Pediatric Hematology Oncology Board Review August 12

Pediatric Hematology Oncology For
Pediatric Board Review
2 N D P E D I AT R I C O N S Q U A R E S B O A R D R E V I E W
6 - 1 3 A U G U S T 2 0 2 2
I B R A H I M A L - H A R B I , M D , F R C P C
C O N S U LTA N T, P E D I AT R I C H E M ATO L O G Y O N C O L O G Y
F R I D AY A U G U S T 1 2 , 2 0 2 2
Pediatric Board Review Hematology Oncology August 12, 2022

Objectives
“Based on Pediatric Saudi Board Objectives”
Pediatric Hematology
— Febrile neutropenia
— Bleeding disorders (Coagulation
Disorders, ITP)
— Treatment of Thalassemia
— Treatment of Thalassemia Iron Overload
— Sickle cell disease
¡ Vaso-occlusive crises
¡ Infection
¡ Acute Splenic Sequestration
¡ Aplastic crisis
— Thrombocytopenia & Platelet Disorders
— Anemia in children:
¡ Approach & Management
Pediatric Oncology
— Leukemia & lymphomas
— Solid Tumors
— Oncology Emergencies
¡ Tumor Lysis Syndrome
¡ Superior Vena Cava
Syndrome
¡ Mediastinal Mass
— Side Effects of
Chemotherapy

Pediatric Hematology

Question 1
A 3 year old girl is not known prior to have any medical problem, presented to the emergency
department with 3 days history of runny nose, dry cough, and high fever. On examination: Temp
39.7 PO, HR 155, BP 100/55, RR 16, O2 Sats 99% on Room Air. No lymphadenopathy. No
hepatosplenomegaly. Laboratory investigations showed WBC 3.1 x 109/L , Hemoglobin 12.3 g/dl,
Platelets of 623. Absolute Neutrophils Count was 90 (0.09 x 109/L ). Blood film showed relative
lymphocytosis with reactive/atypical lymphocytes. What would be the next best action ?
A. Blood Culture, Start IV Piperacillin/Tazobactam (Tazocin) and Admit
B. Blood Culture, One Dose of Ceftriaxone, and Follow up with ER next day
C. Blood Culture, One Dose Ceftriaxone and follow up in 1 week
D. Reassure family this is a viral illness and no need for any antibiotics
E. Discharge patient from ER on a course of oral antibiotics

Viral Infection Associated Neutropenia (VIAN)
— Infectious / Post infectious neutropenia
— Very common
— Two Mechanisms ??
— Diagnosis ? Empirical / Clinical
— Management ?
— Prognosis ?

Neutropenia In Children
— Neutropenia in Children is an extremely common condition
— Estimated 1 in 5 children admitted suffer from Neutropenia
— ANC = (Neutrophil % + Bands %) x WBC / 100
— It frustrates a lot of pediatricians with regard what to do with it
— Most Neutropenia in children is benign, non-life threatening
— Generally divided them into 2 big etiologies: Acquired & Congenital
— This classification is clinically important, and it is relevant.
— Congenital Neutropenia, albeit rare, is a serious condition & can
result in death.

Acquired
Production
Cytotoxic Chemotherapy, Irradiation
Drugs: Chloramphenicol, Phenothiazines
Metabolic disease
Nutritional deficiency: vitamin B12, folate
Infectious Viral—EBV, CMV, hepatitis, HIV, influenza. Bacteriaa: Salmonella, Brucella,
Pertussis, Rickettsia, Mycobacteria, Fungal
Malignant—Leukemia, Lymphoma
Destruction Collagen vascular disease: SLE, Rheumatoid Arthritis, Sjogren’s Syndrome
Drugs—Penicillins, Cephalosporins, Clindamycin, Bactrim
Malignant disease: Leukemia / Lymphoma
Sequestration Hypersplenism
Congenital Severe Congenital Neutropenia (SCN)
Shwachman-Diamond syndrome
Kostmann’s syndrome
Cyclic Neutropenia
Familial Benign Neutropenia
Classification of Neutropenia

Risk of Invasive Bacterial Infections in Noncancer
Febrile Neutropenia
Sung L, Johnston DL. Approach to febrile neutropenia in the general paediatric
setting. Paediatr Child Health. 2007;12(1):19-21. doi:10.1093/pch/12.1.19
Lower-Risk Conditions Higher-Risk Conditions
• Familial Benign Neutropenia
• Autoimmune Neutropenia
• Chronic Benign Neutropenia
• Viral Infection-Associated Neutropenia (VIAN)
• Severe Congenital Neutropenia (Kostmann Syndrome)
• Cyclic Ceutropenia
• Shwachman-Diamond Syndrome
• Reticular Dysgenesis
• Myelokathexis
• Aplastic anemia

Factors That Increase Risk of Invasive Bacterial
Infection in Febrile Neutropenia
August 12, 2022
Pediatric Board Review Hematology Oncology
1. Mucositis
2. Intravascular devices
3. Depression of other immune function
4. Abnormal neutrophil function
5. Longer duration of neutropenia (eg, >7 days)
6. Lower absolute neutrophil count (eg, ≤100 cells/μL)
7. Concurrent immunosuppressant therapy
Sung L, Johnston DL. Approach to febrile neutropenia in the general paediatric setting. Paediatr Child
Health. 2007;12(1):19-21. doi:10.1093/pch/12.1.19

Management of Non-Chemotherapy Induced
Febrile Neutropenia
Monotherapy vs. Dual Drugs
Pediatric high-risk FN and as empirical therapy, use monotherapy:
Antipseudomonal Beta Lactam, or
4th Generation cephalosporin, or
Carbapenem
Reserve addition of a second gram negative agent:
1. Clinically unstable
2. When a resistant infection is suspected
3. In centers with a high rate of resistant pathogens
Robinson PD, Lehrnbecher T, Phillips R, et al: Strategies for empiric management of pediatric fever and neutropenia in patients with cancer and hematopoietic stem-cell
transplantation recipients: A systematic review of randomized trials. JCO 34:2054-2060, 2016

Question 2
— A 5 year old boy came to the emergency department with high fevers. He was found to
have COVID-19 infection confirmed by PCR test. Laboratory investigations showed:
WBC 3.1 x 109/L , Hemoglobin 11.5 g/dl, Platelets of 46. Lymphocytes were 0.34 x
109/L (ALC 340). Neutrophils 1.7 x 109/L (ANC 1700). PT 17.2 (12.1-14.5), INR 1.4
(0.87-1.2), PTT 47 (33.6-402.5). D-Dimer (2-12 years old, 0.4-2.27 mg/L). What are the
most prognostically significant hematologic manifestations of COVID-19 infection in
children:
A. Lymphopenia
B. Thrombocytopenia
C. High Level D-Dimer
D. A & B
E. A & C

Hematological Manifestations of SARS-CoV-2 in Children
— The majority of infected children had a normal leukocyte count
— The most common WBC abnormality was leukopenia.
— Lymphopenia, less common but may be a marker of severe disease
— Neonates & infants: the most common abnormality: lymphocytosis
— Anemia & hypercoagulability: higher in children in MIS-C with
SARS-CoV-2.
Kosmeri C, Koumpis E, Tsabouri S, Siomou E, Makis A. Hematological manifestations of SARS-CoV-2 in children. Pediatr Blood Cancer. 2020 Dec;67(12):e28745

