Ciraparantag, an Anticoagulant Reversal Drug: Mechanism of Action, Pharmacokinetics and Reversal of Anticoagulants

Blood ◽  
2020 ◽  
Author(s):  
Jack Ansell ◽  
Bryan Laulicht ◽  
Sasha H Bakhru ◽  
Allison Burnett ◽  
Xuan Jiang ◽  
...  
Keyword(s):  
Animal Models ◽  
Blood Loss ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Coagulation Factors ◽  
Reversal Agent ◽  
Binding Characteristics ◽  
Drug Mechanism ◽  
Anticoagulant Reversal ◽  
Charge Interaction

Ciraparantag, an anticoagulant reversal agent, is a small molecule specifically designed to bind non-covalently by charge-charge interaction to unfractionated heparin (UFH) and low molecular weight heparin (LMWH). It shows similar binding characteristics to the direct oral anticoagulants (DOAC). Dynamic light scattering methodology was used to demonstrate ciraparantag binding to the heparins and DOACs and its lack of binding to a variety of proteins including coagulation factors and to commonly used drugs. Ciraparantag reaches maximum concentration within minutes following intravenous (IV) administration with a half-life of 12 - 19 minutes. It is primarily hydrolyzed by serum peptidases into two metabolites, neither of which has substantial activity. Ciraparantag and its metabolites are recovered almost entirely in the urine. In animal models of bleeding (rat tail transection and liver laceration) a single IV dose of ciraparantag given at peak concentrations of the anticoagulant, but before the bleeding injury, significantly reduces the amount of blood loss. Ciraparantag given after the bleeding injury also significantly reduces blood loss. Ciraparantag appears to have substantial ability to reduce blood loss in animal models given a variety of anticoagulants and has potential as a useful DOAC reversal agent.

scholarly journals Idarucizumab for the treatment of dabigatran-related nephropathy

2020 ◽  
Author(s):  
Ammar Alsamarrai ◽  
Nicola Eaddy ◽  
Elizabeth Curry
Keyword(s):  
Acute Kidney Injury ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Specific Treatment ◽  
Kidney Injury ◽  
Clinical Syndrome ◽  
Reversal Agent ◽  
Macroscopic Haematuria ◽  
Anticoagulant Reversal

Abstract Anticoagulant-related nephropathy (ARN) is a clinical syndrome of acute kidney injury in patients taking vitamin K antagonists or direct oral anticoagulants. It is associated with increased mortality and there is no specific treatment. We report the case of a 78-year-old man on dabigatran who developed macroscopic haematuria and acute kidney injury 2 weeks after mitral valve repair, reaching a peak creatinine of 415 µmol/L from a normal baseline, which was successfully treated with one course of idarucizumab. This case illustrates the efficacy of an anticoagulant reversal agent for the treatment of ARN.

scholarly journals Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems

Applied Nano ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 98-117
Author(s):  
Yuri B. G. Patriota ◽  
Luíse L. Chaves ◽  
Evren H. Gocke ◽  
Patricia Severino ◽  
Mônica F. R. Soares ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Anticoagulant Therapy ◽  
Test Performance ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Delivery Systems ◽  
Reversal Agent ◽  
Laboratory Assessment ◽  
Administration Routes

Heparin-based delivery systems have been explored to improve their therapeutic efficacy and to reduce toxicity for different administration routes. Regardless of the applied drug delivery system (DDS), the evaluation of anticoagulant performance is instrumental for the development of a suitable DDS. The understanding of the range of anticoagulant assays, together with their key applications and limitations, is essential both within the context of scientific research and for clinical usage. This review provides an overview of the current anticoagulant therapy and discusses the advantages and limitations of currently available anticoagulant assays. We also discuss studies involving low-molecular-weight heparin (LMWH)-based nanocarriers with emphasis on their anticoagulation performance. Conventional anticoagulants have been used for decades for the treatment of many diseases. Direct oral anticoagulants have overcome some limitations of heparins and vitamin K antagonists. However, the lack of an accurate laboratory assessment, as well as the lack of a factor “xaban” (Xa) inhibitor reversal agent, remains a major problem associated with these anticoagulants. LMWHs represent anticoagulant agents with noteworthy efficacy and safety, and they have been explored to improve their outcomes with various nanocarriers through several administration routes. The main problems related to LMWHs have been surmounted, and improved efficiency may be achieved through the use of DDSs.

