A Practical Guide
Pediatric Hematology
1st Edition
2021
A Practical Guide I Pediatric Hematology
i
Copyright © 2021 Muhammad Matloob Alam.
All rights reserved. This book or any portion thereof may not be reproduced or used in any
manner whatsoever without the express written permission of the publisher except for the
use of brief quotations in a book review.
The editor and the authors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. In no way this book should
replace the consultation of original publications, text books or updated product information.
The editor and authors disclaim any representations or warranties of any kind and accept
no responsibility or liability of any acts or omission resulting from reliance on the
information provided in this handbook.
ISBN: 978-969-23633-0-3
A Practical Guide I Pediatric Hematology
ii
A Practical Guide
Pediatric
Hematology
FIRST EDITION
2021
Edited by
Muhammad Matloob Alam
MBBS, FCPS (ped), FCPS (pho), SBPHO
Pediatric Hematologist/Oncologist
Division of Pediatric Hematology, Oncology and
Bone Marrow Transplantation
Department of Oncology
King Faisal Specialist Hospital & Research Center
Jeddah, Saudi Arabia
dr.matloobalam@hotmail.com
A Practical Guide I Pediatric Hematology
iii
Preface
This handbook is an overview of diagnostic approaches and treatment guidelines.
We hope this handbook will provide trainees in pediatric hematology, as well as
staff in related medical or other healthcare disciplines, with an easily accessible
and practical source of information about the basic principles of childhood
hematological disorders, as well as much of the more detailed specialist
knowledge required to care for children with these conditions.
This handbook is divided into seven sections: Anemia, bleeding disorder, platelets
disorders, thrombosis, white blood cells disorders and miscellaneous topics i.e.
neonatal hematology, hematopoietic stem cell transplantation, vascular
anomalies, blood products and morphology. The book concludes with a general
information section, including information about normal values of laboratory tests,
inheritance pattern of pediatric hematological disorders, and some helpful
guidelines for corticosteroid therapy, febrile neutropenia, bleeding assessment
and procedures.
To preserve their easy readability, the text remains structured using short
sentences in bullet points. Detailed mechanistic explanations or descriptions of
the original data underlying recommendations have been avoided. However, all
relevant references are listed at the end of each chapter. Many figures, schematic
diagrams, boxes and tables enhance the usefulness of the text, as does readerfriendly design.
We hope you find it useful.
Muhammad Matloob Alam
On behalf of all the contributors
A Practical Guide I Pediatric Hematology
iv
Dedication
To my families
Salma, my loving mother, thank
you for your endless encouragement and prayers.
Alamgir, my wonderful father,
you are example of insurmountable strength.
Riffat, my wife, thank you for giving me your
unwavering support and unconditional love, you have
given me a better life—and family—than I ever
thought possible.
Maryam, Sarah, Zehra and Yousuf,
you are the light of my life.
And
To my patients and their families
And
To my colleagues, mentors and teachers
who have taught me so much over the years.
A Practical Guide I Pediatric Hematology
v
List of Contributors
Abdullah Al Jefri
Consultant, Pediatric Hematology/BMT
King Faisal Specialist Hospital & Research
Center
Associate Professor, Al Faisal University
Riyadh, Saudi Arabia
Abdul Hafeez Siddiqui
Consultant, Pediatric Hematology/Oncology
American Hospital Dubai
Dubai, UAE
Abdulrhman Alathaibi
Consultant, Pediatric Hematology/Oncology
Department of Hematology/Oncology
Alhada Military Hospital
Taif, Saudi Arabia
Abrar Aljunaid
Pediatric Hematologist/Oncologist
Division of Pediatric Hematology/Oncology
King Faisal Specialist Hospital & Research
Center
Jeddah, Saudi Arabia
Ahmad Mohamamd Tarawah
Consultant, Pediatric Hematology/Oncology
Department of Pediatric Hematology
Madinah Hereditary Blood Disorders Center
King Salman Medical City
Al Madinah Al Munawwarh, Saudi Arabia
Amal Alseraihy Alharbi
Consultant Pediatric Hematology/
Oncology/HSCT
Division of Pediatric Hematology/Oncology/BMT
King Faisal Specialist Hospital & Research
Center
Jeddah, Saudi Arabia
Asim Abdullah Alamri
Consultant, Pediatric Hematology/Oncology
Maternity and children Hospital
King Abdullah Medical City
Al Madinah Al Munawwarh, Saudi Arabia
Azzah Al-Zahrani
Consultant, Pediatric Hematology/Oncology
Head of Pediatrics Hematology
Prince Sultan Military Medical City
Riyadh, Saudi Arabia
Basheer Ahmed Cittana Iqbal
Consultant, Pediatric Hematology/Oncology
Prince Mohammad Bin Nasser Hospital
Jizan, Saudi Arabia
Bushra Moiz
Professor
Section of Hematology and Transfusion Medicine
Department of Pathology and Laboratory
Medicine
Aga Khan University, Karachi, Pakistan
Ali Alomari
Consultant, Pediatric Hematology/Oncology
King Abdullah Specialized Children Hospital
Department of Pediatric Hematology/Oncology
Riyadh, Saudi Arabia
Col Tariq Ghafoor
Consultant Pediatric Oncologist & Stem Cell
Transplant Physician
Armed Forces BMT Centre (AFBMTC)
National Institute of BMT (NIBMT)
Head of Pediatric Oncology, Combined
Al-Jawhara Al-Manea
Military Hospital
Consultant, Pediatric Hematology/Oncology
Professor of Pediatrics, Army Medical College
Section Head of Pediatric Hematology/Oncology Rawalpindi, Pakistan
Department of Pediatrics
King Fahad Armed Forces Hospital
Jeddah, Saudi Arabia
A Practical Guide I Pediatric Hematology
vi
Eman Rashid M Taryam Alshamsi
Consultant, Pediatric Hematology/Oncology
Al Qassimi Women’s & Children’s Hospital
Sharjah, UAE
Fahad M Alabbas
Consultant, Pediatric Hematology/Oncology
Division of Hematology/Oncology,
Department of Pediatric
Prince Sultan Military Medical City
Riyadh, Saudi Arabia
Farrukh Ali Khan
Assistant Professor
Department Head of Clinical Hematology & Bone
Marrow Transplantation
National Institute of Solid Organ & Tissue
Transplant
Dow University of Health Sciences
Karachi, Pakistan
Fawwaz Khalid Yassin
Consultant, Pediatric Hematology/Oncology
Sheikh Khalifa Medical City
Abu Dhabi, UAE
Fauzia Rehman Azmet
Consultant Pediatric Hematology/Oncology
King Saud Medical City
Riyadh, Saudi Arabia
Hassan A. Al-Trabolsi
Head Section and Consultant,
Hematology/Oncology
Department of Oncology
King Faisal Specialist Hospital and
Research Center
Jeddah, Saudi Arabia
Khalid Abdalla
Consultant, Pediatric Hematology/Oncology
Princess Nourah Oncology Centre
King Abdulaziz medical City
Jeddah, Saudi Arabia
Laila Metwally Sherief
Professor of Pediatric Hematology and Oncology
Pediatrics Department, Faculty of Medicine,
Zagazig University Egypt
Lamis Hani Elkhatib
Senior Registrar
Pediatric Hematology/Oncology
Dr Soliman Fakeeh Hospital
Jeddah, Saudi Arabia
Lujain Talib Al Judaibi
Fellow Pediatric Hematology/Oncology
Pediatric King Faisal Specialist Hospital and
Research Center
Jeddah, Saudi Arabia
Huda Abdulhameed El-Faraidi
Consultant Pediatric Hematology and BMT
Prince Sultan Military Medical City (PSMMC)
Riyadh, Saudi Arabia
Hwazen Shash
Assistant Professor
Consultant, Pediatric Hematology/Oncology
King Fahad Hospital of the University
Imam Abdulrahman Bin Faisal University
Khobar, Saudi Arabia
A Practical Guide I Pediatric Hematology
Ibraheem Abosoudah
Consultant, Pediatric Hematology/Oncology
and BMT
King Faisal Specialist Hospital and Research
Center
Department of Oncology
Jeddah, Saudi Arabia
Iman Ragab
Professor of Pediatrics
Ain Shams University, Pediatric Hospital
Hematology Oncology Unit
Cairo, Egypt
Marwa Ibrahim Ali Elhadidy
Clinical Pharmacist; Pediatric Hematology/
Oncology and BMT
Division of Pharmaceutical Care
Department of Clinical Pharmacy
King Faisal Specialist Hospital & Research
Centre, Jeddah, Saudi Arabia
Mohammad Al-Shahrani
Consultant, Pediatric Hematology/Oncology
and BMT
Department of Pediatrics,
Pediatric Oncology Division
Prince Sultan Military Medical City Riyadh
Riyadh, Saudi Arabia
vii
Mohamed Bayoumy
Consultant, Pediatric Hematology/
Oncology/BMT
Department of Oncology
King Faisal Specialist Hospital & Research
Centre
Jeddah, Saudi Arabia
Mona Abdulwahab AlSaleh
Clinical Assistant professor
Consultant, Pediatric Hematology/Oncology
Department of Pediatrics
King Fahad Hospital of Imam Abdulrahaman
Bin Faisal University
Khobar, Saudi Arabia
Mona Ahmed Bahasan
Pediatric infectious disease
Assistant consultant
Department of Pediatric
King Faisal Specialist Hospital & Research
Center
Jeddah, Saudi Arabia
Mouhab Ayas
Head, Section of stem cell transplant and
cellular therapy
Department of Pediatric Hematology Oncology
Associate Professor, Al-Faisal University
Riyadh, Saudi Arabia
Muhammad Matloob Alam
Pediatric Hematologist/Oncologist
Division of Pediatric Hematology/Oncology
and BMT
King Faisal Specialist Hospital &
Research Center
Jeddah, Saudi Arabia
Muhammad Rahil Khan
Pediatric Hematologist/Oncologist
King Faisal Specialist Hospital &
Research Center
Al Madinah, Saudi Arabia
Murtada Hijji Alsultan
Consultant, Pediatric Hematology/Oncology
Ministry of Health, Qatif Central Hospital
Riyadh, Saudi Arabia
