Preclinical and Clinical Data for Factor Xa and “Universal” Reversal Agents

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

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Difficult Intraoperative Heparinization Following Andexanet Alfa Administration

Clinical Practice and Cases in Emergency Medicine ◽

10.5811/cpcem.2019.9.43650 ◽

2019 ◽

Vol 3 (4) ◽

pp. 390-394 ◽

Cited By ~ 2

Author(s):

C. James Watson ◽

Sara Zettervall ◽

Matthew Hall ◽

Michael Ganetsky

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Hemodynamic Instability ◽

The United States ◽

Major Hemorrhage ◽

Reversal Agents ◽

Abdominal Aortic ◽

United States Food ◽

Andexanet Alfa

Direct oral anticoagulants are now commonplace, and reversal agents are recently becoming available. Andexanet alfa (AnXa), approved by the United States Food and Drug Administration in 2018, is a novel decoy molecule that reverses factor Xa inhibitors in patients with major hemorrhage. We present a case of a 70-year-old man taking rivaroxaban with hemodynamic instability from a ruptured abdominal aortic aneurysm. He received AnXa prior to endovascular surgery, and intraoperatively he could not be heparinized for graft placement. Consideration should be given to the risks and benefits of AnXa administration in patients who require anticoagulation after hemorrhage has been controlled.

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The Reversal of Bleeding Caused by New Oral Anticoagulants (NOACs): A Systematic Review and Meta-Analysis

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029618796339 ◽

2018 ◽

Vol 24 (9_suppl) ◽

pp. 117S-126S ◽

Cited By ~ 5

Author(s):

Sariya Udayachalerm ◽

Sasivimol Rattanasiri ◽

Teeranan Angkananard ◽

John Attia ◽

Nakarin Sansanayudh ◽

...

Keyword(s):

Case Reports ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Factor Xa ◽

New Oral Anticoagulants ◽

Thrombin Inhibitor ◽

Aggregated Data ◽

Reversal Agents ◽

Death Studies ◽

Risk Of Death

New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare the efficacy of NOAC antidotes on bleeding reversal and death. Studies were identified from MEDLINE and Scopus databases until May 2018. Case reports/series and cohorts were selected if they assessed reversal or death rates. Data were independently extracted by 2 reviewers. Individual patient data and aggregated data of outcomes were extracted from case reports/series and cohorts. Binary regression was used to estimate outcome rates, risk ratio (RR) along with 95% confidence interval (CI). Interventions were NOACs and reversal agents (ie, DTI-specific, DTI-standard, FXa-specific, and FXa-standard). Among 220 patients of 93 case reports/series, reversal rates were 95.9%, 77.6%, and 71.5% for DTI-specific, FXa-standard, and DTI-standard. Pooled RRs for DTI-specific and FXa-standard versus DTI-standard, respectively, were 1.34 (CI: 1.13-1.60) and 1.09 (CI: 0.84-1.40). Death rate was 0.18 (CI: 0.06-0.57) times lower in DTI-specific versus DTI-standard. For pooling 10 subcohorts, pooled RRs were 1.08 (CI: 1.00-1.16), 1.29 (CI: 1.20-1.39), and 1.13 (CI: 1.01-1.25) for DTI-specific, FXa-specific, and FXa-standard versus DTI-standard. In conclusion, specific reversal agents might be useful for reversal of bleeding and lowering the risk of death than standard reversal agents. Our findings were based on case reports/series and selected cohorts, further comparative studies are thus needed.

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Reversal of direct oral anticoagulants: a practical approach

Hematology ◽

10.1182/asheducation-2016.1.612 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 612-619 ◽

Cited By ~ 16

Author(s):

Andrew W. Shih ◽

Mark A. Crowther

Keyword(s):

Phase 1 ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Antibody Fragment ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Severe Bleeding ◽

Thrombin Time ◽

Ancillary Benefits ◽

Reversal Agents

Abstract Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.

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Utilization of anti–factor Xa levels to guide reversal of oral factor Xa inhibitors in the emergency department

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxab326 ◽

2021 ◽

Author(s):

Anne E Zepeski ◽

Brett A Faine ◽

Anna E Merrill ◽

Grerk Sutamtewagul ◽

Sharathkumar Bhagavathi

Keyword(s):

Emergency Department ◽

Anticoagulation Therapy ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Prothrombin Complex Concentrates ◽

Anticoagulation Reversal ◽

Reversal Agents ◽

Patient Disposition ◽

Rule Out

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Oral factor Xa inhibitors (FXaIs) are increasingly utilized for outpatient anticoagulation therapy; however, laboratory monitoring is not routinely used to assess the safety and efficacy of these agents. We aimed to evaluate the role of chromogenic anti–factor Xa (anti-Xa) assays in the emergency department (ED) in the setting of patients with an acute bleed or requiring emergent procedures. Methods A retrospective review was completed of anti-Xa levels obtained in the ED between June 1, 2019, and April 30, 2020. Data were collected to describe the clinical setting of anti-Xa level collection, oral FXaIs used before admission, administration of reversal agents, and patient disposition to further characterize the role of anti-Xa levels in the management of rivaroxaban and apixaban reversal. Results Thirty anti-Xa levels were included in the final analysis. The median time from sample collection to anti-Xa assay result was 45.9 minutes (interquartile range, 35.3-54.7 minutes). Eleven patients (37%) received anticoagulation reversal after their anti-Xa levels were determined. Anticoagulation reversal agents included either activated prothrombin complex concentrates (aPCCs) or prothrombin complex concentrates (PCCs). Anti-Xa levels were collected in 2 patients who had received PCCs before arrival at our ED. Of the patients with anti-Xa levels below 30 ng/mL, none received aPCCs or PCCs after their anti-Xa levels were determined. Anti-Xa assays were used to rule out the presence of FXaIs in 3 patients. Conclusion This study illustrates the novel role of anti-Xa levels in managing patients with an emergent need for reversal in the ED. The assay may be used to rule out the presence of oral FXaIs and avoid unnecessary administrations of anticoagulation reversal agents.