Question 3
— An 11 months old boy came to your clinic with pallor. You ordered CBC
and Hemoglobin was 6.1 g/dl, MCV 51 fL, MCH 19 pg. Hemoglobin
Electrophoresis showed Hemoglobin F 94.3%, Hemoglobin A2 5.5%.
What is the most likely diagnosis:
A. Iron Deficiency Anemia
B. Beta Thalassemia Major
C. Beta Thalassemia Minor
D. Sickle Cell Disease
E. Homozygous Hb E Disease

Beta Thalassemia Major
— Thalassemia: Greek: Thalass: Sea, Emeia: Blood
— As a disease, first recognized 1925 by Thomas Cooley & Pearl
Lee
¡ A series of infants who became profoundly anemic
¡ Splenomegaly and Bone Changes over the first year of life
— The word ”Thalassemia” was used for the 1st time in 1932
— In 1940, the genetic character of this disorder was fully appreciated
— Most patients come from the Mediterranean region
Whipple GH, Bradford WI. Am J Dis Child 1932;44:336

Beta Thalassemia Major
— Thalassemia: Genetic disorders of Hemoglobin Synthesis
— Characterized by reduction in synthesis of one or more of
the Globin Chains
— This leads to:
¡ Imbalanced globin-chain synthesis
¡ Defective hemoglobin production
¡ Severe Anemia
(Victor et al., 1999)

Diagnosis of Beta Thalassemia
— CBC:
¡ Increased RBC mass
¡ Hypochromic Microcytic anemia with normal RDW, Why ??
— HPLC:
¡ Beta Thalassemia Minor:
÷ Hb F 0.1-5%
÷ Hb A2 ³ 4%
¡ Beta Thalassemia Major:
÷ B0/ B0
¢ HbF up to 95%
¢ Hb A2 ³ 5%
÷ B0/B+
¢ HbF 70–90%
¢ HbA up to 30%
¢ Hb A2 ³ 4%

Question 4
— A 9 year old girl known case of Beta Thalassemia Major on regular
monthly blood transfusion presented to your clinic complaining of
fatigue, SOB, and sometimes feeling her hear beat loudly. She is on
Deferasirox but she is not compliant.
— On examination, she has tachycardia, HR 144, also tachypneic RR 54,
Os Sat 87 RA, BP 100/60. Chest X-Ray showed lung edema and
cardiomegaly. She has hepatomegaly as well. CBC showed Hemoglobin
of 10.8 g/dl (Transfused 1 week ago). Ferritin 13550 ng/ml .. The most
likely cause is:
A. Anemia
B. Congestive Heart Failure
C. Zinc Deficiency
D. Hypothyroidism
E. Vitamin D Deficiency

Dying
RBC
Reticuloendothelial
System
Free
Iron
Liver
Heart
Endocrine
organs
CIRRHOSIS
ARRHYTHMIA HEART
FAILURE
DIABETES
Hypothyroidism

Thalassaemia: Iron Overload
Hepatic fibrosis à Cirrhosis
Arrhythmia
Hypogonadism
Diabetes
Hypothyroidism
Hypoparathyroidism
Cardiomyopathy

How do we know if there’s too much iron?
— Serum ferritin concentration
¡ Used in clinical practice globally
— Liver biopsy
¡ Reference methodology (‘gold standard’)
— Magnetic resonance imaging (T2*MRI)
¡ The CMR with measurement of T2* relaxation time should be
performed in all patients with idiopathic cardiomyopathy.
— Echocardiogram

Cardiomyopathy & CHF in Iron Overload
— Iron deposition in the heart often causes arrhythmias and
progressive systolic dysfunction.
— Manifests as dilated cardiomyopathy with low LVEF
— Can be reversible only if it is diagnosed and treated in
its early stages.
Rivers J, Garrahy P, Robinson W, et al. Reversible cardiac dysfunction in hemochromatosis. Am Heart J 1987; 113: 216-7.

Cardiomyopathy & CHF in Iron Overload
— Patients may be asymptomatic early in the disease.
— Once heart failure develops, there is rapid deterioration.
— Cardiac Assessment is characterized by
¡ Dilated cardiomyopathy with dilated ventricles,
¡ Reduced ejection fraction
¡ Reduced fractional shortening
Rivers J, Garrahy P, Robinson W, et al. Reversible cardiac dysfunction in hemochromatosis. Am Heart J 1987; 113: 216-7.

Hypochromic Microcytic Anemia
— How do you differentiate Hypochromic Microcytic
Anemia that is due to Thalassemia carrier from Iron
Deficiency Anemia only using CBC ?
¡ RBC
¡ MCV
¡ RDW
¡ Mentzer Index

Question 5
A pregnant woman who is 28 year old who has sickle cell disease and
asks you what are the chances her newborn baby would have Sickle
Cell Disease. Her husband has Sickle Cell /Beta Thalassemia Disease.
Choose the BEST answer:
A. 25% chance of having Sickle cell disease
B. 50% chance of having Sickle cell disease
C. 75% chance of having Sickle Cell Disease
D. 100% chance of having Sickle cell disease
E. 50% chance of SCD, 50% chance of Sickle Cell/Beta Thalassemia

Question 5
A pregnant woman who is 28 year old who has sickle cell disease and
asks you what are the chances her newborn baby would have Sickle
Cell Disease. Her husband has Sickle Cell /Beta Thalassemia Disease.
Choose the BEST answer:
A. 25% chance of having Sickle cell disease
B. 50% chance of having Sickle cell disease
C. 75% chance of having Sickle Cell Disease
D. 100% chance of having Sickle cell disease
E. 50% chance of SCD, 50% chance of Sickle Cell/Beta
Thalassemia

Mother
Father
S S
S SS SS
Beta S/Beta S/Beta
SCD Mother and SCD/Beta Thalassemia Father

Sickle Cell Disease’ Syndromes
— Sickle Cell Disease genotypes in order of severity
• Hb SS
• Hb S/βo
• Hb S/β+
• Hb S/α Thal
• Hb S/C
Maria Stella Figueiredo, The compound state: Hb S/beta-thalassemia Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil, rev bras
hematol hemoter. 2 0 1 5;37(3):150–152

Sickle Cell Syndromes in KSA
— Sickle Cell Disease genotypes in order of frequency in
KSA
• Hb SS 72%
• Hb SS with high Hb F 15%
• Hb S/Beta 8 %
• Hb S/Alpha Thal 4-6%
• Hb S/C 1-2 %
El-Hazmi MA. On the nature of sickle-cell disease in the Arabian Peninsula. Hum Genet. 1979;52:323–35.

