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Transfusion Update

Transfusion Update Indian Society of Blood Transfusion and Immunohaematology (ISBTI)

Indian Society of Blood Transfusion and Immunohaematology (ISBTI)

Transfusion Update

Editor-in-Chief

Kanchan Bhardwaj

MD MAMS FIAC FIMSA

Professor and Head Department of Transfusion Medicine Government Medical College, Patiala, Punjab, India

Associate Editors

BL Bhardwaj

MD MAMS FCCP FIMSA FIACP FNCCP FGSI FIACM

Professor Department of Medicine Government Medical College Patiala, Punjab, India

Kusum K Thakur

MD PGDMCH PGDHHM MISBTI MIMA MAATM

Lecturer Department of Transfusion Medicine Government Medical College Patiala, Punjab, India Secretary, ISBTI (Punjab Chapter)

Rajni Bassi

MD MISBTI MIMA

Lecturer Department of Transfusion Medicine Government Medical College Patiala, Punjab, India

Assistant Editor

Harnoor Singh Bhardwaj MBBS

Junior Resident Government Medical College Patiala, Punjab, India

Forewords

KK Talwar TR Raina Neelam Marwaha

An ISBTI Publication

KK Talwar TR Raina Neelam Marwaha An ISBTI Publication The Health Sciences Publisher New Delhi |

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Transfusion Update

First Edition: 2015

ISBN: 978-93-5152-598-1

Printed at

Dedicated to

My loving parents Mrs Surjit Saini and Er BK Saini and my teachers

Contributors

A Surekha Devi MD

Consultant and Head Department of Transfusion Medicine Global Hospitals Hyderabad, Andhra Pradesh, India surekhadevi@gmail.com

Aastha Miranpuri MD

Rochester, New York, USA aasthamiranpuri@gmail.com

Achhar Singh MD

Assistant Professor Department of Pulmonary Medicine Gian Sagar Medical College Banur, Patiala, Punjab, India kusum_gmcbb@yahoo.com

Ajata Shatru Kapoor

Assistant Professor

Department of General Surgery

MM Institute of Medical Sciences and

Research, Ambala, Haryana, India kapoorajatashatru@yahoo.com

Ajay Bahl MD DM

Consultant

Department of Cardiology Postgraduate Institute of Medical Education

and Research (PGIMER)

Chandigarh, India drajaybahl@hotmail.com

Ajit C Gorakshakar PhD

Scientist E (Deputy Director) National Institute of Immunohematology Indian Council of Medical Research KEM Hospital Campus, Parel Mumbai, Maharashtra, India

ajit5678@yahoo.com

Alpna Thakur MD

Assistant Professor Department of Dermatology Hind Institute of Medical Sciences Lucknow, Uttar Pradesh, India

alpna.30@gmail.com

Amit Aggarwal MD

Consultant Fortis Escorts Heart Institute

New Delhi, India

agrawalamit@gmail.com

MS MCh (Plastic Surgery)

Anupam Sachdeva MD

Director Pediatric Hematology-Oncology and Bone Marrow Transplantation Institute for Child Health Sir Ganga Ram Hospital, New Delhi, India anupamace@yahoo.co.in

Anupam Verma MD PDCC

Additional Professor Department of Transfusion Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) Lucknow, Uttar Pradesh, India aver2211@gmail.com aver@sgpgi.ac.in

Aradhna Sharma MD

Medical Officer Department of Transfusion Medicine Government Medical College Patiala, Punjab, India

asharma130798@gmail.com

Arun Bansal

Neurosurgeon Amar Hospital Patiala, Punjab, India drarunneuro@gmail.com

MS MCh (Neurosurgery)

Arvind Chahal MBBS

Junior Resident Department of Medicine Pt BD Sharma Postgraduate Institute of Medical Sciences Rohtak, Haryana, India med.pgims@hry.nic.in

Aseem K Tiwari MD

Associate Director Department of Transfusion Medicine Medanta: The Medicity Hospital Gurgaon, Haryana, India aseem.tiwari@medanta.org

Ashish Jain MD

Assistant Professor Department of Transfusion Medicine Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India

ashishjain16@gmail.com

Ashok Sharma MD

Professor and Head Department of Medicine Indra Gandhi Medical College Shimla, Himachal Pradesh, India drashoksharmamd@me.com

Bharat Singh MD

Consultant Pathologist and Head Regional Blood Transfusion Centre Guru Teg Bahadur Hospital and University College of Medical Sciences New Delhi, India bsdirsbtc@yahoo.co.in

Bimal Kumar Agrawal MD

Professor and Head Department of Medicine

MM Institute of Medical Sciences

and Research

Ambala, Haryana, India

bkagrawal2001@yahoo.com

BK Rana PhD

Joint Director

National Accreditation Board for Hospitals and Healthcare Providers (NABH) Quality Council of India

New Delhi, India

bkrana@nabh.co

BL Bhardwaj

MD MAMS FCCP FIMSA FIACP FNCCP FGSI FIACM

Professor Department of Medicine Government Medical College Patiala, Punjab, India bachan_bhardwaj@yahoo.co.in

Devinder Singh Sandhu

MD (Medicine) DM (Medical Oncology)

Consultant Oncologist and Hematologist Sandhu Cancer Center Ludhiana, Punjab, India drsandhu@sandhucancercentre.com

Dharam Paul MS

Civil Surgeon (Retd)

Khanna, Punjab, India partola@rediffmail.com

Dinesh Ahluwalia MD

Director Dinesh Path Lab Patiala, Punjab, India drdineshahluwalia@gmail.com

DP Singh MS ISS (Cleveland) FICLS

Professor (Surgery) Government Medical College Patiala, Punjab, India

dpsingh.7@gmail.com

Gagandeep Kaur MD

Assistant Professor Department of Transfusion Medicine Government Medical College and Hospital Chandigarh, India

kaurgagandeep2701@gmail.com

Hamed Bashir MD DM

Consultant Cardiology

Max Healthcare Institute

Saket, New Delhi, India

viii

Transfusion Update

Hari Krishan Dhawan MD

Assistant Professor Department of Transfusion Medicine Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India hkdpgimer@gmail.com

Harnoor Singh Bhardwaj MBBS

Junior Resident Government Medical College Patiala, Punjab, India harnoorbhardwaj@yahoo.co.in

Harprit Singh MD

National Programme Officer DBTS, Directorate of AIDS Control New Delhi, India

harprit_1@hotmail.com

Hemchandra Pandey MD

Additional Professor Department of Transfusion Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) Lucknow, Uttar Pradesh, India

Hitish Narang MD

Senior Consultant Transfusion Medicine Satguru Pratap Singh (SPS) Apollo Hospital Ludhiana, Punjab, India hitishnarang@gmail.com

HS Sandhu MD

Professor and Head Department of Medicine Government Medical College Patiala, Punjab, India harendrasandhu@yahoo.co.in

Ishwar Chouhan MBBS

Junior Resident Department of Medicine Government Medical College Patiala, Punjab, India

i.chouhan05@gmail.com

Jitendra Kumar Pehalajani MBBS

Junior Resident Department of Medicine Pt BD Sharma Postgraduate Institute of Medical Sciences Rohtak, Haryana, India jitnanhe@gmail.com

Kanchan Bhardwaj

MD MAMS FIAC FIMSA MISBTI MIAPM MISHTM MIMA

Professor and Head Department of Transfusion Medicine Government Medical College Patiala, Punjab, India drkanchan_bhardwaj@yahoo.com

KK Talwar

MD DM FAMS FNA FACC FIMSA FIACS (Canada) DSc (hc)

Advisor Government of Punjab Health and Medical Education Member Punjab Governance Reforms Commission

Former Chairman Board of Governors Medical Council of India Former President National Academy of Medical Sciences Former Director Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Former Professor and Head Department of Cardiology All India Institute of Medical Sciences (AIIMS) New Delhi, India kktalwar@hotmail.com

Kshitija Mittal MD

Department of Transfusion Medicine Government Medical College and Hospital Chandigarh, India drkmittal@gmail.com

Kulbir Kaur MD

Director Principal Professor (Pathology and Transfusion Medicine) Punjab Institute of Medical Sciences Jalandhar, Punjab, India drkulbirkaur@yahoo.co.in

Kunal R Patel

Consultant MAX Hospital Mohali, Chandigarh, India drkunalpatel@gmail.com

Kusum K Thakur

MD PGDMCH PGDHHM MISBTI MIMA MAATM

Lecturer Department of Transfusion Medicine Government Medical College Patiala, Punjab, India Secretary Indian Society of Blood Transfusion and Immunohaematology (ISBTI) (Punjab Chapter) kusum_gmcbb@yahoo.com

M Joseph John MD DM

Associate Professor Clinical Haematology, Haemato-oncology and Bone Marrow (Stem Cell) Transplant Unit Christian Medical College Ludhiana, Punjab, India mjosephjohn@gmail.com

M Joshua Daniel Jeyakumar MD

Associate Professor and Technical Expert CDC-CMA1 NACO AMS Project Vinayaka Missions Medical College and AMP Hospital Salem, Tamil Nadu, India drjoshuadaniel@gmail.com drjoshuadaniel@yahoo.com

Manisha Shrivastava MD

Associate Professor and Head Department of Transfusion Medicine Bhopal Memorial Hospital and Research Centre Bhopal, Madhya Pradesh, India manishasdr@gmail.com

DNB (Orth) D Orth

Manjit Kaur Mohi MD FICOG FIMSA

Professor and Head Department of Obstetrics and Gynaecology Government Medical College Patiala, Punjab, India manjitmohi@yahoo.co.in

Manoj A Kahar MD PhD (Pursuing)

Blood Bank Department of Pathology Government Medical College Surat, Gujarat, India manoj_kahar@yahoo.com

Manuj Wadhwa MS MCh Ortho (UK)

Ranawat Joint Replacement Fellow (USA) Director and Head

Max

Elite Institute of Orthopaedics

and

Joint Replacement

Mohali, Chandigarh, India manuj.wadhwa@gmail.com

Meenu Bajpai MD

Associate Professor

Transfusion Medicine Institute of Liver and Biliary Sciences

New Delhi, India

meenubajpai@hotmail.com

meenubajpaii@gmail.com

Mina Sidhu MD

Assistant Professor Department of Transfusion Medicine Government Medical College Jammu and Kashmir, India minathapa@gmail.com

Mini Bhatnagar Sud MD

Associate Professor

Department of Medicine

MM Institute of Medical Sciences and

Research, Ambala, Punjab, India

Mohanvir Kaur MD

Assistant Professor Department of Pathology Government Medical College Patiala, Punjab, India mohanvirkaur@gmail.com

Neelam Marwaha MD FAMS FISHTM

Professor and Head

Department of Transfusion Medicine Postgraduate Institute of Medical Education

and Research, Chandigarh, India

neelam2918@yahoo.com

Nidhi Bhatnagar MD

Lead Assessor (NABH Blood Banks) Associate Professor Department of Transfusion Medicine BJ Medical College Ahmedabad, Gujarat, India bhatnagarnidhi@ymail.com

Nidhi Mehta MD

(Secretary-Indian chapter–AATM) Consultant Transfusion Medicine Kokilaben Dhirubhai Ambani Hospital Mumbai, Maharashtra, India drnidhimehta@yahoo.co.in

Contributors

ix

P Arumugam MD

Professor and Head Department of Transfusion Medicine The Tamil Nadu Dr MGR Medical University Chennai, Tamil Nadu, India pothiarumugam@gmail.com

Pankaj Malhotra MD MAMS FICP MACP

Additional Professor (Clinical Hematology) Department of Internal Medicine Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India malhotrapankaj@hotmail.com

Paramjit Dhot

MD Post Doc Haematology AIIMS, FRSH (London), MCHS (Toronto), FISHTM

New Delhi

pamidhot@gmail.com

Paramjit Kaur MD

Assistant Professor Department of Transfusion Medicine Government Medical College and Hospital Chandigarh, India

paramjit.gp71@yahoo.com

Parveen Mittal MD

Professor Department of Pediatrics Government Medical College Patiala, Punjab, India doc_parveen@yahoo.co.in

Poonam Singal MD

Pathologist Mata Kaushalya Hospital Patiala, Punjab, India

bansalrajesh1@gmail.com

Prashant Agarwal

MD (Transfusion Medicine)

PDCC (Apheresis and Component Therapy)

Additional Professor Department of Transfusion Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) Lucknow, Uttar Pradesh, India prashantsgpgi@gmail.com

Prasun Bhattacharya MD

Assistant Professor Department of Immunohaematology and Blood Transfusion Medical College Hospital Kolkata, West Bengal, India Visiting Consultant and Head of Department BM Birla Heart Research Centre Kolkata, West Bengal, India pbhattach@gmail.com

Prathiba L Pujjita MBBS

Junior Resident Vinayaka Missions Medical College and AMP Hospital Salem, Tamil Nadu, India datlapoojith@gmail.com

Praveen C Sobti MD

Professor Department of Pediatrics Dayanand Medical College Ludhiana, Punjab, India parveen_c_sobti@yahoo.co.in

Preeti Dewakar MD

Assistant Professor Department of Pathology University College of Medical Sciences New Delhi, India