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Monitoring and reversal of direct oral anticoagulants

Hematology ◽

10.1182/asheducation.v2015.1.117.3916182 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 117-124 ◽

Cited By ~ 5

Author(s):

Adam Cuker ◽

Deborah Siegal

Keyword(s):

Prothrombin Complex Concentrate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Antibody Fragment ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Severe Bleeding ◽

Thrombin Time ◽

Reversal Agents ◽

Routine Monitoring

Abstract Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

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Surfing the Blood Coagulation Cascade: Insight into the Vital Factor Xa

Current Medicinal Chemistry ◽

10.2174/0929867325666180125165340 ◽

2019 ◽

Vol 26 (17) ◽

pp. 3175-3200 ◽

Cited By ~ 5

Author(s):

Nicolás E. Núñez-Navarro ◽

Fabián M. Santana ◽

Loreto P. Parra ◽

Flavia C. Zacconi

Keyword(s):

Blood Coagulation ◽

Wound Closure ◽

Factor Xa ◽

Mechanisms Of Action ◽

Coagulation Cascade ◽

Reversal Agents ◽

Molecular Features ◽

Current State ◽

Vital Factor ◽

Insight Into

Factor Xa (FXa) plays a key role in haemostasis, it is a central part of the blood coagulation cascade which catalyzes the production of thrombin and leads to clot formation and wound closure. Therefore, FXa is an attractive target for the development of new anticoagulant agents. In this review, we will first describe the molecular features of this fundamental protein in order to understand its mechanism of action, an essential background for the design of novel inhibitors by means of synthetic organic chemistry or using peptides obtained from recombinant methodologies. Then, we will review the current state of the synthesis of novel direct FXa inhibitors along with their mechanisms of action. Finally, approved reversal agents that aid in maintaining blood haemostasis by using these commercial drugs will also be discussed.

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Managing reversal of direct oral anticoagulants in emergency situations

Thrombosis and Haemostasis ◽

10.1160/th16-05-0363 ◽

2016 ◽

Vol 116 (12) ◽

pp. 1003-1010 ◽

Cited By ~ 28

Author(s):

Harry R. Büller ◽

Anna Falanga ◽

Werner Hacke ◽

Jeroen Hendriks ◽

Trudie Lobban ◽

...

Keyword(s):

Task Force ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Therapeutic Benefit ◽

Current Status ◽

Reversal Agent ◽

Medical Specialties ◽

Reversal Agents ◽

Emergency Situations

SummaryAnticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24–7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.

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Clinical Course of Intracranial Bleeding in Patients Anticoagulated With Factor Xa inhibitors Without the Use of Specific Reversal Agents

Neurosurgery ◽

10.1093/neuros/nyz310_835 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Emmalin Nelton ◽

Georgios Maragkos ◽

Sven Richter ◽

Aristotelis Filippidis ◽

Martina Stippler

Keyword(s):

Clinical Outcomes ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Secondary Outcome ◽

Primary Study ◽

Reversal Agent ◽

Anticoagulation Reversal ◽

Reversal Agents ◽

Traumatic Intracranial Hemorrhage ◽

History Of

Abstract INTRODUCTION Factor Xa inhibitors (FXI) are widely used anticoagulants but may cause or worsen acute major bleeding. Andexanet alfa, a novel anticoagulation reversal agent for FXI, was recently approved. Traumatic intracranial hemorrhage (tICH) presents a prime target for this drug, however questions remain regarding its effect on clinical outcomes compared to the natural history of tICH in the setting of FXI. This study aimed to evaluate the hematoma progression and clinical outcomes of patients on FXI who were not administered Andexanet reversal after tICH. METHODS An institutional traumatic brain injury (TBI) registry was queried between 2016 and 2019. Patients with recorded use of apixaban or rivaroxaban <18 h before injury were included. The primary study outcome was good hemostasis on repeated head computed tomography (CT), assessed according to the criteria of the ANNEXA-4 trial for Andexanet treatment. The secondary outcome was neurological worsening or surgical intervention during the hospitalization. RESULTS We identified 24 patients meeting the study inclusion criteria. Their mean (SD) age was 76.3 ± 13 yr and 10 (42%) were female. On admission CT, 15 patients had SDH, 6 had traumatic IPH, and 3 had SAH. All patients had their FXI therapy discontinued immediately after injury. Anticoagulation reversal was attempted in 16 patients, most commonly using prothrombin complex concentrate (PCC). Out of the 24 patients, 19 (79%) were adjudicated as having excellent or good hemostasis. A total of 23 (96%) patients remained neurologically stable throughout admission. CONCLUSION Our results indicate that in patients on FXI with complicated mild TBI it can be reasonably safe not to administer specific anticoagulation reversal. Hemostatic and clinical outcomes in our cohort were largely similar to those reported after Andexanet administration. Further research is necessary to determine if administration of Andexanet improves clinical outcomes.

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