Textbook of Pediatric Hematology and Hemato-Oncology

Editor-in-Chief MR Lokeshwar Consultant Pediatrician and Pediatric Hematologist Oncologist Shushrusha Citizens Co-operative Hospital and Lilavati Hospital and Research Centre, Mumbai, India

Editors Nitin K Shah Bharat R Agarwal President, Indian Academy of Pediatrics, 2006 Head Consultant Pediatrician, PD Hinduja Hospital, Mumbai, India Department of Pediatric Hematology and Oncology Hon. Pediatric Hematologist Oncologist BJ Wadia Hospital for Children Institute of Child Health BJ Wadia Hospital and Lions Hospital, Mumbai, India and Research Centre, Mumbai, India

Co-editors

Mamta Vijay Manglani Anupam Sachdeva Professor and Head BrothersDirector, Pediatric Hematology-Oncology and Department of Pediatrics Bone Marrow Transplantation, Institute for Child Health Chief, Division of Hematology-Oncology Sir Ganga Ram Hospital, New Delhi, India Program Director, Pediatric Center of Excellence for HIV Care Recipient, Dr BC Roy Award Lokmanya Tilak Municipal Medical College and Recipient, Silver Jubilee Research Award General Hospital, Mumbai, India

Publication Editor Asha Pillai Medical Officer Kashyap Nursing Home Mumbai, India

Forewords SS Kamath JaypeeVijay N Yewale

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com Brothers © 2016, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photo­copying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contra­indications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/ or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort hasJaypee been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity.

Inquiries for bulk sales may be solicited at: [email protected] Textbook of Pediatric Hematology and Hemato-Oncology First Edition: 2016 ISBN: 978-93-5152-143-3 Printed at Dedicated to

Zinet Currimbhoy Teacher of Teachers in Pediatric Hematology and Oncology for whom Children with blood disorders and cancerBrothers were the greatest teachers!

Jaypee Contributors

Aditya Kumar Gupta Anand Deshpande MD FNB (Pediatric Hematology Oncology, SGRH) Consultant Assistant Professor Hematopathologist and In-Charge Division of Pediatric Hematology- Transfusion Medicine Oncology PD Hinduja National Hospital Department of Pediatrics Mumbai, India Institute of Medical Sciences [email protected] Banaras Hindu University Varanasi, India Anupa A Joshipura [email protected] Fellow Pediatric Hemato-Oncology BJ Wadia Hospital for Children Ajay Kumar Institute of Child Health and Research Centre Senior Specialist Mumbai, India Department of Neonatology [email protected] Lady Hardinge Medical College and Kalawati Saran Children’s Hospital New Delhi, India Anupama S Borker [email protected] Consultant Pediatric Oncologist Somaiya Ayurvihar Aman Chauhan BrothersAsian Institute of Oncology Internal Medicine and Pediatrics KJ Somaiya Hospital Campus Combined Resident Mumbai, India Louisiana State University Health Science [email protected] Center New Orleans, USA Anupam Sachdeva [email protected] Director Pediatric Hematology-Oncology and Ambreen Pandrowala Bone Marrow Transplantation Clinical Associate Institute for Child Health Lilavati Hospital Sir Ganga Ram Hospital, New Delhi, India Mumbai, India Recipient, Dr BC Roy Award [email protected] Recipient, Silver Jubilee Research Award [email protected]

Amol Dongre Aparna Vijayaraghavan JaypeeAssistant Professor Registrar Department of Medical Oncology Department of Pediatrics Jawaharlal Nehru Medical College Chennai, India Wardha, India [email protected] [email protected] viii Textbook of Pediatric Hematology and Hemato-Oncology

AP Dubey Brijesh Arora Director Professor Professor and Head Division of Pediatric Oncology Department of Pediatrics Tata Memorial Hospital Maulana Azad Medical College and Mumbai, India Associated Lok Nayak Hospital [email protected] New Delhi, India [email protected] Deepak K Changlani Pediatric Interventional Cardiologist Arvind Saili Lilavati Hospital and Research Centre Director Mumbai, India Professor and Head [email protected] Department of Neonatology Lady Hardinge Medical College and Kalawati Saran Children’s Hospital Dilraj Kaur Kahlon New Delhi, India Consultant Pediatric Hemato-Oncologist [email protected] Amandeep Hospital Amritsar, India [email protected] ATK Rau Pediatric Hematologist-Oncologist Professor, Department of Pediatrics Dinesh Yadav MD MS Ramaiah Medical College Consultant Pediatrician Bengaluru, India Vivekanand Hospital, Bhadra, India [email protected] Formerly Assistant Professor Department of Pediatrics Sri Aurobindo Institute of Medical Bharat R Agarwal Sciences, Indore, India Head Brothers [email protected] Department of Pediatric Hematology and Oncology BJ Wadia Hospital for Children Farah Jijina Institute of Child Health and Research Consultant Hematologist Centre, Mumbai, India PD Hinduja Hospital, Mahim, India [email protected] Professor Department of Hematology Seth GS Medical College and Bhavna Dhingra KEM Hospital, Mumbai, India Assistant Professor [email protected] Department of Pediatrics All India Institute of Medical Sciences Gaurav Narula Bhopal, India Associate Professor (Pediatric-Oncology) [email protected] Department of Medical Oncology Tata Memorial Hospital Mumbai, India JaypeeBipin P Kulkarni [email protected] Scientist ‘B’ National Institute of Immunohaematology (Indian Council of Girish Chinnaswamy Medical Research, ICMR) Associate Professor (Pediatric-Oncology) KEM Hospital Campus Department of Medical Oncology Mumbai, India Tata Memorial Hospital [email protected] Mumbai, India www.niih.org.in [email protected] Contributors ix