Question 6
— An 8 year old boy known case of sickle cell disease presented with an inability to walk
on his right leg. On exam, he was febrile 39 °C. He has a focal tenderness over right
distal femur. No pain in any other parts of his body. Labs showed WBC of 29.7 ×
109/L, Hemoglobin 7.3 g/dl (Usually 7-8 g/dl). Platelets of 381. CRP was 131 mg/L,
ESR 96 mm/hr. The most likely etiologic organism causing this condition would be:
A. Salmonella
B. Staphylococcus aureus
C. E. coli
D. Streptococcus group A
E. Streptococcus pneumonia

Osteomyelitis in Children with SCD
— The most serious bone involvement in children with SCD
— Diagnostic Dilemma:
• Clinical
÷ Fever
÷ Inflammatory markers
÷ “Focality”
÷ Decrease range of motion UL / Non-Weight bearing LL
• Radiological:
÷ U/S
÷ Bone scan
÷ MRI
• Why do we care ?

Osteomyelitis in Children with SCD
— How to differentiate Osteomyelitis from Bone Infarction (VOC) in children with SCD
¡ Kocher’s Criteria. (Originally for Septic Arthritis)
÷ Fevers > 38 C
÷ ESR > 40 mm
÷ WBC > 12, 000
÷ Decreased ROM Upper Limbs / Non-Weight Bearing Lower Limbs
¡ MRI: (Gold Standard Imaging Modality))
÷ Periosteal Reaction
÷ Soft Tissue Enhancement
÷ Soft Tissue Edema
÷ Presence of Sequestrum
¡ Bone Scan: Useless, Uptake increased in VOC & Bone Infections
¡ Bone Marrow Scan: decreased uptake on bone marrow scan in a patient with SCD & bone pain almost
invariably indicates infarction, whereas normal uptake strongly suggests the diagnosis of osteomyelitis. Not
widely available
Yolande, D. , Tufong, K. , Jules, T. , Mayah, A. , Charlotte, E. , Njinkui, D. , Enyama, D. , Selangai, H. and Siysi, V. (2021) Osteomyelitis in Children with Sickle Cell Disease: A Challenging Diagnosis: Case Report from
Cameroon. Open Journal of Pediatrics, 11, 208-214.
Sreedhar Rao, MD et al, Scintigraphic differentiation of bone infarction from osteomyelitis in children with sickle cell disease. The Journal of Pediatrics, November 1985, Pages 685-68

Score Likelihood of septic arthritis
1 3%
2 40%
3 93%
4 99%
The Kocher criteria are a tool useful in the differentiation of septic
arthritis from transient synovitis in the child with a painful hip.
They are named for Mininder S. Kocher

Question 7
A 5 year old boy known case of SCD presented to the emergency department
complainging of severe pain in his lower legs. No fevers and no other complaints.
Labs showed WBC 7.1 × 109/L, Hb 8.3 g/dl (his baseline). Platelets 345 × 109/L ,
CRP 35 mg/ml. Pain Score was 9/10. He required one IV Morphine bolus 0.1
mg/kg IV. Pain improved temporarily. After 2 hrs, severe pain returns, and he is
crying in pain. Pain now is 10/10. The best next plan of action:
A.Give a second Morphine bolus 0.1 mg/kg IV and start IV Morphine infusion
B.Give a 2nd Morphine bolus at 0.05 mg/kg and start IV Morphine infusion
C.He is faking it since he took a dose of Morphine 2 hrs ago, so nothing else
D.Give Paracetamol 15 mg/kg PO and observe
E. Give Paracetamol 15 mg/kg IV and observe

Vaso-Occlusive Crisis (VOC)
http://www.nhlbi.nih.gov/sites/ww
w.nhlbi.nih.gov/files/images_290
— VOC is the most common
complication of SCD
— VOCs occur when sickling
& occlusion occur at the
level of capillary and post-
capillary venules that
result in ischemic tissue
injury and pain.
— > 3 admissions for a VOC
/ year = risk of early
death (CSSCD 1985)

Vaso-Occlusive Crisis
— A VOC is the hallmark acute complication of SCD
— Manifests as severe acute pain
— Although VOCs are typically associated with excruciating pain
of sudden onset, some people experience gradual onset of a
VOC
— All SCD will experience a VOC at least once during their
lifetime
— About 50% of VOC in Children with SCD is Unprovoked !

How To Manage Vaso-Occlusive Crisis in Children with SCD
— IV Fluids: If euvolemic, give only maintenance
— Monitor for excessive sedation by measuring sedation with an
objective measurement sedation scale and oxygenation levels.
— Gradually titrate down parenteral opioids as VOC resolves
— NO blood transfusion for VOC unless there are other indications
— In children VOC with an O2 <95 % on RA, ADMINISTER O2
— If IV Morphine is maximized
— PCA then Use Incentive Spirometer
Udezue E, Herrera E. Pain management in adult acute sickle cell pain crisis: a viewpoint. West Afr J Med. 2007;26(3):179-82

Question 8
— An 8 months old girl brought by her parents because of continuous crying and swelling
in her hands for 3 days. She is not known to have any medical problems. She was
product of uncomplicated pregnancy. She was born at a peripheral hospital and
incomplete neonatal screen was done.
— Afebrile but tachycardiac. She looks in pain. Her hands were swollen and looked as in
the photo. Labs showed WBC 19.7 × 109/L, Hb 9.3 g/dl. Platelets 533 × 109/L , CRP 3
mg/ml. ESR 6 mm/hr.
— What is the most likely diagnosis ?
A. Dactylitis (Hand Foot Disease)
B. Psoriatic Arthritis
C. Fracture / Trauma
D. Child Abuse
E. Osteomyelitis

Hand Foot Syndrome (Dactylitis)
— The earliest clinical musculoskeletal manifestation of SCD
— Affects infants and young children 6 months to 6 years
— Highest incidence during the first 6-12 months of life
— Infarction at metacarpals, metatarsals, and phalanges
— Results from sickling of RBCs in the capillary beds
— Histologically ??
— Risk factor for ??

Question 9
— You are on call, and a nurse calls you saying the 11 year old boy known case
of SCD, who was admitted 2 days earlier with severe VOC and now on
Morphine Infusion 40 mcg/kg/hr, is developing shortness of breath and chest
pain. You come to assess him. You find him lethargic, toxic looking,
tachycardiac (130), O2 Sats 82%, and in severe respiratory distress. You assess
him and put him on 10 L. O2. You call PICU. . You order stat Chest Xray,
ABG, and blood culture and CBC LFT, RFT. CBC showed Hb 6.8 g/dl, WBC
34.6, Platelets 110. Retic Count 14%. T-Bilirubin 72 umol/L. LDH 651 IU/L..
CRP 344 mg/ml. PH 7.22, PaO2 44, PaCO2 61. Chest X-Ray showed Right
lower lobe infiltration. The best predictors of poor outcome are:
A. Chest pain, Hypoxemia, Degree of Respiratory Acidosis
B. Lobar involvement, Relative Thrombocytopenia, Hx of Cardiac Disease
C. Lobar Involvement, Hypoxemia, Level of CRP
D. Severity of VOC, Leukocytosis, CRP level
E. CRP Level, Hypoxemia, Chest pain