scholarly journals Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Ali Zalpour ◽  
Thein Hlaing Oo
Keyword(s):  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Current Evidence ◽  
Thrombin Inhibitor ◽  
Prevention And Treatment ◽  
Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

scholarly journals Use of Idarucizumab to Revert the Anticoagulant Effect of Dabigatran in Heart Transplant Surgery: An Institutional Experience

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Álvaro Herrera-Escandón ◽  
Orlando Castaño-Cifuentes ◽  
Carlos A. Plata-Mosquera
Keyword(s):  
Heart Transplant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Previous History ◽  
Waiting List ◽  
Anticoagulant Effect ◽  
Nonvalvular Atrial Fibrillation ◽  
Reversal Agent ◽  
Perioperative Bleeding ◽  
Congestive Liver

Heart transplant is a surgical procedure with a high risk of perioperative bleeding in patients with a previous history of sternotomy, congestive liver disease, and/or use of oral anticoagulants. Anticoagulation is usually done with coumarin agents (warfarin, acenocoumarol), while on the waiting list, vitamin K is available allowing for partial reversal of the anticoagulant effect, although with variable INR and risk of uncontrolled bleeding. Direct oral anticoagulants have emerged as an alternative to the use of coumarins in patients with nonvalvular atrial fibrillation (NVAF). The main disadvantage of this group of drugs is that there was no specific reversal agent available that would allow an urgent reversal of the anticoagulant effect. The recent commercialization of idarucizumab (specific reversal agent) has allowed patients with NVAF on the waiting list for heart transplant to be treated with dabigatran. We present the case of a patient with advanced chronic heart failure and NVAF anticoagulated with dabigatran, who underwent urgent heart transplant after administration of idarucizumab, without complications derived from its use or from anticoagulation.

scholarly journals Mechanisms of action of new oral coagulants

2021 ◽  
Vol 40 (2) ◽  
pp. 33-40
Author(s):  
Arina A. Kokorina ◽  
Margarita O. Sokolova ◽  
Pavel A. Slizhov
Keyword(s):  
Therapeutic Effect ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Coagulation Factors ◽  
Mechanisms Of Action ◽  
Coagulation Cascade ◽  
Active Centers ◽  
Blood Coagulation Factors ◽  
Urgent Surgery ◽  
Direct Anticoagulants

The article provides a brief description of drugs in the class of direct oral anticoagulants. The mechanisms of the therapeutic effect and the ways of excretion of drugs-inhibitors of blood coagulation factors Xa and IIa are considered. It was shown that all of them are characterized by high selectivity to the active centers of target molecules, successfully affect the coagulation cascade and have a quick therapeutic effect. A comparative analysis of drugs of the class of direct oral anticoagulants showed that rivaroxaban, apixaban, edoxaban, betrixaban (inhibitors of FXa) and dabigatran (inhibitor of factor IIa) do not have significant advantages over each other in terms of mechanism and speed of action. A comparison of the main characteristics of direct oral anticoagulants and the indirect anticoagulant warfarin is presented. It is shown that, first of all, the advantage of the former is associated with an immediate pharmacological response. The decision to prescribe this drug requires consideration of risk factors for the patient, such as age, the presence of chronic diseases of the gastrointestinal tract, liver and kidneys. The article presents the most frequent complications of anticoagulant therapy, as well as the mechanisms of action of specific and universal antidotes indicated for use in patients with life-threatening bleeding or in need of urgent surgery when using direct oral anticoagulants. However, such neutralizing agents have not yet found widespread use due to their high cost and low availability. Nevertheless, the emergence of direct anticoagulants on the market has undoubtedly led to significant progress in the treatment of thrombotic and cardiovascular diseases (1 table, bibliography: 28 refs).