Jagdish Chandra Malobika Bhattacharya Director-Professor of Pediatrics Consultant Pediatrics In-Charge, Pediatric Hematology and Kailash Hospital Thalassemia Day Care Centre Greater Noida, India Programme Director, Pediatric Centre of [email protected] Excellence (HIV) Lady Hardinge Medical College and Kalawati Saran Children’s Hospital Mamta Vijay Manglani New Delhi, India Professor and Head [email protected] Department of Pediatrics Chief, Division of Hematology-Oncology Jayashree Mondkar Program Director, Pediatric Center of Professor and Head Excellence for HIV Care, Lokmanya Tilak Department of Neonatology Municipal Medical College and General Director Hospital, Mumbai, India Human Milk Bank [email protected] Lokmanya Tilak Municipal Medical College and General Hospital Mumbai, India Manas Kalra [email protected] Fellowship Pediatric Oncology and BMT-Sydney Kana Ram Jat Consultant, Pediatric Hematologist Assistant Professor Oncologist and BMT Unit Department of Pediatrics Sir Ganga Ram Hospital All India Institute of Medical Sciences New Delhi, India New Delhi, India [email protected] [email protected] BrothersMaya Prasad K Ghosh Assistant Professor Director Department of Medical Oncology National Institute of (Pediatrics) Immunohaematology (ICMR) Tata Memorial Hospital, Mumbai, India KEM Hospital Campus [email protected] Mumbai, India [email protected] MMA Faridi Professor and Head KN Aggarwal MD FIAP FAMS FNA Department of Pediatrics Former Professor and Director In-Charge Institute of Medical Sciences Division of Neonatology Banaras Hindu University University College of Medical Sciences Varanasi, India Guru Teg Bahadur Hospital Former Director New Delhi, India SGPGIMS, Lucknow, India [email protected] JaypeeProfessor Department of Pediatrics UCMS, Bhairwah, Nepal MR Lokeshwar Consultant Pediatrician and Pediatric Madhulika Kabra Hematologist Oncologist Professor, Division of Genetics Shushrusha Citizens All India Institute of Medical Sciences Co-operative Hospital and Lilavati New Delhi, India Hospital and Research Centre [email protected] Mumbai, India [email protected] [email protected] x Textbook of Pediatric Hematology and Hemato-Oncology

Mukesh M Desai MD Nirmalya D Pradhan Hon. Hematologist Oncologist and Senior Pediatric Oncologist Immunologist Department of Pediatric Oncology Professor Tata Memorial Hospital Department of Pediatric Hematology- Mumbai, India Oncology (DNB) [email protected] Department of PHO Chief Division of Immunology Nita Radhakrishnan BJ Wadia Hospital for Children Consultant Pediatric Hematology Honorary Consultant Hematologist Oncology B Nanavati Hospital Institute of Child Health Sir HN Hospital Sir Ganga Ram Hospital Saifee Hospital New Delhi, India Asian Heart Institute, India [email protected] [email protected] Nitin K Shah Narendra Chaudhary President Assistant Professor Indian Academy of Pediatrics, 2006 Pediatric Hematology-Oncology Consultant Pediatrician Department of Child Health PD Hinduja Hospital, Mumbai, India Christian Medical College Hon. Pediatric Hematologist Oncologist Tamil Nadu, India BJ Wadia Hospital and Lions Hospital [email protected] Mumbai, India [email protected] Neerja Gupta Assistant Professor Pankaj Dwivedi Division of Genetics Fellow in Pediatric, Hematology and Department of Pediatrics Oncology All India Institute of Medical Sciences BrothersHospital for Sick Children New Delhi, India Toronto, Canada [email protected] [email protected]

Neha Vilas Dighe Pooja Balasubramanian Fellow Clinical Associate Department of Pediatrics Lilavati Hospital and Research Centre BJ Wadia Hospital for Children Mumbai, India Institute of Child Health and Research Centre [email protected] Mumbai, India [email protected] Pooja Dewan Nirav Buch MD FNB Assistant Professor Pediatric Hematologist-Oncologist Department of Pediatrics [email protected] University College of Medical Sciences [email protected] Jaypee Guru Teg Bahadur Hospital Delhi, India [email protected]

Nirav Thacker Priti Desai Senior Registrar Pediatric Oncology Associate Professor Department of Pediatric Oncology Department of Transfusion Medicine Tata Memorial Hospital Tata Memorial Hospital Mumbai, India Mumbai, India [email protected] [email protected] Contributors xi

PS Patil MD FIAP Rashmi Dalvi Neo Clinic Consultant Pediatric Oncologist Samarth Nagar Bombay Hospital and Medical Research Aurangabad, India Centre [email protected] Mumbai, India

Rajesh B Sawant MD Path Ratna Sharma Consultant—Transfusion Medicine Professor (Pediatrics) PD Hinduja National Hospital and MRC In-Charge Mumbai, India Pediatric Hematology-Oncology [email protected] Dr DY Patil Hospital [email protected] Navi Mumbai, India [email protected]

Rajiv Kumar Bansal Renu Saxena Consultant Pediatrician Professor and Head In-Charge Thalassemia Unit Department of Hematology Santokba Durlabhji Hospital All India Institute of Medical Sciences Jaipur, India New Delhi, India [email protected] [email protected]

Raj Warrier MD FAAP FIAP Revathi Raj Section Head Consultant Pediatric Hematologist Ochsner, Peds Hem/Onc Apollo Hospitals Ochsner for Children Chennai, India Professor Emeritus and Clinical Professor [email protected] Department of Pediatrics Brothers Louisiana State University Health Sciences Center (LSUHSC) New Orleans, USA Rhishikesh Thakre Professor Consultant Neonatologist Department of Pediatrics Neo Clinic Tulane University School of Medicine Aurangabad, India New Orleans, USA [email protected] Professor Department of Pediatrics University of Queensland, Australia Sadhna Arora Manipal University, India Genetics Unit [email protected] Old OT Block [email protected] Department of Pediatrics All India Institute of Medical Sciences (Late) Ram Kumar Marwaha New Delhi, India Professor [email protected] JaypeeDepartment of Pediatrics In-Charge, Division of Pediatric Saroj P Panda Hematology-Oncology DM Trainee (Pediatric Oncology) Advanced Pediatric Centre Department of Medical Oncology Postgraduate Institute of Medical Education and Research (PGIMER) Tata Memorial Hospital Chandigarh, India Mumbai, India [email protected] [email protected] xii Textbook of Pediatric Hematology and Hemato-Oncology

Satya P Yadav Shripad Banavali Senior Consultant and Head Professor and Head Pediatric Hemato-Oncology and BMT Department of Medical Oncology Unit Tata Memorial Hospital Fortis Memorial Research Institute Mumbai, India Gurgaon, India [email protected] [email protected] [email protected] Sonali Sadawarte SB Rajadhyaksha Consultant Hematologist and BMT Professor and Head Physician Royal Hobart Hospital Department of Transfusion Medicine Hobart, Tasmania, Australia Tata Memorial Hospital [email protected] Mumbai, India [email protected]

Sonika Agarwal Seema Gulia Pediatric Neurology Fellow Assistant Professor Baylor College of Medicine Department of Medical Oncology Houston Tata Memorial Hospital TX, USA Mumbai, India [email protected] [email protected]

Shanaz Khodaiji Soundarya M Consultant Hematology and Transfusion Associate Professor Medicine Department of Pediatrics PD Hinduja National Hospital and MRC Kasturba Medical College Mumbai, India Mangalore, India Consultant Hematologist Brothers [email protected] PD Hinduja National Hospital and Medical Research Centre Mumbai, India Sriram Krishnamurthy [email protected] Associate Professor Department of Pediatrics Shilpa Sanjay Borse MD Jawaharlal Institute of Postgraduate Pediatrics Medical Education and Research Dattatraya Nagar (JIPMER) Nagpur, India Puducherry, India [email protected] [email protected]

