Practical transfusion medicine 9781119129424, 1119129427, 9781119129431, 1119129435

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Practical Transfusion Medicine

Practical Transfusion Medicine FIFTH EDITION

Edited By Michael F. Murphy, MD, FRCP, FRCPath, FFPath

Professor of Blood Transfusion Medicine University of Oxford Consultant Haematologist NHS Blood and Transplant and Department of Haematology, Oxford University Hospitals Oxford, UK

David J. Roberts, MB, ChB, D.Phil, FRCPath

Professor of Haematology University of Oxford Consultant Haematologist NHS Blood and Transplant and Department of Haematology, Oxford University Hospitals Oxford, UK

Mark H. Yazer, MD

Professor of Pathology University of Pittsburgh Adjunct Professor of Clinical Immunology University of Southern Denmark Odense, Denmark Medical Director RBC Serology Reference Laboratory, ITXM Centralized Transfusion Service Associate Medical Director ITXM Centralized Transfusion Service Pittsburgh, USA

This edition first published 2017 © 2001, 2005, 2009, 2013 by John Wiley & Sons Ltd All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at www.wiley.com/go/permissions. The right of Michael F. Murphy, David J. Roberts, and Mark H. Yazer to be identified as the author(s) of this has been asserted in accordance with law. Registered Offices John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the authors make no representations or warranties with respect to the accuracy and completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or website is referred to in this work as a citation and/or potential source of further information does not mean that the authors or the publisher endorses the information the organization or website may provide or recommendations it may make. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this works was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the authors shall be liable for any damages arising herefrom. Library of Congress Cataloging‐in‐Publication Data Names: Murphy, Michael F. (Michael Furber), editor. | Roberts, David J. (David John) (Consultant hematologist), editor. | Yazer, Mark H., editor. Title: Practical transfusion medicine / edited by Michael F. Murphy, David J. Roberts, Mark H. Yazer. Description: Fifth edition. | Hoboken, NJ : John Wiley & Sons Inc., 2017. | Preceded by Practical transfusion medicine / edited by Michael F. Murphy, Derwood H. Pamphilon, Nancy M. Heddle. 4th ed. 2013. | Includes bibliographical references and index. Identifiers: LCCN 2016053360 | ISBN 9781119129417 (cloth) | ISBN 9781119129448 (Adobe pdf ) | ISBN 9781119129424 (epub) Subjects: | MESH: Blood Transfusion | Blood Grouping and Crossmatching | Hematopoietic Stem Cell Transplantation | Blood Preservation | Cross Infection–prevention & control Classification: LCC RM171 | NLM WB 356 | DDC 615.3/9–dc23 LC record available at https://lccn.loc.gov/2016053360 Set in 10/12pt Warnock by SPi Global, Pondicherry, India

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Contents List of Contributors  ix Preface  xv 1 Introduction: Two Centuries of Progress in Transfusion Medicine  1 Walter H. (Sunny) Dzik and Michael F. Murphy Part I 

Basic Principles of Immunohaematology  11

2 Essential Immunology for Transfusion Medicine  11 Jaap Jan Zwaginga and S. Marieke van Ham 3 Human Blood Group Systems  20 Geoff Daniels 4 Human Leucocyte Antigens  29 Cristina V. Navarrete and Colin J. Brown 5 Platelet and Neutrophil Antigens  43 Brian R. Curtis 6 Pretransfusion Testing and the Selection of Red Cell Products for Transfusion  58 Mark H. Yazer and Meghan Delaney Part II 

Complications of Transfusions  69

7 Investigation of Acute Transfusion Reactions  69 Kathryn E. Webert and Nancy M. Heddle 8 Haemolytic Transfusion Reactions  81 Edwin J. Massey, Robertson D. Davenport and Richard M. Kaufman 9 Febrile and Allergic Transfusion Reactions  97 Mark K. Fung and Nancy M. Heddle

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Contents

10 Lung Injury and Pulmonary Oedema After Transfusion  108 Steven H. Kleinman and Daryl J. Kor 11 Purported Adverse Effects of ‘Old Blood’  118 Lirong Qu and Darrell J. Triulzi 12 Transfusion‐Induced Immunomodulation  125 Amy E. Schmidt, Majed A. Refaai, Joanna M. Heal and Neil Blumberg 13 Transfusion‐Associated Graft‐Versus‐Host Disease and Microchimerism  136 Beth H. Shaz, Richard O. Francis and Christopher D. Hillyer 14 Posttransfusion Purpura  147 Michael F. Murphy 15 Transfusion‐Transmitted Infections  153 Roger Y. Dodd and Susan L. Stramer 16 Bacterial Contamination  168 Sandra Ramírez‐Arcos and Mindy Goldman 17 Emerging Infections and Transfusion Safety  176 Roger Y. Dodd Part III 

Practice in Blood Centres and Hospitals  184

18 Regulatory Aspects of Blood Transfusion  184 William G. Murphy, Louis M. Katz and Peter Flanagan 19 The Role of Haemovigilance in Transfusion Safety  193 Katharine A. Downes and Barbee I. Whitaker 20 Donors and Blood Collection  203 Marc Germain, Ellen McSweeney and William G. Murphy 21 Blood Donation Testing and the Safety of the Blood Supply  215 Mindy Goldman 22 Production and Storage of Blood Components  222 Marissa Li, Rebecca Cardigan, Stephen Thomas and Ralph Vassallo 23 Blood Transfusion in Hospitals  233 Erica M. Wood, Mark H. Yazer and Michael F. Murphy 24 Blood Transfusion in a Global Context  254 David J. Roberts, Alan D. Kitchen, Stephen P. Field, Imelda Bates, Jean Pierre Allain and Meghan Delaney

Contents

Part IV 

Clinical Transfusion Practice  264

25 Inherited and Acquired Coagulation Disorders  264 Irina Chibisov and Franklin Bontempo 26 Massive Blood Loss  279 John R. Hess 27 Blood Management in Acute Haemorrhage and Critical Care  287 Gavin J. Murphy, Nicola Curry, Nishith N. Patel and Timothy S. Walsh 28 Point‐of‐Care Testing in Transfusion Medicine  302 Matthew D. Neal and Louis H. Alarcon 29 Haematological Disease  312 Lise J. Estcourt, Simon J. Stanworth and Michael F. Murphy 30 Blood Transfusion in the Management of Patients with  Haemoglobinopathies  330 Enrico M. Novelli 31 Heparin‐Induced Thrombocytopenia  341 Andreas Greinacher and Theodore E. Warkentin 32 Immunodeficiency and Immunoglobulin Therapy  357 Siraj A. Misbah 33 Transfusing Neonates and Infants  371 Ronald G. Strauss Part V 

Patient Blood Management  383

34 Development of a Patient Blood Management Programme  383 Jonathan H. Waters 35 Perioperative Patient Blood Management  393 Martin Rooms, Ravishankar Rao Baikady and Toby Richards 36 Restrictive Transfusion Practice and How to Implement It  405 Lawrence Tim Goodnough and Neil Shah 37 Using Data to Support Patient Blood Management  416 Steven M. Frank and Jack O. Wasey