Priyadarshi Ranjan

MS ( Surgery) MCh (Urology) PGI Chandigarh

Consultant Endourologist, Laparoscopic and Kidney Transplant Surgeon Chief, Division of Kidney Transplant Surgery Surgical Director, Incompatible Blood Type Kidney Transplant Fortis Hospital Mohali, Chandigarh, India priydarshiranjanurologist@gmail.com

PS Ghalaut MD

Senior Professor and Head Department of Medicine and Clinical Hematology Pt BD Sharma Postgraduate Institute of Medical Sciences (PGIMS) Rohtak, Haryana, India med.pgims@hry.nic.in

R Krishnamoorthy MD

Associate Professor Department of Transfusion Medicine Sri Ramachandra Medical College and Hospitals Chennai, Tamil Nadu, India

rrkm29@yahoo.co.in

Rajendra K Chaudhary MD DNB

Professor and Head Department of Transfusion Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) Lucknow, Uttar Pradesh, India rkcchaud@sgpgi.ac.in

Rajesh B Sawant MD

Consultant Department of Transfusion Medicine Hinduja Hospital Mumbai, Maharashtra, India

sawantrb72@rediffmail.com

Rajesh C Gopal MD

Former Technical Programme Manager Gujarat State AIDS Control Society Ahmedabad, Gujarat, India dr_rajeshg@yahoo.com

Rajesh Kumar MD

Associate Professor Department of Transfusion Medicine Dayanand Medical College Ludhiana, Punjab, India parul_pulkit@yahoo.co.in

Rajesh Rajput

MD DM (Endocrinology) FICP FIACM FIMSA

Senior Professor and Head Department of Endocrinology Postgraduate Institute of Medical Sciences Rohtak, Haryana, India drrajeshrajput@outlook.com

Rajni Bassi MD MISBTI MIMA

Lecturer Department of Transfusion Medicine Government Medical College Patiala, Punjab, India rajniajata@yahoo.com

Ravi Dara MD

Senior Resident Medanta: The Medicity Hospital Gurgaon, Haryana, India rcdara@gmail.com

Ravisha Bhardwaj MBBS

Junior Resident Department of Orthopedics Government Medical College Amritsar, Punjab, India ravi_misha@yahoo.com

Ravneet Kaur MD

Professor and Head Department of Transfusion Medicine Government Medical College and Hospital Chandigarh, India

rkbedi15@yahoo.com

Reena Das MD DNB

Professor Department of Hematology Postgraduate Institute of Medical Education and Research Chandigarh, India reenadaspgi@hotmail.com

Rekha Hans MD

Assistant Professor Department of Transfusion Medicine Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India drhansrekha@gmail.com

Rimpreet Singh Walia DNB

Consultant and Incharge Life Line Blood Centre Patiala, Punjab, India rimpreet@yahoo.com

RR Sharma MD

Additional Professor Department of Transfusion Medicine Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India rrsdoc@hotmail.com

RS Boparai MS

Professor Department of Orthopedics Government Medical College Amritsar, Punjab, India

x

Transfusion Update

Sandeep Kundra MD PDCC (Neuro-anesthesia, SGPGI, Lucknow)

Associate Professor Department of Anesthesia Dayanand Medical College and Hospital Ludhiana, Punjab, India

sandeepkundra07@gmail.com

Sandeep Puri MD

Professor and Head Department of Medicine Dayanand Medical College and Hospital Ludhiana, Punjab, India drsandeeppuri@yahoo.com

Sangeeta Pathak MD

Senior Consultant and Head-Blood Bank Max Super Speciality Hospital New Delhi, India sangeeta.pathak@maxhealthcare.com

Shanoo Mishra PhD

Programme Officer (QC) Directorate of AIDS Control New Delhi, India poqc.naco@gmail.com

Sharad Jain MD

Associate Professor (Pathology) Netaji Subhash Chandra Bose Medical College and Hospital Jabalpur, Madhya Pradesh and Deputy Registrar MP Medical Science University Jabalpur, Madhya Pradesh, India sharadjain@gmail.com

Sheetal Malhotra MD

Assistant Professor Department of Transfusion Medicine Gian Sagar Medical College Patiala, Punjab, India

sheetalpgi2007@yahoo.com

Shobini Rajan MD

Assistant Director General National AIDS Control Organization Ministry of Health and Family Welfare Director National Blood Transfusion Council New Delhi, India shobininaco@gmail.com

shobininaco1@gmail.com

Shruti Kakkar MD

Fellowship in Comprehensive Hemato-oncology Assistant Professor Department of Pediatrics Dayanand Medical College and Hospital Ludhiana, Punjab, India drahujashruti@gmail.com

Sudhir Varma

MD DM Cardiology

Director and Principal Investigator Sadbhavna Medical and Heart Institute Patiala, Punjab, India drsudhirvarma@gmail.com

Sunil D Khaparde MD PhD

Dengue Deputy Director General DBTS Director of AIDS Control New Delhi, India sdkhaparde.naco@gmail.com

Sunil K Arora MD

Professor Department of Immunopathology Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India arora.sunil@pgimer.edu.in

Suryatapa Saha

Junior Resident Vinayaka Missions Medical College and AMP Hospital Salem, Tamil Nadu, India

Swati Kulkarni PhD

Scientist C National Institute of Immunohaematology (ICMR) KEM Hospital Campus Mumbai, Maharashtra, India swatiskulkarni@gmail.com

Tanvi Sood

Demonstrator Pathology Government Medical College and Hospital (GMCH) Chandigarh, India

Tarangini D MD

Department of Pediatrics Institute For Child Health Sir Ganga Ram Hospital Recipient Dr BC Roy Award Recipient Silver Jubilee Research Award New Delhi, India

Tulika Chandra MD

Associate Professor and Head Department of Transfusion Medicine King George Medical University Lucknow, Uttar Pradesh, India drtulikachandra@gmail.com

Umesh Sharma MS MCH

Consultant Hair Transplant Laser and Cosmetic—Plastic Surgeon Paras Hospital Haryana, India

drumesh02@gmail.com

Varun Sharma MS

Senior Resident Department of Kidney Transplantation and Urology Fortis Hospital Mohali, Punjab, India

Vimarsh Raina MD

Director Lab and Transfusion Services Medanta: The Medicity Hopsital Gurgaon, Haryana, India rainavimarsh@gmail.com

Yazdi Italia PhD

Ex-Hon Director Sickle Cell Anemia Control Program A Go-NGO Partnership Program Department of Health and Family Welfare Government of Gujarat Hon. Secretary Valsad Raktdan Kendra Valsad, Gujarat, India italialabvalsad@gmail.com

Advisor

Government of Punjab Health and Medical Education Member, Punjab Governance Reforms Commission

Education Member, Punjab Governance Reforms Commission Former Chairman , Board of Governors Medical Council of

Former Chairman, Board of Governors Medical Council of India Former President National Academy of Medical Sciences Former Director, PGIMER, Chandigarh Former Professor and Head Dept. of Cardiology, AIIMS, New Delhi

Foreword

Dr KK Talwar MD DM FAMS FNA FACC FlMSA FIACS (Canada) DSc (hc)

It is a great pleasure to write a foreword for Transfusion Update. This is a result of the concentrated efforts of the authors and the editorial team in bringing out a book containing the latest practices in transfusion medicine. While covering a majority of the important and challenging topics in the field of transfusion, the authors and editors have made sincere efforts to bring forth the practical points concerning patient care from the transfusion medicine. The challenging problems seen in the practice of transfusion medicine are dealt with in a simplified manner. Transfusion Update is indispensable for transfusion medicine specialists and clinicians. I am sure that postgraduate students will also find this book containing 81 chapters with pearls of immense value. The book is having four sections consisting of clinical hemotherapy, cellular therapies, blood safety with pathogen reduction technology and miscellaneous. To sum-up, the book is a practical and reference manual for clinicians on issues related to transfusion medicine. As this transfusion medicine update is being released on the occasion of the 39th Annual National Conference of the Indian Society of Blood Transfusion and Immunohaematology (ISBTI) scheduled to be held at Government Medical College, Patiala, Punjab, India, I congratulate Dr Kanchan Bhardwaj, Editor-in-Chief, for taking great pains in bringing out this volume of over 300 pages for the benefit of dedicated and busy clinicians of our country. I hope the TRANSCON 2014 and the book will add to everyone’s knowledge and help everyone to face the challenges of transfusion practice in the years ahead. Dr BL Bhardwaj, Dr Kusum K Thakur and Dr Rajni Bassi deserve special congratulations for successfully completing this important project.

for successfully completing this important project. (KK Talwar) Punjab Governance Reforms Commission, Academic
for successfully completing this important project. (KK Talwar) Punjab Governance Reforms Commission, Academic

(KK Talwar)

Punjab Governance Reforms Commission, Academic Block, Mahatma Gandhi State

Institute of Public Administrations, Institutional Area, Sector-26, Chandigarh 160019

E-mail: kktalwar@hotmail.com

Fax: 91-172-2795121

Foreword

It gives me immense pleasure in writing the foreword for Transfusion Update. At the outset, I congratulate Dr Kanchan Bhardwaj, a simple, dynamic and competent academician who took this tedious challenging job and came out with the book within short period of time which was the need of the hour. Publication of the book is unique in itself because it is for the first time in the history of ISBTI for more than forty years of its inception that a publication of ISBTI in the form of the book has been launched and the credit for this goes to Dr Kanchan Bhardwaj. Blood transfusion services play a vital role in the modern health care system of both developed and developing countries. Importance of transfusion medicine as a branch of medical science can never be undermined and is now considered as an applied para-clinical discipline which demands a significant extent of academic knowledge. In a vastly populated developing country like ours, blood transfusion services remain relatively inadequate, both in quantity and quality of service. In this era of technology, although there is a lot of advancement in the medical field; but, unfortunately, the field of blood transfusion has not kept pace with these advancements. To improve blood transfusion services in our country, there is a genuine need of good textbooks and the endeavor undertaken by Dr Kanchan Bhardwaj is a step towards this side. The book contains all the relevant chapters including more recent topics on Cellular Therapies including Cord Blood Banking and Transplantation which shall be beneficial for all those engaged in the field of transfusion medicine.

for all those engaged in the field of transfusion medicine. TR Raina MD (Path) Former Professor

TR Raina

MD (Path)

Former Professor and Head Department of Transfusion Medicine Government Medical College Jammu, Jammu and Kashmir Secretary General Indian Society of Blood Transfusion and Immunohaematology (ISBTI) Panchkula, Haryana, India

Foreword

Transfusion medicine is a continually involving field. It has a wide spectrum of activities involving the community for purposes of donor motivation, recruitment and retention, complex laboratory technologies for blood component preparation and blood testing, regulatory aspects of blood transfusion services and most importantly clinical transfusion practices, monoclonal antibodies for therapeutics and cellular therapies. Transfusion Update being released on the occasion of TRANSCON 2014 has been diligently compiled by the Organizing Committee, under the initiative of Dr Kanchan Bhardwaj, Organizing Secretary of the Conference. The contents fit in well with the theme—Optimizing Transfusion Therapy. Best practices, recent advances and challenges in clinical transfusion in the fields of medicine, surgery, oncology, obstetrics and neonatology have been included in the scientific program. Articles on scope of apheresis technology, special transfusion support in hemoglobin disorders and hemophilia have also been contributed by experts. A major section has been devoted to cellular therapies—the most challenging and controversial areas in regenerative medicine. The role of platelets as growth and repair promoters, current status of gene therapy, blood grouping and cord blood transplantation have also been included in the contents. The section on blood safety brings into focus the regulatory, ethical and legal issues in transfusion medicine. It also highlights the hazards of blood transfusion–hemovigilance and its reporting mechanism in the country. State-of-the-art technology, platforms for immunohematology, transfusion transmitted viral infections and bacterial contamination of blood components have also been contributed by the experts. The contents also included quality assurance principles and practices in transfusion services. All the contributors deserve appreciation for the efforts, they have made in preparing manuscripts and I wish to put on record my sincere praise and appreciation for the Organizing Committee for compiling updated scientific knowledge in the field of transfusion medicine. Transfusion Update would definitely benefit all the readers and help in improving transfusion practices.

all the readers and help in improving transfusion practices. Neelam Marwaha MD FAMS FISHTM Head Department

Neelam Marwaha MD FAMS FISHTM

Head Department of Transfusion Medicine Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India

Preface

The medical science is changing so fast that it becomes essential for transfusion medicine to keep a pace with the changes. The

transfusion therapy is the backbone of clinical practice and its outcome is a measure of patient care. The objective of this book is to raise the level of our expertise in transfusion technology to latest international standards of safe blood transfusion and to keep abreast with the latest innovations in the field of blood transfusion.

It is a pleasure to present Tranfusion Update to our worthy fellow transfusion specialists, and clinicians across the country.