A Practical Guide I Pediatric Hematology
Naima Ali Al-Mulla
Pediatric Hematology and Oncology
Senior attending
Sidra Medicine and Hamad Medical Corporation
Doha, Qatar
Ohoud Fouad Kashari
Consultant, Pediatric Hematology Oncology
East Jeddah General Hospital
Jeddah, Saudi Arabia
Quratulain Riaz
Consultant, Pediatric Hematology Oncology
National Institute of Blood Diseases and BMT
Karachi, Pakistan
Rahat-Ul-Ain
Assistant Professor
Consultant, Pediatric Hematology/Oncology
Department of Pediatric Hematology Oncology
and BMT
The Children's Hospital and Institute of Child
Health, Lahore, Pakistan
Riffat Matloob
General Pediatrician
Ex resident; Aga Khan University Hospital
Karachi, Pakistan
Saleh Nouh Alshanbari
Consultant Pediatric Hematology/ Oncology
Maternity Children Hospital
Makkah, Saudi Arabia
Salmin Muftah
Consultant Hematopathologist
King Faisal Specialist Hospital &
Research Center
Jeddah, Saudi Arabia
Sami Hussain Albattat
Consultant, Pediatric Hematology/Oncology
Maternity and Children Hospital
Alhassa, Saudi Arabia
Shahbaz Latif Memon
Senior Clinical Fellow (Clinical Associate)
Pediatric Hematology/Oncology and Bone
marrow transplant
The Hospital for Sick Children
University of Toronto, Ontario, Canada
viii
S.M. Wasifuddin
Consultant, Pediatric Hematology/Oncology
National Oncology Centre
Royal Hospital
Muscat, Oman
Zehra Fadoo
Professor Pediatric Hematology/Oncology
Chair and Service Line Chief of Department of
Oncology
Aga Khan University Hospital
Karachi, Pakistan
Zaheer Ullah
Consultant, Pediatric Hematology/Oncology
Fellowship Program Director
King Fahad Medical City
Riyadh, KSA
A Practical Guide I Pediatric Hematology
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Table of Contents
Front Matters……………………………………………………………..……i
Preface……………………………………………………………….…….... iv
Dedication……………………………………………………………………. v
List of Contributors……………………………………………….………… vi
Table of Contents ……………………………………………………….…x
Abbreviations…………………………………………………..………..….xiii
Section I
Anemia
Chapter 1
Anemia in Children: A Diagnostic Approach……………………...…..2
O Kashari, MM Alam, M Riffat
Chapter 2
Nutritional Anemia………………………………………………………….8
MM Alam, M Riffat, O Kashari
Chapter 3
Bone Marrow Failure Syndromes: Aplastic Anemia………………..17
MM Alam, AR Alathaibi, FK Yassin
Chapter 4
Inherited Bone Marrow Failure Syndromes…………………………..29
MM Alam, Amal A Alseraihy
Chapter 5
Hemolytic Anemia: Autoimmune Hemolytic Anemia…………........47
MM Alam, Rahat UA, Abrar A, Sherief LM
Chapter 6
Membranopathy and Enzymopathy……………………………………62
Riffat M, MM Alam, AH Siddiqui
Chapter 7
Sickle Cell Disease………………………………………………………..74
Fahad Alabbas, MM Alam
Chapter 8
Thalassemia Syndrome………………………………………………...116
MM Alam, S Hwazen, Abdullah Al Jefri
A Practical Guide I Pediatric Hematology
x
Section II
Bleeding Disorders
Chapter 9
Evaluation of Bleeding Disorder……………………………………….144
MM Alam
Chapter 10
Hemophilia………………………………………………………………...150
MM Alam, AB Khalid, Huda AE, Ahmad M Tarawah
Chapter 11
Von Willebrand Disease…………………………………………………187
MM Alam, Iman Ragab
Chapter 12
Rare Inherited Coagulation Disorders………………………………..198
MM Alam, Eman RMT Alshamsi, M Alshahrani
Section III
Platelets Disorders
Chapter 13
Evaluation of Platelets Disorders………………………………………208
MM Alam
Chapter 14
Immune Thrombocytopenia…………………………………………..…215
MM Alam, Sami H Albattat
Chapter 15
Inherited Platelets Disorders……………………………………………233
MM Alam, Al-J Al-Manea
Section IV
Thrombosis
Chapter 16
Evaluation of Thrombosis in Children…………………………………249
MM Alam, Azzah Al-Zahrani
Chapter 17
Management of Thrombosis in Children………….….……………….262
MM Alam, Saleh N Al-Shanbari
Chapter 18
Pediatric Stroke……………………………………………………….…...275
MM Alam, Ali Alomari, H Al-Trabolsi
Chapter 19
Antithrombotic Therapy in Children…………………………………...285
MM Alam, Marwa E, Zehra Fadoo
A Practical Guide I Pediatric Hematology
xi
Section V
White Blood Cells Disorders
Chapter 20
Leucocyte Disorders: Neutropenia…………………………………...304
MM Alam, Fauzia R Azmet
Chapter 21
Myeloproliferative Disorder……………………………………………319
MM Alam, Zaheer Ullah
Chapter 22
Lymphoproliferative Disorder in Children…………………………..332
Ibraheem Abosoudah, MM Alam, M Rahil Khan
Section VI
Miscellaneous Topics
Chapter 23
Neonatal Hematology…………………………………………………...341
MM Alam, A Alamri, Col T Ghafoor
Chapter 24
Hematopoietic Stem Cell Transplantation…………………………..356
MM Alam, SL Memon, M Ayas, M Bayoumy
Chapter 25
Vascular Anomalies………………………………………………….....382
MM Alam, Lamis H Elkhatib
Chapter 26
Blood Products/Transfusion…………………………………………..390
MM Alam, Bushra Moiz
Chapter 27
Peripheral and Bone Marrow Morphology………………………….402
MM Alam, S Muftah, Farrukh A Khan
Section VII
Appendix I
Appendix II
Appendix III
Appendix IV
Appendix V
Appendix VI
Appendix VII
Appendix
Normal Laboratory Values……………………………………………..409
MM Alam, Basheer Ahmed
Inheritance and Genetics………………………………………………413
Lujain A, MM Alam
Splenectomy Care…………………………………………………….....415
Muhammad Matloob Alam
Corticosteroid Therapy…………………………………………………418
MM Alam, MA Al-Saleh
Bleeding Assessment Tools…………………………………………..421
Muhammad Matloob Alam
Febrile Neutropenia……………………………………………………..426
Muhammad Matloob Alam
Practical Procedures……………………………………………………430
Muhammad Matloob Alam
Index
A Practical Guide I Pediatric Hematology
xii
Abbreviations
ALL: acute lymphoblastic leukemia
ALPS: autoimmune lymphoproliferative
syndrome
AML: acute myelogenous leukemia
ANC: absolute neutrophil count
APA: antiphospholipid antibody
APCC: activated prothrombin complex
concentrate
APLA: antiphospholipid antibody
AR: autosomal recessive
ARTUS: amegakaryocytic thrombocytopenia
with radioulnar synostosis
ASH: American Society of Hematology
AST: aspartate aminotransferase
AT: antithrombin
ATG: antithymocyte globulin
ATP: adenosine triphosphate
ATRUS: amegakaryocytic thrombocytopenia
with radioulnar synostosis
BAL: bronchoalveolar lavage
BM: bone marrow
BMF: bone marrow failure
BMT: bone marrow transplantation
BSS: Bernard-Soulier syndrome
BT: bleeding time
BU: Bethesda units
CAD: cold agglutinin disease
CAMT: congenital amegakaryocytic
thrombocytopenia
CD40L: CD40 ligand
CDA: congenital dyserythropoietic anemia
CGD: chronic granulomatous disease
cGVHD: chronic graft-versus-disease
CHF: congestive heart failure
CHH: cartilage-hair hypoplasia
CHS: Chédiak-Higashi syndrome
CMV: cytomegalovirus
CNS: central nervous system
CNSHA: congenital nonspherocytic hemolytic
anemia
COX: cyclooxygenase
CR: complete remission
CRF: chronic renal failure
CSA: congenital sideroblastic anemia
CSVT: cerebral sinovenous thrombosis
CT: closure time; computed tomography
CVID: common variable immunodeficiency
CVL: central venous line
CVS: chorionic villus sampling
A Practical Guide I Pediatric Hematology
CXCR4: CXC chemokine receptor 4
CXR: chest radiography
DAT: direct antibody test, direct antiglobulin test
DBA: Diamond-Blackfan anemia
DC: dyskeratosis congenita
DDAVP: 1-deamino-8-d-arginine vasopressin
DEB: diepoxybutane
DFO: desferrioxamine
DFP: deferiprone
DFX: deferasirox
DHR 123: dihydroxyrhodamine 123
DIC: disseminated intravascular coagulation
DIDMOAD: diabetes insipidus, diabetes
mellitus, optic atrophy, and deafness
DIIHA: drug-induced immune hemolytic anemia
2,3-DPG: 2,3-diphosphoglycerate
DRVVT: dilute Russell viper venom time
DS: Down syndrome
DVT: deep venous thrombosis
DWI: diffusion-weighted imaging
EBV: Epstein-Barr virus
EDTA: ethylenediaminetetraacetic acid
EPO: erythropoietin
EpoR: erythropoietin receptor
EPP: erythropoietic protoporphyria
ESRD: end-stage renal disease
ET: essential thrombocythemia
FA: Fanconi anemia
FASLG: FAS ligand
FcR: Fc receptor
FFP: fresh-frozen plasma
FISH: fluorescence in situ hybridization
FN: fever and neutropenia
FNA: fine needle aspiration
FPN1: ferroportin 1
G6PD: glucose-6-phosphate dehydrogenase
G-CSF: granulocyte colony-stimulating factor
G-CSFR: granulocyte colony-stimulating factor
receptor
GFR: glomerular filtration rate
GI: gastrointestinal
GP: glycoprotein
G6PD: glucose-6-phosphate dehydrogenase
GPI: glucose phosphate isomerase,
glycosylphosphatidylinositol
GS: Griscelli syndrome
GT: Glanzmann thrombasthenia
GVHD: graft-versus-host disease
Hb: hemoglobin
HB: Heinz body
HbA: adult hemoglobin
HbF: fetal hemoglobin
HBV: hepatitis B virus
HCV: hepatitis C virus
xiii
HDN: hemolytic disease of the fetus and
newborn; hemorrhagic disease of the newborn
HE: hereditary elliptocytosis
HEP: hepatoerythropoietic porphyria
Hex-A: hexosaminidase A
HHV: human herpesvirus
HiB: Haemophilus influenzae type B
HIM: hyper-IgM syndrome
HIT: heparin-induced thrombocytopenia
HIV: human immunodeficiency virus
HJV: hemojuvelin
HK: hexokinase
HLA: human leukocyte antigen
HLH: hemophagocytic lymphohistiocytosis
HPA-1a: human platelet antigen 1a
HPFH: hereditary persistence of fetal
hemoglobin
HPP: hereditary pyropoikilocytosis
HPS: Hermansky-Pudlak syndrome
HPV: human papillomavirus
HRQoL: Health-related quality of life
HS: hereditary spherocytosis; hypersensitivity
site
HSC: hematopoietic stem cell
HSCT: hematopoietic stem cell transplantation
HSP: heat shock protein; Henoch-Schönlein
purpura
HSt: hereditary stomatocytosis
HSV: herpes simplex virus
HUS: hemolytic uremic syndrome