Sunil Gomber Shrimati Shetty Director Professor Scientist E Department of Pediatrics National Institute of In-Charge Hematology-Oncology JaypeeImmunohaematology (ICMR) University College of Medical Sciences KEM Hospital Guru Teg Bahadur Hospital Mumbai, India New Delhi, India [email protected] [email protected] Contributors xiii

Sunil Udgire FNB Vineeta Gupta Fellow Associate Professor and In-Charge Department of Hemato-Oncology Pediatric Hematology-Oncology BJ Wadia Hospital for Children Department of Pediatrics Institute of Child Health and Research Centre Institute of Medical Sciences Mumbai, India Banaras Hindu University [email protected] Varanasi, India [email protected] Swati Kanakia MD DCH PhD Pediatric Hematologist-Oncologist VP Choudhary Kanakia Health Care, Lilavati Hospital MD FIAP FIMSA FIACM FISHTM and Research Centre Former Professor and Head Raheja Fortis Hospital Department of Hematology Lion Tarachand Bapa All India Institute of Medical Sciences Hospital, Mumbai, India New Delhi, India [email protected] Director Sunflag Hospital Faridabad, India [email protected]

Brothers

Jaypee Foreword

It is both a pleasure and a privilege to write a foreword for this first edition of Textbook of Pediatric Hematology and Hemato-Oncology. Immense advancement has been made over the past decade in the field of hematology and hemato- oncology providing not only enhanced accuracy in the diagnosis of inherited and acquired malignant and nonmalignant blood disorders but also new therapeutic strategies that have resulted in improved patient outcomes. The book with its illustrations, tables, figures and clinical photographs provides a concise yet thorough comprehension of pediatric hematology and will definitely become a reference book for the students and the practitioners. I congratulate the Editor-in-Chief, MR Lokeshwar; Editors, Nitin K Shah and Bharat R Agarwal; Co-editors, Mamta Vijay Manglani and Anupam Sachdeva; Publication Editor, Asha Pillai and the 72 reputed and dedicated pediatric hematologists and hemato-oncologists from across the world who after 3 years of exhausting brainstorming sessions, brought out the remarkable book with 50 chapters spread over 7 sections. I am sure that the information contained herein will be a benchmark in the understanding of the best approaches to the patients that we evaluate and manage.

SS Kamath President, 2015 Indian Academy of Pediatrics (IAP) [email protected] Brothers

Jaypee Foreword

I am delighted to write the foreword for the first comprehensive book Textbook of Pediatric Hematology and Hemato- Oncology. Postgraduate students look up to their teachers for a book by the editorial team of Doynes in the field of Pediatric Hematology and Hemato-oncology with their vast experience in the field and past experience in writing will fill in this void and meet the expectations of the postgraduate students. The Editor-in-Chief, MR Lokeshwar has been well supported by the other editors, Nitin K Shah, Bharat R Agarwal, Mamta Vijay Manglani and Anupam Sachdeva. The descriptive text along with clinical pictures make it an interesting reading material. It covers a vast spectrum of conditions making it very useful to the reader. I congratulate the entire team which includes the contributors, section editors, editorial board and M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, who have worked relentlessly to achieve this milestone for the book. Above all, my hearty congratulations to the ever-enterprising respected Dr MR Lokeshwar who thought of this brilliant idea of Textbook on Pediatric Hematology and Hemato-Oncology. I wish the best for the success and popularity of the publication among both postgraduate students and practitioners. It will be a landmark publication on Pediatric Hematology Oncology in the history of medical literature.

Vijay N Yewale President, 2014 Indian Academy of Pediatrics (IAP) Brothers

Jaypee Preface

Pediatric Hematology and Hemato-Oncology as a pediatric specialty has developed rapidly in the Western countries since last few decades and is now catching-up in developing countries. Gone are the days when the ‘adult’ hematologists and hemato-oncologists used to treat pediatric patients in need of specialized services. To begin with several pediatricians got self-trained in pediatric hematology and hemato-oncology and pioneered training in field of pediatric hematology and hemato-oncology in the form of several informal and formal courses throughout the country. This created interest in budding pediatricians to join this field by undergoing fellowships or even formal training in pediatric hematology and hemato-oncology abroad and now in India. The last step towards the growth of this specialty has been starting of 2 years of Post-Doctorate Fellowship in Pediatric Hematology and Hemato-Oncology by the National Board in India with several pioneering centers now offering this course since last 7 years, as well as 1 year Post-Doctorate Fellowship by the Maharashtra University of Health Sciences (MUHS) and even by the Indian Academy of Pediatrics (IAP). Several formally trained Pediatric Hematologists and Pediatric Hemato-oncologists are now providing the specialized services in private and public hospitals. With the interest created in the field of pediatric hematology and hemato-oncology, there was also a felt need by the students as well as practitioners alike to have a dedicated textbook on pediatric hematology and hemato-oncology. While there are several reputed textbooks on pediatric hematology and hemato-oncology, many of them are also elaborate and at times bogged down with details of molecular science which may not necessarily fulfill the needs of students and practitioners who are looking at complete yet concise book. With the single aim in mind of having a complete and yet easy-to-read textbook on pediatric hematology and hemato- oncology, we have attempted to bring out the first edition after 3 years of brain-storming and grueling process. The 50 chapters spread over 7 sections and authored by 72 reputed pediatric hematologists and hemato-oncologists from India and abroad make the book elaborate enough to give enough to all the readers, yet curtailing it to more than 500 pages making it concise enough! Further powered by illustrations, tables, figures and clinical photographs will make reading a unique and memorable event for the readers. Each chapter Brothersis further enriched by references at the end and is peer- reviewed making it scientifically as complete as possible. This being the first edition is bound to have some errors which might have escaped our attention in spite of our best efforts. We would request all our readers to send their feedback to us which will help us improve upon in the subsequent editions. We are sure that the book will become a reference book for the students and a desk companion to the practitioners!

Editors

Jaypee Acknowledgments

We would like to express our gratitude to many people who saw us sail through the publication of Textbook of Pediatric Hematology and Hemato-Oncology by providing support, talking things over, read, write, offering comments and helping us in bringing out the book. We wish to especially thank the following people for their contributions: • Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Group President), Mr Tarun Duneja (Director-Publishing) without whom the book would have not found its way, Ms Samina Khan (Executive Assistant to Director-Publishing) for guiding us throughout, Mr KK Raman (Production Manager), Mr Sunil Dogra (Production Executive) and other staff of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, for assisting us in the editing, proofreading and designing skills. • All the authors/contributors mentioned in the list of contributors. • Special thanks to Mr Harish Raut for assisting us in the editing, proofreading and designing skills. • All the patients and families for allowing us to continue to learn the subject. • We would also like to thank our family members for their support. Last but not least, we beg forgiveness of all those who have been with us over the course of years and whose names, we have failed to mention.