The challenging problems seen in practice of transfusion medicine are dealt with in a crystal clear manner. The book will be an

indispensible tool in the transfusion medicine specialist and clinician’s kit. I am sure the postgraduates will also find this book containing 81 chapters with particular focus on transfusion therapy very useful. The topics covered under Clinical Hemotherapy are Transfusion Practice in Clinical Medicine, Transfusion in Surgical Practice, Maternal, Fetal and Neonatal Transfusion Practice; Massive Transfusion; Platelet Therapy, Transfusion Practice in Chronically Transfused Patients, Apheresis, Intervention in Bleeding Patients and Transfusion Practice in Oncology. The section on Cellular Therapies has Stem Cell Therapy in Cardiovascular Diseases, Peripheral Artery Disease, Diabetes Mellitus, etc. Blood Safety has NAT, Pathogen reduction technology, leucoreduction, etc. and Miscellaneous has Evidence-based Transfusion Medicine, Blood Bank Accreditation, Molecular Genotyping and its Applications in Transfusion Practice, Rare Blood Group Registry, etc. Details of latest topics will stimulate teachers of transfusion medicine and clinical specialists to do more research in these fields. The book is being released on the occasion of the 39th Annual Conference of Indian Society of Blood Transfusion and Immunohaematology (ISBTI) being held at Government Medical College, Patiala, Punjab, India. I am sure that Transfusion Update will add to everyone’s knowledge and armamentarium to face the challenges of transfusion practice in the years ahead.

I hope the readers will find the book useful for updating their knowledge regarding transfusion practice eventually benefitting their patients.

Kanchan Bhardwaj MD MAMS FIAC FIMSA

Professor and Head Department of Transfusion Medicine Government Medical College Patiala, Punjab, India

Acknowledgments

For the first time in history of Indian Society of Blood Transfusion and Immunohaematology (ISBTI) that scientific lectures

have been compiled in the form of Transfusion Update which will be very useful for postgraduate students and teachers of transfusion medicine, and all clinical specialties during their day-to-day practice. The idea was proposed in governing body meeting of ISBTI at Patiala, Punjab, India, and was appreciated by all present especially Dr Sangeeta Pathak, Treasurer, Indian Society of Blood Transfusion and Immunohaematology (ISBTI), Dr Ravneet Kaur, Editor, Asian Journal of Transfusion Science (AJTS) and Professor and Head, Department of Transfusion Medicine, Government Medical College and Hospital, Chandigarh, India and Shri M Satish, Vice President-Technical, ISBTI. The first and the foremost heartfelt thanks to Dr Yudhbir Singh, National President, ISBTI, whose positive attitude has made this venture a reality. I want to sincerely thank Dr KK Talwar, Advisor to Government of Punjab whose encouraging words has gone a long way in pursuing this venture. I convey my special thanks to Dr TR Raina, Secretary General, ISBTI, who has encouraged me to accomplish this task. I should not forget to pay my gratitude to Dr Neelam Marwaha, Professor and Head, Department of Transfusion Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, for her consistent guidance. Without consistent perseverance of Dr BL Bhardwaj, this uphill task was not possible.

I express my gratitude and thanks to Dr KD Singh, Principal, Government Medical College, Patiala, Punjab, India, for

his kind and expert guidance. I am also thankful to all the clinicians of my institute, who have expressed the need for some

written guidelines about blood transfusion, which can be helpful in their day-to-day clinical practice and can guide the junior residents about how best to utilize the Blood Transfusion Services (BTS) for safety of patients. I convey my special thanks to DrHSSandhu(Medicine);DrVKSharda(Surgery);DrSurinderSingh(Surgery),FormerPrincipal,GovernmentMedicalCollege, Patiala, Punjab, India; Dr HK Rao (Medicine), Former Head (Medicine); Dr Manjit Kaur Mohi; Dr Paramjit Kaur, Dr Khushpreet Kaur and Dr Preet Kamal Sibia (Gynaecology); Dr JS Bhopal (Anesthesia); Dr Manjit Singh and Dr JPS Walia (Orthopedics), Dr Mohinder Singh and Dr DP Singh (Surgery), Dr Ardaman Singh and Dr Naresh Garg (Medicine), Dr Manpreet Kaur and Dr Meena Garg (Gynecology).

I highly appreciate guidance given by my seniors and colleagues from other institutes such as Dr Kulbir Kaur, Principal,

Punjab Institute of Medical Sciences, Jalandhar, Punjab; Dr RR Sharma, Additional Professor, Department of Transfusion Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh; Dr RN Maharishi, Professor and Head, Department of Transfusion Medicine, Guru Gobind Singh Medical College, Faridkot, Punjab; Dr Neeraj Sharma, Professor and Head, Department of Transfusion Medicine, Government Medical College, Amritsar, Punjab; Dr Hitish Narang, Consultant, Satguru Pratap Singh (SPS) Apollo Hospitals, Ludhiana, Punjab; Dr PK Sehgal, Head, Department of Transfusion Medicine, Pt BD Sharma University of Health Sciences, Rohtak, Haryana, India; Dr Amarjit Kaur, Professor and Head, Department of Transfusion Medicine, Dayanand Medical College, Ludhiana, Punjab; Dr Anil Vij, Professor and Head, Department of Medicine, Institute of Medical Sciences, Jalandhar, Punjab; Dr Dharam Paul, Civil Surgeon (Retd); Dr ML Bansal, Editor-in- Chief of Current Medical Journal of North Zone; Dr BK Aggrawal, Professor and Head, Department of Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Haryana; Dr RP Kudiar, Principal, Acharaya Shri

Chander College of Medical Sciences (ASCOM), Jammu, Jammu and Kashmir, India; Dr Anil Kumar Gupta, Professor and Head, Department of Medicine, Acharaya Shri Chander College of Medical Sciences (ASCOM), Jammu, Jammu and Kashmir;

Dr PS Gehlot, Professor and Head, Department of Medicine, Pt BD Sharma University of Health Sciences, Rohtak, Haryana, India; Dr Lovedeep Saini, Dr Sumeet Pal Saini, Dr Sukhwinder Singh, Joint Director, BS and QA, Punjab State AIDS Control Society, Chandigarh; Dr Sartaj Kaur Dhillon and Dr Satwant Singh Dhillon, Wisconsin, USA; Dr AS Grover, Principal, Gian Sagar Medical College and Hospital, Banur, Punjab, India.

I am thankful to all my friends and colleagues, who have helped me in writing the book in one way or the other. My

special thanks to Dr Gurdeep Kaur Bedi, Professor and Head, Biochemistry; Dr Shashi Prabha, Former Head, Department of Transfusion Medicine; Dr MS Bal, Professor and Head, Department of Pathology; Dr Vijay Kumar Bodal, Dr Anil Suri, Dr Mohanveer Kaur, Dr Maninder Kaur, Associate Professor, Biochemistry; Dr Avnish Kumar, Professor Physiology; Dr Usha Chhabra, Professor and Head (Anatomy); Dr Subhash Kaushal, Professor, Department of Anatomy; Dr Anita Gupta, Professor and Head, Pharmacology; Dr KK Aggarwal, Professor, Forensic Medicine; Dr DS Bhullar, Assistant Professor, Department of Forensic Medicine; Dr Aradhana Sharma, Dr Poonam Singhal, Mr Mahesh Kumar, Mr Sukhvinder Singh and Mr Pawan Kumar, Sandeep Kumari who have contributed in one way or the other for this manuscript. I express my special thanks to Dr Manmohan Singh, Former President, Punjab Medical Council and Dr Sudhir Verma for their ever available guidance and help.

xx

Transfusion Update

The book has emerged in its present form due to the untiring efforts of my Associate Editors—Dr BL Bhardwaj, Dr Kusum K Thakur and Dr Rajni Bassi, and Assistant Editor—Dr Harnoor Singh Bhardwaj. My sincere thanks to the eminent contributors for writing their chapters despite their own priorities. I remember Dr Amrendra S Miranpuri, Assistant Professor, Neurosurgery Cerebrovascular, Stroke and Endovascular Surgical, Co-Director, Neuromedicine Critical Care University of Rochester Medical Center, Rochester, New York; Dr Guwatan Singh Miranpuri, Department of Neurosurgery, University of Wisconsin, Madison, USA; Dr Mandeep Batish; Dr Aastha Miranpuri, Dr Ravisha Bhardwaj, Dr Jatinder Kumar, Mrs Ranju Saini, Er Aasheem Saini, Mr Rasheem Saini, Mrs Nisha Bhardwaj, Dr Kavita Bhardwaj, Er Navpreet Singh, Er Shivani Bhardwaj, Er Ankush Bhardwaj, Dr Paritev Singh and Mr Navnik Singh for their unstinting support, constant cooperation and prompt help. My sincere thanks to Shri Jitendar P Vij (Chairman), Mr Ankit Vij (Managing Director), Mr Tarun Duneja (Director- Publishing) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, deserve due credit for their personal involvement in the excellent printing and publication of this book in a record time.

Editor-in-Chief

Contents

Section 1: CliniCal HemotHerapy

transfusion practice in medicine

1. Transfusion in Bone Marrow Failure Syndromes

3

PS Ghalaut, Jitendra Kumar Pehalajani, Arvind Chahal

• Component Therapy 3

• Indications for RBC Transfusion 3

• Indications of Platelet Transfusion 4

• Granulocyte Transfusion 4

• Synthetic Oxygen Carriers 5

2. Transfusion Therapy in Autoimmune Hemolytic Anemia

7

Rajesh B Sawant

• Indications for Transfusion 7

• Responsibilities of Transfusion Medicine 7

• Patient Management 8

• Autoimmune Hemolytic Anemia 8

3. Sugar Free Antibodies: A New Treatment for Idiopathic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia

9

HS Sandhu, Ishwar Chouhan

• Sugar Free Antibodies in Immune Thrombocytopenic Purpura 9

• Sugar Free Antibodies in Autoimmune Hemolytic Anemia 9

• Sugar Free Antibodies in Other Autoimmune Diseases 11

• Future 11

4. Transfusion Practice in Disseminated Intravascular Coagulation

13

Hitish Narang

• Pathophysiology 13

• Diagnosis 13

• Treatment 13

• Prognosis 14

5. Transfusion Practice in Oncology

15

Devinder Singh Sandhu

• Anemia 15

• Thrombocytopenia 16

• Neutropenia 18

6. Transfusion Practice in Coronary Interventions

20

Sudhir Varma

• Why Bleeding and Excess Morality Post Percutaneous Coronary Intervention? 20

• Can Blood Transfusion in Percutaneous Coronary Intervention Patients be Harmful? 21

7.

Neurological ICU: Role of Red Blood Cell Transfusion

24

BL Bhardwaj, Dharam Paul, Arun Bansal

• Role of Red Blood Cell Transfusions 24

• Adverse Effects of Transfusion 25

• Transfusion in the Neuro-ICU 25

8.

Blood Transfusion Alternatives

30

Harnoor Singh Bhardwaj, BL Bhardwaj, Aastha Miranpuri

• Pharmacological Agents 30

• Recombinant Hematopoietic Growth Factors 31

• Red Cell Substitutes 31

• Platelet Substitute 33

9.

Role of Whole Blood in Transfusion Practice

35

Ashok Sharma

Indications of Whole Blood Transfusion 35

 

transfusion practice in Surgery

10.

Management of Preoperative Anemia in Patients Undergoing Elective Surgery

Manisha Shrivastava

 

37

• Prevalence Depends on Many Factors 37

• Recommendations for Detection, Evaluation and Management of Preoperative Anemia in Orthopedic Surgery [Network for Advancement of Transfusion Alternatives (NATA)] 38

11.

Blood Conservation Strategies

40

DP Singh

Methods 40

12.

Thromboelastography

42

Anupam Verma

13.

Transfusion Support in Cardiac Surgery

44

Rajendra K Chaudhary

• Transfusion Variability in Cardiac Surgery 44

• Potential Benefits of Red Blood Cell Transfusion in Cardiac Surgery 44

• Predictors of Allogeneic Red Blood Cell Transfusion during Cardiac Surgery 45

14.

Transfusion Practice in Arthroplasty

48

Manuj Wadhwa, Kunal R Patel

Recent Studies and Recommendations for Specific Orthopedic Problems 48

15.

Restricting Transfusion Requirements in Major Orthopedic Surgery and its Alternatives

51

Ravisha Bhardwaj, RS Boparai

• Techniques Applicable to Orthopedic Surgery 52

• Orthopedic Trauma 53

• Future 53

xxii

Transfusion Update

16.