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Contents

Part VI 

Cellular and Tissue Therapy and Organ Transplantation  429

38 Regulation and Accreditation in Cellular Therapy  429 Zbigniew (Ziggy) M. Szczepiorkowski and Daniel Hollyman 39 Stem Cell Collection and Therapeutic Apheresis  442 Khaled El‐Ghariani and Zbigniew (Ziggy) M. Szczepiorkowski 40 Haemopoietic Stem Cell Processing and Storage  455 Hira Mian, Ronan Foley and Pamela O’Hoski 41 Haematopoietic Stem Cell Transplantation  466 Robert D. Danby, Rachel Protheroe and David J. Roberts 42 Cord Blood Transplantation  477 Rachael Hough and Robert D. Danby 43 Recent Advances in Clinical Cellular Immunotherapy  490 Mark W. Lowdell and Emma Morris 44 Tissue Banking  500 Akila Chandrasekar, Paul Rooney and John N. Kearney Part VII 

Development of the Evidence Base for Transfusion  508

45 Observational and Interventional Trials in Transfusion Medicine  508 Alan T. Tinmouth, Dean Fergusson and Paul C. Hébert 46 Getting the Most Out of the Evidence for Transfusion Medicine  520 Simon J. Stanworth, Susan J. Brunskill, Carolyn Dorée and Sally Hopewell 47 A Primer on Biostatistics  533 Andrew W. Shih and Nancy M. Heddle 48 A Primer on Health Economics  549 Seema Kacker and Aaron A. R. Tobian 49 Scanning the Future of Transfusion Medicine  560 Jay E. Menitove, Paul M. Ness and Edward L. Snyder Index  572

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List of Contributors Louis H. Alarcon

Franklin Bontempo

Nicola Curry

Professor of Departments of Surgery and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA

University of Pittsburgh Medical Center, Pittsburgh, USA; Institute for Transfusion Medicine, Pittsburgh, USA

Oxford Haemophilia & Thrombosis Centre, Churchill Hospital, Oxford, UK

Jean Pierre Allain

Colin J. Brown

NHS Blood and Transplant and Division of Transfusion Medicine, Department of Hematology, University of Cambridge, Cambridge, UK

NHS Blood and Transplant, Histocompatibility and Immunogenetics Services, Colindale Centre, London, UK

Imelda Bates

NHS Blood and Transplant, Systematic Review Initiative, Oxford, UK

Professor of Clinical Tropical Haematology, Liverpool School of Tropical Medicine, Liverpool, UK Ravishankar Rao Baikady

Susan J. Brunskill

Rebecca Cardigan

NHS Blood and Transplant, Cambridge, UK

Consultant in Anaesthesia, The Royal Marsden, NHS Foundation Trust, London, UK

Akila Chandrasekar

Neil Blumberg

Irina Chibisov

Department of Pathology and Laboratory Medicine, University of Rochester; Blood Bank/Transfusion Service of Strong Memorial Hospital, Rochester, USA

University of Pittsburgh Medical Center, Pittsburgh, USA; Institute for Transfusion Medicine, Pittsburgh, USA

NHS Blood and Transplant, Tissue and Eye Services, Liverpool, UK

Brian R. Curtis

Platelet and Neutrophil Immunology Laboratory and Blood Research Institute, Blood Center of Wisconsin, Milwaukee, USA Robert D. Danby

Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Geoff Daniels

International Blood Group Reference Laboratory, NHS Blood and Transplant, Bristol, UK Robertson D. Davenport

University of Michigan Health System, Ann Arbor, USA Meghan Delaney

Bloodworks Northwest and Department of Laboratory Medicine and Paediatrics, University of Washington, Seattle, USA

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List of Contributors

Roger Y. Dodd

American Red Cross, Jerome H. Holland Laboratory for the Biomedical Sciences, Rockville, USA Carolyn Dorée

NHS Blood and Transplant, Systematic Review Initiative, Oxford, UK Katharine A. Downes

Medical Director of Transfusion Medicine, University Hospitals, Cleveland Medical Center; Associate Professor of Pathology, Case Western Reserve University, Cleveland, OH Walter H. “Sunny” Dzik

Department of Pathology and Medicine, Massachusetts General ­Hospital, Harvard Medical School, Boston, USA Khaled El‐Ghariani

NHS Blood and Transplant and Sheffield Teaching Hospitals NHS Trust and University of Sheffield, Sheffield, UK Lise J. Estcourt

NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK Dean Fergusson

Senior Scientist, University of Ottawa Center for Transfusion Research,

Clinical Epidemiology Program, Ottawa, Canada; Health Research Institute, Ottawa, Canada

Marc Germain

Stephen P. Field

Medical Director, Donor and Clinical Services, Canadian Blood Services, Medical Services and Innovation, Ottawa, Canada

Welsh Blood Service, Pontyclun, Wales, UK Peter Flanagan

New Zealand Blood Service, Auckland, New Zealand Ronan Foley

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada Richard O. Francis

Assistant Professor, Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, USA; Director, Special Hematology and Coagulation Laboratory New York Presbyterian Hospital – Columbia University Medical Center, New York, USA Steven M. Frank

Department of Anesthesiology/Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, USA Mark K. Fung

Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, USA

Héma‐Québec, Quebec City, Canada Mindy Goldman

Lawrence Tim Goodnough

Departments of Pathology and Medicine, Stanford University, Stanford, USA Andreas Greinacher

Department of Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany Joanna M. Heal

Department of Pathology and Laboratory Medicine, University of Rochester; Blood Bank/Transfusion Service of Strong Memorial Hospital, Rochester, USA Paul C. Hébert

Professor, Department of Medicine, Centre Hospitalier de L’Université de Montreal; Centre Recherche de le Centre Hospitalier de Montreal, Montreal, Canada Nancy M. Heddle

Department of Medicine, McMaster University and Canadian Blood Services, Hamilton, Ontario, Canada

List of Contributors

John R. Hess

Richard M. Kaufman

Jay E. Menitove

Professor of Laboratory Medicine and Hematology, University of Washington School of Medicine, Seattle, USA; Director, Harborview Transfusion Service, Seattle, USA

Brigham and Women’s Hospital, Boston, USA

Director and CEO, Greater Kansas City Blood Center, Kansas City, USA (Retired)

John N. Kearney

Hira Mian

Christopher D. Hillyer

Chief Executive Officer, New York Blood Center, New York, USA; Weill Cornell Medical College, New York, USA Daniel Hollyman

NHS Blood and Transplant, Tissue and Eye Services, Liverpool, UK Alan D. Kitchen

National Transfusion Microbiology Laboratory and NHS Blood and Transplant, Colindale, London, UK

Department of Oncology, McMaster University, Hamilton, Ontario Siraj A. Misbah

Oxford University Hospitals, University of Oxford, Oxford, UK Emma Morris

Diagnostics Development and Reference Services, NHS Blood and Transplant, Bristol, UK

Steven H. Kleinman

University of British Columbia, Victoria, Canada

Professor of Clinical Cell & Gene Therapy, UCL Institute of Immunity and Transplantation, London, UK

Sally Hopewell

Daryl J. Kor

William G. Murphy

Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK Rachael Hough

University College London Hospital’s NHS Foundation Trust, London, UK Seema Kacker

Medical Student, The Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, USA Louis M. Katz

Chief Medical Officer, America’s Blood Centers, Washington, DC, USA; Adjunct Clinical Professor, Infectious Diseases, Carver College of Medicine, University of Iowa Healthcare, Iowa City, USA

Mayo Clinic, Rochester, USA Marissa Li

United Blood Services, Ventura, USA Mark W. Lowdell

Professor of Cell and Tissue Therapy, University College London; Director of Cellular Therapy, Honorary Consultant Scientist, Royal Free London NHS Foundation Trust, London, UK