Editorial Board Brothers

Jaypee Contents

Section 1 PHYSIOLOGY

1. Ontogeny of Erythropoiesis 3 Nirav Buch 2. Physiology of Blood Coagulation 10 Shrimati Shetty 3. Structure, Function and Physiology of Platelets 15 K Ghosh, Bipin P Kulkarni

Section 2 NEONATAL HEMATOLOGY

4. Variation in the RBC Parameters in the Newborn 23 MR Lokeshwar, Ambreen Pandrowala, Jayashree Mondkar 5. Physiological Anemia of Newborn, Anemia of Prematurity and Role of Erythropoietin in the Management 29 Rhishikesh Thakre, PS Patil 6. Effect of Maternal Iron Status on Placenta, Fetus and Newborn 36 KN Aggarwal, Vineeta Gupta, Sonika Agarwal Brothers 7. Developmental Aspects of Hemostasis in the Fetus and Newborn 41 Bhavna Dhingra, Renu Saxena 8. Anemia in the Newborn 45 Jayashree Mondkar, Shilpa Sanjay Borse, MR Lokeshwar 9. Polycythemia and Hyperviscosity Syndrome 57 MMA Faridi, Sriram Krishnamurthy 10. Vitamin K Deficiency: Bleeding in Newborns 64 Arvind Saili, Ajay Kumar 11. Bleeding Neonate: Approach and Management 68 Mamta Vijay Manglani, Neha Vilas Dighe, Ratna Sharma, MR Lokeshwar 12. Approach to Neonatal Thrombocytopenia 77 Nitin K ShahJaypee Section 3 RBC AND WBC DISORDERS

13. Introduction and Classification of Anemias in Children 87 Manas Kalra, Satya P Yadav, Anupam Sachdeva 14. Nutritional Anemia in Infancy, Childhood and Adolescents 100 MR Lokeshwar, Nitin K Shah xxiv Textbook of Pediatric Hematology and Hemato-Oncology

15. Megaloblastic Anemia 126 Anupa A Joshipura, Nitin K Shah 16. Anemia of Chronic Disease 149 Dilraj Kaur Kahlon, Satya P Yadav, Anupam Sachdeva 17. Thalassemia Syndromes 163 Mamta Vijay Manglani, Ambreen Pandrowala, Ratna Sharma, MR Lokeshwar 18. Sickle Cell Anemia in Children 190 Swati Kanakia, Pooja Balasubramanian, MR Lokeshwar 19. Antenatal Diagnosis of Hemoglobinopathies 204 Neerja Gupta, Sadhna Arora, Madhulika Kabra 20. Red Cell Membrane Disorders (Spherocytosis, Elliptocytosis, Stomatocytosis) 213 Sunil Gomber, Pooja Dewan 21. Red Cell Enzymopathy 219 Bhavna Dhingra, Dinesh Yadav, Jagdish Chandra 22. Autoimmune Hemolytic Anemia 227 Rajiv Kumar Bansal 23. Paroxysmal Nocturnal Hemoglobinuria 238 Farah Jijina, Sonali Sadawarte 24. Diagnosis and Management of Acquired Aplastic Anemia in Children 247 Nitin K Shah 25. Inherited Bone Marrow Failure Syndromes 255 Revathi Raj 26. Benign Disorders of Neutrophils Brothers 258 Bharat R Agarwal

Section 4 BLEEDING DISORDERS

27. Approach to a Bleeding Child 275 Raj Warrier, MR Lokeshwar, Aman Chauhan 28. Diagnosis and Management of Hemophilia Patients 285 Farah Jijina 29. von Willebrand Disease and Other Rare Coagulation Disorders 296 Kana Ram Jat, Ram Kumar Marwaha 30. Acquired Inhibitors of Coagulation 311 ATK Rau, Soundarya M 31. Immune Thrombocytopenic Purpura—Diagnosis and Management 318 MR Lokeshwar,Jaypee Deepak K Changlani, Aparna Vijayaraghavan 32. Platelet Function Disorders 332 Shanaz Khodaiji 33. Pediatric Thrombosis 348 Rashmi Dalvi 34. Disseminated Intravascular Coagulation in Neonates 356 VP Choudhary Contents xxv

Section 5 TRANSFUSION MEDICINE

35. Blood Components in Pediatric Practice 363 Nitin K Shah, Sunil Udgire 36. Nucleic Acid Amplification Testing 372 Anand Deshpande, Rajesh B Sawant 37. Transfusion Transmitted Infections 376 AP Dubey, Malobika Bhattacharya 38. Noninfectious Hazards of Blood Transfusion 384 SB Rajadhyaksha, Priti Desai

Section 6 HEMATO-ONCOLOGY

39. Pediatric Acute Lymphoblastic Leukemia 395 Pankaj Dwivedi, Shripad Banavali 40. Pediatric Acute Myeloid Leukemia 408 Maya Prasad, Shripad Banavali 41. Chronic Myeloid Leukemia 419 Nirav Thacker, Brijesh Arora 42. Juvenile Myelomonocytic Leukemia 430 Gaurav Narula, Nirmalya D Pradhan 43. Pediatric Hodgkin Lymphoma 439 Amol Dongre, Brijesh Arora Brothers 44. Non-Hodgkin Lymphoma in Children and Adolescents 451 Seema Gulia, Brijesh Arora 45. Langerhans Cell Histiocytosis 462 Gaurav Narula, Nirmalya D Pradhan 46. Hemophagocytic Lymphohistiocytosis: Revisited 470 Mukesh M Desai, Sunil Udgire 47. Bone Marrow Transplantation 479 Nita Radhakrishnan, Satya P Yadav, Anupam Sachdeva JaypeeSection 7 GENERAL 48. Gene Therapy 491 Aditya Kumar Gupta, Nita Radhakrishnan, Anupam Sachdeva 49. Monoclonal Antibodies in Pediatric Hematology and Oncology 496 Saroj P Panda, Girish Chinnaswamy 50. Biological Response Modifiers 501 Anupama S Borker, Narendra Chaudhary Index 511 SECTION4

Bleeding Disorders

CHAPTERS OUTLINE 27. Approach to a Bleeding Child Raj Warrier, MR Lokeshwar, Aman Chauhan 28. Diagnosis and Management of Hemophilia Patients Farah Jijina 29. von Willebrand Disease and Other Rare Coagulation Disorders Kana Ram Jat, Ram Kumar Marwaha 30. Acquired Inhibitors of Coagulation ATK Rau, Soundarya M 31. Immune Thrombocytopenic Purpura—Diagnosis and ManagementBrothers MR Lokeshwar, Deepak K Changlani, Aparna Vijayaraghavan 32. Platelet Function Disorders Shanaz Khodaiji 33. Pediatric Thrombosis Rashmi Dalvi 34. Disseminated Intravascular Coagulation in Neonates VP Choudhary Jaypee CHAPTER27