IBMFS: inherited bone marrow failure syndrome
IDA: Iron deficiency anemia
ICH: intracranial hemorrhage
IF: intrinsic factor
IFI: invasive fungal infection
IFN: interferon
Ig: immunoglobulin
IHC: immunohistochemistry
IL: interleukin
IL2RG: interleukin-2 receptor gamma (IL-2R γ)
INR: international normalized ratio
IRIDA: iron-refractory iron deficiency anemia
IST: immunosuppressive therapy
ISTH: International Society on Thrombosis and
Hemostasis
ITP: immune thrombocytopenia purpura
IVIG: intravenous immunoglobulin
JAK: Janus kinase
JMML: juvenile myelomonocytic leukemia
KD: Kostmann’s disease
LA: lupus anticoagulant
LAD : leukocyte adhesion deficiency
LDH: lactate dehydrogenase
A Practical Guide I Pediatric Hematology
LIC: liver iron concentration
LSD: lysosomal storage disease
Mb: myoglobin
MDS: myelodysplastic syndrome
met-Hb: methemoglobin
MHA: May-Hegglin anomaly
MHC: major histocompatibility complex
MLASA: mitochondrial myopathy with lactic
acidosis and sideroblastic anemia
MMF: mycophenolate mofetil
MPD: myeloproliferative disease
MPO: myeloperoxidase
MPS : mucopolysaccharidosis
MPV: mean platelet volume
MRA: magnetic resonance angiography
MRI: magnetic resonance imaging
MTHFR: methylenetetrahydrofolate reductase
(methylene-THF reductase)
NAIT: neonatal alloimmune thrombocytopenia
NATP: neonatal alloimmune thrombocytopenic
purpura
NF-1: neurofibromatosis type 1
NK: natural killer (cell)
NS: Noonan syndrome
NSAID: nonsteroidal anti-inflammatory drug
NTDT: non transfusion dependent thalassemia
PCH: paroxysmal cold hemoglobinuria
PCP: Pneumocystis carinii pneumonia
PCR: polymerase chain reaction
PCV: polycythemia vera
PCV: pneumococcal polysaccharide vaccine
PDGF: platelet-derived growth factor
PF4: platelet factor 4
PFA-100: Platelet Functional Analyzer 100
PFK: phosphofructokinase
PK: pyruvate kinase
PM: primary myelofibrosis
P-5′-N: pyrimidine-5′-nucleotidase
PNH: paroxysmal nocturnal hemoglobinuria
pRBCs: packed red blood cells
PRCA: pure red cell aplasia
PT: prothrombin time
PTLD: posttransplant lymphoproliferative
disease
PTP: posttransfusion purpura
PTS: postthrombotic syndrome
PTT: partial thromboplastin time
PV: polycythemia vera
QoL: quality of life
RA: refractory anemia
RAB27A: member RAS oncogene family 27A
RAEB: refractory anemia with an excess of
blasts
RAEBIT (RAEB-T): RAEB in transformation
xiv
RBC: red blood cell
RDW: red cell distribution width, red cell volume
distribution width
rFVIIa: recombinant activated factor VII
RhAG: Rh-associated glycoprotein
rVIIa: recombinant factor VIIa
RVT: renal vein thrombosis
RVV: Russell viper venom
SAA: severe aplastic anemia
SAO: Southeast Asian ovalocytosis
SBDS: Shwachman-Bodian-Diamond syndrome
SCA: sickle cell anemia
SCID: severe combined immunodeficiency
disease
SCD: sickle cell disease
SCN: severe congenital neutropenia
SDS: Shwachman-Diamond syndrome
SH2D1A: SH2-containing protein 1A, Src
homology 2 domain–containing protein 1
SLAM: signaling lymphocyte activation
molecule
SLE: systemic lupus erythematosus
SLP3: stomatin-like protein 3
SQUID: superconducting quantum interference
device
STAT: signal transducer and activator of
transcription
STX11: syntaxin 11
STXBP2: syntaxin binding protein 2
SVC: superior vena cava
SWiTCH: Stroke With Transfusions Changing to
Hydroxyurea study
TAFI: thrombin-activatable fibrinolysis inhibitor
TAM: transient abnormal myelopoiesis
TDT: transfusion dependent thalassemia
TBI: total-body irradiation
TE: thromboembolism
TEC: transient erythroblastopenia of childhood
TEG: thromboelastography
TF: tissue factor
tHcy: plasma total homocysteine
TIA: transient ischemic attack
TI: thalassemia intermedia
TIBC: total iron-binding capacity
TMD: transient myeloproliferative disorder
TMP-SMX: trimethoprim-sulfamethoxazole
TM: thalassemia major
A Practical Guide I Pediatric Hematology
TNF: tumor necrosis factor
TORCH: toxoplasmosis, rubella,
cytomegalovirus, and herpesvirus infections
tPA: tissue plasminogen activator
TPI: triose phosphate isomerase
TPN: total parenteral nutrition
TPO: thrombopoietin
TPOR: thrombopoietin receptor
TRALI: transfusion-related acute lung injury
TfR: transferrin receptor
TT: thrombin time
TTP: thrombotic thrombocytopenic purpura
uPA: urokinase plasminogen activator
URD: unrelated donor
URO-D: uroporphyrinogen decarboxylase
UTI: urinary tract infection
VACTERL: vertebral abnormalities, anal atresia,
cardiac abnormalities, tracheoesophageal
fistula, and/or esophageal atresia, renal
agenesis and dysplasia, and limb defects
VK: vitamin K
VKDB: vitamin K–dependent bleeding
VLBW: very low birth weight
VOD: veno-occlusive disease
VTE: venous thromboembolism
V/Q: ventilation-perfusion
VWD: von Willebrand disease
VWF: von Willebrand factor
VWF:Ag: von Willebrand factor antigen
VWF:CB: collagen-binding assay for von
Willebrand factor
VWFpp: von Willebrand factor propeptide
VWF:RCo: VWF activity by ristocetin cofactor
assay
VZV: varicella-zoster virus
WAS: Wiskott-Aldrich syndrome
WASP: Wiskott-Aldrich syndrome protein
WBC: white blood cell
WHIM: warts, hypogammaglobulinemia,
infections, myelokathexis (syndrome)
XIAP: X-linked inhibitor of apoptosis
XLA: X-linked agammaglobulinemia
XLP: X-linked lymphoproliferative syndrome
XLPD: X-linked lymphoproliferative disease
XLSA: X-linked sideroblastic anemia
XLT: X-linked thrombocytopenia
ZPP: zinc protoporphyrin
xv
A Practical Guide I Pediatric Hematology
Chapter 5 I Hemolytic Anemia: Autoimmune
Chapter 5
Hemolytic Anemia:
Autoimmune Hemolytic Anemia
MM Alam, Rahat UA, Abrar A, Sherief LM
Chapter Outline
INTRODUCTION........................................................................................................48
Classification of Hemolytic Anemia ....................................................................48
EVALUATION FOR SUSPECTED HEMOLYTIC ANEMIA ............................................48
Hemoglobinuria...................................................................................................50
IMMUNE HEMOLYTIC ANEMIAS .............................................................................51
Classification of Immune Hemolytic Anemias ...................................................51
AUTOIMMUNE HEMOLYTIC ANEMIA .....................................................................51
Differential Diagnosis ..........................................................................................52
Evaluation for Suspected Immune Hemolytic Anemia .....................................52
Types of Autoimmune Hemolytic Anemias .......................................................53
Management of Autoimmune Hemolytic Anemia ............................................54
Acute Supportive Management .....................................................................54
General Measures ..........................................................................................54
Treatment of Warm Autoimmune Hemolytic Anemia ......................................55
Corticosteroid Therapy ..................................................................................55
Intravenous Immunoglobulin (IVIG) ..............................................................57
Therapeutic Plasma Exchange (Plasmapheresis) ..........................................57
Treatment of Chronic or Refractory AIHA .........................................................57
Rituximab (anti CD20 antibody) .....................................................................57
Splenectomy ...................................................................................................57
Alternative Immunotherapeutic Agents........................................................58
Other options ..................................................................................................58
Paroxysmal Cold Hemoglobinuria (PCH) ............................................................58
SECONDARY AUTOIMMUNE HEMOLYTIC ANEMIA ................................................58
Evans Syndrome ..................................................................................................59
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) .........................................60
SELECTED REFERENCE .............................................................................................61
A Practical Guide I Pediatric Hematology
47
MM Alam, Rahat UA, Abrar A, Sherief LM
INTRODUCTION
Hemolytic anemia (HA) is not very uncommon in children. Many children are hospitalized
every year due to sequelae of this heterogeneous group of disorders.
In this chapter we will discuss classification, general approach to hemolytic anemia and
immune mediated hemolytic anemia. Other causes of hemolytic anemia; RBC membrane
defect, RBC enzyme deficiency, hemoglobinopathy and other rare causes will be
discussed in separate chapters (see chapter 6, 7 and 8).
Classification of Hemolytic Anemia
Hemolytic anemia can be classified by various way (see box 5.1)
 Extravascular/Intravascular Hemolysis (see table 5.1)
 Extracorpuscular (Immune/ Nonimmune)/Corpuscular causes
 Acquired or Inherited
Box 5.1 Classification of Hemolytic Anemia
Classification of Hemolytic Anemia
Corpuscular Causes of Hemolytic Anemia: usually inherited