Irish Blood Transfusion Service, and University College Dublin, Dublin, Republic of Ireland Gavin J. Murphy

British Heart Foundation Professor of Cardiac Surgery, School of Cardiovascular Sciences, University of Leicester, Leicester, UK Cristina V. Navarrete

NHS Blood and Transplant, Bristol, UK

NHS Blood and Transplant, Histocompatibility and Immunogenetics Services, Colindale Centre, London, UK; University College London, London, UK

Ellen McSweeney

Matthew D. Neal

Edwin J. Massey

Irish Blood Transfusion Service, National Blood Centre, Dublin, Republic of Ireland

Assistant Professor of Departments of Surgery and Critical Care Medicine,

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List of Contributors

University of Pittsburgh School of Medicine, Pittsburgh, USA Paul M. Ness

Director, Transfusion Medicine Division: Professor, Pathology and Medicine, Johns Hopkins Medical Institutions, Baltimore, USA Enrico M. Novelli

Division of Hematology/ Oncology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, USA Pamela O’Hoski

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada Nishith N. Patel

Clinical Research Fellow in Cardiac Surgery, School of Clinical Sciences, University of Bristol, Bristol, UK Rachel Protheroe

Bristol Adult Bone Marrow Transplant Unit, University Hospitals Bristol, Bristol, UK Lirong Qu

Department of Pathology, University of Pittsburgh, Pittsburgh, USA; Institute for Transfusion Medicine, Pittsburgh, USA Sandra Ramírez‐Arcos

Development Scientist, Canadian Blood Services, Medical Services and Innovation, Ottawa, Canada

Majed A. Refaai

Department of Pathology and Laboratory Medicine, University of Rochester; Blood Bank/Transfusion Service of Strong Memorial Hospital, Rochester, USA

Transfusion Medicine Fellowship Program, McMaster University, Hamilton, Canada Edward L. Snyder

Professor of Surgery, University College London, London, UK

Director, Transfusion Medicine Service, Cellular Therapy Center, Yale‐New Haven Medical Center, Yale University, New Haven, Connecticut, USA

Martin Rooms

Simon J. Stanworth

Toby Richards

Consultant in Anaesthesia, The Royal Marsden, NHS Foundation Trust, London, UK Paul Rooney

NHS Blood and Transplant, Tissue and Eye Services, Liverpool, UK Amy E. Schmidt

Department of Pathology and Laboratory Medicine, University of Rochester; Blood Bank/Transfusion Service of Strong Memorial Hospital, Rochester, USA Neil Shah

Department of Pathology, Stanford University, Stanford, USA Beth H. Shaz

Chief Medical and Scientific Officer, New York Blood Center, New York, USA; Columbia University Medical Center, New York, USA Andrew W. Shih

Department of Pathology and Molecular Medicine,

NHS Blood and Transplant, Oxford University Hospitals, Oxford, UK; Department of Hematology, Oxford University Hospitals, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK Susan L. Stramer

American Red Cross, Scientific Support Office, Gaithersburg, USA Ronald G. Strauss

Professor Emeritus, Department of Pathology and Pediatrics, University of Iowa College of Medicine, Iowa City, USA; Associate Medical Director, LifeSource/ITxM, Chicago, USA Zbigniew (Ziggy) M. Szczepiorkowski

Transfusion Medicine Service, Cellular Therapy Center, Dartmouth‐ Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Hanover, USA

List of Contributors

Stephen Thomas

Ralph Vassallo

Assistant Director – Manufacturing Development, NHS Blood and Transplant, Watford, UK

Adjunct Associate Professor of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia

Alan T. Tinmouth

Timothy S. Walsh

Head, Division of Hematology, Department of Medicine, Ottawa Hospital, Ottawa, Canada; Scientist, University of Ottawa Centre for Transfusion Research, Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Canada

Professor of Critical Care, Clinical and Surgical Sciences, Edinburgh University, Edinburgh, Scotland, UK; Anaesthetics and Intensive Care, Edinburgh Royal Infirmary, Edinburgh, Scotland, UK

Aaron A. R. Tobian

Associate Professor of Pathology, Medicine and Epidemiology, The Johns Hopkins University School of Medicine and Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, USA Darrell J. Triulzi

Department of Pathology, University of Pittsburgh, Pittsburgh, USA; Institute for Transfusion Medicine, Pittsburgh, USA S. Marieke van Ham

Head, Department of Immunopathology, Sanquin Research, Landsteiner Laboratory, Academic Medical Center, and SILS, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands

Theodore E. Warkentin

Department of Pathology and Molecular Medicine and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Canada; Transfusion Medicine, Hamilton Regional Laboratory Medicine Program and Service of Clinical Hematology, Hamilton Health Sciences, Hamilton, Ontario, Canada Jack O. Wasey

Department of Anesthesiology/Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, USA Jonathan H. Waters

Department of Anesthesiology, Magee Womens Hospital of UPMC, Pittsburgh, USA; Departments of

Anesthesiology and Bioengineering, University of Pittsburgh, Pittsburgh, USA; Patient Blood Management program of UPMC; Acute Interventional Pain Program of UPMC Barbee I. Whitaker

Senior Director, Research and American Association of Blood Banks Center for Patient Safety, Bethesda, USA Kathryn E. Webert

Canadian Blood Services, and Department of Medicine and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Erica M. Wood

Transfusion Research Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia; Department of Clinical Hematology, Monash Health, Melbourne, Australia Jaap Jan Zwaginga

Jon J. van Rood Center for Clinical Transfusion Research, Sanquin, Leiden and the Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

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Preface The pace of change in transfusion medicine is relentless, with new scientific and technological developments and continuing efforts to improve clinical transfusion practice through patient blood management (PBM), which implores us to use the best available evidence when optimising pre-, peri- and post-operative management to reduce anaemia, prevent blood loss and reduce the need for transfusions. This fifth edition has become necessary because of rapid changes in transfusion medicine since the fourth edition was published in 2013. The primary purpose of the fifth edition remains the same as the first: to provide a comprehensive guide to transfusion medicine. This book aims to include information in more depth than contained within handbooks of transfusion medicine and yet to present that information in a more concise and approachable manner than seen in more formal standard reference texts. The feedback we have received from reviews and colleagues is that these objectives continue to be achieved and that this book has a consistent style and format. We have again striven to maintain this in the fifth edition to provide a text that will be useful to the many clinical and scientific staff, both established practitioners and trainees, who are

involved in some aspect of transfusion medicine and require an accessible text. We considered that this book had become big enough for its purpose, and the number of chapters has only been increased by one from 48 to 49. It is divided into seven sections that systematically take the reader through the principles of transfusion medicine, complications of transfusion, practice in blood centres and hospitals, clinical transfusion practice, PBM, cellular and tissue therapy and organ transplantation and development of the evidence base for transfusion. The final chapter on Scanning the Future of Transfusion Medicine has generated much interest, and it has been updated for this edition by three new authors. We wish to continue to develop the content and to refresh the style of this book and are very pleased to welcome Professors David Roberts and Mark Yazer as co-editors. The authorship likewise has become more international with each successive edition to provide a broad perspective. We are very grateful to the colleagues who have contributed to this book at a time of continuing challenges and change. Once again, we acknowledge the enormous support we have received from our publishers, particularly James Schultz and Claire Bonnett.