Approach to a Bleeding Child

Raj Warrier, MR Lokeshwar, Aman Chauhan

Hemostasis is maintained by many processes in the Local Versus Systemic circulating blood and the blood vessels designed to stop hemorrhage. These functions are delicately balanced Local cause should be suspected when: so that we will neither clot nor bleed to death. Clotting • Bleeding even if recurrent from the same site, e.g. reactions are initiated in response to injury to vessels and recurrent epistaxis from one nostril may be due to leads to formation of a fibrin platelet plug that stops the excoriation of a superficial vessel in the Kisselbach blood loss but ultimately results in elimination of the clot, triangle. repair of any damage to the vessels and normal blood flow • Nose picking, polyps, foreign bodies (Fig. 1A) or rarely through the affected site. vascular anomalies may cause frequent nose bleeds. Hemostasis involves a complex interplay between the • Profuse prolonged, bilateral nose bleeds that occur vessel wall, platelets, and coagulation factors. Brothersspontaneously without any trauma and are difficult The main three components of hemostasis are: to stop are suggestive of a coagulation defect. Rarely 1. Vascular and extra vascular factors an angiofibroma or Rendu-Osler-Weber (Hereditary 2. Platelets hemorrhagic telangiectasia) may cause profuse epis­ 3. Plasma factors—coagulation factors, fibrinolytic factors, taxis (Figs 1A and B). natural inhibitors of coagulation and fibrinolysis. • Generalized petechiae, purpura, bruising, hematuria Successful management of an acute bleeding episode in especially if associated with past history of bleeding a child depends on: from dental extractions or circumcision should arise • Detailed history and clinical examination leading to suspicion of a bleeding disorder. appropriate diagnostic tests. • Ordering an array of available diagnostic tests without IS THE DEFECT INHERITED OR ACQUIRED? a clinical diagnosis is neither economically viable nor therapeutically ideal. Inherited Disorders • Prompt implementation of therapeutic measures. • Inherited disorders usually present in infancy and early childhood. HISTORY • Family history of bleeding disorder. • SignificanceJaypee of bleeding • Inherited disorers in milder forms may not be seen in • Nature and site of bleeding early infancy and may present later in life with bleeding • Local vs generalized causes following injury or during surgery—mild hemophilia, • Acquired or hereditary disorder von Willebrand disease. • Vascular, platelet or factor deficiency • The development of bleeding later in childhood usually • Is it due to a local cause? indicates an acquired disorder. 276 Section-4 Bleeding Disorders

liver dependent factors. Medication can also exacerbate bleeding in those with existing coagulation defects—use of aspirin in patient with hemophilia or low platelets.

INDICATIONS FOR EVALUATION Investigations for bleeding disorders are done when there is: • Recent bout of bleeding—unusual, spontaneous, pro­ longed, or delayed bleeding. Postsurgical and trau­ matic bleeding that is unexpected, prolonged or disproportionate to extent of injury. • Family history of bleeding • Abnormal coagulation test results obtained as a part of preoperative evaluation—preparation for surgery or invasive procedures A B • Systemic diseases known to be associated with bleed­ Figs 1A and B (A) Persistent recurrent bleeding from left nostril ing disorders, e.g. liver disorder, renal disorder, DIC due to foreign body; (B) Bleeding from both nostrils and over the and sepsis, etc. skin (DIC) (Courtesy: MR Lokeshwar) Is the Bleeding due to Vascular, Platelet or a Acquired Disorders Coagulation Abnormality or a Combination of • Usually present later in life. Immune thrombocyto­ these? penic purpura (ITP) may however present during early Vascular disorder, thrombocytopenia or functional platelet childhood, i.e. 3 to 5 years of age. disorders: • Have a negative family history. • Usually in the form of subcutaneous and mucus • Underlying medical disorder that may affect hemo­ membrane bleeds like petechiae, purpura (Fig. 2C), stasis. ecchymoses, epistaxis and subconjunctival hemorrhage – Hepatic disorders, malabsorption syndrome, may (Fig. 2B) be associated with vit. K dependent coagulation • Brothers Mucous membrane bleeding and menorrhagia can factors. occur in von Willebrand disease also. – Renal disease: Uremia can interfere with platelet Factor deficiency: function. • Hematomas (Fig. 3): Intramuscular, soft tissue bleeding – Low-molecular-weight coagulation proteins (factors • Hemarthrosis, retroperitoneal bleeds IX and XI) are lost through the kidney in children • Post-traumatic bleeds are often delayed, some times with nephrotic syndrome. hours after the injury. – Cyanotic congenital heart disease with polycy­ Mucous membrane bleeding (epistaxis, excessive themia may have thrombocytopenia and hypofibri­ menorrhagia, bleeding from gums) is often the conse­ nogenemia with risk of bleeding and or thrombosis. quence of a problem with primary hemostasis. Namely a • Infections: Meningococcemia with DIC platelet disorder or von Willebrand disease (VWD). • A detailed menstrual history should be obtained when • Hereditary hemorrhagic telangiectasia may also be applicable. The prevalence of bleeding disorders manifested as mucosal bleeding in women with menorrhagia is as high 20 percent • Umbilical stump bleeding is typically seen with factor conversely; menorrhagia is a common initial symptom XIII deficiency, but it may also occur with deficiencies in women with VWD and has been reported to occur of prothrombin, factor X, and fibrinogen more than 90 percent of patients. • The immediate history often provides useful clues • Past surgicalJaypee procedures, serious injuries, fractures to diagnosis. A sick child with fever, shock, mucocu­ and tooth extractions without any abnormal bleeding taneous purpura frequently has intravascular coagu­ is good evidence against the presence of a congenital lation (DIC) (Fig. 6) associated with bacterial infection. hemorrhagic disorder. • Medications: Aspirin and other nonsteroidal anti- Family History of Bleeding inflammatory agents affect platelet aggregation. Pro­ longed use of antibiotics can lead to decreased levels of History of unusual bleeding in family members is present vitamin K deficiency leading to decreased production of in hemophilia, von Willebrand and platelet function Chapter-27 Approach to a Bleeding Child 277

A B C Figs 2A to C (A) Bleeding in the knee joint; (B) Subconjunctival hemorrhage; (C) Purpura (Courtesy: MR Lokeshwar)

Proper pedigree chart, covering at least 2 to 3 genera­ tions also should take note of members who have expired, especially due to bleeding.