Transfusion Support in Neurosurgery

55

Sandeep Kundra

• Threshold for Transfusion in Neurosurgery is Uncertain 55

• Blood Conservation Strategies 57

maternal, Fetal and neonatal transfusion practice

 

17. Noninvasive Prenatal Screening for Rh Hemolytic Disease

60

 

Manjit Kaur Mohi

• Possible Sources of Error 61

• Ethical Aspects 61

• Cost/Availability 61

18. Antenatal Antibody Screening and Intrauterine Transfusion in Pregnancy

62

 

Amit Aggarwal

• Antenatal Testing and HDN Status in Developing Countries 62

• Intrauterine Transfusion 63

19. Antenatal Screening of Thalassemia

65

 

Reena Das

20. Neonatal Transfusion Practice

67

 

A Surekha Devi

• General Recommendations (Fetuses, Neonates, Infants and Children) 67

• Transfusions of Preterm Infants 68

• Neonatal Transfusions 69

• Transfusions in Necrotizing Enterocolitis (NEC) 70

• Transfusions in Extracorporeal Membrane Oxygenation (ECMO) 70

 

transfusion practice in transplantation

21. Transfusion Practice in Bone Marrow Transplantation and HLA Matching

71

 

M Joseph John

• HLA Typing 71

• Transfusion Practices 71

• ABO Incompatibility in BMT: Graft Management 73

• Blood Groups used for Transfusion Support 74

22. Transfusion Practice in Renal Transplants Recipients

76

 

Vimarsh Raina, Aseem K Tiwari, Ravi Dara

• Auto-recognition 76

• Allo-recognition 76

• Allograft Rejection 76

• Evolution of Transfusion in Renal Transplantation 77

23. Incompatible Blood Type Kidney Transplantation

81

Varun Sharma, Priyadarshi Ranjan

• ABO Antigens and Antibodies 81

• History 82

A BOi-KT Preoperative Management 82

• Use of IVIG 84

• Accommodation 84

• Current Protocol of ABOi-KT 84

• Minimize Immunosuppression 84

• Histological Findings in ABOi-KT 84

• Incidence of Acute Cellular and Antibody Mediated Rejection in ABOi-KT 85

• Adverse Effect of ABOi-KT 85

24. Transfusion Practice in Heart Transplant

87

Hari Krishan Dhawan

• Pretransplant Work-up 87

• Provision of Leukoreduced Blood Components 87

• Transfusion Requirements during Transplant 87

• Follow-up of Transplant Patients 87

• Role of Photopheresis and Therapeutic Plasma Exchange in Cardiac Transplant Patients 88

25. Transfusion Practice in Liver Transplantation

89

A Surekha Devi

• Transfusion Predictors 89

• Drugs that Minimize Blood Loss 91

• OLT without Transfusion 92

• Transfusion Support 92

massive transfusion

26. Massive Transfusion Protocol

95

Kanchan Bhardwaj, Rajni Bassi

• Rationale 95

• Definition of Massive Transfusion 95

• Physiology of Hemorrhagic Shock 95

• Coagulopathy of Hemorrhage and Massive Transfusion 96

• Predicting Need for MTP 96

• Adjuncts to MTP 96

• Hypothermia 96

• Rewarming Strategies 96

• Acidosis 98

• Tranexamic Acid 99

• Resuscitation in Patients Requiring Massive Transfusion 99

• Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) 99

• Factor rVIIA and MTP 99

• Complications of MTP 99

• MTP after Control of Hemorrhage 100

• MTP in Pediatrics 100

27. Massive Transfusion in Obstetrical Hemorrhage

102

Sangeeta Pathak

• Principle 102

• Definition 102

• Blood Component Therapy 103

• Recombinant Factor VIIA 104

• Adverse Effects of Massive Transfusion 104

Contents xxiii

platelet therapy

28. Inherited and Acquired Platelet Disorders:

Diagnosis and Therapy

R Krishnamoorthy

• Methodology 108

• Discussion 108

• Diagnosis 109

• Management 109

29. Transfusion Practice in Dengue

108

110

BL Bhardwaj, Harnoor Singh Bhardwaj

• Clinical Management 110

30. Fetal and Neonatal Alloimmune Thrombocytopenia

Prasun Bhattacharya

• Pathogenesis of FNAIT 116

• Clinical Presentation 116

• Laboratory Investigations 116

• Therapy and Management 117

• Newborns 117

116

31. Clinicopathological Syndrome in Immune- mediated Heparin-induced Thrombocytopenia 118

P Arumugam

• Pathogenesis 118

• Clinical features 118

• Diagnosis 119

• Management 121

• Prevention 122

• Information to the Patient and Record Keeping 122

32. Single Donor Platelets Versus Random Donor Platelets

 

123

Rajni Bassi, Ajata Shatru Kapoor

• Preparation of Platelet Concentrate 123

• Random Donor Platelets 123

• Single Donor Platelets/Plateletpheresis 124

33. Prophylactic Platelet Transfusion

126

Poonam Singal

Transfusion Triggers 126

 

apheresis

34. Maximizing the Resources: Multicomponent Collection

129

Prashant Agarwal

35. Therapeutic Plateletpheresis

131

Tulika Chandra

Therapeutic Plateletpheresis 131

36. Therapeutic Plasma Exchange

133

Aseem K Tiwari

• Plasma Exchange as an Alternative to Immunoglobulin 134

37. Therapeutic Erythrocytapheresis and Leucapheresis

135

Nidhi Mehta

• Plasma Exchange (PE) 135

• Cytapheresis 135

38. Red Cell Exchange in Clinical Practice

137

Joshua Daniel Jeyakumar, Prakash H Muddegowda, Jyothi B Lingegowda

• Red Blood Cell Exchange Technique 137

• Indications of Red Blood Cell Exchange 137

• Sickle Cell Disease 137

• Malaria 138

• Babesiosis 138

• Nitrobenzene and Other Poisonings 138

• Hemolytic Disease of Newborn 138

• Miscellaneous 138

Chronically transfused patients

39. Transfusion Practice in Thalassemia

140

Gagandeep Kaur

• Pathophysiology 140

• Transfusion Therapy 140

• Whom to Transfuse 140

• Compatibility Testing 140

• Transfusion Regimen 141

• Transfusion Interval 141

• Characteristics of Blood Products for Transfusion 141

• Effectiveness of Transfusion Therapy 141

• Problem of Thalassemia Transfusion Programs is Developing Countries 142

40. Pediatrician and β-Thalassemia

143

Parveen Mittal

• Road Map 143

• Management 144

• Complications of Thalassemia 144

• Follow-up 145

• Prognosis 145

• Prevention 145

• Prenatal Diagnosis 145

41. Iron Overload in Chronically Transfused Patients: Diagnosis and Treatment

147

Praveen C Sobti, Shruti Kakkar

• Assessment of Iron Overload 147

• Desferrioxamine 149

42. Transfusion in Sickle Cell Anemia

153

Yazdi Italia

43. Advanced Therapies for Treatment of Hemophilia

155

Tarangini D, Anupam Sachdeva

• Advanced Therapies for Hemophilia under Trial 155

• Management of Inhibitors 156

• Management of Hemophilic Arthropathy 156

xxiv

Transfusion Update

intervention in Bleeding patients

44. Bleeding Disorders: Lab Diagnosis

157

Mohanvir Kaur, Dinesh Ahluwalia

• General Aspects 157

• Laboratory Investigations 157

45. Management of Coagulopathy in Liver Diseases

162

Meenu Bajpai

• Defects in Primary Hemostasis 162

• Defects in Secondary Hemostasis 162

• Overview of Management 163

46. Recombinant Activated Factor VII in Clinical Practice

166

Ravneet Kaur, Kshitija Mittal, Tanvi Sood

• Mechanism of Action 166

• Indications 166

• Off-label Uses 166

47. Plasma Versus Recombinant Clotting Factors

168

Rajesh C Gopal

• Clotting Factor Concentrate 168

• Demerits of Plasma Factor Concentrates 168

48. Solvent Detergent Treated Plasma in Clinical Use

171

M Joshua Daniel Jeyakumar, Suryatapa Saha, Prakash H Muddegowda, Prathiba L Pujjita

• Production of SD Plasma 171

• Properties of SD Plasma 171

• Octaplas Follow-up Study 172

• Pharmacoeconomics 172

• Conclusion with European SD Plasma 172

49. Cryoprecipitate

174

Aradhna Sharma

• Cryoprecipitate Constituents and their Stability 174

• Indications 174

• Common Misuses 174

• Doses and Administration of Factor VIII Concentrates 174

• Preparation, Storage and Quality Control 175

• Pooling of Cryoprecipitate 176

• Potential Adverse Reactions 176

Section 2: Cellular tHerapieS

50. Stem Cell Transplantation: Brief Overview

179

Pankaj Malhotra

51. Stem Cell in Regenerative Medicine:

Applications and Cautions

181

RR Sharma

• Translation of Stem Cell Science into Regenerative Medicine 181

• Threats to Clinical Translation and to the Integrity of Regenerative Medicine 182

52. Stem Cell Therapy in Cardiovascular Diseases

184

Hamed Bashir, Ajay Bahl, KK Talwar

• Embryonic Stem Cell 184

• Adult Stem Cells 184

• Mechanism of Action of Stem Cells 184

• Types of Cells Contemplated for Cellular Regenerative Therapy 184

• Methods of Stem Cell Delivery 185

• Stem Cell Therapy for Cardiac Repair 185

• Results of Stem Cell Transplant in Clinical Trials 186

• Concerns 187

53. Stem Cell Therapy for Diabetes Mellitus

189

Rajesh Rajput

• Stem Cell Therapy for Diabetes 190

• Ethical Issues with Use of Stem Cells 191

54. Stem Cell Therapy in Peripheral Artery Disease

193

Bimal Kumar Agrawal, Mini Bhatnagar Sud

• ABI and Diagnosis of PAD 193

• Stem Cell Therapy for PAD 194

• Clinical Trials on Stem Cell Therapy for PAD

195

• Current Status of Stem Cell Therapy in PAD

196

55. Role of Platelet Rich Plasma in Regenerative Medicine

197

Kusum K Thakur, Alpna Thakur, Achhar Singh

• Historical Perspective 197

• Basic Science of Platelet Rich Plasma 197

• Platelet Rich Plasma Therapy 198

• Preparation of Platelet Rich Plasma and its Application 198

• Therapeutic Platelet Products 199

• Indications 199

• Contraindications 199

• Safety Profile 199

• Future of Platelet Rich Plasma in Regenerative Medicine 200

 

56. Role of Platelet Rich Plasma in Plastic Surgery

202

Umesh Sharma

• Platelet Rich Plasma 202

• Rationale for Use of Platelet Rich Plasma 202

 

• Platelet Rich Plasma in Plastic Surgery 202

• Safety, Complications, Contraindications to Use of Platelet Rich Plasma 203

57. Cord Blood Banking and Transplantation

204

Paramjit Dhot

58. Erythropoiesis Stimulating Agents versus Red Cell Transfusion

206

Sandeep Puri

• Erythropoiesis Stimulating Agents 206

• Red Cell Transfusion 208

Contents xxv

59. Natural Killer Cells in Tumor and Transplantation

211

Sunil K Arora, Rajendra Kumar

• Origin and Distribution of Natural Killer Cells 211

• Mechanism of Cytotoxicity 211

• Role of Natural Killer Cells in Transplant Immunology 212

• Natural Killer Cells and Cancer Surveillance 212

60. Potential and Hazards of Gene Therapy

214

Ajit C Gorakshakar

• Historical Aspect 214

• Gene Therapy in Transfusion Medicine 214

• Prerequisite for Gene Therapy 215

• Gene Delivery Systems 215

• Vector Design 215

• Viral Delivery Systems 215

• Nonviral Delivery Systems 215

• Regulatory Issues 216

Section 3: Blood SaFety

61. Leucoreduction

221

Kanchan Bhardwaj

• Approximate Leucocytes in Various Red Blood Cell Preparations 221

• Clinical Indications for Leucoreduction 221

• Methods of Leucodepletion 222

• Adverse Effects of Filtration and Leucodepletion 224

• Universal Leucodepletion versus Selective Leucodepletion 224

• Leucodepletion—Indian Perspective 225

62. Improving Blood Donor Screening by Nucleic Acid Technology

226

Rekha Hans

• Need for Nucleic Acid Technology 226

• Nucleic Acid Technology 226

• Blood Donor Screening 226

• Experiences of Different Countries 227

63. ID-NAT Versus MP-NAT

230

Rajesh Kumar

64. Occult HBV Infection: A Risk for Transfusion

232

Sheetal Malhotra

65. Current Status of Bacterial Detection in Blood Components

236

Mina Sidhu

• Clinical Relevance 237

• Methods to Reduce Risk of Post-transfusion Sepsis 237

• Methods to Detect Bacterial Contamination in Blood Component 237

• Indirect Rapid Bacterial Detection Tests 237

• Direct Methods of Bacterial Detection 238

• Direct Rapid Detection Methods 239

• Pathogen Reduction 239

66. Pathogen Reduction Technology

242

Kanchan Bhardwaj

• Pathogen Inactivation in Platelet Concentrates 242

• Platelet Concentrates with Amotosalen Photochemical Treatment 242

• Riboflavin and Ultraviolet Light Treated Platelets 243

• Methylene Blue Treated Platelets 243

• Pathogen Inactivation in Fresh Frozen Plasma Preparation 243

• Potential System for Pathogen Inactivation in Red Cell Concentrates 243

67. Discarding of Blood and Blood Components

245

Bharat Singh, Preeti Dewakar

Recommendations 251

68. Adverse Transfusion Reactions

252

Manoj A Kahar

• Classification 252

• Acute Adverse Transfusion Reaction with Immune Causes 252

• Investigations to be Done for Immediate Hemolytic Transfusion Reaction 254

• Acute Adverse Transfusion Reaction with Nonimmune Causes 256

• Delayed Adverse Transfusion Reaction with Immune Causes 257

• Delayed Adverse Transfusion Reaction without Immune Causes 258

69. Hemovigilance and its Launch in India

260

Neelam Marwaha

• Hemovigilance Systems 260

• Outcome of Hemovigilance around the World 260

70. Advances in Serological Assays for Screening Blood Donors for Infectious Agents

264

Paramjit Kaur

 