Question 9
— You are on call, and a nurse calls you saying the 11 year old boy known case of
SCD, who was admitted 2 days earlier with severe VOC and now on Morphine
Infusion 40 mcg/kg/hr, is developing shortness of breath and chest pain. You come
to assess him. You find him lethargic, toxic looking, tachycardiac (130), O2 Sats
82%, and in severe respiratory distress. You assess him and put him on 10 L. O2.
You call PICU. . You order stat Chest Xray, ABG, and blood culture and CBC LFT,
RFT. CBC showed Hb 6.8 g/dl, WBC 34.6, Platelets 110. Retic Count 14%. T-
Bilirubin 72 umol/L. LDH 651 IU/L.. CRP 344 mg/ml. PH 7.22, PaO2 44, PaCO2
61. Chest X-Ray showed Right lower lobe infiltration. The best predictors of poor
outcome are:
A. Chest pain, Hypoxemia, Degree of Respiratory Acidosis
B. Lobar involvement, Relative Thrombocytopenia, Hx of Cardiac Disease
C. Lobar Involvement, Hypoxemia, Level of CRP
D. Severity of VOC, Leukocytosis, CRP level
E. CRP Level, Hypoxemia, Chest pain

Acute Chest Syndrome
— 2nd most common cause of hospitalization
— leading cause of SCD mortality in adults
— Management is largely determined by the experience of
individual practitioners
— No conclusive randomized controlled clinical trials to guide
therapy
— 50% of ACS happen in SCD children admitted with VOC

Definition of ACS
— ACS: acute pulmonary illness that occurs in patients with SCD
— ACS is currently defined as a new infiltrate on chest radiograph in conjunction with 1
other new symptom or sign:
¡ Chest pain
¡ Cough
¡ Wheezing
¡ Tachypnea
¡ Fever (> 38.5°C)
Charache S, Scott JC, Charache P. “Acute chest syndrome” in sickle cell anemia. Microbiology, treatment, and prevention. Arch Intern Med. 1979;139(1):67-69

Pulmonary Fat Embolism (PFE)
— Why ACS is different than pneumonia ?
— Fat from bone marrow embolizes to the lungs
• PFE is associated with activation of:
• Secretory phospholipase A2 (sPLA2)
• Free fatty acids (Toxic to Lung Tissues)
• Serum levels of sPLA2: initially uniformly elevated in ACS
• In NACSS, 80% of subjects with ACS had sPLA2 elevation.
• The administration of PRBCs in pts with VOC & é sPLA2 leads to ?
Elliott P. Vichinsky, M.D, et al, Causes and Outcomes of the Acute Chest Syndrome in Sickle Cell Disease (NACSS) , N Engl J Med 2000; 342:1855-1865

Clinical and Laboratory Predictors of Development of
Acute Chest Syndrome
1. Young age ?
2. Low HbF
3. High steady-state WBC
4. Severe genotypes (HbSS and HbSb0 thalassemia)
5. More than > 3 severe VOC episodes in the preceding year
6. Asthma/airway hyperreactivity
7. Tobacco smoke exposure (TSE)
8. Recent surgery
Jain S, Bakshi N, Krishnamurti L. Acute Chest Syndrome in Children with Sickle Cell Disease. Pediatr Allergy Immunol Pulmonol. 2017 Dec 1;30(4):191-201.

Question 10
— A 1 year old boy known case of SCD & G6PD presented to
ER with history of runny nose and mild cough, and then
sudden onset of significant pallor. On Exam: He had mild
URTIs symptoms, T 37.1 Ax, HR 160, RR 28, BP 90/45.
— No HSM. CBC Hb 3.2 g/dl, Hct 9.6, Retic count 1.2%, LDH
420 IU/L, T-Bilirubin 42 μmol/L.
— What is the most likely diagnosis:
A.Acute Hemolytic Crisis
B.Hyperhemolytic Crisis
C.Aplastic Crisis
D.Transient Erythroblastopenia of Childhood (TEC)
E. Acute Splenic Sequestration

Corrected Retic Count
— CRC = ( Hematocrit / Normal Hematocrit ) * (
Reticulocyte %)
CRC = (9.6/45) * 1.2 = 0.26 % Relative Reticulocytopenia

Aplastic Crisis
— Bone marrow temporarily shuts down.
— Acute fall in haemoglobin levels - by up to 1 g per dl per day
— There is a complete absence of reticulocytes in the blood film.
— The causative agent is usually human parvovirus B19.
— This leads to profound anaemia over a period of a few days.
Koch WC, Massey GV. Aplastic crisis. Pediatr Rev. 1990 Nov;12(5):142-8

Aplastic Crisis
— This virus infects RBC progenitors in bone marrow,
— In SCD, RBC lifespan is greatly shortened (usually 10-20 days),
— Very rapid drop in Hb occurs.
— Bone marrow recovery occurring in 7-10 days
— Followed by brisk Reticulocytosis

Aplastic Crisis
— Aplastic crises is characterised by:
¡ Reticulocytopaenia – seen 5 days post exposure, last for 7–10 d
¡ Symptomatic anaemia
¡ Serum IgM antibodies to parvovirus B19 or Positive PCR

Question 11
— You are on call, and a 2 year old boy known case of SCD,
presented to ER with pallor and inability to move his right
side. He is tachycardiac (170), but afebrile. Spleen is 6 cm
BCM (usually not-palpable). CBC showed Hb 2.1 g/dl,
WBC 6.3, Platelets 150. Retic Count 28%. T-Bilirubin 72
umol/L. LDH 432 IU/L.. MRI showed Left MCA Stroke.
The most likely diagnosis explaining the whole scenario is:
A.Acute Stroke
B.Acute Splenic Sequestration
C.Acute Hemolytic Crisis
D.Hypersplenism
E. Splenic Infarction

Splenic Complications of SCD
— Acute Splenic Sequestrations
— Hypersplenism
— Splenic Infarction
— Splenic Abscess
— Splenomegaly without Sequestration

Question 12
— A 1 year old boy with sudden onset of pallor, jaundice, associated
with viral illness. On examination, he has splenomegaly (6 cm
below costal margin). CBC showed Hemoglobin of 5.8 g/dl.
MCV was 80 fL, MCH was 28 pg (NR 23-31), and MCHC was
41 g/dl (NR 32-36). Reticulocyte count was 9.3 %. Platelet count
255. Direct antilobulin’s test (Coomb’s test) was negative.
Ferritin 55 ng/ml . Coagulation profile was normal. The most
likely cause is:
A. Iron deficiency anemia
B. Beta Thalassemia Major
C. Hereditary Spherocytosis
D. Pyruvate Kinase Deficiency

Hereditary Spherocytosis
— HS is the most common RBC membranopathy (RBC Membrane Disorders)
— Autosomal Dominant Inheritance
— Characterized by anemia, jaundice, and splenomegaly, susceptibility to GB Stones
— Prevalence ??
— Clinical severity is variable
— Genetic: mutations in the 7 genes coding for RBC membranes:
¡ α spectrin
¡ β spectrin
¡ ankyrin
¡ Band 3 Deficiency
¡ Protein 4.1 Mutation
¡ Protein 4.2 mutation
¡ Actin
— Diagnosis:
¡ Blood film: ³ 15-20 % spherocytosis
¡ Osmotic Fragility Test
¡ Flowcytometry
¡ Genetic: WES/NGS
Silverio Perrotta, Patrick G Gallagher, Narla Mohandas , Hereditary spherocytosis Lancet 2008; 372: 1411–26