X-linked Recessive Pattern Maternal brothers, cousins, uncles and maternal grand­ father may be affected with X-linked transmission while the females remain asymptomatic carriers. Bleeding disorders which have a sex-linked recessive inheritanceBrothers are: • Hemophilia A (factor VIII deficiency) • Hemophilia B (factor IX deficiency) • Wiscott-Aldrich’s syndrome. Fig. 3 Cephalhematoma in bleeding disorder Autosomal recessive disorders: In autosomal recessive (Courtesy: MR Lokeshwar) disorders, the parents of affected person are heterozygote and hence have a 50 percent plasma concentration of the relevant clotting factors. History of consanguinity should be asked for. This genetic pattern is typical of disorders of factor II, V, VII, X, XI, XII, XIII, prekallikrein and high molecular weight kininogens. However, lack of plasma factor XII, prekallikrein or high molecular weight kininogens do not usually cause any clinically significant bleeding.

Autosomal Dominant Pattern of Inheritance Jaypee • Von Willebrand disease Fig. 4 Hemorrhagic disease of newborn • Qualitative platelet defects (Courtesy: MR Lokeshwar) • Dysfibrinogenemia • Hereditary hemorrhagic telangiectasia. disorders. Approximately a third of infants and young This type of inheritance may show a variable pene­ children with newly diagnosed hemophilia have a negative trance and expressivity. Many members in different gene­ family history. rations of the family may be affected. 278 Section-4 Bleeding Disorders

A B C Figs 5A to C (A and B) Bleeding in the joints in hemophilia; (C) Glanzmann’s thrombasthenia (Courtesy: MR Lokeshwar)

• A well-looking child covered with petechiae often has immune thrombocytopenia (Figs 2C and 9) • Hematuria with bruising localized to the gluteal region, ankles, and feet—Henoch-Schönlein purpura (Figs 10A and B).

ASSOCIATED UNDERLYING DISORDERS Certain characteristic hemostatic defects are associated with specific clinical conditions. • Liver diseases with factor II, VII, IX and X deficiency and Brothersfibrinolysis due to decreased clearance of activators and hypercoagulable state because of antithrombin III and protein C deficiency. • Malabsorption states may be associated with multiple factor deficiencies, i.e. Vitamin K dependent factors. Fig. 6 Intravascular coagulation (DIC) (Courtesy: MR Lokeshwar) • Acute promyelocytic leukemia is known to be associ­ ated with DIC due to increased cellular procoagulant activities. • Negative family history does not rule out the possibility • Myeloproliferative disorder may have platelet defects, of inherited bleeding disorders. thrombocytopenia and thrombocythemia. • Family history might be negative, if the coagulation • Amyloidosis may be associated with factor X deficiency defect is mild. and capillary fragility. • Spontaneous mutation, as is seen in 20 percent of • Systemic lupus erythematosis—antibody to acidic patients with hemophilia A phospholipase, autoantibodies to coagulation proteins • Exsanguinating bleeding is uncommon due to bleeding and glycoproteins may be present, resulting in lupus disorders and is more likely to be due to injury to major inhibitors, factor deficiency, thrombocytopenia and vessels. thrombocytopathy. History andJaypee physical examination can often help you make a specific diagnosis and point one to the right diagnostic tests. CERTAIN SYNDROMES KNOWN TO BE • A male toddler who has just started crawling exhibits ASSOCIATED WITH BLEEDING DISORDERS extensive bruising and or joint bleeding—diagnosis hemo­philia A or B (Figs 2A, 5A and B) • Hereditary hemorrhagic telangiectasia is associated • A girl who has had severe menorrhagia with frequent with characteristic telangiectatic lesions in the nose bleeds—possible VWD mucus membrane and skin and may manifest with Chapter-27 Approach to a Bleeding Child 279

A

Fig. 7 von Willebrand disease (Courtesy: MR Lokeshwar)

BrothersB Figs 10A and B Henoch-Schönlein purpura (Courtesy: MR Lokeshwar)

epistaxis, melena and bleeding per rectum. Presence Fig. 8 Qualitative platelet defects (Glanzmann’s thrombasthenia) of telangiectasia in the mucous membrane of nose, (Courtesy: MR Lokeshwar) bulbar conjunctiva, tongue, lips and tips of fingers is the hallmark of diagnosis. • Keloids may be seen in children with afibrinogenemia and factor XIII deficiency. • Cigarette paper scar, hyperextensible joints suggest Ehler-Danlos syndrome. • Presence of syndactyly with history of bleeding episode is known to be due to factor V deficiency. • Wiskott-Aldrich syndrome (Fig. 11A) is associated with thrombocytopenia,­ recurrent infection, otitis media, Jaypee and eczema. • Children with albinism may have qualitative functional defects of platelets. • Thrombocytopenia with absent radius (TAR syndrome) is easy to diagnose because of skeletal anomaly. • Kasabach-Merritt syndrome is characterized by giant hemangioma associated with evidence of clinical Fig. 9 Immune thrombocytopenic purpura and subclinical DIC and thrombocytopenia (Figs 11B (Courtesy: MR Lokeshwar) and C). 280 Section-4 Bleeding Disorders

A B C

Figs 11A to C (A) Wiskott-Aldrich syndrome; (B and C) Kasabach-Merritt syndrome (Courtesy: MR Lokeshwar)

Hemarthrosis (spontaneous), bleeding in the muscles Table 1 Screening laboratory tests in hemostatic disorders without significant trauma points towards inherited Platelet BT PT APTT Interpretation coagu­lation disorders. ↓ ↑ Normal Normal Thrombocytopenia ↓ ↑ ↑ ↑ DIC LABORATORY ASSESSMENT (TABLE 1) ↓ ↑ Normal ↑ Type 2A vWD Sample Collection and Technique Normal ↑ Normal ↑ vWD Platelet Normal ↑ Normal Normal • A properly drawn blood sample is crucial for Dysfunction interpretation of the results of coagulation test. NormalBrothersNormal ↑ Normal Factor VII deficiency • For coagulation assays blood should be obtained by Normal Normal Normal ↑ XII, XI, IX, VIII clean venipuncture without air bubbles and without Liver disease, Vit K Normal Normal ↑ ↑ contamination by tissue fluids def, Combined def • Drawing of samples from catheter often results in Normal Normal Normal Normal XIII def, vascular ‘sample contamination or intravenous fluids and spuriously abnormal values • Screening tests are done after evaluating the nature • Improper sample collection is one of the most common and clinical circumstances of bleeding and prior to reasons for abnormal coagulation test surgery if indicated • Samples should be tested within 2 hours of collection • Specific tests need to be done to confirm the diagnosis if maintained at room temperature or within 4 hours if after the history, physical examination and screening kept cold test point to a possible diagnosis. • Plasma samples must be frozen if not tested within this time frame. When they are to be analyzed, frozen samples should be rapidly thawed at 37°C and tested Screening Tests immediately These are the tests for the initial assessment for bleeding • A panel of screening tests should be ordered, including tendency and include: a completeJaypee blood count with evaluation of platelet • CBC and PS examination number, morphology-smear examination, PT, APTT, • Platelet count PFA (Platelet function analysis). • Bleeding time/PFA Though a thorough history and clinical evaluation • Clot retraction helps in suspecting the nature and type of bleeding • Prothrombin time/INR disorder, laboratory investigations are required to make a • APTT. specific diagnosis, they can be conveniently divided into CBC can reveal involvement of other cell lines in cases screening tests and special tests. suspected to have leukemia, aplastic anemia, etc. Chapter-27 Approach to a Bleeding Child 281

