Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies

Abstract

The direct oral anticoagulants targeting coagulation factor Xa or thrombin are widely used as alternatives to vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation. In case of bleeding or emergency surgery, reversal agents are helpful to counteract the anticoagulant therapy and restore hemostasis. While idarucizumab has been established as an antidote for the direct thrombin inhibitor dabigatran, reversal strategies for the direct factor Xa inhibitors have been a focal point in clinical care over the past years. In the absence of specific reversal agents, the off-label use of (activated) prothrombin complex concentrate and recombinant factor VIIa have been suggested as effective treatment options during inhibitor-induced bleeding complications. Meanwhile, several specific reversal agents have been developed. In this review, an overview of the current state of nonspecific and specific reversal agents for the direct factor Xa inhibitors is provided, focusing on the biochemistry and mechanism of action and the preclinical assessment of newly emerging therapies.

2021 Eberhard F. Mammen Award Announcements: Part II—Young Investigator Awards

“…The most recent arising publications are also listed in the reference list for the benefit of the readership. 2 3 4 5 6 7 8 9 10 11 12 13 I have mentioned several times my personal gratification that most of the papers from earlier years have subsequently appeared in several annual top 100 listings. Of further interest, some of these papers or the young investigators themselves have subsequently won one of the most popular awards (see Table 1 for a list of prior editorials on these awards).…”

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation

“…However, its role is not restricted to the coagulation cascade, because it also stimulates multiple intracellular signaling pathways through G-protein-coupled protease-activated receptors (PARs) as well protein-coupled protease-activated receptors (PARs) as well as inducing inflammato and fibrotic responses [4]. At present, direct FXa inhibitors are among the most wid applied oral anticoagulants for the effective treatment of thromboembolic disorde Interestingly, Eliquis ® (apixaban) was the fifth best-selling drug in the world in 2021 [ Moreover, xabans have been increasingly used as alternatives to vitamin K antagonists the management of VTE and nonvalvular atrial fibrillation, and their use is considered t preferred anticoagulant therapy [3]. Historic anticoagulant use was accompanied w restrictions and inconveniences such as the risk of drug-food interactions (dieta influences) and the need for monitoring for potential dose adjustment.…”

“…Direct oral anticoagulants (DOACs) are an important and a relatively new class of synthetic anticoagulant drugs commonly prescribed for the prevention of venous thrombosis following surgery or during atrial fibrillation, and for the treatment of venous thromboembolism (VTE) [ 1 , 2 , 3 ]. Dabigatran, released in 2010, is a direct thrombin inhibitor.…”

“…Interestingly, Eliquis ® (apixaban) was the fifth best-selling drug in the world in 2021 [ 5 ]. Moreover, xabans have been increasingly used as alternatives to vitamin K antagonists in the management of VTE and nonvalvular atrial fibrillation, and their use is considered the preferred anticoagulant therapy [ 3 ]. Historic anticoagulant use was accompanied with restrictions and inconveniences such as the risk of drug–food interactions (dietary influences) and the need for monitoring for potential dose adjustment.…”

Recent Advances in Thrombosis and Hemostasis: Part VI

“…In the last full paper, another Eberhard Mammen Young Investigator Award recipient, Schreuder et al provide a beautifully illustrated review of current reversal agents for the direct factor Xa inhibitors. 12 They also explain how future antidotes are developed and will work. This is indeed an enjoyable final reading of the composite 10 papers in this issue.…”