Hereditary Spherocytosis
— The classic laboratory features of HS include the following
¡ Mild to moderate anemia
¡ Reticulocytosis
¡ Increased mean MCHC
¡ Spherocytes on the peripheral blood smear
¡ Hyperbilirubinemia
¡ Abnormal results on the incubated osmotic fragility test
— Complications of spherocytosis may include
¡ Megaloblastic / Aplastic crisis
¡ Gallbladder Stones (Cholelithiasis / Cholecystitis)
¡ Hemolytic Crisis
Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ. Guidelines for the diagnosis and management of hereditary spherocytosis - 2011 update. Br J Haematol. 2012 Jan. 156(1):37-49

Question 13
— An 8 year old boy presented to the emergency department with
history of pallor and petechiae over last 4 weeks. He also has
fevers during the same period. Vague history of URTI 2 months
prior with cough, runny nose and sore throat. Examination
showed a pale child, no hepatosplenomegaly. CBC: WBC 1.1 ×
109/L, Hb 5.2 g/dl, Platelets 7, ANC 120 (0.12 × 109/L). Bone
marrow Aspiration & Biopsy was done later and showed 75 %
hypocellular marrow. The most likely diagnosis:
A. Bone Marrow Suppression post viral infection
B. Diamond Blackfan Anemia
C. Fanconi Anemia
D. Severe Aplastic Anemia
E. Very severe Aplastic Anemia

Aplastic Anemia
— Definition:
¡ Bone marrow failure disorder that is characterized by:
÷ Peripheral pancytopenia
÷ Bone marrow hypoplasia
¡ peripheral blood pancytopenia secondary to bone marrow hypocellularity
(<30%)
— Diagnosis Criteria for AA:
o Bone marrow hypocellular with no abnormal cells.
o At least 2 of the following:
o Hb <10 g/dL
o Platelet count <50 × 10^9/L
o Absolute neutrophil count <1.5 × 10^9/L
Killick SB, Bown N, Cavenagh J, et al; British Society for Standards in Haematology. Guidelines for the diagnosis and management of adult aplastic
anaemia. Br J Haematol. 2016;172:187-207

Aplastic Anemia
Severity Classification (Gamitta’s Classification)
— Severe AA
• Bone marrow cellularity <25% or cellularity <50% with <30%
residual hematopoietic cells
• At least 2 of the following:
÷ Absolute reticulocyte count <1%
÷ Platelet count <20 × 10^9/L
÷ Absolute neutrophil count < 500 (0.5 × 10^9/L)
— Very severe AA
o Absolute neutrophil count < 200 (0.2 × 10^9/L)
o AND fulfils rest of the criteria for severe AA
— Non-severe AA
¡ Patients not fulfilling the criteria for severe or very severe AA
Camitta BM. Pathogenesis and treatment of aplastic anemia. Rinsho Ketsueki. 1984;25:459–469.
Samarasinghe, S., Veys, P., Vora, A. and Wynn, R. (2018), Paediatric amendment to adult BSH Guidelines for aplastic anaemia. Br J Haematol, 180: 201-205

Question 14
— A 2 weeks old boy who just had a circumcision. He had a
massive bleeding 3 hours after the procedure. In ER, he was
investigated. Prothrombin (PT) was 12.3 (normal 11-14 seconds).
International Normalized Ratio (INR) was 1.1 (normal 1-1.2).
Activated Partial Thromboplastin Time (APTT) 119 seconds
(Normal 30-40 seconds). Factors FVIII and FIX levels requested
but are still pending. The most likely diagnosis is:
A. Factor VIII Deficiency
B. Factor II Deficiency
C. Factor V Deficiency
D. Factor XIII Deficiency
E. Von Willebrand Deficiency

Hemophilia A
— FVIII Deficiency
— The most common inherited factor deficiency
— X-Linked recessive pattern
— Affects 1: 5000 boys
— Of all patients with Hemophilias, Hemophilia A represents about 85%
— Severe hemophilia is characterized by a factor level of less than < 1%
— Moderate hemophilia the clotting factor level is between 1 and 5 %
— Mild hemophilia FVIII or FIX levels are greater than 5 % but < 30%
Gitschier J, Wood WI, Goralka TM, et al.: Characterization of the human factor VIII gene. Nature. 312:326-330 1984

Hemophilia A
— 70% are X-Linked Recessive inheritance
— 30 % are new mutations
— 10 % are qualitative dysfunction of FVIII
— 90% are quantitative
— Affects mainly males
— Females can be affected if they are homozygous
— Hemarthrosis (Joint bleeding), is the main site of bleeding
in 75% of patients
Goodeve A. Molecular genetic testing of hemophilia A. Semin Thromb Hemost. 2008;34:491-501. http://www.ncbi.nlm.nih.gov/pubmed/19085648

Hemophilia B
— Factor IX deficiency
— The 2nd most common factor deficiency
— Major cause of morbidity and mortality in children
— Like all factor deficiencies, it is divided into:
¡ Mild > 5 %
¡ Moderate 1-5 %
¡ Severe <1%
— There is sometimes variation between level of factor IX
and the clinical picture of the disease

Epidemiology of Hemophilia A & B
— Hemophilia A is more common than hemophilia B
— Hemophilia A is also more likely to be severe
— Hemophilia A –1 in 5000 live male births
¡ Approximately two-thirds have severe disease
(ie, factor VIII activity <1 percent of normal).
— Hemophilia B –1 in 20,000 live male births.
¡ Approximately half of them have severe disease
(ie, factor IX activity <1 percent of normal).

Question 15
— A 3 weeks old girl who has recurrent bleeding from the umbilicus
as well as delayed detachment of the cord presented to your clinic
with yet another episode of bleeding from the umbilicus. You
assessed her and ordered some investigations. Hemoglobin was
8.4 g/dl, Platelet count was 290. PT was normal at 12 seconds
(normal 11-14). INR 1.1 (normal 1.0-1.1), PTT 33 seconds
(normal 30-40). The most likely diagnosis:
A. Factor XIII Deficiency
B. Factor VIII Deficiency
C. Von Willebrand Disease
D. Bernard Soulier Syndrome
E. Glanzmann’s Thrombosthenia

Factor XIII Deficiency
— AR, Chromosome 6 , p25-p24
— “Delayed bleeding”
— The “Trauma today=bleeding tomorrow” factor J
— Fibrin stabilizing factor, Half life 5-7 days
— Other symptoms of factor XIII deficiency include:
• Delayed umbilical cord hemorrhage
• Delayed separation of the umbilical stump (beyond 4 weeks)
• Intracranial hemorrhage with little or no trauma
• Poor wound healing
• Recurrent spontaneous abortions in women
Muszbek L, Bereczky Z, Bagoly Z, et al.: Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 91 (3):931-972

