Precision Anticoagulation Medicine: A Practical Guide [1st ed. 2020] 978-3-030-25781-1, 978-3-030-25782-8

Table of contents :
Front Matter ....Pages i-xv
Coagulation and Anticoagulants (Hadi Goubran, Mark Bosch, Julie Stakiw)....Pages 1-53
Routine Anticoagulation for the Provoked and Unprovoked VTE (Mark Bosch)....Pages 55-75
Anticoagulation in Cardiac Patients (Haissam Haddad, Udoka Okpalauwaekwe, Nishant Sharma, Jay S. Shavadia, Alex Zhai, Tony Haddad)....Pages 77-102
Thrombosis and Anticoagulation in Children (Ahmed Maher Kaddah, Iman Fathy Iskander)....Pages 103-126
Cancer-Associated Thrombosis (CAT) (Mohamed Elemary, Otto Moodley, Derek Pearson, Hadi Goubran)....Pages 127-145
Anticoagulation in Pregnancy and Lactation (Otto Moodley, Derek Pearson, Hadi Goubran)....Pages 147-157
Anticoagulation in Autoimmune Rheumatic Diseases (Gaafar Ragab, Mohamed Tharwat Hegazy, Veronica Codullo, Mervat Mattar, Jérôme Avouac)....Pages 159-179
Antiphospholipid Syndrome (Mervat Mattar, Hamdy M. A. Ahmed, Gaafar Ragab)....Pages 181-201
Anticoagulation in Patients with Renal Insufficiency (Rashad S. Barsoum, Hanaa Wanas, Tamer Shehab)....Pages 203-238
VTE Prophylaxis in General and Orthopedic Surgery (Ahmed Abdulgawad, Vinita Sundaram, Ibraheem Othman, Hadi Goubran)....Pages 239-254
Thromboprophylaxis for Hospitalized Medical Patients (Hany Guirguis, Mark Bosch, Kelsey Brose, Hadi Goubran)....Pages 255-266
Perioperative Management of Anticoagulation and Antiplatelet Therapy (Cherine El-Dabh, Joshua Nero, Hadi Goubran)....Pages 267-286
Anticoagulation Reversal Guide and Reversal Agents (Waleed Sabry, Caroline Hart, Hadi Goubran)....Pages 287-301
Back Matter ....Pages 303-308

Citation preview

Precision Anticoagulation Medicine A Practical Guide Hadi Goubran Gaafar Ragab Suzy Hassouna  Editors

123

Precision Anticoagulation Medicine

Hadi Goubran • Gaafar Ragab • Suzy Hassouna Editors

Precision Anticoagulation Medicine A Practical Guide

Editors Hadi Goubran Saskatoon Cancer Centre College of Medicine University of Saskatchewan Saskatoon, SK Canada

Gaafar Ragab Faculty of Medicine Cairo University Giza Egypt

Suzy Hassouna College of Human Medicine Michigan State University East Lansing, MI USA

ISBN 978-3-030-25781-1    ISBN 978-3-030-25782-8 (eBook) https://doi.org/10.1007/978-3-030-25782-8 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms 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 specific 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 affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to our beloved families, Hanaa, Mariam and Farah Goubran Samia, Ahmed and Sherif Ragab and the memory of Prof Suzy Hassouna