RBC membrane disorders: Hereditary spherocytosis, hereditary elliptocytosis, hereditary
stomatocytosis

Hemoglobinopathies (SCA, thalassemias), other unstable Hb variants (HbE)

RBC enzyme deficiencies (G6PD/PK/others deficiency)
Extracorpuscular Causes Hemolytic Anemia
Immune Hemolytic Anemia (Coombs positive)

Autoimmune hemolytic anemias (Primary/Secondary)

Drug-Induced hemolytic anemias

Alloantibody-Induced hemolytic anemias
Nonimmune Hemolytic Anemia (Coombs negative)

Microangiopathic hemolytic anemia, other consumptive coagulopathy

Infection (infectious mononucleosis, viral hepatitis, streptococcal, E. coli, clostridium,
bartonella, malaria, histoplasmosis)

Drugs and chemicals

Hematologic disorders (leukemia, aplastic anemia, megaloblastic anemia)

Misc (i.e. Wilson disease, erythropoietic porphyria, hypersplenism)

Lipid metabolism defects (e.g. abetalipoproteinemia, spur cell anemia, LCAT deficiency)
EVALUATION FOR SUSPECTED HEMOLYTIC ANEMIA
Early recognition and diagnosis are very important for successful management and
outcome of hemolytic anemia. The evaluation of hemolytic anemia (HA) includes a
thorough history assessing for evidence of chronic hemolytic anemia and possible
precipitants of an acute event (see figure 5.1).
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Chapter 5 I Hemolytic Anemia: Autoimmune
Figure 5.1 Evaluation of Suspected Hemolytic Anemia
Suspect
Hemolytic Anemia
Rapid/chronic onset of anemia (pallor or fatigue) +/jaundice, dark urine, fever or acute abdominal pain
Evaluation of Suspected Hemolytic Anemia
Present History:
h/o fever, chills, abdominal/back pain and dark urine
h/o recent infections (URTI, AGE), exposure to drugs or vaccination, h/o recent
travel (malaria), open wound/burns (clostridium septicemia), prior transfusion
(transfusion reaction), intensive exercise (march hemoglobinuria)
Past Medical History: [Personal and/or family]
h/o acute/persistent/recurrent anemia/jaundice and/or dark urine (after certain
drugs, foods or infection).
h/o cyanosis/polycythemia, h/o transfusion (first time/frequency)
splenectomy, unexplained gallstones, autoimmune disorder (arthritis, rash, mouth
ulcers) or immunodeficiency (recurrent infection, abscesses, pneumonia etc.)
Physical Exam: Pallor (Anemia; tachycardia, tachypnea, new murmur, gallop,
hypotension, or shock), fever, facial bone changes (extramedullary hematopoiesis),
growth retardation (chronic anemia or autoimmune disease), jaundice,
petechiae/bruising, splenomegaly, hepatomegaly, lymphadenopathy (malignancy),
chronic leg ulcers and cyanosis.
Initial Labs: CBCD, Indices, peripheral smear (RBC morphology), Retic, LFT, LDH,
haptoglobin, Coombs (DAT)
Expected finding in hemolysis: Low Hb, low or absent haptoglobin
Increased Retic, MCV, RDW, normoblasts and nucleated RBC’s
Increased indirect bilirubin, LDH and plasma free Hb
Increased urinary urobilinogen and hemoglobinuria
DAT (Coombs) positive
Immune Hemolytic Anemia
Autoimmune HA
Drug-Induced HA
Alloantibody-Induced HA
DAT (Coombs) negative
Corpuscular Defects
Membranopathy
Enzymopathy
Hemoglobinopathy
CDA
Extracorpuscular Defects
Idiopathic or secondary
[infection, drugs and
chemicals, burns,
hypersplenism, mechanical
destruction (prosthetic
valves), MAHA, misc]
Abbreviations: h/o; history of, HA; hemolytic anemia, Hb; hemoglobin, DAT; direct antiglobulin test,
LFT; liver function test, CDA; congenital dyserythropoietic anemia, MAHA; microangiopathic
hemolytic anemia.
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MM Alam, Rahat UA, Abrar A, Sherief LM
Hemoglobinuria