Section 4: miSCellaneouS

71. The Evidence-based Transfusion Medicine

269

Kulbir Kaur

• Evidence-based Red Blood Cells Utilization Guidelines 270

• Evidence-based Platelet Utilization Guidelines 270

• Evidence-based Fresh Frozen Plasma Utilization Guidelines 271

• Evidence-based Cryoprecipitate Utilization Guidelines 271

• Limitations of Evidence-based Transfusion Medicine 271

xxvi

Transfusion Update

72. Blood Bank Accreditation

273

 

BK Rana

• Types of Blood Banks/Centres 273

 

• Scope of Accreditation 273

73. National Plasma Policy for Access to Plasma Derived Proteins for Clinical/Therapeutic Use

278

Harprit Singh, Shobini Rajan, Shanoo Mishra, Sunil D Khaparde

Objectives of the Policy 278

74. Ethical Issues in Transfusion Medicine

281

Kusum K Thakur, Achhar Singh

• International Society of Blood Transfusion Code of Ethics 281

• A Code of Ethics for Blood Donation and Transfusion 281

• Ethical Issues Related to Donors 282

• Ethical Issues Related to Patients 283

• Ethical Issues Related to Blood Establishments 283

• Future Prospectives 283

75. Gel Based Technology: Past, Present and Future

285

Nidhi Bhatnagar

• Principle of Gel Technology 285

• Practical Applications of Gel Technology 286

• Advantages of Gel Technology 286

• Past, Present and Future 287

76. Automated Blood Grouping and Antibody Screening

288

Ashish Jain

• Automation in Serologic Testing 288

• Solid-phase Immunoassays 288

• Erythrocyte-magnetized Technology 289

• Validation of Automated Systems 291

• Edge of Automation 291

77. Molecular Genotyping and its Applications to Transfusion Medicine

292

Swati Kulkarni

• Solving ABO Blood Group Discrepancies 292

• Identification of Weaker and Partial Variants of RhD Gene 293

• RhD Zygosity Testing 293

• Identification of DEL Phenotypes 293

• Prenatal Diagnosis of RhD in Fetus 293

• Antigen Profiling in DAT Positive Cases 294

• Differentiation between Alloantibody and Autoantibody 294

• Quality Control in Reagent Red Cells 294

• Screening for Rare Blood Group Donors 294

78. Rare Blood Group Registry

297

Swati Kulkarni

• Defining Rare Blood 297

• International Rare Donor Program 297

• National Status 298

• Need for National Registry 298

• Identification of Rare Donors 299

• Methods for Typing Blood Group Types 299

• Future Directions 299

79. New Versus Old Blood

301

Rimpreet Singh Walia

80. Importance of Safe Blood Administration Practices

305

Sharad Jain

81. Strategies to Reduce Unnecessary Transfusions

308

Hemchandra Pandey, Rajendra K Chaudhary

Index

311

Clinical

Section

1

Hemotherapy

Transfusion Practice in Medicine

Transfusion in Bone Marrow Failure Syndromes

PS Ghalaut, Jitendra Kumar Pehalajani, Arvind Chahal

1

IntroductIon

Bone marrow failure syndromes may primarily affect a single or multiple hematopoietic lineages, which may result in decrease in one or more cell line in the blood. They can be congenital or acquired. 1

congenital/Inherited Aplastic Anemia

1. Fanconi anemia (FA)

2. Dyskeratosis congenita (DC)

3. Shwachman-Diamond syndrome (SDS)

4. Congenital amegakaryocytic thrombocytopenia (CAMT)

5. Thrombocytopenia with absent radii

6. Kostmann’s syndrome

7. Congenital dyserythropoietic anemias.

Acquired Bone Marrow Failure

1. Acquired aplastic anemia

2. Idiopathic thrombocytopenic purpera

3. MDS

4. PNH

5. Megaloblastic Anemia

6. Hematological malignancy—Lymphoma, leukemia, mul- tiple myeloma, myelodysplastic syndromes, myeloprolif- erative syndromes.

7. Toxins and drugs. Management of these etiologies are important. It is also

imperative to maintain the near normal blood counts by blood transfusion. Appropriate and early transfusion can also decreases mortality as well as morbidity of the patients. It has been also proven useful to transfuse only the component

article discusses the indications

which

of blood and blood products in the bone marrow failure syndrome.

is

deficient.

This

coMponent therApy

Component therapy is also called “Quiet revolution in Blood Transfusion Therapy”. 2

One unit of blood can be separated into:

(i)

A red cell preparation containing all the red cells of a unit of whole blood.

(ii)

A

platelet concentrates having approx. 70%

of

the

platelets.

 

(iii)

Residual plasma is fractionated into

Albumin

Immunoglobulin

Preparation of various clotting factors.

IndIcAtIons For rBc trAnsFusIon 3

1. Hemoglobin < 7 g/dL in asymptomatic patients.

2. Hemoglobin < 10 g/dL in cases of increased risk of ischemia, i.e. IHD, pulmonary disease.

3. Transfusion for a predetermined therapeutic program such as bone marrow suppression, i.e. PNH, AA.

4. Symptomatic anemia resulting in:

– Tachycardia

– Mental states changes

– Angina/ECG changes of ischemia

– Shortness of breath, and dizziness on mild exertion.

precautions

• Leuco-reduced packed red blood cells (PRBC) and platelets should be used to reduce the risk of alloimmunization and adverse reactions.

• It is important to avoid transfusion of blood from any blood relative to prevent the risk of graft versus host- disease (GvHD).

• The risk of CMV transfusion can be reduced by screening by CMv antibodies or by using leuco-reduced blood component.

Red cell concentrates: Suspension of red cells prepared by removing approx. 200 mL of plasma from whole blood. Concentrated red cells and colloid or electrolyte are equally effective. It is a very effective means to correct anemia. It also reduces the risk of hypervolemia. Hematocrit of whole blood is around 40%, in comparison to it hematocrit of red

4

Section 1 Clinical Hemotherapy

Table 1: Comparison between rCC and whole blood

 

RCC

Whole blood

Total volume

300

500

red cell volume

200

200

Plasma volume

100

300

Hematocrit

70

40

Albumin content

4

12

cell concentrate is around 70% (saline may be added to decrease hematocrit). 4 The various differences between red cell concentrate and whole blood are as given in Table 1.

Packed red cells: In 90% of cases anemia is chronic and requires red cells only. Transfusion with packed red cell is twice as efficient as whole blood in correcting anemia. Plasma can be saved for use in others patients.

Frozen thawed red cell: These can be done with cryopreservation techniques. It is an expensive process. Blood can be stored up to 10 years by such means.

Table 2: recommended coagulation parameters for common procedures

Procedure

Platelet count/µL

INR

Lumbar puncture

50,000

1.5

Paracentesis

30,000

2.0

Thoracentesis

50,000

1.5

Transbronchial lung biopsy

50,000

1.5

Subclavian/IJV line

30,000

1.5

renal biopsy

50,000

1.5

Liver biopsy

50,000

1.5

• Mucosal/retinal hemorrhage or purpura in a patient with thrombocytopenia is an indication for platelet transfusion repeated transfusion may be needed.

• Failure to control bleeding may be due to infection, splenomegaly and antibodies against leucocytes/platelet antigens.

• Frequent platelet transfusion and use of HLA-compatible PC may help to control bleeding.

Indications

• Provision of red blood cells to individuals with rare blood groups.

• Autotransfusion to individuals with red cell alloantibody which make the provision of compatible donor blood difficult.

• Clinical situations with the need to minimize alloimmunization in individuals undergoing chronic transfusion therapy.

• Reconstituted thawed red cells not to be stored longer than 24 hrs.

platelet transfusion to prevent Bleeding

Platelet are not given for stable afebrile patients, if the platelet count is above 10,000/µL. In febrile patients a higher threshold of 20,000/µL is taken. In stable patients, platelet transfusion should be given to maintain the platelet count at the chosen level. Transfusion, every 2 or 3 days is usually sufficient. As invasive procedures are to be done cautiously in patients with coagulation disorders, recommended platelets levels and INR for various procedures are given as in Table 2.

Leukocyte depleted red cells 5

platelet concentrate

– Indicated in severe febrile non hemolytic transfusion reactions.

– Special filters are used along with micro aggregate filters for removal of platelets, WBC and fibrin (40 micron).

IndIcAtIons oF plAtelet trAnsFusIon

It can be in form of platelet rich plasma (PRP) or platelet concentrate. PRP of same ABO blood type as of the patients can be used only. Platelet concentrates are 15–20 mL per unit. It requires 6–8 units of platelet concentrates/m 2 . Platelets should be given intravenous in plastic syringes in thrombocytopenia with bleeding. The average rise in platelet count with relation to body weight and platelet transfusions are given in Table 3. 7

Platelet transfusion is to be given to prevent bleeding due to thrombocytopenia. In a bleeding patient a platelet count above 50,000 µL should be maintained. In a surgical patient, 30,000–50,000 µL will be adequate for most surgeries but for risk procedures a count of 100,000 µL is recommended. Family donor or human leukocyte antigen (HLA) matched platelets are indicated when patients have become refractory to random donor platelet transfusion. Platelet transfusion may be contraindicated in thrombotic thrombocytopenic purpura (TTP) and in idiopathic thrombocytopenic purpura (ITP) increments are usually poor. 6

platelet transfusion to control Bleeding

• Aim of platelet transfusion is to balance the risk of introduction of modern apheresis techniques, the use of

Severe bacterial and fungal infections in the setting of prolonged chemotherapy-associated neutropenia continues to be a significant source of morbidity and mortality in the modern treatment of malignancy. The risk of serious bacterial infection first appears as the neutrophil count falls to <1.0 × 10 9 /L and risk increases rapidly at <0.5 × 10 9 /L. The

GrAnulocyte trAnsFusIon

Impact of neutropenia

Chapter 1 Transfusion in Bone Marrow Failure Syndromes

5

Table 3: Expected platelet increment

 

Weight

1 Unit 1.0 × 10 11

4 Units 4.0 × 10 11

6 Units 6.0 × 10 11

(kg)

23 kg

22,000

88,000

132,000

45 kg

11,000

45,000

66,000

68 kg

7,400

30,000

44,000

91 kg

5,500

22,000

33,000

Indications of Granulocyte transfusions 9

• Granulocyte therapy may warrant consideration in severely neutropenia patients with bacterial infections that are unresponsive to typical antimicrobial therapy.

• A brief trial of granulocyte infusions may be warranted in patients with self-limited neutropenia and documented fungal infection who are refractory to standard antifungal therapy.

• Although prophylactic granulocyte transfusion may decrease the risk of septicemia, the increased incidence of adverse effects observed with this therapy may outweigh the beneficial effects.

doses and target level

• The recommended dose is 1 × 10 9 granulocytes/kg of body weight.

• Granulocytes should be administered on a daily basis until the patient’s endogenous neutrophil count rises to 0.5 × 10 9 /L or until the infection clears.

synthetIc oxyGen cArrIers

various oxygen carrier compound available including the following:

Perfluorochemicals: These are fluorinated hydrocarbons, Stored in frozen state Fluosol-DA has been found to decrease the size of myocardial and cerebral infarctions in animals.

Chemically modified hemoglobin solutions: They are used to increase oxygen transport in place of viable red cells. They have been used to supply oxygen in experimental animals.

transfusion related risks

Following infection can be transmitted. 10

The current estimated risks are

• HIV <1:1,900,000

• Hepatitis C < 1:1,000,000

• Hepatitis B <1:1,000,000

• HTLV I and II < 1:641,000

• CMV negative, immunosuppressed and HIV positive patients are at high risk for CMv infection.

• Bacterial testing in platelet concentrates has significantly decreased this risk from platelet transfusion.

transfusion reactions

A transfusion should be stopped immediately whenever a

transfusion reaction is suspected.

Hemolytic transfusion reaction: Fatal hemolytic transfusion occurs once in 60,000 transfusions. It usually occurs after transfusion of incompatible blood component. Fever, hypotension, nausea, vomiting, tachycardia, dyspnea, chest or back pain and hemoglobinuria are various signs and symptoms. May cause renal failure and DIC.

Delayed hemolytic transfusion reaction: These reactions occurs in previously sensitized patient and can cause symptomatic or asymptomatic hemolysis several days after transfusion.

Febrile transfusion reaction: These reactions are due to sensitization to antigens on cell components particularly leukocytes. Leukocyte depletion and removal of plasma may be helpful. Rarely may be due to bacterial contamination.

Transfusion related acute lung injury: These reactions occur when donor plasma contains antibodies against the patient’s HLA or leukocyte specific antigen. Symptoms include dyspnea, hypotension and fever usually 30 minutes to 6 hrs after transfusion. ventilatory support may be required.