Reversal strategies in patients treated with direct oral anticoagulants

VASA ◽  
2019 ◽  
Vol 48 (5) ◽  
pp. 389-392 ◽  
Author(s):  
Paul Gressenberger
Keyword(s):  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Invasive Procedure ◽  
Bleeding Risk ◽  
Study Data ◽  
Current Evidence ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Reversal Agent

Summary. Administration of direct oral anticoagulants (DOACs) for the treatment of venous thrombotic events (VTE) or non-valvular atrial fibrillation (AF) is now standard of care and has demonstrated clinical efficacy and safety in numerous clinical studies. Usually these substances have lower overall mortality and less risk of cerebral hemorrhage, but depending on the substance and study, they are more likely to cause gastrointestinal bleeding than vitamin K antagonists (VKA), the medication that used to be standard for VTE and AF. Since DOACs have very short plasma elimination half-lives compared to VKA, for most bleeding events, expert opinions suggest that withdrawal of DOACs and supportive care will likely suffice to stop a bleeding episode. Because there is a bleeding risk associated with DOACs, reversal strategies may be needed if a patient receiving DOAC therapy bleeds during surgery or an invasive procedure. So far, idarucizumab has been the only available antidote that binds specifically to dabigatran and safely and quickly reverses its anticoagulant effects. Idarucizumab has no effects on anti Xa inhibitors or other anticoagulants. To date, treatment of serious, life-threatening bleeds in patients with anti-Xa-inhibitor has involved 4 factor prothrombin complex concentrates (PCC). PCC restores normal hemostasis laboratory values in most patients with major bleeding events after anti Xa inhibitor intake. Recently, the US Food and Drug Administration (FDA) approved andexanet alfa as the first specific antidote for the anti-Xa inhibitors apixaban and rivaroxaban. So far clinical experience with this substance and data comparing it with PCC are lacking. Currently ciraparantag is under investigation as a universal reversal agent for all DOACs and low molecular weight heparin as well. Because it is so broadly applicable, ciraparantag might be a good future option for the management of most bleeding complications under anticoagulant treatment. The aim of this review is to summarize recent study data and recommendations on nonspecific and specific DOAC reversal strategies and to present the current evidence.

Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects

2021 ◽  
Author(s):  
Jack Ansell ◽  
Sasha Bakhru ◽  
Bryan E Laulicht ◽  
Gregory Tracey ◽  
Stephen Villano ◽  
...  
Keyword(s):  
Steady State ◽  
Anticoagulant Activity ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Hot Flashes ◽  
Elderly Subjects ◽  
Reversal Agent ◽  
Post Dose ◽  
Healthy Elderly ◽  
Complete Reversal

Abstract Aims  Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults. Methods and results  Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50–75 years. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing. Conclusions  Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.

Dabigatran Reversal With Idarucizumab in 2 Patients With Portal Vein Thrombosis Undergoing Orthotopic Liver Transplantation

2021 ◽  
pp. 108925322098218
Author(s):  
Cynthia Williams ◽  
Erin Stewart ◽  
Kendra D. Conzen ◽  
Scott Wolf ◽  
Timothy T. Tran
Keyword(s):  
Liver Transplantation ◽  
Portal Vein ◽  
Portal Vein Thrombosis ◽  
Orthotopic Liver Transplantation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Case Series ◽  
Reversal Agent ◽  
Vein Thrombosis ◽  
Cirrhotic Patients

There are limited data to guide the use of anticoagulation in cirrhotic patients prior to liver transplantation especially when using direct oral anticoagulants. In this article, we present 2 cases. The first is a 42-year-old male with cirrhosis complicated by portal vein thrombosis (PVT) treated with dabigatran who underwent orthotopic liver transplantation without complication. The second case is a 65-year-old man with alcoholic cirrhosis complicated by PVT treated with dabigatran who underwent orthotopic liver transplantation and required reoperation for surgical bleeding. Both patients were treated with dabigatran’s reversal agent idarucizumab prior to incision. In this case series, we discuss the treatment of cirrhotic patients with various anticoagulants, considerations for anticoagulant selection and reversal prior to liver transplant, and questions for future investigation.

Managing reversal of direct oral anticoagulants in emergency situations

2016 ◽  
Vol 116 (12) ◽  
pp. 1003-1010 ◽  
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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