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Introduction: Two Centuries of Progress in Transfusion Medicine Walter H. (Sunny) Dzik1 and Michael F. Murphy2 1 2

Department of Pathology and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA University of Oxford; NHS Blood and Transplant and Department of Haematology, Oxford University Hospitals, Oxford, UK

‘States of the body really requiring the infusion of blood into the veins are probably rare; yet we sometimes meet with cases in which the patient must die unless such operation can be performed’. So begins James Blundell’s ‘Observations on transfusion of blood’ published in The Lancet, marking the origins of transfusion medicine as a clinical discipline. Blundell (Figure  1.1) was a prominent London obstetrician who witnessed peripartum haemorrhage and whose interest in transfusion had begun as early as 1817 during his medical education in Edinburgh. He established that transfusions should not be conducted across species barriers and noted that resuscitation from haemorrhage could be achieved using a volume of transfusion that was smaller than the estimated blood loss. Despite life‐saving results in some patients, clinical experience with transfusion was restricted by lack of understanding of ABO blood groups – a barrier that would not be resolved for another century. The Nobel Prize‐winning work of Karl Landsteiner (Figure 1.2) established the primacy of ABO blood group compatibility and set the stage for safer transfusion practice. Twentieth‐ century transfusion was advanced by the leadership of many physicians, scientists and technologists and repeatedly incorporated new diagnostics (monoclonal antibodies, genomics)

and new therapeutics (plasma fractionation, apheresis and recombinant proteins) to improve patient care. Today, the field of transfusion medicine is composed of a diverse range of disciplines including the provision of a safe blood supply; the fields of haemostasis, immunology, transplantation and cellular engineering; apheresis technology; treatment using recombinant and plasma‐derived plasma proteins; and the daily use of blood components in clinical medicine (Figure  1.3). Without transfusion resources, very little of modern surgery and medicine could be accomplished. For decades, the challenge of transmitting new information in transfusion fell to Dr Patrick Mollison (Figure  1.4) whose textbook became the standard of its era. Mollison highlighted the importance of both laboratory practice (immunohaematology, haemostasis, complement biology) and clinical medicine in our field. Practical Transfusion Medicine, here in its fifth edition, seeks to build on that tradition and to give ­readers the foundation knowledge required to contribute both academically and clinically to our discipline. For readers about to enjoy the content of this book, the following provides a sampling of the topics presented within the text by leading experts in our field.

Practical Transfusion Medicine, Fifth Edition. Edited by Michael F. Murphy, David J. Roberts and Mark H. Yazer. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.

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Practical Transfusion Medicine

Donor services

Component production

Clinical use of blood

Transfusion Medicine

Plasma derivatives Blood storage & preservation

Adverse effects Apheresis Stem cell HLA

Matching: Immunohaematology

Figure 1.3  The range of transfusion medicine.

Figure 1.1  James Blundell. Figure 1.4  Patrick Mollison. Source: Garratty, Transfusion 2012;52:684–85. Reproduced with permission of John Wiley & Sons.

Figure 1.2  Karl Landsteiner.

­Blood Donation Worldwide Each year, approximately 100 million blood donations are made worldwide (Figure  1.5). A  safe and adequate blood supply is now an

essential infrastructure requirement of any modern national healthcare system. The recruitment and retention of healthy blood donors is a vital activity of the field and the challenges and responsibilities faced by stewards of the blood supply are presented to readers in Chapters 18–22. Whilst the economically advantaged nations of the world have established all volunteer donor programmes with great success, data from the World Health Organization presented in Chapter  24 document that blood donation rates per capita in many low‐income nations are insufficient to meet their needs. More research and investment is required so that all regions of the world can rely upon an adequate supply of safe blood.

Chapter 1: Introduction: Two Centuries of Progress in Transfusion Medicine

­Changing Landscape of Transfusion Risks During the final two decades of the twentieth century, intense focus on screening blood donations for infectious diseases led to substantial

Figure 1.5  Blood donation.

progress in blood safety and a significant reduction in the risk of transfusion‐transmitted ­diseases (Figure 1.6). Chapters 15–17 present an authoritative summary of this success. We currently enjoy a grace period when the risk of transfusion‐transmitted infections is at an all‐ time low. However, progressive encroachment of humans upon the animal kingdom is expected to result in the emergence of new infections that cross species barriers. Haemovigilance, robust screening technologies and chemical pathogen inactivation are all being applied to address this concern and are reviewed within the text. With the advent of the twenty‐first century, the landscape of transfusion risk shifted its emphasis towards non‐infectious hazards (Figure  1.7). Recent years have focused on improved understanding and prevention of transfusion‐related acute lung injury, a topic covered in detail in Chapter 10. More recently, we have learned that circulatory overload from

Risk per unit

SARS Monkey pox Leishmania Influenza DENV Babesia CHICKV XMAV

WNV

SFV

PTLVs

Bacteria vCJD

ICL

1:1000

Trypanosome cruzi

Emerging infectious disease threats 1:100

1:10 000

1:100 000

HCV HBV HIV

1:1 000 000

>1984 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 Revised donor deferral criteria

HBsAg screening

HIV Ab screening

HCV Ab screening

p24 Ag testing

NANB hepatitis surrogate testing

Figure 1.6  Risks of transfusion‐transmitted infections over time.

HCV and HIV NAT

WNV NAT

HBV NAT

vCjD deferral criteria T cruzi Ab screening

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Practical Transfusion Medicine Paling risk scale for major transfusion hazards 108

107

106

105

104

HIV

102

101

100

General anaesthesia

HCV Prion

103

HBV Bacteria Mis-Transfusion TRALI TA-GVHD Elderly

Selected patient groups:

Volume overload (TACO)

Metabolic risk neonates Inadequate transfusion

Figure 1.7  Paling scale of transfusion risk.

excessive transfusion is far more common than previously recognised. Yet Blundell himself specifically warned of it in his first description of transfusion: ‘to observe with attention the countenance of the patient, and to guard … against an overcharge of the heart’ [1]. In addition, haemolytic reactions remain a serious hazard of transfusion. It is quite surprising that despite unimagined advances in internet connectivity, most nations still do not have a system for sharing patient blood group results or antibody profiles between hospitals, thereby failing to share information that would prevent acute and delayed reactions. Much can still be done to further reduce non‐infectious hazards of transfusion. Readers will find that Chapters 7–17 provide state‐of‐the‐art summaries of our current understanding regarding the full range of adverse effects and complications of transfusion.

­Immunohaematology Knowledge of the location and functional role of red cell surface proteins that display blood group epitopes has brought order out of what

was once a chaotic assembly of information in blood group serology (Figure 1.8). Readers will enjoy an up‐to‐date treatment of this topic in Chapters 2–6. Today, red cell genomics has become a practical clinical tool and DNA diagnostics in immunohaematology extends far beyond the reach of erythrocyte blood groups. Genotyping has always been the preferred method for defining members of the human platelet antigen system and is well established for HLA genes in the field of histocompatibility (Figure 1.9). The clinical practice of transfusion medicine is now supported by DNA diagnostics targeting a wide range of genes, including those coding for complement proteins, human neutrophil antigens, haemoglobin polymorphisms and coagulation factors. Despite advances in defining antigens, both clinical illness and blood group incompatibilities remain dominated by antibody responses of the patient. A robust form of antibody analysis and better control of the immune response remain important frontiers of our field. The ability to downregulate specific alloimmune responses would revolutionise the approach to

Chapter 1: Introduction: Two Centuries of Progress in Transfusion Medicine Single-pass Type 1 N

Polytopic (multi-pass) Type 3

Type 2 C

GPI anchored Type 5 N

N

N

C

C Glycophorins Kell A to D Lutheran, LW, Knops, Indian, Vel

RhD, RhCcEe, RhAG, Kidd, Diego, Colton, Gill, Kx, RAPH Junior, Lan

C Duffy

Yt, Dombrock, Cromer, JMH

Figure 1.8  Red blood cell antigens. Source: Daniels G, Bromilow I. Essential Guide to Blood Groups, 3rd edn. Wiley: Chichester, 2014. Reproduced with permission of John Wiley & Sons.