Preface

Venous thromboembolism and thromboembolic complications of atrial fibrillation are the leading cause of morbidity and mortality across the globe accounting for one in four deaths worldwide in 2010. Its annual incidence rates range from 0.75 to 2.69 per 1000 individuals and increase with age to between 2 and 7 per 1000 among those aged ≥70 years. For decades, physicians and patients had only two therapeutic options to prevent thrombosis: parenteral unfractionated heparin, one of the oldest medicines currently in use, first discovered in 1916, and the oral warfarin discovered in the late 1930s which necessitated close monitoring with prothrombin time testing. In the early 1990s, low molecular weight heparins became available as subcutaneous preparations that were offered for both prophylaxis and therapy. The simplicity of their use and dosage fostered a wider use of anticoagulation and allowed for outpatient management of venous thrombosis. In an effort to address heparin-induced thrombocytopenia, injectable direct antithrombin inhibitors were developed and introduced into our practice algorithms. In less than two decades later, direct oral anticoagulants with variable therapeutic profiles including direct thrombin inhibitors and anti-factor Xa preparations were offered as therapeutic and prophylactic alternatives to patients with venous thrombosis, for the prevention of thromboembolic complications of atrial fibrillation and as prophylactic tools. Clinicians are now confronted with an arsenal of anticoagulants and a plethora of clinical trials and guidelines positioning different agents for a given indication and for a particular patient’s profile. Many large thrombosis bodies developed apps and therapeutic algorithms to help direct practitioners on how to optimize the use of anticoagulation. Anticoagulation, therefore, is moving toward a personalized approach where one should choose from the wide palette of anticoagulants, the suitable agent for a given indication in a given profile. For a clinician in the various medical disciplines today to make an evidence-­ based anticoagulation decision, a road map is needed to navigate through the different agents, indications, and intrinsic patients’ characteristics. vii

viii

Preface

Anticoagulant Agents

Agent of Choice Given Indication

Patient’s Profile

In this book, and with the contribution of a large group of clinicians from different disciplines and different parts of the world, we tried to draw an anticoagulation guide map based on the different therapeutic options available, the approved or accepted indications supported by clinical evidence, and patients’ profiles. This book is not meant at all to replace any local, regional, or national guideline as many institutions, scientific bodies, and nations have developed their own specific guidelines that should be followed rigorously. It is meant only to integrate most of the available resources in a comprehensive format. The first chapter of this book attempted at reviewing the commonly available anticoagulants with simple prescription tools to help their administration and monitoring. The following chapters address the anticoagulation based on patients and diseases including anticoagulation in the general population, in cardiac patients, in the pediatric population, in the context of cancer, or in pregnancy and lactation. Anticoagulation in rheumatic patients and in patients with the antiphospholipid syndrome as well as anticoagulation in renal patients was also addressed separately. Thromboprophylaxis in surgical and medical patients is also given their due consideration. The last two chapters describe the indications and methods to bridge anticoagulation in the context of procedures and surgical interventions as well as the tool to reverse their action in case of bleeding. A better understanding of coagulation and the underlying pathophysiology of thrombosis in the different clinical contexts calls for the development of newer targeting anticoagulants. The field is therefore in rapid evolution moving steadily toward a more precise, personalized approach.

Preface

ix

It is sad that Dr. Hassouna, our coeditor, passed away peacefully on October 2018 during the early preparation of this book. She was Professor of Medicine, Division of Thrombosis, Elsa D. and Carl E.  Rehberg Hematology Research Professor, and Director, Special Coagulation Center at Michigan State University (MSU). In her proliferative career, she contributed tremendously to the understanding of blood coagulation, particularly the vitamin K-dependent factors and also, therefore, natural anticoagulants like protein C.  In 1989, she was the first in the world to publish a second biochemical cause in protein C associated with thrombosis by documenting resistance to inactivation of both activated factor V and factor VIII by activated protein C. She will always be remembered as a delightful personality and an outstanding researcher and medical educator. In a famous quote, Dr. Samuel Johnson said: “knowledge is of two kinds. We know a subject ourselves or we know where we can find information upon it.” In the ever-expanding horizons of thrombosis and anticoagulation, we do not claim to have the knowledge, but we can modestly hope to offer our reader a tool to navigate and our fellow physicians an instrument that helps in decision-making. Saskatoon, SK, Canada  Hadi Goubran Giza, Egypt  Gaafar Ragab