Patients with AIHA often present with dark urine caused by intravascular hemolysis
and hemoglobinuria.
Other causes of dark urine include concentrated urine, bilirubin or porphyrin
precursors in the urine, hematuria, and myoglobinuria.
– Hemoglobinuria can be distinguished from most of these on the basis of the
urinalysis (in patients with hemoglobinuria, the dipstick test is positive for
blood and protein, but the microscopic analysis does not reveal red blood
cells).
– Myoglobinuria produces similar urinalysis findings and can be distinguished
from hemoglobinemia on the basis of the serum haptoglobin level, which is
typically normal in the absence of hemolysis.
Box 5.2 Etiology of Hemoglobinuria
Etiology of Hemoglobinuria
Acute: Acute hemolytic transfusion reactions, AIHA (Warm)
Drugs/chemicals, toxins (spider bites, snake venoms),
Infections [blackwater fever (malaria), open wound/burns (Clostridium septicemia), h/o recent
AGE (HUS)]
Microthrombi in circulation - DIC, MAHA (TTP, HUS, aHUS)
mechanical trauma (Prosthetic valves, ECMO, cardiopulmonary bypass)
Chronic: PCH, PNH, cold agglutinin hemoglobinuria, march hemoglobinuria (intensive
exercise)
Table 5.1 Intravascular Versus Extravascular Hemolysis
Location of RBC clearance
Antibody type (if immune)
Mechanism of Hemolysis
Symptoms
Lab findings
Example
50
Intravascular Hemolysis
Extravascular Hemolysis
Inside vessels
In spleen, marrow, and/or liver
lgM (occ lgG)
lgG
Complement or shear mediated Macrophages digest RBCs
Acute abdominal/back pain
Tender splenomegaly;
and fever
hepatomegaly
↑ bilirubin (marked)
Hemoglobin-uria/emia;
↑ bilirubin (mild)
Normal or ↑ LDH
↑ LDH
↓ hepatoglobin
↓/Absent heptoglobin
↑ fecal/urinary urobilinogen
PCH, PNH
Warm AIHA, HDN, HS
A Practical Guide I Pediatric Hematology
Chapter 5 I Hemolytic Anemia: Autoimmune
IMMUNE HEMOLYTIC ANEMIAS
Many extrinsic agents and disorders may lead to premature destruction of red blood cells.
Among the most clearly defined are antibodies associated with immune hemolytic anemias
(IHA). The hallmark of this group of diseases is the positive result of the direct antiglobulin
(Coombs) test, which detects a coating of immunoglobulin or components of complement
on the RBC surface.
Classification of Immune Hemolytic Anemias
Immune hemolytic anemias can be classified broadly into autoimmune, drug induced or
alloantibody induced immune hemolytic anemia (see box 5.3).
Box 5.3 Classification of Immune Hemolytic Anemias
Autoimmune Hemolytic Anemias

Warm reacting AIHA
Primary (idiopathic)
Secondary (LPD, CTD – SLE, nonlymphoid neoplasms (e.g., ovarian tumors), chronic
inflammatory diseases (e.g., ulcerative colitis), Immunodeficiency disorders, Evans
syndrome, drugs

Cold reacting AIHA
Primary (idiopathic)
Secondary (LPD, Infections; mycoplasma pneumoniae, EBV)

Paroxysmal cold hemoglobinuria
Primary (idiopathic)
Viral syndromes (most common)
Congenital or tertiary syphilis

Mixed type AIHA
Drug-Induced Immune Hemolytic Anemia (DIIHA)
Penicillin, quinine or quinidine, methyldopa, aminosalicylic acid, ceftriaxone, tetracycline,
rifampin, sulfonamides, chlorpromazine, insulin; lead etc
Alloantibody-Induced Immune Hemolytic Anemia

Hemolytic disease of the fetus and newborn

Hemolytic transfusion reaction
Abbreviations: LPD; lymphoproliferative disorders, CTD; connective tissue disease, SLE; systemic
lupus erythematosus, EBV; Epstein–Barr virus
AUTOIMMUNE HEMOLYTIC ANEMIA


Autoimmune hemolytic anemia (AIHA) in childhood is an uncommon condition caused
by the presence of auto-antibodies directed against RBCs Ag, leading to premature
destruction of the cells.
AIHA is generally categorized as "warm" or "cold" based on the thermal reactivity of
the autoantibodies (see table 5.2) and is classified as primary (idiopathic) or
secondary based on whether or not an underlying disease process is present (see
box 5.2).
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MM Alam, Rahat UA, Abrar A, Sherief LM

Etiology often idiopathic (37%), post-infective (10%), or secondary (53%); in this last
case, AIHA is part of a more complex disease, usually of immunological, infective or
neoplastic nature.
Diagnosed by positive DAT (Coombs' test) with the appropriate clinical and laboratory
findings (i.e., jaundice, elevated unconjugated bilirubin, and anemia with
reticulocytosis).
In children the majority are acute and self-limited; arising 1-3 weeks after a viral
infection and disappearing in 3 months.
Overall mortality rate is 4% in children.
A positive mixed IgG/C3 DAT is more likely associated with chronic disease and
younger children with an abrupt onset of symptoms have a better prognosis.




Differential Diagnosis
Box 5.4 Differential Diagnosis Autoimmune Hemolytic Anemia
Spherocytic Anemias

DAT Positive: Autoimmune hemolytic anemia (warm > PCH > CAD)

DAT Negative: Hereditary spherocytosis, clostridial sepsis, ABO – HDN, severe burns or
RBC thermal injuries, severe hypophosphatemia, Wilson disease or CDA II
Dark urine or hemoglobinuria: Paroxysmal nocturnal hemoglobinuria
DAT Positive: DHTR, DIIHA

Delayed hemolytic transfusion reaction (if h/o transfusion)

Drugs (piperacillin, cefotetan, and ceftriaxone); hemolysis ceases within days of
discontinuation of the drug. Serologic evaluation for DIIHA
Evaluation for Suspected Immune Hemolytic Anemia
Early recognition and diagnosis are very important for successful management and
outcome of hemolytic anemia. The evaluation of suspected immune hemolytic anemia
(IHA) includes a thorough history, physical examination and laboratory workup assessing
for evidence of acute hemolytic anemia, possible diagnosis of an acute event, to evaluate
for concurrent causes and to rule out alternative causes (see figure 5.1).
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Chapter 5 I Hemolytic Anemia: Autoimmune
Figure 5.2 Evaluation for Suspected Immune Hemolytic Anemia
Suspected IHA: rapid onset of anemia (pallor, fatigue, shortness of breath, dizziness)
+/- jaundice and dark urine; fever or acute abdominal pain
Initial Labs: CBCD, RBC Indices, peripheral smear (RBC morphology), Retic count, LFT,
LDH, UDR, haptoglobin, Coombs (direct antiglobulin test); urinalysis and kidney function.
Expected finding in hemolysis: (Low Hb, high indirect bilirubin, high
LDH, low haptoglobin, and/or elevated plasma free hemoglobin)
DAT Positive: Autoimmune Hemolytic Anemias
*Clinical assessment: detailed history/PMH/ROS and physical
Examination (see evaluation of hemolytic anemia)
*Evaluate for concurrent causes:
autoimmune disease,
immunodeficiency, LPD, CTD,
malignancy, infection, and DIIHA
Rule out alternative causes: HTR,
HDN, post transplantation (ABO
mismatch/PLS), post IVIG, unrelated
causes of HA with an incidental + DAT
DAT-negative AIHA
Seen in 5-10% of all AIHAs; if strong
clinical suspicion. Retest with a
column agglutination DAT method
that includes monospecific antiIgG/M/A and anti-C3d and for
Donath-Landsteiner in children with
haemoglobinuria
If still negative – do red cell eluate
Coombs specificity (warm/cold antibody; IgG, C3 or both or IgM,
Donath Landsteiner antibody on red cells)
Warm reactive antibody
AIHA: IgG at ≥ 37°C
Cold reactive antibody AIHA
IgM at 4°C + C3
Paroxysmal Cold
Hemoglobinuria
*Further investigation in selected patients with AIHA
– Antinuclear antibody testing
– Quantitative immunoglobulins
– Bone marrow examination
– Infection screen [serologic testing for Mycoplasma pneumoniae and Epstein-Barr virus
(in patients with cold AIHA only)]
– Review of the patient's medications
– Antibody screen to detect alloantibodies in patients who have been exposed to foreign
RBCs by previous transfusion
– Imaging as CT chest, pelvic and abdomen
Additional testing is performed in patients with concerning clinical findings (e.g., history of
recurrent infections, family history of autoimmune disease or immunodeficiency, other cytopenias
[neutropenia and/or thrombocytopenia], lymphadenopathy, and/or organomegaly).
Important Considerations:
If concurrent thrombocytopenia; consider ITP (Evans syndrome); MAHA (i.e. TTP, HUS, SLE).
Reticulocytopenia could be due to distinct autoantibody directed at erythroid progenitor cells
(parvovirus).
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Types of Autoimmune Hemolytic Anemias
Table 5.2 Summary of Different types of Autoimmune Hemolytic Anemias
Treatment
Characteristic
Frequency
Immunoglobulin
Thermal reactivity
Fixes complement
Mechanism of
Hemolysis
DAT
4°C
37°C
Plasma titer
Antigenic
specificity
Site of RBC
destruction
Acute First
line
Second line
Third Line
Refractory
cases
Warm Reactive
60-70%; 50% secondary
IgG; rare IgM and IgA
≥ 37°C
± (usually not)
Macrophages digest Abcoated RBCs
Not performed
IgG ± C3
Low/absent
Rh and others
(“common” Ag)
RES;Spleen
(extravascular
clearance)
Corticosteroids
Rituximab,
IVIG,
Splenectomy
Other
Immunosuppressive
Alemtuzumab,
High-dose
cyclophosphamide
Cold AIHA*
20-25%
IgM
4°C
Yes
Complement mediated
C3
C3
High
I/i
PCH
6-12%
IgG
4°C
Yes
Complement
mediated
IgG, C3
C3
Moderate
P
Liver, intravascular
Intravascular
Avoid cold, plasma
exchange for severe ds
Rituximab
Supportive care
-
-
Eculizumab,
Bortezomib
Steroids
Rituximab
*Red cell clumping on the peripheral blood smear
Management of Autoimmune Hemolytic Anemia
Acute Supportive Management
 Notify the blood bank that AIHA is suspected and that transfusion may be required.
Send extra pink top to blood bank as soon as Coombs+ is established to expedite
typing.
 Call the blood bank medical director if there is any delay, because failed cross
matching initiates a workup that is always too slow.
 Transfusion with ABO, Rh and K matched blood is appropriate.
General Measures
 Watchful waiting and judicial in action.
 Avoid exposure to the cold in cold AIHA/ paroxysmal nocturnal hemoglobinuria.
 Maintain a good hydration status, urine output and cardiac status if hemolysis is
severe.
 Manage the underlying disorder, if identifiable (i.e.; infection)
 Folic acid supplement.
 Calcium and Vitamin D supplementation (with steroid therapy).
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Chapter 5 I Hemolytic Anemia: Autoimmune
Careful monitoring should require
 Check hemoglobin level (every 4-8 hourly )
 Daily (Retic, hemoglobinuria, splenic size)
 Weekly - DAT and haptoglobin level
Transfusion Therapy
 Only recommended for symptomatic and/or very severe anemia.
 Use “least incompatible” matched PRBCs; start slowly.
 Do not delay transfusion if retic count is not robust.
 Transfuse for Hb < 5 in children and < 6 in teens unless very confident they are on
the way up. Strongly consider transfusion in new/ freshly active AIHA if Hb < 6 in
children and < 7 in teens with counts falling and inappropriate reticulocytosis.
 Use even more liberal criteria (treat for higher Hb) in the setting of ICU illness of known
heart or renal disease.
 It is recommended that only quantities sufficient to improve symptoms (approximately
3-5 mL/kg) are transfused, in order to minimize the complications of overload and
incompatibility.
 For Cold/PCH: Use blood warmer! If hemolysis worsens with transfusion, consider
transfusion of washed RBC’s to reduce amount of complement provided.
Treatment of Warm Autoimmune Hemolytic Anemia
Primary Treatment
Corticosteroid Therapy
Starting dose depends on patient/disease severity.
In a patient with acute warm AIHA or PCH:
 In case of rapid hemolysis and severe anemia –
– IV methylprednisolone 1-2 mg/kg every 6 hour for 1 to 3 days
– Consider blood transfusion/IVIG
– Once the patient’s Hb level begins to rise and is clinically stable, shift to oral
prednisone as below doses
 In clinically stable patient – Start oral prednisone [ 2 mg/kg/day for children and 1
mg/kg/day for adolescents] for 2-4 weeks
 If patient < 1 year of age, consider sending immune work-up prior to starting steroids
 An overall clinical response ~80%, but ~60% of these loses their response upon
weaning or discontinuing steroids.
 Lack of response to steroids after 21 days should be considered steroid failure.
Tapering of Corticosteroid