Question 16
— You are asked to assess a newborn girl with purpura fulminans.
Upon taking the medical history, you learn that this child had a
male sibling who died in the neonatal period after presenting with
purpura fulminans as well. On exam: she is vitally stable. You
noticed large areas of dark bluish discoloration of the skin with
bruising spots especially over upper and lower limbs. She has 3
other siblings who are healthy. Parents are consanguineous. What
is the most likely cause of this newborn purpura fulminans:
A. Sepsis
B. Factor XII Deficiency
C. Protein C Deficiency
D. Von Willebrand Disease
E. Meningitis

Etiology of “Neonatal Purpura Fulminans”
“A Common Pediatric Question”
— Congenital/inherited states
¡ 1. Homozygous protein C deficiency
¡ 2. Homozygous protein S deficiency
— Acquired causes
¡ Increased consumption:
1. Infection, e.g. group B streptococcus infection
2. Disseminated intravascular coagulation
3. Acute venous thrombosis
4. Antiphospholipid antibodies
5. Cardiac bypass
¡ Decreased synthesis:
6. Severe hepatic dysfunction
7. Galactosemia
8. Severe congenital heart disease

Physiology of Protein C
What is the role of Protein C ?

Protein C Deficiency
— AD, Protein C is 62-kD vitamin K-dependent glycoprotein
— The PROC gene is found on chromosome 2
— Synthesized in the liver as a single-chain zymogen
— Clipped into a serine-protease-like enzyme on phospholipid cell
surfaces by thrombin (aFII)
— Homozygous disease occurs in 1 out of every 200, 000 births
— Prognosis for Homozygous cases is usually poor.
— Can cause miscarriage or intrauterine thrombosis, or present soon
after birth.
— Symptoms are directly related to the degree of Protein C
deficiency

Question 17
— A 7 year old girl who presented to ER with fever of 39 °C.
Physical exam showed height and weight below 5th
percentile. She also has small triangular face and a few café
au lait spots. CBC showed Hb of 6.2 g/dl, platelets count of
7, and Neutrophil count of 0.15 (ANC 150). What is the
most likely diagnosis?
A.Aplastic Anemia
B.Diamond Blackfan Syndrome
C.Schwachman-Diamond Synrome
D.Fanconi Anemia
E. Dyskeratosis Congenita

Fanconi Anemia
— It is the most common inherited bone marrow failure syndrome
— AR, At least 23 genes are detected up to now
— 80-90% of cases are due to 3 genes: FANCA, FANCC, and FANCG
— 1:200 carrier status worldwide
— 1:70 in Spanish Gypsies and 1:77 in Ashkenazi Jews
— FA patients have a striking hypersensitivity to DNA interstrand cross-links
— Increase risk of malignancy (700 folds):
• MDS
• AML
• SCC
Justin Triemstra, MD; et al, A Review of Fanconi Anemia for the Practicing Pediatrician, Pediatr Ann. 2015;44(10):444-
445,448,450,452.

Fanconi Anemia
— Skin (Café –Au-Lait spots)
— MSK:
÷ Thumbs (35%): absent or hypoplastic; supernumerary, bifid, duplicated
÷ Radii (7%): absent or hypoplastic
÷ Hands (5%): clinodactyly; hypoplastic thenar eminence
— Endocrine: Short stature, Hypothyroidism
— Eyes: Small eyes, strabismus, epicanthal folds, short or almond-shaped
palpebral fissures, hypertelorism
— Kidneys 20%: Ectopic or pelvic; abnormal, horseshoe, hypoplastic, or
dysplastic
Glanz A, Fraser FC: Spectrum of anomalies in Fanconi anaemia.J Med Genet. 19:412-416 1982

Question 18
— You are evaluating a 12 year girl who was admitted to the
hospital with anemia due to significant vaginal bleeding.
Her onset of menarche was 3 weeks ago. Blood work and
CBC showed WBC 6.8 × 109/L , Hb 9.2 g/dl, Platelets 68,
PT 12.3, PTT 53.2, INR 1.1. What would be the most likely
diagnosis ?
A.Von Willebrand Disease type 1
B.Von Willebrand Disease type 2A
C.Von Willebrand Disease type 3
D.Von Willebrand Disease type 2B
E. Pseudo (platelet-type)-von Willebrand disease

Question 18
— You are evaluating a 12 year girl who was admitted to the hospital
with anemia due to significant vaginal bleeding. Her onset of
menarche was 3 weeks ago. Blood work and CBC showed WBC
6.8 × 109/L , Hb 9.2 g/dl, Platelets 68, PT 12.3, PTT 33.2, INR
1.1. VWF Ag 77% (NR 60-120 %), Ristocetin Cofactor (VWF
Activity) 28%. Which of the following is the most likely
diagnosis ?
A. Von Willebrand Disease type 1
B. Von Willebrand Disease type 2A
C. Von Willebrand Disease type 3
D. Von Willebrand Disease type 2B
E. Pseudo (platelet-type)-von Willebrand disease

Classification of VWD
A- Quantitative deficiency of VWF
Type 1: Partial quantitative deficiency of vWF
Type 1c: Increased clearance, ê levels of vWF
Type 3: Virtually complete deficiency of vWF
B- Qualitative deficiency of VWF
Type 2A: Qualitative variants with decreased platelet dependent function
associated with the absence of high and intermediate molecular
weight vWF multimers
Type 2B: Qualitative variants with increased affinity for platelet GPIb
Type 2M: Qualitative variants with decreased platelet dependent function
not caused by the absence of high-molecular weight vWF multimers
Type 2N: Qualitative variants with markedly decreased affinity for factor VIII

Question 19
— A 3 year old boy was brought to the emergency room with pallor, dark red
urine and jaundice. He had a recent history of fevers and lower abdominal
pain, went to polyclinic, urinalysis showed +ve Nitrite and Urine Culture
showed E.coli and he was given Co-Trimoxazole antibiotic (Bactrim). 5 days
after, he became pale, jaundiced and urine became dark red.
— In ER, CBC showed WBC of 19.6 × 109/L , hemoglobin level of 5.2 g/dl,
platelets of 344. T-Bilirubin was 96 umol/L. LDH was 1156 U/L.
— Blood film showed Heinz bodies. Which of the following medications would
be safe to use in a child with G6PD:
A. Co-Trimoxazole
B. Nitrofurantoin
C. Cefixime
D. Vitamin C
E. Hydroxychloroquine

Question 20
— A 6 year old girl who was diagnosed with Iron Deficiency
Anemia. Her initial Hemoglobin was 7.1, MCV 69 fl, MCH 19
pg. After 2 months course of Iron therapy, Her Hemoglobin is
still 7.2. Which one of these would explain the unresponsiveness
to treatment?
A. Non-Compliance
B. Malabsorption (e.g Celiac Disease)
C. Using Proton Pump Inhibitors PPI /Antacids
D. Iron Refractory Iron Deficiency Anemia (IRIDA)
E. All of the above