Urticarial and allergic type reactions: Most commonly due to allergies due to specific proteins in donor’s plasma. If severe washed RBC’s should be used. IgA deficiency may be thought in severe reactions.

conclusIon

Early diagnosis of the etiology and specific therapy is imperative in bone marrow failure syndromes. Appropriate and timely transfusion can reduce mortality as well as

morbidity of the patients, thus the judicious use of the blood product is needed to minimize the side effect. It is essential

to use blood component therapy and not the whole blood so

that not only there is no waste of other blood component but also there are less complications and transfusion reactions.

reFerences

1. Young NS (Ed). Bone Marrow Failure Syndromes. Philadelphia, WB Saunders. 2000;24:12-5.

2. Mintz PD, Dzik WH. Transfusion. 2009;49(7):1282-5.

3. Liumbruno G. Recommendations for the transfusion of red blood cells. Blood Transfus. 2009;7(1):49-64.

4. Corwin HL, Carson JL. N Engl J Med. 2007;356(16):1667-9.

6

Section 1 Clinical Hemotherapy

5. Bordin JO, Heddle NM, Blajchman MA. Biologic effects of leukocytes present in transfused cellular blood products. Blood. 1994;84:1703-21.

6. Slichter SJ, et al. NEJM. 2010;362:600-13.

7. Stroncek DF, Rebulla P. Platelet transfusions. Lancet. 2007;

370(9585):427-38.

8. Darmon M, Azoulay E. Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients. Intensive Care Medicine. 2002;28:1775-80.

9. Seidel MG, Einsele H. Randomized phase III study of

granulocyte transfusions in neutropenic patients. Bone Marrow Transplantation. 2008. p. 237.

10. Eleftherios C vamvakas, Morris A. Blajchman transfusion and the available strategies for their preventionTransfusion-related mortality: the ongoing risks of allogeneic blood. 2009;113:

3406-17.

Transfusion Therapy in Autoimmune Hemolytic Anemia

Rajesh B Sawant

2

IndIcatIons for transfusIon

Red blood cell transfusion is a significant component of the supportive care for all patients with Autoimmune hemolytic anemia (AIHA). Although many patients will present with mild to moderate anemia that does not require urgent transfusion, an occasional patient presents with life-threatening anemia, and the need for red blood cell transfusions is emergent. Patients with auto-antibodies requiring transfusion may pose difficulties in compatibility testing, and may be at risk for hemolyzing transfused blood and/or developing alloantibodies. Careful communication between the clinician and the transfusion service is required, since transfusion may be required before the serologic evaluation is completed. Even after thorough serologic evaluation, the optimal blood for transfusion may be serologically incompatible. The clinician mustunderstandthatinsomecases,serologicallyincompatible blood is safe for transfusion and can be expected to have in vivo survival comparable to the patient’s own red cells. Reluctance to transfuse these patients because of serologic incompatibility or an incomplete work-up can be devastating. Patients with severe anemia may appear to be hemodynamically stable, but these patients have life-threatening anemia and should be transfused immediately regardless of the status of the serologic evaluation or compatibility.

responsIbIlItIes of transfusIon MedIcIne

clinical

• Advise the clinician(s) of the duration of delay in obtaining compatible blood or discuss transfer of the patient to a larger center.

• Be familiar with the policies, processes, and procedures to release “least incompatible” blood.

• If the case is complex and the transfusion services cannot readily perform the appropriate investigations or provide appropriate blood, then the transfusion medicine-MD should consult a hematologist.

technical

• Investigations should be expedited to obtain crossmatch compatible blood as quickly as possible.

• Perform appropriate technical procedures.

• If the transfusion service is unable to perform these investigations, send samples immediately to a reference regional laboratory for investigation.

• Consult with seniors as indicated in technical procedures, or as necessary based on technologist’s skills, additional information on the clinical situation, or laboratory examination results.

pretransfusion examinations

The following examinations need to be done on pre- transfusion samples:

• Preliminary antibody investigation to determine whether the auto-antibody demonstrates any specificity.

• Other examinations to identify underlying alloantibodies. Such as prewarm, autoadsorption, differential alloadsorp- tion.

• Full red blood cell phenotype may be required in some cases.

• Red cells provided for transfusion should not express clinically significant antigens which the patient lacks, or should be negative for clinically significant antigens, if the patient phenotype is unknown.

selection of blood for transfusion

Transfusion management is complicated for patients with AIHA, due to their serologic complexities. Although patients

8

Section 1 Clinical Hemotherapy

with AIHA can present with an ABO discrepancy, ABO typing can usually be performed following removal of IgG autoantibody in warm AIHA or warm washing red cells to remove IgM autoantibody in cold agglutinin syndrome. In an emergency or if results are not clear-cut, Group O donor red cells can be used. Rh typing can also be difficult if the patient’s cells are heavily coated with autoantibody. Low protein, monoclonal reagents are available for Rh typing in the setting of immunoglobulin-coated red cells. The most pressing problem in a patient with previous pregnancy or transfusions is detecting and identifying alloantibody, which may be hidden or masked by the autoantibody. The exclusion of underlying clinically significant allo-antibodies is time consuming, and the clinical situation may not allow for completion of these studies before transfusion is needed. In the untransfused patient, autologous adsorption studies are required to investigate the presence of underlying alloantibody. If the patient has been transfused in the preceding 3 months, more complex, differential allogeneic adsorption studies are required. In the un-transfused patient, determination of the red cell phenotype is invaluable. Techniques and procedures are available to dissociate autoantibody so that phenotyping can be performed. Once a red cell phenotype has been determined, this phenotype can guide the exclusion of allo- antibodies by indicating which antigen specificities are at risk of eliciting an alloantibody. Shirey et al (2002) has shown that when available, phenotypically matched red cells are an efficient method for providing safe red cells for transfusion in this setting. Additionally, patients with AIHA are at risk for requiring chronic transfusion therapy; knowing the red cell phenotype of the patient is helpful in identifying alloantibodies if they develop over time.

patIent ManageMent

• In a stable patient, hemoglobin levels as low as 60 g/L may be tolerated in an attempt to avoid exposing the patient to blood transfusion, and the attendant risk of alloantibody development.

• In a symptomatic patient, blood transfusion should not be withheld and can be initiated under a steroid cover.

• Red cells for transfusion should be selected that are the “least incompatible”, now preferably termed “Best Matched” with the patient’s plasma/serum to minimize the risk of alloantibody formation.

role of steroids in treatment of aIHa

The mainstay of treatment of newly diagnosed primary warm antibody autoimmune hemolytic anemia (WAIHA) is glucocorticoids (steroids). According to accepted recommen- dations, start treatment immediately with an initial dose of 1 mg/kg/d prednisone orally or methylprednisolone intravenously. This initial dose is administered until a

hematocrit of greater than 30% or a hemoglobin level greater than 10 g/dL is reached. Once the treatment goal is achieved, the dose of prednisone is reduced to 20–30 mg/d within a few weeks. Thereafter, the prednisone dose is tapered slowly (by 2.5–5 mg/d per month) under careful monitoring of hemoglobin and reticulocyte counts. An alternate-day regimen (reducing the dose gradually to nil on alternate days) may reduce the side effects of steroids. If the patient is still in remission after 3–4 months at a dose of 5 mg of prednisone/ day, an attempt to withdraw steroids is made. If a patient is refractory to the initial corticosteroid treatment, a diagnostic re-evaluation with regard to a possible underlying disease should be made. Patients with malignant tumors, benign ovarian teratomas, or with warm IgM antibodies are often steroid-refractory.

autoIMMune HeMolytIc aneMIa

controversies regarding transfusing crossmatch-Incompatible blood

In patients with autoimmune hemolytic anemia (AIHA), antibodies are present, which react with both the patient’s own red blood cells and nearly all donor RBCs. Therefore, serologically compatible blood is rarely available for transfusion. The inability to provide crossmatch-compatible blood has led to concerns that transfusion of these patients could precipitate acute hemolysis with potentially severe consequences (hemoglobinemia, hemoglobinuria, acute renal failure, disseminated intravascular coagulation and death). These concerns are based on a few published reports of post-transfusion hemolysis in such cases. Because of the limited amount of this data and anecdotal experience suggesting a lack of severe adverse events after transfusion, the indications for and advisability of transfusion in these patients remain controversial issues. Concern regarding the precipitation of acute hemolytic transfusion reactions leading to morbidity and mortality after transfusion of red blood cells in patients with autoimmune hemolytic anemia stems from a few early reports of fatalities in these patients. While a temporal relationship between transfusion and hemoglobinemia/hemoglobinuria has been seen in a handful of cases, a careful analysis of these reports does not support a cause and effect relationship between transfusion and death. The available safety and efficacy data for transfusion in patients with autoimmune hemolytic anemia, while somewhat limited, suggests that blood transfusion is well-tolerated and efficacious.

suggested readIng

1.

Kohan et al. Vox Sanguinis. 1994;67(2):195-8.

2.

Mauro et al. Blood. 2000; 95(9):2786-92.

3.

Narvios et al. Curr Issues Trans Med. 2001;9(3):1-5.

4.

Shirey et al. Transfusion. 2002;42(11):1435-41.

Sugar Free Antibodies: A New Treatment for Idiopathic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia

HS Sandhu, Ishwar Chouhan

3

IntroductIon

Autoimmune destruction of self-tissue is the consequential result of a convergence of several factors, both genetic and environmental, that effectively dislocates the immune system’s ability to tolerate self-antigens but simultaneously retains its focus on those perceived as foreign. Although many of these autoimmune targeted self-antigens are known, immune system triggers can be more elusive. Nevertheless, once autoimmunity has been initiated, immune complexes (IC) play as a significant driving force in maintaining chronic inflammation and subsequently pathology in many of these conditions. ICs are antibody/antigen assemblies, usually IgG antibody subtype, sometimes found systemically but primarily at the site of autoimmune self-antigen recognition. 1 Sugar free antibodies are deglycosylated IgG having a dominant suppressive effect on inflammation and points to a unique class of therapeutic immunoglobulins for the treatment of autoimmunity. The enzyme EndoS from Streptococcus pyogenes is an immunomodulatory molecule hydrolyzing the conserved glycans in the effector part of immunoglobulin G (IgG). EndoS is remarkably specific for IgG, and hydrolysis having profound effects on IgG effector functions. EndoS pre- treatment of IgG, or direct administration to animals with experimental antibody-mediated autoimmune diseases, inhibits development of disease or cures animals from established disease. The properties of EndoS make it a unique experimental tool and an attractive alternative to current therapies of conditions involving pathogenic antibodies. 2

Sugar Free antIbodIeS In Immune thrombocytopenIc purpura

Collin et al. 3 adopt a novel experimental approach to this challenge: enzymatic removal of carbohydrates from IgG Fc in vivo. The enzyme chosen, EndoS, is isolated from a common human pathogen Streptococcus pyogenes and specifically hydrolyzes the Fc glycans between the two core GlcNAc residues. This modification of Fc abolishes the binding of IgG to Fc receptors and reduces complement activation.

In their study, Collin et al. first showed that EndoS, at low concentration, efficiently hydrolyzes the glycan on IgG in the complex environment of human blood in vitro. They then went on to show that the hydrolysis could be achieved efficiently in the circulation of a live animal by injecting rabbits with EndoS and monitoring total IgG. Low concentrations of EndoS were effective without perturbing the total IgG concentration or disrupting other serum glycoproteins. Furthermore, the IgG glycan hydrolysis effect was observed even in the face of a host antienzyme response. To investigate whether the glycan modification might have utility in modifying IgG activity, they chose a mouse model of a human autoimmune disease, immune thrombocytopenic purpura (ITP), in which platelets are targeted by autoantibodies. In the model, polyclonal antiplatelet IgG is injected into the mice to cause disease. Collin et al. showed that pretreatment of the antiplatelet IgG with EndoS or treatment of the mice with EndoS after initiation of disease prevented lethal thrombocytopenia in the majority of animals. Most impressively, even if disease was allowed to proceed to symptoms, as might be the case for humans presenting with ITP, EndoS treatment was able to provide considerable benefit. 3

how does endoS exercise a protective Function?

One plausible mechanism is that “activating” signals from C1q, Fc_Rs, and MBL binding are all reduced or abolished, whereas the interaction with the “inhibitory” Fc_RIIB receptor is preserved. This mechanism may reflect the natural immunosuppressive role of this enzyme. S. pyogenes has evolved several mechanisms to evade and diminish the adaptive immuneresponse, one of these appears to effectively switch off the effector functions of IgG.