Proper Smear Examination also helps in Evaluating The most widely used method is the modified ivy BT Extent of Thrombocytopenia if Present performed with a template. The BT is performed with a tourniquet maintained at 40 mm Hg and placement of the • Presence of clumps of platelets rules out platelet template device on an area of the forearm (Just below the deficiency and absence of platelets indicates severe elbow), blade makes a linear cut 1 to 2 mm deep. thrombocytopenia usually less than 10,000–20,000/ With a stop watch and filter paper, the blood coming cumm from the cut is gently blotted away while taking care to not • Presence of platelets but not in clumps—indicates touch the filter paper to the cut (which would remove the absence of aggregation, suggesting platelet functional fragile platelet plug). A normal BT is 3 to 9 minutes with disorder normally functioning platelets. The BT is an approximate • Large platelets simulating size of the lymphocytes measure of the relationship between platelet number and suggest possibility of Bernard-Soulier syndrome function. • Large platelets also indicate younger platelets as seen Prolongation of bleeding time usually occurs at platelet in regenerative type of thrombocytopenia where there count of < 50,000/cumm to 100,000/uL. At counts below is peripheral destruction of platelets 10,000/cumm, bleeding time is usually prolonged and is • Large platelets are also seen in the hereditary giant often 15 minutes or longer and hence BT should not be platelet syndromes performed when platelets are low. • Small platelets are characteristic Wiskott-Aldrich The BT can also be prolonged with congenital and syndrome. acquired platelet defects.

Platelet Count Prolonged Bleeding Time with Nearly Normal Platelet Count • It is a simple first step in evaluating the cellular aspect of hemostasis Qualitative Platelet Disorders (Table 2) • However, manual count is not reliable and not • Glanzmann’s thrombasthenia (Figs 5C and 8) reproducible and hence platelet count should be • Bernard-Soulier syndrome done on particle cell counter or using phase contrast • Storage pool disorder microscope • Wiskott-Aldrich syndrome • A spuriously low automated platelet count (pseudo • Brothers Acquired defects, uremia and cyanotic congenital thrombocytopenia) may result from ethylene diamine heart disease tetra acetic acid (EDTA) anticoagulant plus an IgG or • Vasculitis (e.g. Henoch-Schönlein purpura) 1gM platelet antibody, platelet cold agglutinins, or • Connective tissue disorders such as Ehlers-Danlos platelet clumping from a partially clotted sample. The syndrome normal platelet count (for all ages) ranges from 150,000 • Drugs like aspirin and nonsteroidal anti-inflammatory to 450,000/uL agents • In the setting of thrombocytopenia increased or • Von Willebrand disease (Fig. 7). decreased platelet size may suggest platelet turnover Bleeding time has been replaced by the platelet or decreased production, respectively function analyzer (PFA) which is a rapid and automated • If platelet type of bleeding (petechiae, purpura, form of platelet function assessment. mucosal bleeding) is seen with normal platelet count or Clot retraction: This is not any more a commonly marginally low platelet count, then platelet functional ordered test as a screening or diagnostic test any more. disorders should be kept in mind. Retraction and exudation of the serum after one hour • Electronic particle counters also provide a mean is observed in the clotting tube. Normally, 50 percent platelet volume and (size) distribution. exudation at the end of one hour of the original blood Jaypee volume is taken as normal retraction. Bleeding Time Prothrombin Time The bleeding time (BT) is a measure of the interaction of platelets with the blood vessel wall. This test evaluates Normal (reference) range varies depending on the labora­ primary hemostatic stage. It has major drawbacks and has tory (its instrumentation and the lot of thromboplastin), been discarded in children by most hematologists. but it is generally 10 to 11 seconds. The BT is an approximate measure of the relationship • PT measures extrinsic clotting system and the common between platelet number and function. pathway, the activities of factors I (fibrinogen), II 282 Section-4 Bleeding Disorders

Table 2 Platelet aggregation response Comment/ Condition Platelet Aggregation with Further tests Count Size ADP Col Ri AA A23187 IIb/IIa Thrombasthenia N N 0 0 1 0 0 expression Bernard-Soulier Low Large N N O N N Gp1b expression syndrome Storage pool N N 1 R 1 1/0 R ATP: ADP pools defect (d) Cyclo- Responds to oxygenase N N 1/N R N R R endoperoxide deficiency Thromboxane synthetase N N 1/N R N R/0 N deficiency Aspirin ingestion NSAID N N 1 R N R/0 N/R Stop aspirin and retest Ehlers-Danlos N N N N N N N syndrome von Willebrand Assay vWF:Ag N N N N 0/R N N disease and RiCoF