Contents

1 Coagulation and Anticoagulants������������������������������������������������������������    1 Hadi Goubran, Mark Bosch, and Julie Stakiw 2 Routine Anticoagulation for the Provoked and Unprovoked VTE������   55 Mark Bosch 3 Anticoagulation in Cardiac Patients������������������������������������������������������   77 Haissam Haddad, Udoka Okpalauwaekwe, Nishant Sharma, Jay S. Shavadia, Alex Zhai, and Tony Haddad 4 Thrombosis and Anticoagulation in Children ��������������������������������������  103 Ahmed Maher Kaddah and Iman Fathy Iskander 5 Cancer-Associated Thrombosis (CAT)��������������������������������������������������  127 Mohamed Elemary, Otto Moodley, Derek Pearson, and Hadi Goubran 6 Anticoagulation in Pregnancy and Lactation����������������������������������������  147 Otto Moodley, Derek Pearson, and Hadi Goubran 7 Anticoagulation in Autoimmune Rheumatic Diseases��������������������������  159 Gaafar Ragab, Mohamed Tharwat Hegazy, Veronica Codullo, Mervat Mattar, and Jérôme Avouac 8 Antiphospholipid Syndrome ������������������������������������������������������������������  181 Mervat Mattar, Hamdy M. A. Ahmed, and Gaafar Ragab 9 Anticoagulation in Patients with Renal Insufficiency��������������������������  203 Rashad S. Barsoum, Hanaa Wanas, and Tamer Shehab 10 VTE Prophylaxis in General and Orthopedic Surgery������������������������  239 Ahmed Abdulgawad, Vinita Sundaram, Ibraheem Othman, and Hadi Goubran 11 Thromboprophylaxis for Hospitalized Medical Patients ��������������������  255 Hany Guirguis, Mark Bosch, Kelsey Brose, and Hadi Goubran xi

xii

Contents

12 Perioperative Management of Anticoagulation and Antiplatelet Therapy������������������������������������������������������������������������  267 Cherine El-Dabh, Joshua Nero, and Hadi Goubran 13 Anticoagulation Reversal Guide and Reversal Agents ������������������������  287 Waleed Sabry, Caroline Hart, and Hadi Goubran Index������������������������������������������������������������������������������������������������������������������  303

Contributors

Ahmed  Abdulgawad, MB.BCh, MSc, MD, MD (Hematology) MRCP  Hematology Department, Faculty of Medicine, Cairo University, Giza, Egypt Hamdy  M.  A.  Ahmed, MB.BCh, MSc, MD  Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA Rheumatology and Clinical Immunology, Faculty Of Medicine Cairo University, Giza, Egypt Jérôme Avouac, MD, PhD  Université Paris Descartes, Service de Rhumatologie, Hôpital Cochin, Paris, France Rashad  S.  Barsoum, MB.BCh, MD, FRCP, FRCP Edin  The Cairo Kidney Center, Cairo, Egypt Department of Internal Medicine and Nephrology, Kasr-El-Aini Medical School, Cairo University, Cairo, Egypt Mark  Bosch, MD, FRCPC  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Kelsey  Brose, MD, FRCPC  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Veronica Codullo, MD, PhD  Université Paris Descartes, Service de Rhumatologie, Hôpital Cochin, Paris, France Cherine  El-Dabh, MD  Cleveland Clinic and Lerner School of Medicine, Abu Dhabi, UAE Mohamed Elemary, MB.BCh. MSc, MD  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Hadi  Goubran, MB.BCh, MSc, MD, FACP, FRCP Edin (UK)  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada xiii