Sugar Free antIbodIeS In autoImmune hemolytIc anemIa

The presence and pathogenicity of autoantibodies directed against red blood cells (RBCs) have been extensively

10

Section 1 Clinical Hemotherapy

investigated and implicated in a number of autoimmune diseases, such as autoimmune hemolytic anemia (AIHA) and systemic lupus erythematosus. 4 The RBC surface contains many epitopes recognizable by alloantibodies and autoantibodies, including more than 300 blood group antigens located on glycoproteins and glycolipids but also nonpolymorphic/nonblood group protein structures. 5 The most common targets of pathogenic RBC autoantibodies are epitopes on the Rh protein, encoded by 2 homologous genes on chromosome 1, RHD and RHCE. 6 More than half

of all autoantibody specificities in patients with AIHA of

the common so-called warm type include immunoglobulin

G (IgG) antibodies against these Rh epitopes, which are

consequently often used to model AIHA experimentally. Human antibodies against RhD (anti-D) or rabbit antibodies against human RBC (anti-RBC) can result in accelerated phagocytosis and removal of RBC from the circulation by monocytes/macrophages in the spleen and

liver. 7,8 Fcγ receptor (FcγR)-mediated erythrophagocytosis,

in addition to other IgG effector functions, such as activated

complement, oxidative burst, and cytokine production by

FcγR expressing effectors cells, play an essential role in shortened RBC survival. 9-13 The ability of normal human monocytes to bind and phagocyte IgG sensitized RBCs via FcγR and mediate immune RBC destruction is highly related

to the glycosylation status of the Fc domain on the anti-RBC

antibodies. 14-19 A study was undertaken to establish the effects of EndoS on antibody-mediated destruction of RBCs with a future therapeutic application in mind. Here it was shown, using monocytes from blood and the THP-1 monocytic cell line, that pretreatment of anti-RBC with EndoS abrogates erythrophagocytosis and subsequent activation of monocytes. The complement-dependent hemolytic effects of anti-RBC added to whole human blood were greatly decreased by pretreatment of this antibody with EndoS. Finally and most importantly, EndoS showed inhibitory effects on a model of AIHA in mice. These results suggest that anti-RBC antibodies can be rendered less pathogenic by treatment with EndoS, which may be regarded as a possible future inhibitor of antibodymediated destruction of RBCs and AIHA.

mechanism of action

Treatment of Anti-D with EndoS does not Affect the Binding of Anti-D to RBCs

EndoS inhibits binding of IgG to soluble and monocyte- bound FcγR by hydrolyzing the N-linked glycan on the heavy chain of IgG. 20 In a study conducted by Allhorn M, the results showed that the treatment of anti-D with EndoS did not affect the antigen recognition by this antibody and the amount of RBC-bound IgG was not influenced by EndoS treatment.

EndoS Inhibits Phagocytosis and Adherence of Sensitized RBCs by Monocytes

The effect(s) of EndoS on phagocytosis of anti-D sensitized RBCs by monocytes was analyzed using monocyte monolayer assay. Monolayers of monocytes were cultured on slides, and RBCs presensitized with anti-D were added to the monolayers. The degree of phagocytosis was determined using light microscopy and expressed as the number of monocytes with adherent/phagocytosed RBCs by analyzing 100 monocytes. As expected, the phagocytosis of anti-D– sensitized RBCs was significantly greater than nonsensitized RBCs and was efficiently eliminated by pretreatment of anti-D with EndoS (p < 0.001). This clearly shows that the treatment of anti-D with EndoS before sensitization of RBCs abrogates the phagocytosis-enhancing activity of anti-D and decreases the accumulation of intracellular hemoglobin in monocytes.

EndoS Inhibits Oxygen Metabolite Production by Monocytes Induced by Sensitized RBCs

In an attempt to further elucidate the effects of EndoS on monocyte-driven cell cytotoxicity to sensitized RBCs, we measured the release of oxygen metabolites from monocytes using a chemiluminescence test. RBCs were opsonized with immune plasma with high titers of anti-D from 3 persons. Monocyte responses to sensitized RBCs were compared with their response to unsensitized cells and expressed as a ratio (opsonic index). RBCs incubated with immune plasma gave positive results in chemiluminescence test with opsonic index 2.5. In contrast, monocyte responses to RBCs incubated with immune plasma pretreated with EndoS were significantly decreased (plasma 1, p < 0.07; plasma 2, p < 0.02; plasma 3, p < 0.015) and in some cases even below the control plasma. These results suggest that treatment of immune plasma with EndoS abrogates in vitro metabolic oxidative responses by monocytes.

EndoS Inhibits IL-8 Secretion from Monocytes Induced by Sensitized RBCs

It has been reported that IL-8, besides being produced by monocytes in response to lipopolysaccharide, tumor necrosis factor-α, or IL-1, is implicated as an indicator of RBC incompatibility and mediator of the pathologic events in hemolysis in, for example, hemolytic transfusion reactions. 21-23 It has been shown that monocytes exposed to sensitized RBC’s release IL-8, which was measured by ELISA method, as expected a significant rise in levels of IL-8 were observed. Noticeably, RBCs sensitized with anti-D pretreated with EndoS showed significantly decreased secretion of IL-8 in THP-1 cells (p < 0.001) and bloodmonocytes (p < 0.003), which was comparable with the secretion of IL-8

Chapter 3 Sugar Free Antibodies: A New Treatment for Idiopathic Thrombocytopenic Purpura

11

by THP-1 cells and monocytes because of stimulation with nonsensitized RBCs (p < 0.001 and p < 0.002, respectively. These results demonstrate that EndoS does not have any direct cytotoxic effects on monocytes.

EndoS Inhibits Hemolysis of Sensitized RBCs and Prevents Binding of C1q to IgG-sensitized RBCs

Human anti-D antibodies of IgG isotype do not generally activate the complement pathway, and RBCs coated with these antibodies are preferentially cleared by mononuclear phagocytic cells via FcγRs. It was clearly shown that pre- treatment of antibody by EndoS is not a prerequisite for inhibition of hemolysis and that a direct addition of EndoS to blood was sufficient to exclude the hemolytic effect of anti- RBC (p < 0.001). EndoS by itself did not have any effect on hemolysis (p < 0.001). Furthermore, addition of increasing concentrations of anti-RBC IgG to whole blood caused a strong agglutination reaction as expected. Remarkably, addition of EndoS-treated antibody abrogated this effect. In conclusion, these data indicate that EndoS possesses antihemolytic activities as demonstrated by pretreatment of anti-RBC with enzyme or by a direct addition of EndoS to anti-RBC-containing blood. It has been reported that C1q, the recognition subunit of the first component of the classic complement pathway, binds to IgG-sensitized RBCs. 24 Because the binding of C1q to IgG is dependent on the glycosylation state of IgG, we decided to explore the effect(s) of EndoS on deposition of C1q onto IgG-sensitized RBCs and with this further elucidate the mechanism for the antihemolytic effects of EndoS. There was significantly decreased fluorescence intensity in the samples containing RBCs sensitized with EndoS-treated anti-RBC (p < 0.001) compared with RBCs treated with native antibody. These results indicated an inability of C1q to bind to these RBCs, providing further evidence for the complement- inhibitory/antihemolytic properties of EndoS.

EndoS Inhibits AIHA In Vivo

The deposition of C1q and C3 on RBCs was analyzed by flowcytometry 24 hours after injection of EndoS. This revealed a significant decrease in C1q and C3 deposition on RBCs in mice treated with EndoS compared with PBS-treated mice (mean fluorescence intensity: C1q, 28.4 ± 6.5 vs 42.6

± 7.8, p < 0.02; C3, 13.1 ± 4.8 vs 29.6 ± 9.7, p < 0.01), suggesting

a reduced activation ofcomplement. The results showed that there was a substantial reduction of iron deposits in livers from mice treated with EndoS, compared with mice without treatment of EndoS. In addition, the effect of EndoS on 34-3C IgG1 and IgG2a class-switch variants was also determined. We found protective effect of EndoS on IgG1 induced anemia but not on IgG2a-induced anemia. When measuring the extent

of C1q and C3 deposits in mice injected with complement- activating 34-3C IgG2a, no significant differences were visible compared with mice without EndoS treatment. Data indicate that EndoS partially inhibits development of anemia mediated by anti-RBC reactive antibodies in an IgG subclass- dependent manner in mice.

Sugar Free antIbodIeS In other autoImmune dISeaSeS

Nandakumar et al. used the mouse anticollagen type II (anti- CII) mediated-arthritis model to show that deglycosylated IgG,regardlessofFabantigenspecificity,reducesinflammation in a dose-dependent manner. 1 This finding suggests that deglycosylated IgG has a dominant suppressive effect on inflammation and points to a unique class of therapeutic immunoglobulins for the treatment of autoimmunity. 1

Future oF thIS therapeutIc modalIty

The idea that antibody-mediated autoimmunity could be therapeutically controlled by a single enzyme is certainly an attractive one, but will Fc deglycosylation become a therapeutic reality? Several questions remain. EndoS is a bacterial protein and is readily targeted for removal by antibodies, which would normallylimitthehalf-lifeoftheproteinintheblood.However, Collin et al. report that, although antibodies to EndoS were observed in their study, the enzyme nonetheless exhibited reasonable pharmacokinetics. A possible explanation for this observation is that the normal Fc-mediated mechanisms for clearing foreign proteins are reduced, because the IgGs bound to the enzyme are themselves deglycosylated by the enzyme. Another potential obstacle might be that EndoS would cleave glycans other than those on IgG with unknown consequences. Encouragingly, however, EndoS appears unusually specific for the glycans on IgG, probably a consequence of its intrinsic affinity for Fc.

reFerenceS

1. Nandakumar KS, et al. Dominant suppression of inflammation by glycan-hydrolysed IgG. Pro Natl Acad Sci USA. 2013;

110:10252-7.

2. Allhorn M, Collin M. Sugar-free antibodies: the bacterial solution to autoimmunity? Ann NY Acad Sci. 2009;1173:664-9.

3. Collin M, Shannon O, Björck L. Proc Natl Acad Sci USA.

2008;105:4265-70.

4. Kavai M, Szegedi G. Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus. Autoimmun Rev. 2007;6(7):497-502. [PubMed: 17643939].

5. Daniels G. Naming blood groups and the genes that control them. ISBT Science Series. 2009;4(1):118-20.

6. Suto Y, Ishikawa Y, Hyodo H, et al. Gene organization and rearrangements at the human Rhesus blood group locus

12

Section 1 Clinical Hemotherapy

 

revealed by fiber-FISH analysis. Hum Genet. 2000;106(2):164- 71.[PubMed: 10746557].

coated erythrocytes in the rat. Immunology. 1989;68(1):126-32. [PMCID: PMC1385516] [PubMed: 2530153].

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Kumpel BM, Goodrick MJ, Pamphilon DH, et al. Human Rh D monoclonal antibodies (BRAD-3 and BRAD-5) cause accelerated clearance of Rh D+ red blood cells and suppression of Rh D immunization in Rh D− volunteers. Blood.1995;86(5):1701-9. [PubMed: 7655002].

17. Malaise MG, Franchimont P, Mahieu PR. The ability of normal human monocytes to phagocytose IgG-coated red blood cells is related to the number of accessible galactosyl and mannosyl residues in the Fc domain of the anti-red blood cell IgG antibody molecules. J Immunol Methods. 1989;119(2):231-9.

8.

Kávai M, Gyimesi E, Szucs G, et al. Binding and endocytosis of

[PubMed: 2723441].

erythrocytes sensitized with rabbit IgGvia Fc gamma receptors of human monocytes. Immunology. 1991;74(4):657-60. [PMCID: PMC1384775][PubMed: 1838354].

18. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313(5787):670-3. [PubMed: 16888140].

9.

Schreiber AD, Frank MM. Role of antibody and complement in the immune clearance and destruction of erythrocytes: In vivo effects of IgG and IgMcomplement-fixing sites. J Clin Invest.

19. Nimmerjahn F, Anthony RM, Ravetch JV. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc Natl Acad Sci USA. 2007;104(20):8433-7. [PMCID:

1972;51(3):575-82.[PMCID: PMC302163] [PubMed: 4536807].

PMC1895967][PubMed: 17485663].

10.

Clynes R, Ravetch JV. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity. 1995;3(1):21-6. [PubMed:

20. Allhorn M, Olin AI, Nimmerjahn F, et al. Human IgG/Fc gamma R interactions are modulated by streptococcal IgG glycan

7621075].

hydrolysis. PLoS ONE. 2008;3:e1413. [PMCID: PMC2173940]

11.

Meyer D, Schiller C, Westermann J, et al. FcgammaRIII (CD16)-

[PubMed: 18183294].

12.

deficient mice show IgG isotype-dependent protection to experimental autoimmune haemolytic anemia. Blood. 1998;92(11):3997–4002. [PubMed: 9834201].

21. Davenport RD, Burdick MD, Strieter RM, et al. In vitro production of interleukin-1 receptor antagonist in IgG- mediated red cell incompatibility. Transfusion. 1994;34(4):297- 303. [PubMed: 8178326].

Flesch BK, Voge K, Henrichs T, et al. Fc gamma receptor- mediated immune phagocytosis depends on the class of Fc gamma R and on the immunoglobulin coated target cell. Vox Sang. 2001;81(2):128-33.[PubMed: 11555474].

22. Davenport RD, Strieter RM, Standiford TJ, et al. Interleukin-8 production in red blood cell incompatibility. Blood. 1990;76(12):2439-42. [PubMed: 1702325].

13.

Davenport R. Cytokines and erythrocyte incompatibility. Curr Opin Hematol. 1994;1(6):452-6. [PubMed: 9371322].

23. Wikman A, Axdorph U, Gryfelt G, Gustafsson L, Björkholm M, Lundahl J. Characterization of red cell autoantibodies

15551098].

14.

Hadley AG, Zupanska B, Kumpel BM, et al. The glycosylation of

in consecutive DAT-positive patients with relation to in

red cell autoantibodies affects their functional activity in vitro. Br J Haematol. 1995;91(3):587-94. [PubMed: 8555059].

vivo haemolysis. Ann Hematol. 2005;84(3):150-8. [PubMed:

15.