After 2-4 weeks of initial therapy tapering should be started gradually to avoid
relapses.
Goal is to maintain a stable Hb with a relatively low dose of corticosteroids and,
preferably, an every-other-day regimen.
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

10% to 20% taper with each dose change is reasonable.
Tapering of the corticosteroids is guided by the patient’s Hb and reticulocyte count
and, to a lesser degree, the DAT results.
When a patient relapse, a very high dose of prednisone is usually required to achieve
remission again.
Total duration of corticosteroid therapy: 3-12 months after remission is achieved.
Adverse effects of prolonged corticosteroid use should be considered (see appendix
IV).



Figure 5.3 Proposed Treatment Plan of Warm antibody AIHA
Corticosteroid Therapy (prednisone)
nd
Assessment
at week 3
NR: excluded DDx; shift to 2 line treatment
CR: Continue for 1 more weeks (at least total of 4 weeks)
PR: Continue for 2 more weeks
Assessment
at week 6
In any case, after 6 weeks, steroid must be tapered
Assessment
at 6 month
CR: Stop treatment
PR: Steroid dependence – check prednisone dosage
nd
If > 0.1-0.2 mg/kg/day; switch to 2 line
If < 0.1-0.2 mg/kg/day; Continue low dose prednisone
Tapering schedule: The full dosage is reduced by 25-50% over 4 weeks, thereafter,
the reduction must be gradual, in order to extend the treatment for at least 6 months
If a relapses or exacerbation of the hemolysis is observed, during the tapering process,
the dosage should be brought back at the previous level.
Abbreviations: CR; complete response, PR; partial response, NR; no response, DDx; differential
diagnosis
Response Assessment
Box 5.4 AIHA Response Assessment
Response Assessment
Complete Response
(CR)
Partial
Response (PR)
No Response (NR)
56
Achievement of a Hb > lower normal limit for age, with no signs of
haemolysis, i.e. normal reticulocyte count and bilirubin concentration
An increase of Hb of ≥2 g/dL, without the Hb concentration reaching
a normal value
for the patient's age
An increase of Hb <2 g/dL and/or dependence on transfusions
A Practical Guide I Pediatric Hematology
Chapter 5 I Hemolytic Anemia: Autoimmune
Intravenous Immunoglobulin (IVIG)



It may be considered as adjunctive therapy to steroids, in more severe cases and in
a patient who is not responding to steroids.
Dose range of 0.4 to 2 gm/kg/day for 2 to 5 days.
Beneficial in 55%, but whether they were receiving combined corticosteroid therapy
is not reported.
Therapeutic Plasma Exchange (Plasmapheresis)



Although more effective in IgM-induced HA.
In severely ill child with IgG-induced HA may be considered as a temporizing who has
a suboptimal response to either transfusion or pharmacological therapy or may not
have had time to respond to corticosteroid therapy.
Each cycle can remove up to 65% of the circulating autoantibodies, so, it is frequently
necessary to repeat the procedure.
Treatment of Chronic or Refractory AIHA
Must evaluate for secondary causes.
Rituximab (anti CD20 antibody)





Indications: Non-responder/refractory to steroids, or who respond to steroids but have
significant adverse effects.
Standard dose (375 mg/m2 weekly) for 1 to 6 weeks.
> 90% of patients have a complete response that lasts 7 to 28 months.
If taking corticosteroids before the initiation of rituximab, should continue steroids until
a response to rituximab is clearly established.
Adverse Effects: severe infusion reactions, infection, progressive multifocal
leukoencephalopathy, and reactivation of hepatitis B and fulminant hepatitis.
– Contraindication: Untreated hepatitis B infection
– Immunizations should be delayed until the B-cell recovery
– Post treatment hypogammaglobulinemia should be treated with prophylactic
administration of IVIG.
Splenectomy


Splenectomy in childhood AIHA considered a third line treatment option.
Indication: If the hemolytic process is brisk despite the use of high-dose corticosteroid
therapy, rituximab, and transfusions and the patient cannot maintain a reasonable
hemoglobin level safely, or if chronic hemolysis develops.
 Whenever possible, children should be older than 5 years of age and the disease
should be present for at least 6-12 months with no significant response to medical
treatment prior to undertaking splenectomy.
 Splenectomy is beneficial in 60-75% of patients.
 Pre/post splenectomy management plan should be instituted (see appendix III).
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Alternative Immunotherapeutic Agents




Indications: corticosteroids non responder, rituximab, and splenectomy or for patients
who have contraindications to those therapies.
Cyclophosphamide, cyclosporine, azathioprine (6-mercaptopurine), MMF
(mycophenolate mofetil, Cell-Cept) and Campath-1H.
A response may take months, and thus treatment should be continued for up to 6
months before it is considered to have failed.
40-60% response rate.
Other options



Danazol effectiveness is controversial.
Monoclonal antibodies have been successfully used in patients with resistant disease.
Campath-1 HI (Alemtuzumab): anti CD52 antibody.
HSCT is a potential option with limited experience (Allogenic > Autologous HSCT).
Paroxysmal Cold Hemoglobinuria (PCH)




PCH is an acute illness, often seen after viral URTI (Measles, mumps, varicella,
syphilis, mycoplasma)
Cold reactive anti-erythrocyte autoantibodies of the IgG subtype (Donath Landsteiner
Antibody) act against P antigen autoantigen on RBC surfaces and fixes complement
at 4°C. On warming to 37°C, the complement is activated and hemolysis induced.
PCH should be considered if the patient has hemoglobinuria and C3 alone is present
on the RBC.
Treatment
– Self-limited illness, mostly resolved in days to weeks with supportive care only.
– Treat underlining cause e.g. infection
– Steroids (stop once diagnosis of PCH confirmed if empirically started)
– Splenectomy not usually helpful
SECONDARY AUTOIMMUNE HEMOLYTIC ANEMIA