Iron Deficiency Anemia
— The single most important nutritional deficiency in the world
— Children are the first & second age category for suffering from IDA
— Affects about 30% of Saudi children
— Can be a diagnostic dilemma
— Classic IDA Diagnosis: ↓ Hb, ↓ MCV, ↓ MCH, ↑ RDW, ↓ Iron, ↓ Ferritin, ↑ TIBC
— Best diagnostic marker is low ferritin
— sTfR is the best when patient is sick children who have high ferritin
— Retic-Hb is a cheap test & has a sensitivity of almost 100% for IDA
— If persistent, TMPRSS6 gene mutation should be suspected (IRIDA)
— Remember: management: non-pharmacological + pharmacologic
Luigia DeFalco, Mayka Sanchez, Laura Silvestri, Caroline Kannengiesser, MartinaMuckenthaler, Achille Iolascon, Laurent Gouya, Clara Camaschella, Carole Beaumont, Iron Refractory Iron
Deficiency Anemia. Haematologica June 2013 98: 845-853

Gelaw Y, Woldu B, Melku M. The Role of Reticulocyte Hemoglobin Content for Diagnosis of Iron
Deficiency and Iron Deficiency Anemia, and Monitoring of Iron Therapy: a Literature Review. Clin Lab.
2019;65(12):10.7754/Clin.Lab.2019.190315. doi:10.7754/Clin.Lab.2019.190315

AAP & Iron Deficiency Anemia In Children
1. AAP recommends screening for all children between 9-12 mo with Hgb or Hct.
2. Adjunct screening (ferritin or zinc protoporphyrin to heme ratio, ZPPH) for ID only
3. Rescreening is recommended 6-12 months later in high-risk populations
4. Additional screening for IDA should be considered for:
a. Adolescent females within a year of onset of menses
b. Children with special health considerations including:
i. Children with Restricted Diet
ii. Children with GI dysfunction
iii. Children with BMI >95th percentile
iv. Children with Restless Leg Syndrome
5. AAP recommends giving breastfed infants 1 mg/kg/day of a liquid Iron supplement until iron
containing solid food is introduced.

Question 21
— A 3 day old infant is brought to the ER due to a seizure. A
CT scan demonstrates massive intracranial hemorrhage. On
your examination, the child has numerous bruises on the
abdomen and trunk. No sepsis risk factors are present. PT,
PTT and INR are all prolonged, Fibrinogen normal. Platelets
count 322. Which of the below scenarios is most likely:
A.The baby was born to an infant of a diabetic mother.
B.The baby was born at home
C.The baby is exclusively breastfed.
D.The baby has trauma
E. The baby was born to a hypothyroidism mother

Hemorrhagic Disease of The Newborn
— Early Onset HrDN:
¡ Occurs within 24 hrs
¡ Usually due to maternal meds; antiepileptics, certain antibiotics, anticoagulants (W)
— Classical HrDN: (2-7 days)
¡ Typically, in those who did not receive Vitamin K Prophylaxis (Home Delivery)
— Late HrDN (1-6 mo)
o Commonly in; Malabsorption , Hepatitis , biliary atresia , Cystic fibrosis, Alpha1-
antitrypin deficiency, Short bowel syndrome, Intestinal bacterial overgrowth, Chronic
exposure to broad spectrum antimicrobials
o Low levels of vitamin K and subsequent low vitamin K–dependent clotting factors.
Bör, Ö., Akgün, N., Yakut, A., Sarhuş, F. and Köse, S. (2000), Late hemorrhagic disease of the newborn. Pediatrics International, 42: 64–66.
doi:10.1046/j.1442-200x.2000.01173

Question 22
— A full term baby boy at 1 day age was noticed in nursery to be very
jaundiced. T-Bilirubin was measured, and it was 398 μmol/L . CBC
showed Hb 7.9 g/dl. Direct Antiglobulin Test DAT (Coomb’s Test) was
strong positive (4 +). He was transferred to NICU. Started on
Phototherapy, IVIG and double volume exchange transfusion.
— Mother is G2P1, O- but received Rhogam (Anti-D on 28 week & at 34
week of GA). Baby was O+. Which of the below scenarios is most
likely:
A. Hemolytic Disease of Newborn Due to Rh D
B. Hemolytic Disease of Newborn Due to ABO Incompatibility
C. Hemolytic Disease of Newborn Due to probably other Rh antigens
D. Hemolytic Disease of Newborn due Duffy antigen
E. Baby probably has autoimmune hemolytic anemia

Question 22
— A full term baby boy at 1 day age was noticed in nursery to be very jaundiced. T-
Bilirubin was measured, and it was 398 μmol/L . CBC showed Hb 7.9 g/dl.
Direct Antiglobulin Test DAT (Coomb’s Test) was strong positive (4 +). He was
transferred to NICU. Started on Phototherapy, IVIG and double volume
exchange transfusion.
— Mother is G2P1, O- but received Rhogam (Anti-D on 28 week & at 34 week of
GA). Baby was O+. Which of the below scenarios is most likely:
A. Hemolytic Disease of Newborn Due to Rh D
B. Hemolytic Disease of Newborn Due to ABO Incompatibility
C. Hemolytic Disease of Newborn Due to probably other Rh antigens
D. Hemolytic Disease of Newborn due Duffy antigen
E. Baby probably has autoimmune hemolytic anemia

Hemolytic Disease of Newborn (HDN)
August 12, 2022
— HDN is a potentially fatal disease
— Caused by immune destruction of fetal RBCs via transplacentally acquired maternal antibodies
— Incidence – 6-7/1,000 live births in U.S. (CDC 2020)
• Dramatic decrease in cases since introduction of anti-D immunoglobulin
— Most involved Antigens:
• Anti-Rh (D, C, c, E, and e)
• ABO
• Anti-Kell (K and k)
• Anti-Duffy (Fya)
• Anti-Kidd (Jka and Jkb)
— Treatment:
• Phototherapy
• Exchange transfusion in severe cases
• IVIG / Corticosteroids
• PRBCs
Isabelle M. C. Ree, Vivianne E. H. J. Smits-Wintjens, Johanna G. van der Bom, Jeanine M. M. van Klink, Dick Oepkes & Enrico Lopriore (2017) Neonatal management and outcome in alloimmune hemolytic
disease, Expert Review of Hematology, 10:7, 607-616

Prevalence of Rh Antigens
August 12, 2022
— The Rh genes are 97% identical
— Located next to each other on chromosome 1.
— Highly Immunogenic
— D: 85% Caucasians, 92% Blacks, 99% Asians
C: 68% Caucasians, 27% Blacks, 93% Asians
E: 29% Caucasians, 22% Blacks, 39% Asians
c: 80% Caucasians, 96% Blacks, 47% Asians
e: 98% Caucasians, 98% Blacks, 96% Asians

Question 23
— A 2 days old newborn started to have a seizure that lasted about 20 minutes and
received Phenobarbital infusion. CBC showed Hb of 16.2 g/dl, Platelets of 4, WBC
11.7 × 109/L . Maternal Platelets was 346. No mottling, no respiratory symptoms.
Immediate CT scan showed moderate intracranial hemorrhage. IVIG was given and
showed a good response and platelets increased to 72. What is the most likely
diagnosis:
A. Disseminated Intravascular Coagulopathy (DIC)
B. Congenital Thrombocytopenia
C. Maternal ITP
D. Neonatal Alloimmune Thrombocytopenia (NAIT)
E. Drug Induced Thrombocytopenia

