Impact of antithrombin deficiency on efficacy of edoxaban and antithrombin-dependent anticoagulants, fondaparinux, enoxaparin, and heparin.

Abstract

INTRODUCTION:

Oral factor Xa (FXa) inhibitors are a novel class of anticoagulants that, unlike heparins, are expected to demonstrate antithrombotic effects independent of plasma antithrombin (AT) concentrations. We utilized heterozygous AT-deficient (AT+/-) mice to determine the impact of AT deficiency on anticoagulant and antithrombotic effects of edoxaban, a direct FXa inhibitor, and compared with heparins (fondaparinux, enoxaparin, and unfractionated heparin [UHF]).

MATERIALS AND METHODS:

The effects of edoxaban and heparins on in vitro prothrombin time and activated partial thromboplastin time were measured in plasma obtained from wild type (AT+/+) and AT+/- male mice. To assess the antithrombotic effects of these anticoagulants in vivo, venous thrombosis was induced in the inferior vena cava by FeCl3 treatment. Potency ratios of antithrombotic effects in AT+/- compared with AT+/+ mice were analyzed by a parallel line assay.

RESULTS:

In vitro studies demonstrated that the clotting-time prolongation effects of edoxaban were not affected by heterozygous AT deficiency whereas those of AT-dependent anticoagulants were attenuated. In AT+/- mice, the antithrombotic effects of AT-dependent anticoagulants were less potent than those in AT+/+ mice. In contrast, edoxaban was equipotent in preventing thrombus formation in both wild-type and AT-deficient mice. The attenuated antithrombotic effects of fondaparinux, enoxaparin, and UFH in AT-deficient mice were restored by AT supplementation. Edoxaban exerts a comparable antithrombotic effect even in mice with low plasma AT antigen and activity to that in wild-type mice.

CONCLUSION:

Edoxaban may potentially be prioritized over AT-dependent anticoagulants in patients with lower plasma AT concentration.

• Authors: Toshio Fukuda, Chikako Kamisato, Yuko Honda, Tadashi Matsushita, Tetsuhito Kojima, Taketoshi Furugohri, Yoshiyuki Morishima, Toshiro Shibano
• Journal: Thrombosis research (Thromb Res) Vol. 131 Issue 6 Pg. 540-6 (Jun 2013) ISSN: 1879-2472 [Electronic] United States
• PMID: 23673387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Anticoagulants
• Enoxaparin
• Factor Xa Inhibitors
• Polysaccharides
• Pyridines
• Thiazoles
• Antithrombin III
• Fondaparinux
• edoxaban

Topics

• Animals
• Anticoagulants (pharmacology, therapeutic use)
• Antithrombin III (genetics, metabolism)
• Blood Coagulation Tests
• Enoxaparin (pharmacology, therapeutic use)
• Factor Xa Inhibitors
• Female
• Fondaparinux
• Gene Deletion
• Hemostasis (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Polysaccharides (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Thiazoles (pharmacology, therapeutic use)
• Venous Thrombosis (blood, drug therapy)