Kumpel BM, Wang Y, Griffiths HL, et al. The biological activity of human monoclonal IgG anti-D is reduced by beta-galactosidase treatment. Hum Antibodies Hybridomas. 1995;6(3):82-8.[PubMed: 8597627].

24. Basta M, Fries LF, Frank MM. High doses of intravenous immunoglobulin do not affect the recognition phase of the classical complement pathway. Blood. 1991;78(3):700-2. [PubMed: 1859883].

16.

Malaise MG, Hoyoux C, Franchimont P, et al. Effects of mannose and mannose derivatives on the clearance of IgG antibody-

Transfusion Practice in Disseminated Intravascular Coagulation

Hitish Narang

4

Disseminated intravascular coagulation (DIC) is characteri­ zed by systemic activation of blood coagulation, which results ingenerationanddepositionoffibrin,leadingtomicrovascular thrombi in various organs and contributing to multiple organ dysfunction syndrome (MODS). 1 Consumption and subsequent exhaustion of coagulation proteins and platelets (from ongoing activation of coagulation) may induce severe bleeding, though microclot formation may occur in the absence of severe clotting factor depletion and bleeding. 2 Derangement of the fibrinolytic system further contributes to intravascular clot formation, but in some cases, accelerated fibrinolysis may cause severe bleeding. Hence, a patient with disseminated intravascular coagulation (DIC) can present with a simultaneously occurring thrombotic and bleeding problem, which obviously complicates the proper treatment. Definition of DIC by International Society on Thrombosis and Hemostasis: “An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction”. 3 Disseminated intravascular coagulation is not itself a specific illness; rather, it is a complication or an effect of the progression of other illnesses. It is always secondary to an underlying disorder and is associated with a number of clinical conditions, generally involving activation of systemic inflammation such as: 4 Sepsis, Trauma, Organ dysfunction, malignancy, Severe transfusion reactions, obstetric complica­ tions, Vascular abnormalities, Hepatic failure and heat stroke. Disseminated intravascular coagulation is estimated to be present in approximately 1% of hospitalized patients. 5

PathoPhysiology

The hematologic derangements seen in DIC result from the following four simultaneously occurring mechanisms: 6

1. Tissue factor mediated thrombin generation.

2. Dysfunctional physiologic anti­coagulant mechanisms.

3. Impaired fibrin removal due to depression of fibrinolytic system.

4. Inflammatory activation.

Diagnosis

The diagnosis of DIC is not made on a single laboratory value, but rather the constellation of laboratory markers and a consistent history of an illness known to cause DIC. Laboratory markers consistent with DIC include: 79

• Characteristic history

• Prolonged prothrombin time and activated partial thromboplastin time

• Fibrinogen level

• Rapidly declining platelet count

• High levels of fibrin degradation products, including D­Dimer

• Peripheral blood smear showing schistocytes.

treatment

• Treatment of underlying condition

• Transfusion of platelets, fresh frozen plasma and packed red cells

• Transfusion of cryoprecipitate when fibrinogen level is low

• Treatment of Thrombosis with heparin, antithrombin and antifibrinolytics is not usually used

• Recombinant factor VII. 15

administration of Blood Components and Coagulation Factors

Platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.

14

Section 1 Clinical Hemotherapy

Platelets

Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding (e.g. in the early postoperative phase or if an invasive procedure is planned). The threshold for transfusing platelets varies. Platelet replacement is usually required in non­bleeding patients if platelet counts drop below 20 × 10 9 /L. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings. 10 In actively bleeding patients, platelet levels from 20 × 10 9 /L to 50 × 10 9 /L are grounds for platelet transfusion (1 or 2 U/kg/ day).

Coagulation Factors

Cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (e.g. factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk. Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjunction with fresh frozen plasma administration. The consumption­induced deficiency of coagulation factors can be partially rectified by administering large quantities of fresh frozen plasma (FFP), particularly in patients with an international normalized ratio (INR) higher than 2.0, a 2-fold or greater prolongation of the aPTT, or a fibrinogen level below 100 mg/dL. 11 The suggested starting dose is 15 mg/kg. 12 Repeated measurement of global clotting tests (e.g. aPTT and PT) might be useful for monitoring the coagulation defect. In case of a (relative) vitamin K deficiency in the face of consumption, administration of vitamin K may be required. 5,13,14 FFP: 10–20 mL/kg of body weight will increase factor levels by 20–30%. Frequency of transfusion depends on the half-life of the deficient factor(s).

Prognosis

Prognosis varies depending on the underlying disorder and the extent of intravascular thrombosis. The prognosis for DIC, regardless of underlying cause, is often grim: between 10 and

50% patients will not survive. DIC with sepsis has a significantly higher rate of death than DIC associated with trauma. 16

reFerenCes

1.

Vincent JL, De Backer D. Does disseminated intravascular coagulation lead to multiple organ failure? Crit Care Clin.

2005;21(3):469­77. [Medline].

2.

Levi M, Ten Cate H. Disseminated intravascular coagulation.

N

Engl J Med. 1999;341(8):586­92. [Medline].

3.

[Guideline] Taylor FB Jr, Toh CH, Hoots WK, Wada H,

Levi M. Towards definition, clinical and laboratory criteria, and

a

scoring system for disseminated intravascular coagulation.

Thromb Haemost. 2001;86(5):1327­30. [Medline].

4.

Levi M, de Jonge E, van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med. 2004;36(1):

41­9. [Medline].

5.

Matsuda T. Clinical aspects of DIC–disseminated intravascular coagulation. Pol J Pharmacol. 1996;48(1):73-5. [Medline].

6.

Franchini M, Lippi G, Manzato F. Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated

intravascular coagulation. Thromb J. 2006;4:4. [Medline]. [Full Text].

7.

Levi M. “Disseminated Intravascular Coagulation”. Critical Care Medicine. 2007;35(9):2191­5.

8.

Hematology: Basic Principles and Practice, 6th edn. Elsevier Saunders. 2012. ISBN 1437729282.

9.

Levi M, Toh CH, et al. “Guidelines for the diagnosis and management of disseminated intravascular coagulation”. British Journal of Haematology. 2009;145(5):24­33.

10.

Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006;10(4):222. [Medline]. [Full Text].

11.

Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010;125(1):

6­11. [Medline].

12.

Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology.

Br

J Haematol. 2009;145(1):24­33. [Medline].

13.

Levi M. Disseminated intravascular coagulation: What's new? Crit Care Clin. 2005;21(3):449­67. [Medline].

14.

Levi M. The coagulant response in sepsis. Clin Chest Med. 2008;29(4):627­42, viii. [Medline].

15.

Franchini M, Manzato F, Salvagno GL, et al. Potential role of recombinant activated factor VII for the treatment of severe bleeding associated with disseminated intravascular coagulation: a systematic review. Blood Coagul Fibrinolysis. 2007;18(7): 589.

16.

Becker, Joseph U, Charles RW. Disseminated intravascular coagulation at eMedicine, 10 September 2009.

Transfusion Practice in Oncology

Devinder Singh Sandhu

5

ANEMIA

Background

Anemia is a common complication in patients with malignancy. It can impair the patient's functional status, diminish physiologic reserve, and cause fatigue that can be disabling. In addition to causing symptoms, the presence of anemia has been linked to an adverse prognosis in several malignancies. This has been attributed in part to a poorer response to anticancer treatment, since ionizing radiation and some forms of chemotherapy are dependent upon adequate tissue oxygen levels for cytotoxicity. These observations have been used to provide an additional rationale for aggressively treating anemia in patients receiving cancer therapy.

Multiple Factors can Cause or Contribute to Anemia in Patients with Malignancy

• As can occur with other chronic inflammatory conditions, some cancer patients have an anemia that is a consequence of the disease and unrelated to treatment. This type of anemia is typically mild (hemoglobin level >10 g/dL), and the symptoms may be difficult to distinguish from those caused by the underlying malignancy. Occasionally,

anemia may be more severe, impairing functional status, diminishing physiologic reserve, and reducing quality of life (QOL).

• Anemia is often exacerbated by myelosuppressive cancer treatment, particularly in patients who are undergoing intensive chemotherapy or combined modality treatment with both chemotherapy and radiation therapy. 1-5

• In addition to direct effects of the malignancy or its treatment, other causes of anemia may coexist in these patients (e.g. blood loss, hemolysis, deficiencies of iron, folate, or vitamin B 12 ). These causes should be actively sought, and when present, treated appropriately.

Management of Anemia in Cancer Patients

Definitive therapy for cancer-related anemia is eradication of the underlying malignancy. However, in many cases, this is not possible and short-term red blood cell (RBC) support may be needed.

• Transfusion: Red blood cell (RBC) transfusions are almost universally successful in raising Hb levels. Transfusions can often ameliorate the patient's symptoms rapidly and improve health-related QOL. Exceptions include patients unable to be transfused because of the presence of multiple alloantibodies and those who refuse transfusions based on religious beliefs. In such cases, erythropoietin stimulating agents (ESAs) may be beneficial (Table 1).

Table 1: Comparison of risks and benefits of erythropoiesis-stimulating agents versus red blood cell transfusion for chemotherapy-related anemia in patients with solid tumors

 

Erythropoiesis stimulating agents

Red blood cell transfusion

Risks

Thrombotic events Potentially decreased survival

Transfusion reactions Circulatory overload Viral infection Iron overload Development of multiple alloantibodies

Benefits

Gradual improvement in hemoglobin/hematocrit Gradual clinical improvement, avoidance of RBC transfusions in some patients, net reduction in transfusion requirements

Rapid improvement in hemoglobin/hematocrit Rapid clinical improvement

16

Section 1 Clinical Hemotherapy

ESAs: Epoetin and darbepoetin: Clinical trials have established that epoetin and darbepoetin are effective in raising hemoglobin levels and decreasing transfusion

The use of ESA should be discontinued after eight weeks if the Hb has not increased by more than 1 to 2 g/dL or there is no diminution in the need for RBC transfusion. 6,7

requirements in a substantial number of patients with chemotherapy-induced anemia. Both ESAs appear to be equivalent with regard to efficacy and safety. 6,7

For all patients treated with ESAs, supplemental iron be given to maintain a transferrin saturation ≥20% and a serum ferritin ≥100 ng/mL.

Choice of Agent, Dose Titration, and Supplemental Iron

• The ESAs epoetin and darbepoetin appear to be similarly effective. Darbepoetin may be more convenient, based upon a lower frequency of administration.

• The approved starting dose of epoetin is 150 U/kg three times weekly or 40,000 U weekly, subcutaneously; the approved starting dose for darbepoetin is 2.25 micro- gram/kg weekly or 500 micrograms every three weeks, subcutaneously.

• The dose should be adjusted in each patient to maintain the lowest hemoglobin level sufficient to avoid red cell transfusions; dose modification guidelines are presented in the table (Table 2).

THROMBOCYTOPENIA

Background

Thrombocytopenia is defined as a platelet count below the 150 × 10 9 /L. 8 Typically, platelet counts higher than 50 × 10 9 /L do not lead to clinical problems unless platelet dysfunction coexists with the low count. Medical help is usually sought by a patient with platelet counts less than 30 × 10 9 /L, suffering from spontaneous bruising and purpura or with continuous/ relatively long-lasting bleeding from injuries and wounds. Clinically significant spontaneous bleeding does not usually occur until the platelet count is less than 10 × 10 9 /L. Thrombocytopenia arises from three main causes:

Ineffective production of platelets by bone marrow, accelerated destruction of platelets, or splenic sequestration.

Table 2: Dosing guidelines for epoetin and darbepoetin in adults

 
 

Three times weekly dosing

Weekly dosing

Epoetin Alfa

Starting dose (adults)

150 units/kg subcutaneously (SC) three times weekly

40,000 units SC

Reduce dose by 25% if

Hemoglobin reaches a level needed to avoid transfusion or increases >1 g/dL in any two-week period.

Withhold dose if

Hemoglobin exceeds a level needed to avoid red blood cell (RBC) transfusion; restart at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required.

Increase dose

To 300 units/kg SC three times weekly, if response is not satisfactory (rise in hemoglobin<1 g/dL after four weeks of therapy and remains below 10 g/dL) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.

To 60,000 units SC weekly, if response is not satisfactory (rise in hemoglobin<1 g/dL after four weeks of therapy and remains below 10 g/dL) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.

Discontinue if

After completion of chemotherapy course or if after eight weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.

 

Weekly dosing

Once every three weeks dosing

Darbepoetin Alfa

Starting dose (adults)

2.25 microgram/kg SC once weekly

500 micrograms SC every three weeks

Reduce dose by 40% if

Hemoglobin exceeds a level needed to avoid transfusion, or increases >1 g/dL in any two-week period.

Withhold dose if

The hemoglobin exceeds a level needed to avoid RBC transfusion; restart at 40% below the previous dose when the hemoglobin approaches a level where transfusions may be required.

Increase dose

To 4.5 microgram/kg, if response is not satisfactory (no reduction in transfusion requirements or rise in hemoglobin by <1 g/dL after six weeks of therapy in the absence of a RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.

N/A

Discontinue if