xiv

Contributors

Hany  Guirguis, MB.BCh, MSc, FRCP Edin, FRCPC  Scarborough Health Network, Toronto, ON, Canada Haissam  Haddad, BSc,MD,FRCPC,FACC,FAAC,FRCP Edin  Department of Medicine, Division of Cardiology, University of Saskatchewan, Saskatoon, SK, Canada Tony Haddad, MD  Department of Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Caroline  Hart, MD, FRCPC  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Mohamed Tharwat Hegazy, MB.BCh, MSc, MD  Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt Iman Fathy Iskander, MB.BCh, MSc, MD  Pediatrics & Neonatology, College of Medicine, Cairo University, Giza, Egypt Ahmed  Maher  Kaddah, MB.BCh, MSc, MD  Pediatrics and Pediatric Hematology, College of Medicine, Cairo University, Giza, Egypt Mervat Mattar, MB.BCh, MSc, MD  Internal Medicine and Hematology, Cairo University, Giza, Egypt Otto  Moodley, MD, FRCPC  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Joshua Nero, MD, FRCPC  Section of Gastroenterology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada Udoka  Okpalauwaekwe, MD, FRCPC  Division of Cardiology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Ibraheem Othman, MB.BCh, MSc, MD  Alain Blair Cancer Centre and College of Medicine, University of Saskatchewan, Regina, SK, Canada Derek  Pearson, MD, FRCPC  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Gaafar Ragab, MB.BCh, MSc, MD  Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Giza, Egypt Waleed  Sabry, MB.BCh, MSc, MD  Saskatoon Cancer Centre and Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Nishant  Sharma, MD, FRCPC  Division of Cardiology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada

Contributors

xv

Jay  S.  Shavadia, MD, FRCPC  Division of Cardiology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Tamer Shehab, MB.BCh, MRCP (UK)  The Cairo Kidney Center, Cairo, Egypt Department of Nephrology, Sahel Teaching Hospital, Ministry of Health, Cairo, Egypt Julie  Stakiw, MD, FRCPC  Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada Vinita  Sundaram, MB.BCh. MD  Saskatoon Cancer Centre, Saskatoon, SK, Canada Hanaa Wanas, PhD  The Cairo Kidney Center, Cairo, Egypt Department of Pharmacology, Kasr-El-Aini Medical School, Cairo University, Cairo, Egypt Alex  Zhai, MD, FRCPC  Division of Cardiology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada

Chapter 1

Coagulation and Anticoagulants Hadi Goubran, Mark Bosch, and Julie Stakiw

Abbreviations ACCP American College of Chest Physicians AF Atrial fibrillation APC Activated protein C aPTT Activated Partial thromboplastin time AT Antithrombin AUC Area under the curve BID Twice daily C4BP C4b-binding protein CAD Coronary artery disease Cmax Maximum (or peak) serum concentration CrCl Creatinine clearance CYP Cytochrome DOACs Direct oral anticoagulants DVT Deep venous thrombosis ECT Eccrine time HIT Heparin-induced thrombocytopenia HMK High-molecular-weight kininogen LMWH Low-molecular-weight heparin MI Myocardial infarction NOACs Non-vitamin K antagonist oral anticoagulants

H. Goubran (*) · M. Bosch · J. Stakiw Saskatoon Cancer Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2020 H. Goubran et al. (eds.), Precision Anticoagulation Medicine, https://doi.org/10.1007/978-3-030-25782-8_1

1

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PAD Peripheral artery disease PCI Percutaneous coronary intervention PE Pulmonary embolization P-gp Permeability glycoprotein PK Pre-kallikrein SC Subcutaneous STEMI ST segment elevation myocardial infarction TAFI Tissue factor pathway inhibitor TF Tissue factor THR Total hip replacement TKR Total knee replacement TT Thrombin time UFH Unfractionated Heparin VKA Vitamin K antagonist VKORC1 Vitamin K epoxide reductase VTE Venous thromboembolism

Introduction The coagulation process that leads to hemostasis involves numerous reactions that culminate into the conversion of soluble fibrinogen to insoluble strands of fibrin which entraps platelets to forms a stable thrombus.