120

130

G A T A A AT C T G G T C T T AT T T C C

Figure 1.9  DNA sequence.

solid organ transplantation, haemophilia complicated by inhibitors, platelet refractoriness, red cell allosensitisation, haemolytic disease of the newborn and a host of other challenges that confront transfusion specialists every day. In the meantime, we can offer patients powerful, yet nonspecific immune suppressants. And while the focus of many treatments is on reduction of pathological antibodies, it is increasingly clear that antibodies themselves do not injure tissues nearly as much as the complement proteins that antibodies attract.

Complement is at the centre of a wide variety of disorders, including drug‐mediated haemolysis or thrombocytopenia, severe alloimmune or autoimmune haemolysis, cryoglobulinaemic vasculitis, HLA antibody‐mediated platelet refractoriness and organ rejection, paroxysmal nocturnal haemoglobinuria, atypical haemolytic‐uremic syndrome, hereditary angioedema, glomerulonephritis and age‐related macular degeneration. With the development in the future of better agents to suppress complement, it can be anticipated that the focus of treatment may shift from removal of pathological antibodies to control of their effect.

­ linical Use of Blood C Components: Evolution Based on Evidence Recent years have witnessed a growing body of evidence derived from clinical research and focused on the proper use of blood components (Figure  1.10). While such research has lagged for plasma products, progress has been made

5

6

Practical Transfusion Medicine

for both red cells and platelets. Ever since the landmark publication of the TRICC trial by Hebert and others [2], clinical investigators have repeatedly challenged the traditional 100  g/L haemoglobin threshold for red cell transfusion. There are now at least 11 well‐designed, sufficiently powered randomised controlled trials documenting that a conservative haemoglobin threshold for red cell transfusion is as beneficial

for patient outcomes as a more liberal threshold (Figure  1.11). These studies cut across a broad range of patient categories from infants to the elderly. As a result, in hospitals worldwide, red cell use is more conservative and transfusions are now withheld in nonbleeding patients until the haemoglobin concentration falls to 70 g/L. Looking ahead, we anticipate that future clinical research will seek to further refine the indication for red cells by addressing the fact that the haemoglobin concentration is but one dimension of tissue oxygenation and that the decision to transfuse red cells should include measures of both oxygen delivery and tissue oxygen consumption. The last decade has also witnessed evidence‐ based refinements in the indication for platelet transfusion. The modern era of evidence begins with the work of Rebulla et al [3] who documented that a platelet threshold of 10 × 109/L was equivalent to 20 × 109/L for prophylactic platelet transfusions. Further advances came with the TRAP trial [4], demonstrating that reducing the number of leucocytes (and not the number of donors) was key to preventing HLA alloimmunisation, and the PLADO trial [5] which demonstrated that the traditional dose of platelets (approximately equivalent of that found in 4–6 units of whole blood) resulted in the same outcome as transfusion of three units or

Figure 1.10  RBC transfusion. Source: REX by Shutterstock. © Garo.

Randomised trials of RCB transfusion threshold Author

Name

Setting

Trigger

‘n’

Hebert, 1999

TRIC

Adult ICU

7 vs 9

836

Kirpalami, 2006

PINT

Infants  C

rs5918

HPA‐1b

26% a/b GPIbα

Thr145Met

GPIBA

482C > T

rs6065

GPIIb

Ile843Ser

ITGA2B

2621 T > G

rs5911

GPIIIa

Arg143Gln

ITGB3

506G > A

rs5917

GPIa

Glu505Lys

ITGA2

1600G > A

rs10471371

rs13306487

2% b/b HPA‐2a

85% a/a

HPA‐2b

14% a/b 1% b/b

HPA‐3a

37% a/a

HPA‐3b

48% a/b 15% b/b

HPA‐4a

>99.9% a/a

HPA‐4b

0.05 (please note there will be a 1 in 20 chance that the confidence interval does not include the true value). Such is the case in this example. Perhaps, the most important aspect of displaying the results graphically in this way is that it helps the reader look at the overall effects for each trial. Therefore, in this example, it should prompt the reader to ask why the results for one trial seem to be so different from the others (Thomas, 1991)?

Figure 46.1  A hypothetical forest plot.

A hierarchy of evidence for effectiveness Increasing validity • RCT • Controlled trial • Other experimental designs • Observational research • Experience

• S Y S T E M A T I C R E V I E W

• T R A D I T I O N A L R E V I E W

• S I N G L E S T U D Y

Figure 46.2  A guide for judging the validity of evidence for treatment decisions from different types of studies and reviews.

decisions for the different types of studies, trials and reviews mentioned in this section. Although sometimes criticised for their overemphasis on methodology at the expense of clinical rele­ vance, and the inappropriate use of meta‐analysis, systematic reviews have an important place in clinical practice as a means of transparently summarising evidence from multiple sources. As for RCTs, guidelines for the reporting of systematic reviews have been developed, includ­ ing Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) for the reporting of systematic reviews of RCTs and Meta‐analysis of Obser­ vational Studies in Epidemiology (MOOSE) for the reporting of systematic reviews and meta‐analyses of obser­ vational studies [8,9]. Quality assessment tools have also been developed for critical appraisal of systematic reviews (the Critical Appraisal Skills Programme, CASP) (Box 46.3).

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Box 46.3  Key components of the critical appraisal process for systematic reviews. Did the review ask a clearly focused question? Do you think all the important, relevant studies were included? Did the authors look for the right type of papers? Did the review’s authors do enough to assess the quality of the included studies? If the results of the review have been combined, was it reasonable to do so? What are the overall results of the review? How precise are the results? Were all the important outcomes for the review question considered? Can the results be applied to the local population? Are the benefits worth the harms and costs? Source:  Adapted from  the  Critical Appraisal Skills Programme worksheets (www.casp‐uk.net), copyright http://­ creativecommons.org/licenses/by‐nc‐sa/3.0/.

Evaluating Systematic Reviews and Guidelines

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool has been devised as a system for evaluating and rat­ ing the quality of evidence in systematic reviews and grading the strength of recommendations in guidelines. The system is designed for reviews and guidelines that examine alternative man­ agement strategies or interventions, which may include no intervention or current best man­ agement. An example relevant to trans­fusion ­medicine is the recent guidelines on immune thrombocytopenia from the American Society of Hematology, which utilised GRADE method­ ology to evaluate the strength of recommenda­ tions [10].

