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Anticoagulation
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Louis M. Fink, Nicole A. Massoll, Alex A. Pappas
Revasc (Revasc Norartis, Basal, Switzerland) has been compared with both UFH and LMWH in the prophylaxis of DVT after total hip replacement. In these studies, 15 mg b.i.d. of Revasc provided better outcome than heparin or enoxaparin. Thrombin inhibitors and hirudin have an extremely short T1/2 of about 30–40 min. Molecular engineering of prothrombin molecules has resulted in variants that can complex with hirudin to neutralize its anticoagulant effects. All of the antithrombin agents produce anticoagulant effect in such global tests as PT and aPTT. The mechanism of action of each of these agents is different; therefore differences in their prolongation of the clot-based assays may not be an indication of their anticoagulant/autothrombotic potency. A new clot-based assay known as the ecarin clotting time has been developed recently for the specific monitoring of antithrombin agents. Ecarin represents snake venom that converts prothrombin to meizothrombin, eventually producing a clotting end point. Each thrombin in-hibitor has its own distinct anticoagulant effect in this assay. In addition, ELISA-based assays have also been developed for absolute drug concentrations (74).
Haemostasis and fibrinolysis
Published in Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland, Manual of Venous and Lymphatic Diseases, 2017
Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland
The ecarin clotting time can be used to monitor treatment with direct thrombin inhibitors (e.g. argatroban, dabigatran). Ecarin activates prothrombin to intermediate meizothrombin which forms complexes with direct thrombin inhibitors.
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].
Pharmacokinetic-Pharmacodynamic Analysis’ Role in Design of Phase ⅠClinical Trials of Anticoagulant Agents: A Systematic Review
Published in Expert Review of Clinical Pharmacology, 2020
Nan Zhao, Qian Xiang, Zhiyan Liu, Xia Zhao, Yimin Cui
APTT, PT, INR, thrombin time (TT)/thrombin clotting time (TCT), ecarin clotting time (ECT), activated clotting time (ACT) were increased with the dose and plasma drug concentration of direct thrombin inhibitors. However, APTT-concentration relationships of several FⅡa inhibitors were curvilinear, suggesting that it may not be suitable for precise quantification of effects [21–24]. The flat concentration–response curve of PT/INR limits the utility of their usage in FⅡa inhibitor mornitoring [20,23,25]. The sensitivity of the TT assay to FⅡa inhibitors are too high that resulted in coagulation times above the reference range at the high plasma concentration [20,21,23–25]. Some trials suggested that ECT may provide a more accurate measurement of FⅡa inhibitors than the other parameters [20,23,24].
Treatment strategies for patients with atrial fibrillation and anticoagulant-associated intracranial hemorrhage: an overview of the pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2020
José Miguel Rivera-Caravaca, María Asunción Esteve-Pastor, Anny Camelo-Castillo, Inmaculada Ramírez-Macías, Gregory Y. H. Lip, Vanessa Roldán, Francisco Marín
Idarucizumab is a specific monoclonal antibody antidote that specifically binds dabigatran and rapidly, safely, and dose-dependently reverses its effects without over-correction or thrombin generation. In the REVERSE-AD (Reversal of Dabigatran Anticoagulant Effect with Idarucizumab) study, idarucizumab 5 g was administered intravenously in two bolus doses of 2.5 g no more than 15 min apart to dabigatran-treated patients with anticoagulation emergencies (either ongoing severe or life-threatening hemorrhage, or emergency procedures on therapy). In this study, the primary endpoint of maximum reversal of the anticoagulant effect of dabigatran within 4 hours was 100% as assessed by dilute thrombin or Ecarin clotting time and was achieved in all patients. Based on these results, idarucizumab was approved in 2015 by the US Food and Drug Administration and the European Medicines Agency [4,22,29,98,105,116–120]. The full cohort analysis of the REVERSE-AD showed that the median time to the cessation of bleeding was 2.5 hours in patients with uncontrolled bleeding. Treatment with idarucizumab was safe with no significant adverse effects and a 6.3% and 7.4% rate of thrombotic complications (in the group with severe/life-threatening hemorrhage, and emergency procedures on therapy, respectively) [116]. However, if thrombolysis is performed after dabigatran reversal in acute ischemic stroke patients, the effectiveness and safety of the antidote could be underestimated.
Incomplete dabigatran reversal with idarucizumab
Published in Clinical Toxicology, 2018
Aaron P. Steele, Jin A. Lee, William E. Dager
His family elected to proceed with surgical intervention, aware of its associated risks. His anticoagulation panel at this time suggested a marked coagulopathy. Fresh frozen plasma (FFP) and packed red blood cells (pRBC) were given during the 4-h procedure with an estimated 250 cc blood loss that continued post-operatively. Idarucizumab 5 g and factor eight inhibitor bypass activity (FEIBA) 21 units/kg were also given, decreasing INR from >13.6 to 1.93. Post-mortem analysis of samples drawn upon return from the procedure confirmed a dabigatran concentration of 1170 ng/mL (reference range 40–240 ng/mL) using the chromogenic ecarin clotting time assay that we have previously described [3,4]. After administration of idarucizumab, the dabigatran serum concentration decreased to 447 ng/mL (Table 1). Postoperative hemorrhaging continued and the patient was ultimately transitioned to comfort care. He expired on hospital day 6.