The Coagulation Cascade Classically the coagulation cascade has been described as a dual model pathway with the intrinsic and extrinsic pathways merging into a common pathway that, following the activation of factor X, leads to the generation of thrombin which then converts fibrinogen into fibrin [1]. This model reflects to the screening coagulation laboratory tests, prothrombin time (PT) and activated partial thromboplastin time (aPTT), which correspond to the extrinsic and intrinsic pathways respectively. Factor XII, high-molecular-weight kininogen (HMK), or Pre-Kallekrein (PK) ­deficiency, on the other hand, does not cause a clinical bleeding tendency. The “extrinsic” and “intrinsic” pathways are interdependent in vivo as it was recognized that the factor VIIa/tissue factor (TF) complex can activate factor IX as well as factor X [2]. Figure 1.1 illustrates the coagulation cascade. Thrombin is capable of directly activating factor XI on the charged surface of activated ­platelets [3, 4]. Factor XII, HMK, and PK might therefore not be required for hemostasis. This led to a concept of hemostasis in which TF is the primary ­physiologic activator [5].

1  Coagulation and Anticoagulants

XII

3

XIIa XI

XIa IX

Intrinsic pathway aPTT

IXa VIII

TF VIIIa

VIIa

X

Common pathway

Xa

VII

Extrinsic pathway PT

Prothrombin Va V Thrombin Fibrinogen

Fibrin

XIIIa

Stable FIBRIN

Stable clot

Fig. 1.1  The coagulation cascade with its intrinsic and extrinsic pathway leading to a common pathway and the formation of a stable fibrin clot

Cell-Based Model of Hemostasis Another model of hemostasis, the cell-based model, highlights the important interactions between cells directly involved in hemostasis and coagulation factors and views hemostasis as occurring in three overlapping phases. It represents a more accurate description of the interaction between cellular activity and coagulation proteins that leads to thrombus formation and hemostasis [6]. The initiation phase of coagulation is triggered when a break in the vessel wall allows plasma to come into contact with TF-bearing extravascular cells [7]. Cancer cells or microparticles can also express TF [8, 9]. Factor VII in plasma tightly binds to cellular TF rapidly activating coagulation [7]. If the procoagulant stimulus is sufficiently strong, adequate amounts of factors Xa, IXa, and thrombin are formed, successfully igniting the coagulation process [5]. Amplification of the coagulant response occurs at the platelet surface where the procoagulant stimulus is amplified as platelets become activated and accumulate activated cofactors on their surfaces. Activated factor X causes a burst of thrombin production. Microparticles are irregularly shaped vesicles that are smaller than platelets (125

Repeat x1 Repeat ½ 0 0 0 0 0

0 0 0 0 0 30 min 60 min

Inc 450 U/h

6h 6h 6 Next A.M. 6h 6h 6h

Inc 300 U/h Inc 150 U/h NO CHANGE Dec 150 U/h Dec 300 U/h Dec 450 U/h

1  Coagulation and Anticoagulants Anti-Xa(IU/ml) 1.7

9

UFH bolus

Hold Infusion 0 0 0 0 0 60 min 90 min

Repeat 40 U/kg Repeat 20 U/kg 0 0 0 0 0

Rate Change

Repeat aPTT

Inc 3 U/kg/h Inc 2 U/kg/h

6h 6h 6 Next A.M. 6h 6h 6h

Inc 1 U/kg/h NO CHANGE Dec 1 U/kg/h Dec 2 U/kg/h Dec 3 U/kg/h

(b) Low intensity, gradual (cardiovascular indications/high bleeding risks)) using aPTT and anti-Xa for control ATPP (sec)

UFH bolus

Hold Infusion

Rate Change

Repeat aPTT

Less than 45 45–59 60–84 85–94 95–110 >110

Repeat x1 or 0 0 0 0 0 0

0 0 0 0

Inc 200 U/h Inc 100 U/h

6h

N change Dec 100 U/h Dec 200 U/h Dec 300 U/h

60 min 120 min

6h Next a.m 6h 6h 6h

Anti-Xa(IU/ml)