­Comparative Effectiveness Research Comparative effectiveness research (CER) is gaining support from both researchers and funding agencies, particularly in the USA and Canada. CER is defined as the conduct and synthesis of systematic research comparing different interventions and strategies to pre­ vent, diagnose, treat and monitor health condi­ tions. While experimental study designs like

RCTs are highly valued methods of CER, they are costly and resource intensive and their results may not be easily generalisable to non­ study patients. Nonexperimental approaches using observational data are also useful tools for CER but they are inherently limited by ­heterogeneous methodologies, diverse designs and susceptibility to bias. As methods of obser­ vational studies continue to be refined, the data they derive may become more widely applicable, such as advances in the design of clinical registries and the use of encounter‐ generated data from sources such as electronic medical records. The informing fresh‐versus‐old red cell man­ agement (INFORM) pilot trial is an example of CER in transfusion medicine [11]. The design was pragmatic; patients were randomised to receive one of two treatments that are already routinely used, thus obviating the need for indi­ vidual informed consent; data were collected in real time from existing electronic databases, thereby reducing costs; and study procedures were streamlined, enabling randomisation of more than 900 patients from a single centre in six months at very low cost. A larger pragmatic RCT with a similar design is planned to answer the question of the risk of mortality with fresh‐ versus‐older blood [12]. These data will continue to address policy­decisions around the maximum

Chapter 46: Getting the Most Out of the Evidence for Transfusion Medicine

storage threshold that would optimise the bal­ ance between adequate supply and accepta­ ble risk.

­ vidence Base for Transfusion E Medicine So, how good is the evidence base for transfu­ sion medicine? As a first step, identification of all relevant RCTs in transfusion medicine is essential. The UK Blood Services’ Transfusion Evidence Library (www.transfusionevidencelibrary. com) is a comprehensive online database of systematic reviews and RCTs relevant to transfusion medicine (updated monthly). The Transfusion Evidence Library includes high‐ quality systematic reviews and RCTs from 1950 to the present, identified from compre­ hensive searches of MEDLINE and from extensive handsearching of transfusion‐ related conference proceedings. It also con­ tains a growing number of clinical commentaries on recent important research articles in transfusion, in which the findings of the research are discussed within the con­ text of other research, the difference the research could make to clinical practice is explained and any opportunities for further research are highlighted. Another excellent resource is the Cochrane Collaboration’s database of RCTs; the Cochrane Central Register of Controlled Trials (CENTRAL) (updated monthly) is a good starting point. This database uses sensitive literature search filters that aim to identify all  RCTs that have been catalogued on MEDLINE from 1966 and on the European medical bibliographic database EMBASE from 1980. Other online resources containing collections of high‐level evidence for clini­ cians include the TRIP Database, BMJ Clinical Evidence and PubMed’s Clinical Queries. Box  46.2 presents a list of suggested sources that can be searched to identify relevant reports of clinical trials and systematic reviews.

Evidence Base for Transfusion Medicine: Individual Examples

In the following section, we provide two examples of developments in the evidence base for the practice of transfusion medicine following a systematic review. The first is an updated review on platelet transfusions, the second is a systematic review on an alterna­ tive to transfusion: activated recombinant factor VII (rFVIIa). Platelets

An update of previous Cochrane systematic reviews on the use of platelet transfusions has been recently published [13]. The aim was to determine whether a therapeutic‐only platelet transfusion policy (platelet transfusions given to treat bleeding) was as effective and safe as a prophylactic platelet transfusion p ­ olicy (plate­ let transfusions given to prevent bleeding usu­ ally when the platelet count falls below a given trigger level) in patients with haematological disorders undergoing myelosuppressive chem­ otherapy or haemopoietic stem cell transplan­ tation (HSCT). An important point illustrated by this review is that it represents an update of previous systematic reviews [14–16]. It there­ fore illustrates the iterative process for new reviews to incorporate new trial evidence. These earlier reviews also addressed the follow­ ing questions. ●●

●●

●●

What is the appropriate threshold platelet count to trigger prophylactic platelet transfusions? What is the optimal dose for platelet transfusions? What is the evidence that a strategy of pro­ phylactic platelet transfusions is superior to the use of platelet transfusions only in the event of bleeding (therapeutic‐only use)?

In total seven RCTs met the predefined selec­ tion criteria (one of which is still ongoing), leaving a total of six trials eligible for the review and a total of 1195 participants. These trials were carried out over a 35‐year period. For the

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systematic review’s primary outcome (number of patients with at least one bleeding episode within 30 days), significant heterogeneity was noted (I2 = 88%). This heterogeneity may in part reflect the different methodology and grading systems used to analyse and categorise bleeding in the individual studies. Four studies in the review reported clinically significant bleeding events and all showed a similar effect: higher rates of bleeding in participants receiving a therapeutic‐only platelet transfusion strategy. But major differences were noted between the four studies, including indications for platelet transfusion, red cell transfusion policy and study end points, as well as classification of bleeding events. A meta‐analysis could not be performed with the data from these four studies. The conclusions of the systematic review were that overall prophylactic platelet trans­ fusions appeared to reduce the number of bleeding events and the number of days with clinically significant bleeding, therefore sup­ porting the continued use of prophylactic platelet transfusions [13]. The studies in the review showed that major bleeding events did occur despite prophylactic platelet trans­ fusions at platelet counts greater than 10 × 109/L. The limitation of the review to combine studies in a meaningful way raises important concerns about the reporting of bleeding outcomes, and the need for consist­ ency in platelet transfusion trials. This was also a key message in a Cochrane review of platelet pathogen inactivation [17].

haemophilia [18]. This literature provides a more robust means of assessing the effective­ ness and safety of rFVIIa, and formed the basis of a recent updated Cochrane review. When combined in meta‐analysis, the trials showed modest reductions in total blood loss or red cell transfusion requirements (equivalent to less than one unit of red cell transfusion). However, the reductions were likely to be overestimated due to the limitations of the data. For other end points, including clinically relevant outcomes, there were no consistent indications of benefit and almost all the findings in support of and against the effectiveness of recombinant factor VIIa could be due to chance. The one, and important, exception was thromboembolic events. In both groups of trials, there was an overall trend to increased thromboembolic events in patients receiving rFVIIa. The forest plot for total arterial thromboembolic events is shown in Figure  46.3 and reaches statistical significance. Common Practices of Transfusion and Interventions to Improve Transfusion Practice

Systematic reviews may also be applied to important questions about the evidence base for common or well‐established practices in transfusion [19–21]. For example, reviews based on observational, nonrandomised studies have addressed the following question. ●●

Alternatives to Transfusion

Many patients without haemophilia have now been treated, off‐licence, with activated recom­ binant factor VII (rFVIIa). The patient settings are very diverse, including surgery (especially cardiac), gastrointestinal bleeding, liver dys­ function, intracranial haemorrhage and trauma, for example. Data from 25 RCTs enrolling around 3500 patients have now evaluated the use of rFVIIa as both prophylaxis to prevent bleeding (14 trials) or therapeutically to treat major bleeding (11 trials), in patients without

●●

●●

What is the maximum time that one unit of red cells can be out of the fridge before it becomes unsafe? [19] How often should blood administration sets be changed while a patient is being trans­ fused? [20] Which blood transfusion administration method – one‐person or two‐person checks – is safest? [21]

It is surprising and salutary to realise that some of these common recommendations appear to have little firm evidence base, yet are commonly reproduced in guidelines and protocols.

