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From Pharmacology to Clinical Practice Riccardo Proietti Ahmed Alturki Nicola Ferri Vincenzo Russo T Direct Oral Anticoagulants From Pharmacology to Clinical Practice Riccardo Proietti Ahmed AlTurki Nicola Ferri Vincenzo Russo T. Jared Bunch Editors 123 Direct Oral Anticoagulants Riccardo Proietti • Ahmed AlTurki Nicola Ferri • Vincenzo Russo T. Jared Bunch Editors Direct Oral Anticoagulants From Pharmacology to Clinical Practice Editors Riccardo Proietti Ahmed AlTurki Cardiac Rehabilitation Unit Ospedale McGill University Sacra Famiglia Fatebenefratelli Montreal, QC Erba, Italy Canada Nicola Ferri Vincenzo Russo Department of Pharmaceutical Department of Medical and Pharmacological Sciences Translational Sciences University of Padua University of Campania Padova, Italy “Luigi Vanvitelli” - Monaldi Hospital Naples, Italy T. Jared Bunch Division of Cardiology, Department of Internal Medicine University of Utah School of Medicine Salt Lake City, UT USA ISBN 978-3-030-74461-8 ISBN 978-3-030-74462-5 (eBook) https://doi.org/10.1007/978-3-030-74462-5 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microflms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifc statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Contents 1 The Coagulative Cascade �������������������������������������������������������������������������� 1 Marina Camera 2 Clinical Indications for Direct Acting Oral Anticoagulants . 9 Ahmed AlTurki and Riccardo Proietti 3 Pharmacokinetics and Pharmacodynamics of DOAC ���������������������������� 27 Nicola Ferri 4 Drug–Drug Interaction with DOACs . 41 Alberto Corsini and Nicola Ferri 5 Direct Oral Anticoagulant Reversal for Management of Bleeding and Emergent Surgery . 71 Sanela Music, John Eikelboom, and Thao Huynh 6 Risk Stratification For and Use of DOAC Therapies for Stroke Prevention in Patient with Atrial Fibrillation . 93 Alfredo Caturano, Raffaele Galiero, Serenella Spiezia, and Pia Clara Pafundi 7 Use of DOAC in Patients with Kidney Disease ���������������������������������������� 121 Riccardo Vio, Riccardo Proietti, and Lorenzo Calo’ 8 Anticoagulation in Elderly Patients with Atrial Fibrillation Authors . 131 Andreina Carbone, Roberta Bottino, Antonello D’Andrea, Paolo Golino, Gerardo Nigro, and Vincenzo Russo 9 The “Obesity Paradox” and the Use of NOAC ���������������������������������������� 149 Roberta Bottino, Andreina Carbone, Biagio Liccardo, Paolo Golino, Gerardo Nigro, and Vincenzo Russo 10 Direct Oral Anticoagulation in Cancer Patients . 179 Roberta Bottino, Andreina Carbone, Biagio Liccardo, Antonello D’Andrea, Paolo Golino, Gerardo Nigro, and Vincenzo Russo v vi Contents 11 DOACs and Dementia in Patients with Atrial Fibrillation . 199 Ahmed AlTurki, Hasan AlTurki, Riccardo Proietti, and T. Jared Bunch 12 Non-vitamin K Antagonists and Cardiac Implantable Electronic Devices . 211 Ahmed AlTurki, Riccardo Proietti, and Vidal Essebag 13 Direct Oral Anticoagulants and Atrial Fibrillation Ablation . 225 Ahmed AlTurki, Riccardo Proietti, and Vidal Essebag 14 DOAC Therapy in Patients Post Left Atrial Appendage Occlusion or Isolation �������������������������������������������������������������������������������������������������� 235 T. Jared Bunch 15 Use of Direct Oral Anticoagulants After Transcatheter Aortic Valve Replacement . 247 Andrea Scotti, Mauro Massussi, Antonio Landi, and George Besis 16 Use of Direct Oral Anticoagulants After Percutaneous Coronary Intervention . 255 Antonio Landi, Mauro Massussi, Andrea Scotti, and George Besis 17 Direct Oral Anticoagulants and Left Ventricular Thrombosis: The Evidence for a Good Therapeutic Approach . 