58
In pediatric studies, secondary causes were found in 24-63% of cases, 10% were
purely post-infectious, and in 53% an underlying immunologic disorder was found.
Common secondary causes of AIHA in children include autoimmune disease,
immunodeficiency, Evans syndrome, malignancy, infection, transplantation, and
drugs (see box 5.5).
Children < 1 year of age warrants evaluation for an underlying immunodeficiency prior
to corticosteroid or immunosuppressive agents.
All patients with AIHA should be evaluated for the presence of concurrent causes.
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Chapter 5 I Hemolytic Anemia: Autoimmune
Box 5.5 Etiology of Secondary Immune Hemolytic Anemias
Etiology of Secondary Immune Hemolytic Anemias
Infection: Epstein-Barr virus, mycoplasma pneumonia, parvovirus B19, Cytomegalovirus,
varicella, hepatitis C
rubella
Drugs: Piperacillin, cefotetan, ceftriaxone (most common)
Autoimmune disease: Evans syndrome, SLE, Autoimmune hepatitis/thyroiditis, Graves
disease, vitiligo, rheumatic disease, type 1 DM, IBD
Autoimmune lymphoproliferative disease
Immunodeficiency: CVID, combined immunodeficiency,
ADA deficiency, HIV/AIDS, Wiskott-Aldrich syndrome
Cancer: Acute leukemia, lymphoma, myelodysplasia
Abbreviations: SLE: Systemic lupus erythematosus, DM: diabetes mellitus, IBD: inflammatory bowel
disease, CVID: common variable immunodeficiency, ADA: adenosine deaminase deficiency, HIV:
human immunodeficiency virus, AIDS; acquired immune deficiency syndrome.
Management


Successful treatment of underlying condition may also improve the AIHA.
If the associated condition does not require treatment, AIHA can usually be
approached in a similar fashion to primary AIHA, although treatment decisions must
be individualized.
Evans Syndrome






Evans Syndrome (ES) accounts for 13%-73% of pediatric AIHA cases.
In ES autoantibodies are directed at specific antigens on erythrocytes, platelets, or
neutrophils but are not cross-reactive.
Patients may present with AIHA (direct antiglobulin test positive), ITP, and/or
autoimmune neutropenia either concurrently or sequentially.
ES is a chronic disorder, characterized by frequent exacerbations and remissions.
ES is a diagnosis of exclusion (exclude acquired causes of cytopenias: autoimmune
lymphoproliferative syndrome (ALPS), SLE, CVID, IgA deficiency, and HIV/AIDS etc.
ES may also develop after HSCT or can be associated with Castleman disease.
Management





First-line therapy is corticosteroids with or without IVIG. Repeated courses of IVIG
may be helpful for some patients.
Prednisolone: initial dose 1–2 mg/kg; higher doses (4–6 mg/kg/d for the first 72 h) in
the case of severe clinical symptoms in patients with more aggressive forms.
Rituximab, second-line therapy for persons who either experienced a recurrence or
failed to respond to corticosteroids, IVIG, or other immunosuppressive agents.
Additional second-line therapies include splenectomy, cyclosporine, MMF
(mycophenolate mofetil, Cell-Cept), vincristine, and danazol.
For patients with severe, relapsing ES who do not respond to first- and second-line
therapies, remaining options include cyclophosphamide, alemtuzumab, and HSCT.
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PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

PNH is a non-malignant, non-familial clonal expansion of hemopoetic stem cell due
to somatic mutation at PIG-A.
Characterized by insidious onset/chronic, intravascular hemolysis caused by
uncontrolled activation of the terminal complement pathway.

Clinical Features/ Complications
 Fatigue, lethargy, asthenia, abdominal pain, dyspnea, chest pain, male impotence,
erectile dysfunction, headache and jaundice.
 Paroxysmal nocturnal IV hemolysis (DAT negative), bone marrow failure (anemia,
macrocytosis, cytopenia(s) pancytopenia - evolution to severe aplastic anemia, MDS
or AML), tendency to venous thrombosis and infections.
Box 5.6 Classification of Paroxysmal Nocturnal Hemoglobinuria
Category
Hemolysis
Bone Marrow
Clinical PNH
PNH + BMFS
Subclinical
Florid
Mild
No
Cellular
+ MBFS
+ MBFS
Flowcytomety
(GPI %)
>50%
<50%
<1%
Eculizumab
benefit
Yes
+/No
Diagnosis: Definitively diagnosed by flow cytometry for (GPI)-linked cell surface proteins
(e.g., CD59) on peripheral blood/bone marrow (all blood cell lineages can be analyzed thus
RBCs transfusion not an issue, however granulocytes have higher sensitivity).
Management
Box 5.7 Management of Paroxysmal Nocturnal Hemoglobinuria
Supportive Therapy

Packed RBCs transfusion (for symptomatic anemic)

G-CSF for persistent cytopenia

Long-term anticoagulant therapy for venous thrombosis

Iron and folate supplements

Sildenafil to improve dysphagia/intestinal spasm and impotence
Specific Treatment

Prednisone 1-2 mg/kg daily for 2-3 days can ameliorate hemolysis during acute episode.

Eculizumab preventing the formation of C5a and is the standard of care (reduces hemolysis
and thromboembolism, and improves quality of life); consider Neisseria meningitidis
vaccination before starting.