UFH bolus

Hold Infusion

Rate Change

Repeat aPTT

1.7

Repeat 20 U/kg 0 0 0 0 0

0 0 0 0 60 min

Inc 2 U/kg/h Inc 1 U/kg/h N change

6h 6 Next a.m. 6h

90 min

Dec 3 U/kg/h

Dec 1 U/kg/h Dec 2 U/kg/h

6h 6h

(ii). SC monitored UFH, the aPTT, or anti-Xa should be measured 6  h after the administered doses maintaining APTT at 2–2.5 times baseline values. The following nomogram highlights the approach for dose adjustment. Anti-Xa (IU/ml) 1

Intervention Inc 48 U/kg/12 h Inc 24 U/kg/12 h No change Dec 24 U/kg/12 h Dec 48 U/kg/12 h

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Side Effects A. Bleeding: minimized by careful patient selection, close control of dosage, and proper monitoring. B. Osteoporosis and mineral deficiencies have been described with prolonged heparin use. C. Heparin induced thrombocytopenia [HIT] [35] occurs in 1–4% of patients treated for a minimum of 7 days (see Chap. 2). Contraindications UFH is contraindicated in HIT, hypersensitivity to the medication and in the presence of active or recent bleeding or bleeding diathesis and in the presence of significant thrombocytopenia. Reversal Discontinuation often results in avoiding excessive anticoagulation. If reversal is needed, protamine sulfate may be given at a dose of 1 milligram for every 100 units of UFH. The rate of the infusion should not exceed 50 milligrams per 10 min. (see Chap. 13). Low-Molecular-Weight Heparins [LMWHs] In contrast to UFH, LMWHs inhibit activated factor X and to a lesser extent factor IIa. Numerous studies have demonstrated that they are as efficacious as UFH for the treatment and prevention of venous thromboembolism. LMWHs are administered subcutaneously and do not require monitoring if given in the therapeutic dose and in the presence of adequate kidney functions with predictable pharmacokinetics [36]. LMWHs are frequently used for perioperative prophylaxis and prophylaxis in medical patients. In addition, LMWHs can be used as initial anticoagulants, given for 7–10 days prior to bridging to warfarin or as extended anticoagulants in cancer patients. They also have many cardiovascular indications [37]. Epidural or spinal hematomas may occur in patients undergoing anticoagulation with LMWHs or heparinoids who receive neuraxial (epidural or spinal) anesthesia or spinal puncture [38]. Figure 1.4 illustrates the different LMWH and their corresponding therapeutic and prophylactic doses with the percentage of renal and hepatic elimination. Low-molecular-weight heparins are not interchangeable as they differ with respect to their pharmacological properties and their capacity to inhibit factor Xa vs. factor IIa varies greatly. They increase the release and activity of tissue factor pathway inhibitor (TFPI) from endothelial cells under both static conditions and arterial shear stress [47].

3–5 h

4.5 h

Dalteparin (Fragmin®) [41]

Enoxaparin (Clexane-Lovenox) [42]

Renal

CrCl 1% risk of bleeding) and intrinsic, patient-related ones and are highlighted in Fig 10.3. The choice of thromboprophylaxis strategy therefore rests on the balance between the thrombotic risks and the bleeding risks of individual patients.

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1 point Age 41–60 years

2 points Age 61–74 years

Minor surgery

Arthroscopic surgery Major open surgery (>45 minutes) Laparoscopic surgery (>45 minutes) Malignancy Confined to bed (>72 hours)

BMI >25 kg/m2

Swollen legs

Varicose veins Pregnancy or postpartum History of unexplained or recurrent spontaneous abortion

3 points Age ≥75 years History of VTE Family history of VTE

Factor V Leiden

5 points Stroke ( =30 Ongoing hormonal treatment

0 0 0 0 0 0 0 0 0 0 0

3 3 3 3 2 1 1 1 1 1 1

11  Thromboprophylaxis for Hospitalized Medical Patients

257

• Padua Score