271 Mauro Massussi, Andrea Scotti, Antonio Landi, and George Besis Index �������������������������������������������������������������������������������������������������������������������� 281 The Coagulative Cascade 1 Marina Camera Introduction The blood coagulation cascade is an integral part of hemostasis, a biological process evolved as important defense mechanism to prevent bleeding from a damaged ves- sel and to restore vascular integrity (Davidson et al. 2003). Within the hemostatic process two distinct phases are recognized, primary and secondary hemostasis, where different key players and mechanisms are taking part. Despite this division, the interplay between these processes is very tight. Primary hemostasis is initiated by accumulation and activation of platelets at the site of vascular injury. During secondary hemostasis, activation of coagulation rein- forces the platelet plug through deposition of an insoluble fbrin network generated by thrombin activity on fbrinogen molecules (Smith et al. 2015). Under normal conditions, anticoagulant mechanisms ensure careful control of coagulation and they prevail over the procoagulant forces. Aberrant activation of coagulation can, however, lead to the formation of intravascular clots that underpin pathological thrombotic disorders, including myocardial infarction, stroke, and venous thromboembolism (Furie and Furie 2008). The restitutio ad integrum of the damaged vessel is mediated by fbrinolysis, the last phase of hemostasis. During this process, the activation of plasminogen and urokinase leads to accelerated degradation of blood clots, with generation of fbrin degradation products, including d-dimers. M. Camera (*) Department of Pharmaceutical Sciences, University of Milan, Milan, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2021 1 R. Proietti et al. (eds.), Direct Oral Anticoagulants, https://doi.org/10.1007/978-3-030-74462-5_1 2 M. Camera The Cell-Based Model of Blood Coagulation The coagulation cascade consists of an ordered sequence of reactions that lead to the careful and balanced generation of thrombin, key effector enzyme, at the level of vascular damage. Coagulation reactions lead to activation of zymogens (inert precursors of enzymes) to functional enzymes via limited proteolysis. At each stage, a zymogen is converted to an active protease by cleavage of one or more peptide bonds in the precursor molecule. The fnal active protease generated is thrombin with the role of converting fbrinogen into the fbrin mesh to stabilize the platelet plug. The enzymes generated during this process are catalytically active serine proteases, yet they have low inherent enzymatic activity as isolated proteins. Binding of a typical clotting protease to a specifc protein cofactor on a suitable phospholipid membrane surface markedly potentiates the protease’s activity, often by as much as fve order of mag- nitude or more (Bom and Bertina 1990). On this regard, phosphatidylserine (PS) exposure on the membrane of activated platelets is a key event in the control of blood coagulation (Lentz 2003). In mammalian blood coagulation, fve zymogens (factor VII [FVII]; factor IX [FIX]; factor X [FX]; protein C [PC], and prothrombin [PT]) act with fve cofactors (tissue factor [TF]; factor V [FV]; factor VIII [FVIII]; thrombomodulin and protein S) to control the generation of fbrin. The protein cofactors of the blood coagulation cascade also generally circulate in the plasma as inert procofactors that must be converted into active cofactors via limited proteolysis. When zymogens and proco- factors are converted to the active form, an “a” is appended to the Roman numerals (i.e., FVII → FVIIa). According to the most recent theory, in a cell-based model, blood coagulation is initiated by the binding of FVII to membrane-associated TF (also called tissue thromboplastin or FIII or CD142; Fig. 1.1) leading to activation of FVIIa (Kirchhofer and Nemerson 1996). A fraction of FVII (~1%) circulates in blood as active enzyme. Free FVIIa is a very weak enzyme, but the TF:FVIIa complex is an extremely potent activator of coagulation. TF binds both FVII and FVIIa. TF has several characteristics that make it unique among the coagulation pro- teins (Morrissey 2001). First, TF is the only coagulation factor that is not synthe- sized by the liver and released into circulation as a mechanism to avoid unintended activation of coagulation. Second, membrane anchoring is essential for full proco- agulant activity. Indeed, it is an integral membrane protein constitutively expressed at high levels by fbroblasts of the adventitial layer of the vessel wall, as well as by epithelial cells, and at sites where bleeding could be catastrophic (brain, lungs) (Drake et al. 1989; Fleck et al.
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