Immune suppressive therapy: Cyclosporine and anti-thymocyte globulin (ATG) lead to
improvement in aplastic anemia
Curative Treatment: hematopoietic stem-cell transplantation is the only curative and therapy of
choice if full matched family donor is available, especially if bone marrow failure developed.
Outcome
 Variable: spontaneous remission or leukemia transformation or aplastic anemia
 Common cause of death: Venous thrombosis followed by bone marrow failure.
60
A Practical Guide I Pediatric Hematology
Chapter 5 I Hemolytic Anemia: Autoimmune
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2018;2018(1):382-389. doi:10.1182/asheducation-2018.1.382.
[link]
Nathan and Oski’s hematology and oncology of infancy and childhood. — 8th Ed (2015), page
411-429.
Ladogana S, et al. Diagnosis and management of newly diagnosed childhood autoimmune
haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric
Haemato-Oncology Italian Association. Blood Transfus. 2017;15(3):259-267. [Link]
Hill QA, et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br
J Haematol. 2017;176(3):395-411.
[Link]
Aladjidi N, Jutand MA, Beaubois C, et al. Reliable assessment of the incidence of childhood
autoimmune hemolytic anemia. Pediatr Blood Cancer 2017; 64.
Chou ST, Schreiber AD. Autoimmune hemolytic anemia. In: Nathan and Oski's Hematology
and Oncology of Infancy and Childhood, 8th ed, Orkin SH, Fisher DE, Look T, Lux SE, Ginsburg
D, Nathan DG (Eds), WB Saunders, Philadelphia 2015. p.411.
Aladjidi N, et al. New insights into childhood autoimmune hemolytic anemia: a French national
observational study of 265 children. Haematologica 2011; 96:655.
Barcellini W, Fattizzo B, Zaninoni A. Current and emerging treatment options for autoimmune
hemolytic anemia. Expert Rev Clin Immunol 2018; 14:857.
Teachey DT, Lambert MP. Diagnosis and management of autoimmune cytopenias in
childhood. Pediatr Clin North Am 2013; 60:1489.
Naithani R, Agrawal N, Mahapatra M, et al. Autoimmune hemolytic anemia in children. Pediatr
Hematol Oncol 2007; 24:309.
Vagace JM, Bajo R, Gervasini G. Diagnostic and therapeutic challenges of primary
autoimmune haemolytic anaemia in children. Arch Dis Child 2014; 99:668.
Sankaran J, Rodriguez V, Jacob EK, et al. Autoimmune Hemolytic Anemia in Children: Mayo
Clinic Experience. J Pediatr Hematol Oncol 2016; 38:e120.
Aladjidi N, et al. New insights into childhood autoimmune hemolytic anemia: a French national
observational study of 265 children. Haematologica 2011; 96:655.
Barros MM, Blajchman MA, Bordin JO. Warm autoimmune hemolytic anemia: recent progress
in understanding the immunobiology and the treatment. Transfus Med Rev 2010; 24:195.
Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica 2014;
99:1547.
Jaime-Pérez JC, et al. Current approaches for the treatment of autoimmune hemolytic anemia.
Arch Immunol Ther Exp (Warsz) 2013; 61:385.
Naithani R, Agrawal N, Mahapatra M, et al. Autoimmune hemolytic anemia in children. Pediatr
Hematol Oncol 2007; 24:309.
Barcellini W, Fattizzo B, Zaninoni A. Current and emerging treatment options for autoimmune
hemolytic anemia. Expert Rev Clin Immunol 2018; 14:857.
Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program
2018; 2018:382.
Miano M. How I manage Evans Syndrome and AIHA cases in children. Br J Haematol 2016;
172:524.
Norton A, Roberts I. Management of Evans syndrome. Br J Haematol 2006; 132:125.
Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124:2804.
Curran KJ, Kernan NA, Prockop SE, et al. Paroxysmal nocturnal hemoglobinuria in pediatric
patients. Pediatr Blood Cancer 2012; 59:525.
A Practical Guide I Pediatric Hematology
61
Index
A
Abdominal Crisis, 75
Acanthocyte, 402
Acquired Aplastic Anemia, 17
Acute Abdominal Pain, 75
Acute Chest Syndrome, 75
Acute Ischemic Stroke, 75
Acute Pediatric VTE, 262
Albinism Neutropenic Syndrome, 304
Alloimmune Thrombocytopenia, 341
Anatomic Thrombophilia, 249
Anticoagulation Therapy, 262
Antifibrinolytic Agents, 198
Antiplatelet Therapy, 285
ANTITHROMBIN LEVEL, 285
Antithrombotic Agents, 285
Aplastic Crisis, 76
Arterial Ischemic Stroke, 275
Arteriovenous Malformations, 382
Autoimmune Hemolytic Anemia, 47
Autoimmune Neutropenia, 304
B
Basophilic Stippling, 402
Benign Ethnic Neutropenia, 304
Bleeding Assessment, 144
Bleeding Child, 144
Bone Marrow Failure Syndrome, 17
C
Cartilage Hair Hypoplasia, 29
Catheter-Related Thrombosis, 262
Cerebral Sinovenous Thrombosis, 275
Cerebrovascular Accident, 75
Che´diakhigashi Syndrome, 233
Chediak Higashi Syndrome, 304
Cholelithiasis, 75
Chronic Blood Transfusion (CBT), 75
Chronic Granulomatous Disease, 304
Chronic Idiopathic Neutropenia, 304
CMV Negative Blood, 390
Conditioning Regimens, 356
Congenital Amegakaryocytic
Thrombocytopenia, 29
Congenital Dyserythropoietic Anemia, 29
436
Congenital Hemangiomas, 382
Congenital Thrombocytopenia, 29, 233
Corticosteroid Therapy, 47
Cyclic Neutropenia, 304
D
Dactylitis (Hand-Foot Syndrome), 75
Deep Vein Thrombosis, 262
Deferasirox (Dfx), 116
Deferiprone (Dfp), 116
Delta Beta Thalassemia, 116
Desferoxamine (Dfo), 116
Diamond Blackfan Anemia, 29
Direct Oral Anticoagulants, 285
Drug-Induced Immune Thrombocyopenia, 215
Drug-Induced Neutropenia, 304
Dyskeratosis Congenita, 29
E
Echinocyte, 402
Emperipolesis, 403
Engraftment Syndrome, 356
Epoetin Alfa, 8
Essential Thrombocythemia, 320
Evans Syndrome 59, 47
Exchange Transfusion, 75
F
Factor Replacement Therapy, 198
Familial Benign Neutropenia, 304
Fanconi Anemia, 29
Fever And Neutropenia, 356
G
Gata2 Deficiency Syndrome, 29
Gaucher Cells, 402
Giant Platelets, 402
Glucose-6-Phosphate Dehydrogenase (G6pd)
Deficiency, 62
Graft Failure, 356
Graft-Versus-Host Disease, 356
Granulocytosis, 304
Griscelli Syndrome, 304
H
Hb Lepore, 116
A Practical Guide I Pediatric Hematology
Hbe Disease, 116
Heinz Bodies, 402
Hematopoietic Stem Cell Transplantation, 17,
75, 116, 356
Hemoglobin C Crystal, 402
Hemoglobin H Inclusions, 402
Hemoglobinuria, 47
Hemolytic Anemia, 47
Hemolytic-Uremic Syndrome, 208
Hemophilia, 152, 341
Hemorrhagic Cystitis, 356
Hemorrhagic Stroke In Neonates, 275
Hemostatic Agents, 198
Hemostatic Factors, 198
Heparin-Induced Thrombocytopenia, 215, 285
Hereditary Elliptocytosis 67, 62
Hereditary Hemochromatosis, 29
Hereditary Pyropoikilocytosis, 62
Hereditary Spherocytosis, 62
Hereditary Stomatocytosis, 62
Hereditary Xerocytosis, 62
Hermansky - Pudlak Syndrome, 233, 304
Howell-Jolly Body, 402
Hrombotic Microangiopathic Disorders, 208
Hydroxyurea, 75, 116
Hydroxyurea (Hydroxycarbamide), 75
Hypereosinophilic Syndrome, 320
Hypersplenism, 76
Hyposegmented Bilobed Neutrophils, 402
Hyposplenism, 76
I
Imerslund- Grasbeck Syndrome, 29
Immune Hemolytic Anemias, 47
Immune Thrombocytopenia, 215
Immunodeficiency, 304
Immunosuppressive Therapy, 17
Inherited Bone Marrow Failure Syndrome, 29
Inherited Platelet Disorders, 233
Internuclear Chromatin Bridge, 403
Intravenous Immunoglobulin, 47
Iron Chelation Therapy, 116
Iron Deficiency Anemia, 8
Iron Overload, 116
Iron Refractory Iron Deficiency Anemia, 29
Iron Replacement Therapy, 8
Irradiated Blood, 390
J
Juvenile Myelomonocytic Leukemia, 320
A Practical Guide I Pediatric Hematology
K
Kaposiform Hemangioendothelioma, 382
Kasabach-Merritt Syndrome, 208
L
Leukocyte-Poor Blood, 390
Low Molecular Weight Heparin, 285
Lymphatic Malformations, 382
M
Macrocytic Anemia, 8
Macrocytosis, 402
Management Of Stroke, 275
Megaloblastic Anemia, 8
Metabolic Disorders, 304
Miscellaneous Enzyme Deficiencies, 62
Montreal Platelet Syndrome, 233
Mucocutaneous Bleeding, 208
Multi System Organ Failure (Msof), 76
Myelofibrosis, 402
Myh9-Related Thrombocytopenia Disorders,
233
N
Neonatal Alloimmune Thrombocytopenia
(Nait), 215
Neonatal Anemia, 341
Neonatal Circumcision - Hemophilia, 341
Neonatal Immune Neutropenia, 341
Neonatal Purpura Fulminans, 341
Neonatal Thrombocytopenia, 341
Neonatal Venous Thromboembolism, 262,
341
Neutropenia, 304
O
Opioid Use Disorder, 76
Osteomyelitis, 76
P
Painful Crisis Or Vaso-Occlusive Crisis (Voc),
75
Pancytopenia, 17
Pappenheimer Bodies, 402
Paroxysmal Nocturnal Hemoglobinuria, 47
Pearson Syndrome, 29
437
403
Pediatric Stroke, 275
Pediatric Vte Treatment Guidelines, 262
Perinatal Stroke, 275
Pernicious Anemia, 29
Platelet Clumping, 402
Platelet Concentrates, 390
Poikilocytosis, 402
Polycythemia Vera (Pv), 320
Portal Vein Thrombosis, 262
Posterior Reversible Encephalopathy
Syndrome, 356
Post-Thrombotic Syndrome In Childhood, 249
Post-Transfusion Purpura, 390
Post-Transfusion Purpura: Alloimmune, 215
Post-Transplantation Lymphoproliferative
Disorders, 356
Prenatal Testing, 116
Priapism, 75
Primary Myelofibrosis, 320
Protein Deficiencies, 249
Pulmonary Complications, 356
Pulmonary Embolism (Pe), 262
Pyruvate Kinase (PK) Deficiency, 62
Q
Qualitative Genetic Mutations, 249
Quebec Platelet Disorder (Fv Quebec), 233
R
Rare Inherited Bleeding Disorders, 198
Red Blood Cell (RBCS), 390
Red Blood Cell Transfusion, 75
Red Cell Enzyme Disorders, 62
Red Cell Membrane Disorders, 62
Refractory Cytopenia Of Childhood, 320
Renal Vein Thrombosis (Rvt), 262
Reticular Dysgenesis, 29
Ring Sideroblasts, 403
Rituximab, 47
Rogers Syndrome, 29
S
Scott Syndrome, 233
Septic Arthritis, 76
Severe Congenital Neutropenia, 29, 304
Shwachman Diamond Syndrome, 29
Sickle Cell Disease, 75, 76
438
Sickle Cells, 402
Sideroblastic Anemias, 29
Simple Blood Transfusion, 75
Sinusoidal Obstruction Syndrome , 356
Specific Site Thrombosis, 262
Spherocytes, 402
Splenectomy, 47, 116
Splenic Sequestration, 208
Stroke Emergencies, 275
Stroke Prevention, 75
T
Tanscranial Doppler (Tcd), 75
Target Cells, 402
Teardrop Cells, 402
Thalassemia, 116
Therapeutic Plasma Exchange, 47
Thiamine Responsive Megaloblastic Anemia,
29
Thrombocytopenia, 215, 208
Thrombocytopenia With Absent Radii, 29
Thrombolytic Therapy, 285
Thrombophilia And Hormonal Therapy, 249
Thrombophilia Testing, 249
Thromboprophylaxis, 262
Thrombotic Thrombocytopenic Purpura, 208
Transcobalamin II Deficiency, 29
Transfusion Reactions, 390
Transfusion-Associated Graft-Versus-Host
Disease (TA-GVHD), 390
Transient Ischemic Attack, 275
Transplant-Associated Thrombotic
Microangiopathy, 356
U
Unfractionated Heparin, 285
V
Vascular Anomalies, 382
Venous Malformations, 382
Vitamin K Deficiency Bleeding (VKDB) Of
Early Infancy 353, 341
W
Warfarin, 285
Whim Syndrome/ Myelokathexis, 304
A Practical Guide I Pediatric Hematology