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Coagulopathy
Published in Stephen M. Cohn, Alan Lisbon, Stephen Heard, 50 Landmark Papers, 2021
Several specific reversal agents are available: idraucizumab, a monoclonal antibody that irreversibly binds dabigatran, andexenet alfa, a modified recombinant fXa protein that binds and sequesters Xa inhibitors, and ciraparantag, a small molecule that binds to and prevents heparins and Xa and thrombin inhibitors from binding to their respective targets. While these specific reversal agents are highly effective, whether or not they have an effect on outcomes has yet to be definitively shown. In addition, the cost of these agents remains a limitation as they range in the thousands of dollars per dose [11]. Recombinant factor VII is another commonly used treatment in coagulopathy, however, when used off-label it has been associated with an increase in arterial thromboembolic events [12].
Preanesthetic evaluation
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Essentials of Anesthesia for Neurotrauma, 2018
Julia Martinez Ocón, Ana Ruiz Pardos, Ricard Valero
However, the other direct factor Xa inhibitors still present a challenge. In a retrospective study of 18 TBI patients with intracranial or subarachnoid hemorrhage who were taking rivaroxaban or apixaban, PCC was a good option to potentially reduce hematoma expansion.5 Andexanet alfa, Xa inhibitor, and ciraparantag, Xa factor, and II factor inhibitors are in phase III clinical trials.
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Monitoring of anticoagulant therapy is essential to avert unwanted bleeding. The prothrombin time (PT) is measured is to assess the activity of vitamin-K dependent factors, which include factor II, VII, IX and X. When calcium ions with an excess of thromboplastin added to anticoagulated plasma is a direct measure of the prothrombin amount in the plasma. In normal plasma, this clot formation takes 10 to 13 seconds. PT results are expressed in terms of international normalized ratios (INRs) due to variances in commercially available thromboplastins. Patients on warfarin therapy are optimally maintained with an INR of 2.0 to 3.0. However, this is varied depending on the individual patients with multiple circumstances. Heparin therapy is based on the assay named activated partial thromboplastin time (aPTT). In the aPTT assay, a surface activator (elegiac acid, kaolin, or silica) is used to activate the intrinsic pathway and clot formation begins. Like PT, the time taken for this clot formation is recorded. In normal plasma, the average aPTT result is 25 to 45 seconds. A therapeutic aPTT in a patient receiving heparin is 70 to 140 seconds usually. This assay mainly monitors factor II and X [5]. Direct thrombin inhibitors also monitored by aPTT assay. Other assay procedures are activated clotting time (ACT), ecarin clotting time (ECT), prothrombinase-induced clotting time (PiCT), chromogenic anti-IIa, diluted thrombin time (dTT), and anti-Xa assays. However, PT and aPTT assay are significant in monitoring [5, 132–138]. Apart from the monitoring, there is a need for a reversal agent or antidote to control the bleeding risk. Protamine sulfate is established reversal agent for heparins. For direct oral anticoagulats, most authorities recommend the use of four-factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is insufficient. At the present time, there are three reversal agents. Idarucizumab is a monoclonal antibody, which is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a recombinant protein and a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag (Figure 7.17) is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. It consists of two L-arginine units connected with a piperazine containing linker chain [139–147].
A comprehensive evaluation of apixaban in the treatment of venous thromboembolism
Published in Expert Review of Hematology, 2020
Jennifer L Koehl, Bryan D. Hayes, Hanny Al‐Samkari, Rachel Rosovsky
Additional areas of research are needed to address both the reversal agents as well as the monitoring of apixaban. Currently, the clinical utility, thrombotic potential, and place in practice of andexanet alpha remain poorly defined due to the cost and rebound anticoagulation that is seen when the infusion ends. Ciraparantag, a small synthetic water-soluble new molecular entity that binds to heparin and the oral direct FXa and factor IIa inhibitors offers promise as a ‘universal’ antidote. There is an ongoing phase 2 study (NCT03288454): ‘Apixaban Reversal by Ciraparantag as Measured by Whole Blood Clotting Time’ addressing this exact issues. Questions around the Pharmacokinetics and Pharmacodynamics of apixaban in morbidly obese patients also must be further elucidated to determine if alternate dosing strategies are needed to achieve effective anticoagulation parameters. Last, a readily available laboratory test offering both accuracy and precision for anticoagulation measurement currently is not widely available. This would be helpful to not only monitor patients on apixaban but also to identify if the drug is still present in trauma patients or those requiring emergent surgery. High-quality tests that establish therapeutic ranges must become routinely available as this drug continues to be widely used.
Mechanisms of action and clinical use of specific reversal agents for non-vitamin K antagonist oral anticoagulants
Published in Scandinavian Cardiovascular Journal, 2018
Kristoffer Andresen, Dan Atar, Erik Gjertsen, Waleed Ghanima, Svein Roseth, Odd Erik Johansen
Ciraparantag is a universal antidote in clinical development [36], targeted to reverse both direct thrombin inhibitors, factor Xa inhibitors, as well as the indirect inhibitor, enoxaparin and UFH. It is a synthetic water-soluble compound (512 Da) that binds directly to unfractionated and low molecular weight heparin [36]. It binds by charge–charge interaction (non-covalent) and prevents the anticoagulants from binding to their endogenous targets, thus reversing anticoagulation. Ciraparantag also binds to the target-specific IIa and Xa inhibitors (dabigatran, rivaroxaban, apixaban and edoxaban) removing them or preventing them from binding to their respective targets. Thus, ciraparantag serves as a potential universal antidote for several different classes of anticoagulant drugs.
Andexanet alfa for the treatment of hemorrhage
Published in Expert Review of Hematology, 2018
Ciraparantag (PER977, Perosphere) is a small molecule antidote that binds unfractionated and low molecular weight heparins, the oral factor Xa inhibitors, and direct thrombin inhibitor, dabigatran, and has been shown to correct a hemostatic index in vitro and in animal models [20]. Infusion of ciraparantag in healthy persons receiving edoxaban and enoxaparin restored hemostatic parameters within 10–30 min of administration with mild and transient side effects [21,22]. Further phase 2 clinical trials are underway (clinicaltrials.gov, identifier NCT02207257).