Chapter 46: Getting the Most Out of the Evidence for Transfusion Medicine Control rFVIIa Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95%Cl Planinsic 2005 Friederich 2003 Bosch 2004 Boffard 2005a Boffard 2005b Chuansumrit 2005 Diprose 2005 Lodge 2005a Mayer 2005a Mayer 2005b Pihusch 2005 Raobaikady 2005 Ekert 2006 Ma 2006 Mayer 2006 Shao 2006 Johansson 2007 Pugliese 2007 Sachs 2007 Bosch 2008 Mayer 2008 Narayan 2008 Gill 2009 Hauser 2010a Hauser 2010b

6 1 2 1 2 0 2 2 16 4 5 0 0 0 4 1 0 0 8 3 39 6 4 16 2

64 24 121 69 70 16 10 132 303 36 77 24 40 11 32 151 9 10 36 176 558 61 104 224 46

2 0 0 0 1 0 2 0 0 0 0 0 0 0 3 0 0 0 2 0 11 4 1 11 1

Risk Ratio M-H, Random, 95%Cl

19 5.3% 0.89 [0.20, 4.06] 1.2% 12 1.56 [0.07, 35.67] 1.3% 5.00 [0.24, 103.07] 121 1.2% 3.21 [0.13, 77.60] 74 1.83 [0.17, 19.69] 64 2.1% Not estimable 9 10 3.9% 1.00 [0.17, 5.77] 2.59 [0.13, 53.28] 68 1.3% 96 1.5% 10.53 [0.64, 173.88] 2.92 [0.17, 50.37] 11 1.5% 3.38 [0.19, 59.02] 23 1.5% Not estimable 24 Not estimable 36 Not estimable 11 7.4% 0.33 [0.09, 1.20] 8 1.2% 1.62 [0.07, 39.28] 81 Not estimable 9 Not estimable 10 1.44 [035, 5.94] 13 6.0% 1.4% 3.56 [0.19, 68.16] 89 1.67 [0.87, 3.21] 263 28.3% 0.89 [0.27, 2.93] 36 8.4% 2.62 [0.30, 22.90] 68 2.6% 1.62 [0.77, 3.42] 250 21.7% 1.74 [0.16, 18.47] 40 2.2%

2404 1445 100.0% 1.45 [1.02, 2.05] Total (95% cl) Total events 124 38 Heterogeneity: Tau2 = 0.00; Chi2 = 11.34, df = 18 (P = 0.88); l2 = 0% 0.01 0.1 1 10 100 Test for overall effect: Z = 2.10 (P = 0.04) Favours rFVlla Favours control

Figure 46.3  The forest plot for total arterial thromboembolic events.

­ re There Limitations to A Evidence‐Based Practice? It is important to acknowledge some of the limita­ tions of EBM that have been discussed by critics and supporters alike. EBM alone cannot provide a clinical decision; instead, the findings generated from EBM are one strand of input driving deci­ sion making in clinical practice. Each clinician will also need to consider the available resources and oppor­tunities, the values and needs (physical, psychological and social) of the patient, the local clinical expertise and the costs of the intervention. Patients enrolled in clinical trials are not always the same as the individual patients requiring treatment, and generalising to d ­ ifferent clinical settings may not be appropriate. It has also been said that, within EBM, there is an overemphasis

on methodology at the expense of clinical rele­ vance, with the risks of generating conclusions that are either overly pessimistic or inappropriate for the clinical question. Perhaps we need to get away from the mentality that ‘there is no good RCT evidence available to answer this clinical question’ to thinking more about why this should be so, what can be learned from those studies that have already been completed and what design of trial would answer the main area of uncertainty in this transfusion setting.

­Conclusion This chapter has attempted to explain why it is essential to assess the quality of primary clinical research and consider the risks of evidence being

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Part VII: Development of the Evidence Base for Transfusion

misleading, for example in the case of few trials or a failure to identify appropriate clinical research questions. Systematic reviews and the statistical method of meta‐analysis are useful tools to achieve this, but, like trials themselves, can become out­ dated and must be carefully scrutinised to ensure unbiased results. Transfusion medicine is no different from many other branches of medicine, and the evidence base that informs much of the practice has not developed to the point that it can be universally applied with confidence. There is a need to recognise these uncertainties and to identify those transfusion issues that require high priority for clinical research. Appraising the evidence base for transfusion medicine is one part of improving practice; another is the effective dissemination of the evi­ dence to clinicians. For example, clinicians may not have the time to search and evaluate the evi­ dence themselves given the increasing numbers of publications and journals. As many of the sources are web based, access at any one moment may be easier but the skills of appraisal need to be regularly maintained.

There has been growing recognition that research, especially empirical research (based on observing what has happened), has been underu­ tilised in making healthcare decisions at all levels. This appears to be as true for transfusion medi­ cine as for other clinical areas. EBM is an approach to developing and improving skills to identify and apply research e­ vidence to clinical decisions. Even the most ardent proponents of EBM have never claimed it is a panacea, and there is recognition that it should amplify rather than replace clinical skills and knowledge, and be a driver for keeping healthcare practices up to date. Systematic reviews can help bring together relevant literature on a particular problem and assess its strengths, weaknesses and overall meaning. Such reviews can be used in different ways, including improving the precision of esti­ mates of effect, generating hypotheses, provid­ ing background to new primary research or informing policy. Progress is being made to ensure that most areas in transfusion medicine are being systematically reviewed and some of these have encouraged plans for new RCTs.

KEY POINTS ●●

●●

The process of EBM consists of question ­formulation, searching for literature, critically appraising studies (identifying strengths and weaknesses) and decisions around applicability to one’s patients. It is essential to assess the quality of primary clinical research and consider the risks of evidence being misleading, for example in the case of few trials or a failure to identify appropriate clinical research questions.

●●

●●

Systematic reviews of RCTs combine evidence most likely to provide valid (truthful) answers on particular questions of effectiveness, and form an important component to the evaluation of evidence‐based practice in transfusion medicine. There is a common perception that much of transfusion medicine practice is based on limited evidence, but this is changing and systematic reviews are an important tool to collate, analyse and update the evidence base.

References 1 Sackett DL, Strauss SE, Richardson WS,

Rosenberg W, Haynes RB. Evidence Based Medicine: How to Practice and Teach EBM, 2nd edn. Churchill Livingstone, Edinburgh, 2000.

2 The Streptomycin in Tuberculosis Trials

Committee, Streptomycin treatment of pulmonary tuberculosis. BMJ 1948;2(4582):769–82. 3 Moher D, Hopewell S, Schulz KF et al. CONSORT 2010 explanation and elaboration:

Chapter 46: Getting the Most Out of the Evidence for Transfusion Medicine

updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869. 4 Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332. 5 www.casp‐uk.net 6 Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, for the STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007;147(8):573–7. 7 Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, for the STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370(9596):1453–7. 8 Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses: the PRISMA Statement. PLoS Med 2009;6(7):e1000097. 9 Stroup DF, Berlin JA, Morton SC et al, for the MOOSE (Meta‐analysis of Observational Studies in Epidemiology) Group. Meta‐ analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000;283(15):2008–12. 10 Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knotterus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011;64(4):380–2. 11 Heddle NM, Cook RJ, Arnold DM et al. The effect of blood storage duration on in‐hospital mortality: a randomized controlled pilot feasibility trial. Transfusion 2012;52(6):1203–12. 12 Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion. Heddle NM, Cook RJ, Arnold DM, Liu Y, Barty R, Crowther MA et al. N Engl J Med 2016;375:1937–45.