(prothrombin), V, VII, and X. PT is prolonged with to 54 seconds) in term infants (and often even longer in deficiencies of plasma factor VII, X, V, II and fibrinogen premature infants). and inhibitors of these factors The APTT measures factors I (fibrinogen), II (pro­ • Prolongation of the PT beyond the reference range is thrombin),Brothers V, VIII, IX, X, XI, and XII; prekallikrein; and not generally seen until the functional level of one of high-molecular-weight kininogen. these factors is less than 30 percent or until fibrinogen is less than 100 mg/dL Activated Partial Thromboplastin Time is • A prolongation of PT with normal PTT indicates factor Prolonged VII deficiency OR early in the course of anticoagulant therapy, Vitamin K deficiency (Fig. 4) or liver diseases • During deficiency or abnormalities of high molecular • The PT is also used to monitor the effect of coumarin- weight kininogen, prekallikren, factor XII and XI, IX, type anticoagulants. VIII, X, V, II and fibrinogen • By inhibitors of blood coagulation such as lupus inhib­ Activated Partial Thromboplastin Time itors, heparin, fibrin/fibrinogen degradation product • Deficiency of any of the latter three factors (prekal­ Activated partial thromboplastin time (APTT) is an likrein; and high-molecular-weight kininogen) can excellent screening test for determining abnormality of result in a markedly prolonged APTT in the absence of intrinsic and common pathway. clinically significant bleeding • It should be noted that the sensitivity and repro­ • Isolated prolongation of the APTT in a patient with ducibility of the APTT are highly dependent on the clinical bleeding is likely to result from a deficiency of specific reagentsJaypee used (particularly the activator in the factor VIII, IX, or XI. partial thromboplastin reagent) Mixing study in prolonged PTT: The presumption • With most APTT reagents, the APTT will not he is that addition of normal plasma to a 50 percent mix prolonged until the amount of factor VIII is less than should correct the PTT if it is due to factor deficiency. 35 percent (0.35 U/mL). Among hospitalized infants or children, unintentional The reference range will generally be approximately contamination of patient samples with heparin is a 20 to 35 seconds for children and adults but longer (30 common cause of an unexpected prolongation of the APTT Chapter-27 Approach to a Bleeding Child 283 that does not correct on mixing. Failure to correct after aggre­gation with ADP, epinephrine and collagen but a mix of 50 percent of normal plasma is indicative of the absence of platelet aggregation with ristocetin but with presence of inhibitors or antibody that indiscriminately normal levels of von Willebrand factor. (not specific against any factor) suppresses fibrin formation In Glanzmann’s thrombasthenia, the patient’s platelets in patients and normal plasma. Lupus anticoagulant (a will agglutinate normally with ristocetin but not at all with misnomer as it is not necessarily associated with SLE) is a the addition of adenosine diphosphate, epinephrine, very common cause of isolated prolonged PTT in children collagen, or arachidonic acid. In Bernard-Soulier synd­ with adenotonsillar hypertrophy and infections. rome, platelet agglutination will occur normally on addi­ tion of each of these agonists except ristocetin. Thrombin Clotting Time Bleeding disorders not associated with any abnor-­ malities in screening tests are: The thrombin clotting time (TCT or TT) measures the • Factor XIII deficiency thrombin-induced conversion of fibrinogen to fibrin and • Alpha 2 antiplasmin deficiency, amyloidosis (may or is performed by adding bovine thrombin to the patient’s may not be associated with factor X deficiency) citrated plasma and recording the clotting time. • Vascular disorders like hemorrhagic telangiectasia An extremely prolonged TT usually indicates a heparin (Rendu-Osler-Weber syndrome) effect. Reptilase, a snake venom protease, clots fibrinogen • Scurvy—prolonged BT in the presence of heparin and thus can be used to • Ehlers’-Danlos syndrome—prolonged BT identify heparin as the cause of a prolonged TT. Thus, in • Henoch-Schönlein’s purpura—prolonged BT the presence of heparin the TT is prolonged, whereas the • Mild factor deficiencies—factor assay reptilase time is normal. • Battered baby syndrome (Figs 12A and B).

Thrombin Clotting Time is Abnormal in Patients Special Confirmatory Tests with • Specific coagulation factors: Each of the coagulation • Hypofibrinogenemia whether acquired or congenital or factors of the intrinsic pathway (prekallikrein, high- • Dysfibrinogenemia molecular–weight kininogen, and factors VIII, IX, XL, and • In presence of inhibitors like heparin, myeloma XII) can be measured by one stage, APTT based method proteins and fibrin degradation products which block • Brothers FDPs are usually measured in serum samples because either thrombin cleavage of fibrinopeptide or fibrin these degradation products consist predominantly of monomer polymerization. nonclottable derivatives that remain in solution after clot • A normal or minimally low platelet count with • The D-dimer assay will identify only cross-linked FDPs prolonged BT or abnormal PFA and poor clot retraction (indicating that fibrin has formed intravascular, has indicates the possibility of platelet functional disorders been cross-linked, and has then been cleaved into • Platelet aggregation studies: Low and high concen­ D-dimers by plasmin tration of ADP, epinephrine, collagen and Ristocetin • Euglobulin clot lysis time. are used for aggregation studies. First phase of aggre­ The euglobulin clot lysis time (ECLT) is a screening gation is induced by low concentration of ADP and by test for excessive fibrinolysis. The normal ECLT is 60 to direct effect of certain agents notably epinephrine and 300 minutes. It is shortened in conditions characterized

thrombin. Second phase is mediated by throm­boxane A2 by increased fibrinolysis (e.g. antiplasmin deficiency, and endogenous ADP released in response to numerous plasminogen activator inhibitor 1 deficiency or systemic pharmacological and naturally occurring­ substance fibrinolysis). like ADP itself. Absence of first phase of aggregation— Lupus anticoagulant: Abnormal mixing study followed unresponsiveness to ADP in any concen­tration is by dilute russel vipor venom test (DRVVT) and platelet characteristic of Glanzmann’s disease. Deficiency of neutralization procedure (PNP) and for confirmation. platelet fibrinogenJaypee and specific glycoproteins GP-II Solitary thrombocytopenia may be due to either: and GP-III confirm the diagnosis • Reduced production or increased destruction of the • von Willebrand disease has characteristic lack of platelets aggregation with ristocetin alone • Idiopathic thrombocytopenic purpura is characterized • The classical laboratory findings in Bernard-Souiler by acute onset of isolated thrombocytopenia in other­ syndrome are—prolonged bleeding time, throm­ wise healthy children. Other cell lines are normal and bocytopenia, very large platelets on peripheral smear, the smear reveals normal RBC, white cells with low deficient platelet adhesion and normal platelet number of platelets and occasional macrothrombocytes 284 Section-4 Bleeding Disorders

A B Figs 12A and B Battered baby syndrome—hematoma over the forehead and punch mark over the thigh (Courtesy: Raj Warrier)

• Thrombocytopenia due to decreased production may BIBLIOGRAPHY be either due to involvement of only megakaryocytes 1. Blanchette V, Bolton-Maggs P. Childhood immune as seen in TAR syndrome or in amegakaryocytic thrombocytopenic purpura: diagnosis and management. thrombocytopenic purpura and is characterized by Pediastr Clin N Am. 2008;55:393-420. thrombocytopenia and platelet type of bleeding. 2. James AH, Manco-Johnson MJ, Yawn BP, Dietrich JE, Nichols WL. von Willebrand disease: key points from the CONCLUSION 2008 National Heart, Lung, and Blood Institute guidelines. Obstet Gynecol. 2009;114(3):674-8. Review. Detailed history, thorough clinical examination and 3. Petrini P, Seuser A. Haemophilia care in adolescents- screening tests usually give sufficient information to Brotherscompliance and lifestyle issues. Haemophilia. 2009;15 decide, whether bleeding is due to local causes or a (Suppl 1):15-9. Review. generalized bleeding disorder. 4. Rodeghiero F, Kadir RA, Tosetto A, James PD. Relevance Depending upon type and nature of the bleeding of quantitative assessment of bleeding in haemorrhagic disorder, further tests such as factor assay, aggregation disorders. Haemophilia. 2008;14(Suppl 3):68-75. Review. 5. Rossbach HC. The rule of four: a systematic approach to tests, etc. have to be carried out to confirm the diagnosis diagnosis of common pediatric hematologic and oncologic before planning therapy. disorders. Fetal Pediatr Pathol. 2005;24(6):277-96. Review.

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