noncoagulopathic individuals who received therapeutic [12,13,28] or experimental [11,18,27] anticoagulation. Our current experience in the patients reported here are also corroborative.…”

“…The suggestion that RFVIIa concentrate could effectively reverse the anticoagulant effects of indirect factor X inhibitors initially emerged from ex vivo studies in which the anticoagulated plasma samples obtained from normal volunteers treated with the synthetic heparin pentasaccharides, fondaparinux, and idraparinux [14,15,18,30] were spiked with RFVIIa. Endogenous thrombin generation in vitro was partially restored, but never reached normal levels.…”

Practical aspects of the oral new anticoagulants

“…For the factor Xa inhibitors these agents may also work by the similar principle of providing more factor X or Xa. In theory recombinant factor VIIa may also work in factor Xa bleeding given its benefit with the indirect Xa inhibitor fondaparinux [39,40]. There is also in development a novel ''universal'' antidote to reversal all Xa inhibitors [41].…”

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

“…In human volunteers, recombinant factor VIIa has been shown to reduce the aPTT following the administration of fondaparinux [53]. However, the risk of inducing venothromboembolic events after the administration of recombinant factor VIIa needs to be weighed against the risk of bleeding.…”