13 Estcourt LJ, Wood EM, Stanworth S, Trivella

M, Doree C, Tinmouth A, Murphy MF. A therapeutic‐only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation. Cochrane Database Syst Rev 2015;9:CD010981. 14 Cid J, Lozano M. Lower or higher doses for prophylactic platelet transfusions: results of a meta‐analysis of randomized controlled trials. Transfusion 2007:47(3):464–70. 15 Estcourt L, Stanworth SJ, Hopewell S, Heddle N, Tinmouth A, Murphy MF. Prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation. Cochrane Database Syst Rev 2012;4:CD004269. 16 Tinmouth AT, Freedman J. Prophylactic platelet transfusions: which dose is the best dose? A review of the literature. Transfus Med Rev 2003;17(3):181–93. 17 Butler C, Doree C, Estcourt LJ et al. Pathogen‐ reduced platelets for the prevention of bleeding. Cochrane Database Syst Rev 2013;3:CD009072. 18 Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev 2012;3:CD005011. 19 Brunskill S, Thomas S, Whitmore E et al. What is the maximum time that a unit of red blood cells can be safely left out of controlled temperature storage? Transfus Med Rev 2012;26(3):209–23. 20 Blest A, Roberts M, Murdock J, Watson D, Brunskill S. How often should a red blood cell administration set be changed while a patient is being transfused? A commentary and review of the literature. Transfus Med Rev 2008;18(2):121–33. 21 Watson D, Murdock J, Doree C et al. Blood transfusion administration – 1 or 2 person checks, which is the safest method? Transfusion 2008;48(4):783–9.

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Further Reading Centre for Reviews and Dissemination. Systematic Reviews CRD’s guidance for undertaking reviews in healthcare. CRD, University of York, 2009. Available at: www. york.ac.uk/crd/(accessed 21 November 2016). Egger M, Davey Smith G, Altman DG. Systematic Reviews in Health Care. Meta‐analysis in Context, 2nd edn. BMJ Publishing Group, London, 2001. Greenhalgh T. How to Read a Paper: The Basics of Evidence Based Medicine, 5th edn. Wiley, Chichester, 2014. Guyatt GH, Rennie D. Users’ Guide to the Medical Literature: Essentials of Evidence‐ Based Clinical Practice. American Medical Association, Chicago, 2002. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions,

Version 5.1.0. Cochrane Collaboration, 2011. Available at: www.cochrane‐handbook.org (accessed 21 November 2016). Hyde CJ, Stanworth SJ & Murphy MF. Can you see the wood for the trees? Making sense of the forest plot. 1. Presentation of the data from the included studies. Transfusion 2008; 48(2): 218–220. Hyde CJ, Stanworth SJ, Murphy MF. Can you see the wood for the trees? Making sense of the forest plot. 2. Analysis of the combined results from the included studies. Transfusion 2008;48(4):580–3. The Equator Network. Enhancing the Quality and Transparency of Health Research. Available at: www.equator‐network.org/(accessed 21 November 2016).

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47

A Primer on Biostatistics Andrew W. Shih1 and Nancy M. Heddle2 1

Department of Pathology and Molecular Medicine, Transfusion Medicine Fellowship Program, McMaster University, Hamilton, Canada 2 Department of Medicine, McMaster University and Canadian Blood Services, Hamilton, Ontario, Canada

­Incidence and Prevalence There are several measures of disease frequency that are used in epidemiological and medical literature. Two commonly used terms are prevalence and incidence. In general, statistics pertaining to prevalence are geared towards the question ‘How many people have this disease at the moment or during a specific period?’ and incidence is related to the question ‘How many people newly acquire this disease?’ Incidence can be calculated as an incidence proportion (typically referred to as risk) or as an incidence rate (typically calculated from cohort studies with long‐term follow‐up). Definitions of these terms and their calculations are summarised in Figure 47.1.

­Statistics in Diagnostic Testing A perfect diagnostic test would always identify patients as positive if they have the disease and would always be negative in patients without a disease. Unfortunately, the perfect diagnostic test rarely occurs in medical practice. There is typically variation in valid test results for both

patients with and without a disease and, a certain degree of overlap between the two. To help clinicians using diagnostic tests for clinical management, statistics are used to describe the accuracy characteristics of the test, derived from a 2 × 2 table with the test results generally on the y‐axis (positive or negative) and disease/outcome (present or absent) generally on the x‐axis (Table  47.1). Disease status is typically categorised by a test termed the ‘gold standard’. Table 47.2 defines the characteristics that describe various aspects of a diagnostic test and their calculations. The terms most commonly used in the literature are sensitivity and specificity, where a test with a high sensitivity can be used to rule out disease if negative and a test with a high specificity can be used to rule in disease if positive. An example from the literature is demonstrated in Table 47.3. Statistics used in diagnostic testing can assist clinicians in determining the probability of disease after the results of diagnostic testing are received. The pretest probability of having disease is often the prevalence of the disease in the population, if there are no other factors to adjust the pretest probability. With knowledge of the pretest probability, the result of the diagnostic test and the likelihood ratio of that test (defined in Table 47.4), the post‐test

Practical Transfusion Medicine, Fifth Edition. Edited by Michael F. Murphy, David J. Roberts and Mark H. Yazer. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.

Observation Period January

February

March

April

May

June

July

August

September

Patient #1

Patient #2 Patient #3

Patient #4

Patient #5

Start of follow-up Time followed End of follow-up Development of disease (or event)

Measure

Formula

Example

Point prevalence

New and existing cases/total population(at a specific time point)

Point prevalence in July: 1 case/5 patients = 20%

Period prevalence New and existing cases/total population (in a specific period of time)

Period prevalence from January to September: 2 cases/5 patients = 40%

Incidence proportion

New cases within a time period/total population at risk within a time period

Incidence proportion from January to September: 2 case/5 patients = 40%

Incidence rate

New cases within a time period/total person-time of observation of those at risk

Incidence rate from January to September: 2 cases/(3 person-months + 7 + 8 + 3 + 4) = 2 cases/25 person-months

Figure 47.1  Measurements of disease/case frequency. Table 47.1  Example of a 2 × 2 table for diagnostic tests. Disease (often categorised by a test result considered the gold standard)

Test result

Present

Absent

Positive

A: True positives

B: False positives

Negative

C: False negatives

D: True negatives

Table 47.2  Statistical terms used for diagnostic testing. Descriptive statistic

Definition

Method of calculation

Sensitivity

The proportion of positives identified of those who have the disease. Tests with high sensitivity are commonly used for ruling out disease if negative (if the test is negative, the rate of false negatives is low)

True positive/(true positive + false negative) A/(A + C)

Specificity

The proportion of negatives identified of those who do not have the disease. Tests with high specificity are commonly used for ruling in disease if positive (if the test is positive, the rate of false positives is low)

True negative/(true negative + false positive) D/(B + D)

Positive predictive value

The probability that a positive test correctly identifies an individual who has the disease. This value is affected by the prevalence of the disease in the population

True positive/(true positive + false positive) A/(A + B)

Negative predictive value

The probability that a negative test correctly identifies an individual who does not have the disease. This value is affected by the prevalence of the disease in the population

True negative/(true negative + false negative) D/(C + D)

Positive likelihood ratio

The probability that the patient with disease tests positive divided by the probability that the patient without disease tests positive. The higher the positive likelihood ratio, the better the test when positive to rule in disease. Excellent positive likelihood ratios are usually >10

Sensitivity/ (1–specificity) True positives/false positives

Negative likelihood ratio

The probability that the patient with disease tests negative divided by the probability that the patient without disease tests negative. The lower the negative likelihood ratio, the better the test when negative to rule out disease. Excellent negative likelihood ratios are usually