Neonatal Alloimmune Thrombocytopenia
August 12, 2022
— NAIT : platelet destruction due to maternal Abs against fetal platelets antigens
— Parents are incompatible for human platelet antigens HPA1a or HPA5b.
— NAIT should be strongly suspected in ??
— In contrast to HDN, the first-born child is often affected with NAIT
— Accurate diagnosis is essential to provide appropriate care to the affected neonate
Peterson, J. A., McFarland, J. G., Curtis, B. R. and Aster, R. H. (2013), Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and
management. Br J Haematol, 161: 3–14. doi:10.1111/bjh.12235

Question 24
— A 5 year old girl presented with recent history of upper
respiratory tract infection about 3 weeks ago. Now she presented
with severe epistaxis and bruises all over her body. CBC showed
WBC 12.3 × 109/L, Hemoglobin of 11.4 g/dl, Platelets of 4. She
is Group O negative. The first line therapy for management of
this child is:
A. IVIG
B. Rituximab
C. Anti-D
D. Eltrombopag
E. Romiplostim

Idiopathic Thrombocytopenia Pupura (ITP)
— ITP is the most common Pediatric Platelet Disorder
— Immune Mediated Thrombocytopenia
— Often follows a viral illness or immunization
— Some Children with ITP require no treatment
— 80-85% resolve within 6 months
— 15-20 % progress to chronic ITP
— “Serious Bleeding” in Acute ITP is RARE but it can happen

Clinical Manifestations
— Petechiae, Ecchymosis, and purpura
— Nosebleed
— GI / GU Bleeding
— ICH

Diagnosis of ITP
—Clinical Diagnosis: Hx and P/E
—CBC
—Blood film
—Bone Marrow: Indications ??

Risk Factors for Serious Bleeding / ICH in Children with ITP
1. Extreme Thrombocytopenia: Plts < 10 in 75% of children with ICH.
2. Timing: 50% children developed ICH within 7 days of diagnosis of ITP
3. Head Trauma
4. Hematuria
5. NSAID Use (When ?)
6. Presence of Cerebral AVM
Bethan Psaila et al, 2009 114: 4777-4783, Prepublished online September 18, 2009; Blood Journal

Predictors of Chronicity in Pediatric ITP
1. Age
2. Female gender
3. Platelet count at presentation
4. Absence of mucosal bleeding with low platelet count at diagnosis
5. No history of preceding upper respiratory tract infection
6. Recent MMR vaccine
7. ANA positivity
Heitink-Pollé KM, Nijsten J, Boonacker CW, de Haas M, Bruin MC. Clinical and laboratory predictors of chronic immune thrombocytopenia in
children:
a systematic review and meta-analysis. Blood. 2014 Nov 20. 124(22):3295-307

Management of ITP
— No treatment
— IVIG
— Corticosteroids
— Anti-D
— Other treatments
— Role of TPO-RA in Children

Thrombopoietin Agonists
— Eltrombopag: (Promacta Novartis) Approved by FDA 10 July 2015
¡ Children with chronic ITP
¡ Who are older than 6 year
¡ Have ITP for 12 months
¡ Who have insufficient response to corticosteroids, IVIG, or splenectomy.
— Romiplostim: (Nplate Amgen) Approved by FDA 14 December 2018 for
¡ Children with ITP
¡ Who are older than 1 year
¡ Have ITP for at least 6 mo
¡ Who have insufficient response to corticosteroids, IVIG, or splenectomy.

Question 25
— Which of the following is not associated with Leukemoid
Reaction in children (WBC count >50,000/μL)
A. Shigellosis
B. Septicemia
C. Salmonellosis
D. Chronic Granulomatous Disease (CGD)
E. Leukocyte Adhesion Deficiency

Leukemoid Reaction
— Definition: ↑ in the WBC count, which can mimic leukemia.
— 3 broad differential:
¡ Infectious Process
¡ Leukemic Process
¡ Leukocyte adhesion syndrome
— What will make it likely infectious ?
— Leukocyte alkaline phosphatase (LAP)
Vissaria Sakka, Sotirios Tsiodras, Evangelos J. Giamarellos-Bourboulis, Helen Giamarellou, An update on the etiology and
diagnostic evaluation of a leukemoid reaction, European Journal of Internal Medicine 17 (2006) 394–398

Question 26
— A 9 year old boy presented with severe pallor. He was also
found on physical examination to have splenomegaly.
— CBC showed WBC of 9.7 × 109/L , Hemoglobin of 4.2,
Platelets count of 344. Reticulocyte count was 9.4%. Direct
Coomb’s Test was positive 3+ IgG. The first line in
management of this condition is:
A.Corticosteroids
B.IVIG
C.Splenectomy
D.Packed Red Blood Transfusion (PRBCs)
E. Eryhtropoietin

Autoimmune Hemolytic Anemia
— Primary AIHA:
• Warm AIHA
• Cold AIHA
• Paroxysmal AIHA
— Secondary:
• Autoimmune disorders: SLE
• Immunodeficiencies
• Medications
• Infections

Question 27
— A strictly vegan 12 years old girl presented to your clinic
with pallor, irritability, loss to taste, CBC showed WBC
2.2 x 109/L, Hb 6.2, MCV 110 fL, MCH 17, MCHC 29
%. Platelets 92. Blood film showed hypersegmented
neutrophils (> 5 segments). LDH 944 U/L. What is the
most likely diagnosis:
A. Iron Deficiency Anemia
B. Vitamin B 12 Deficiency
C. Vitamin D Deficiency
D. Vitamin B1 Deficiency
E. Vitamin B6 Deficiency

Vitamin B12
August 12, 2022
1.Vitamin B12 is a family of related compounds containing a
cobalt atom (cobalamins).
2.The two dietary forms of vitamin B12 are available and they
are known as methylcobalamin (meth yl-B12) and 5-
deoxyadenosylcobalamin (coenzyme-B12).
3.Synthetic forms of vitamin B12 are known as hydroxy-
cobalamin and cyanocobalamin (not occur naturally in
foods).
4.Structure of B12 is very complicated and based on a corrin
ring, similar to porphyrin ring found in heme, chlorophyll,
and cytochrome.

Absorption of vitamin B12
August 12, 2022
vVitamin B12 in food is bound to protein.
v HCl of the stomach releases the free vitamin B12.
vOnce released, vitamin B12 combines with glycoprotein
intrinsic factor (IF) secreted by the parietal cells of
stomach to form a complex which can be absorbed from
ileum.

Functions of Vitamin B12
August 12, 2022
1. Essential with folic acid in RBCs maturation (it protects
against Pernicious anemia).
2. Folate metabolism. Vitamin B12 is vital in activation of
folate to the active THF. In vitamin B12 deficiency, tissue
stores of folate are “trapped” as inactive methylated forms,
and a functional folate deficiency results.
3. Protein metabolism: Act as coenzyme with THF in the
synthesis of methionine from homocysteine.

Functions of Vitamin B12
August 12, 2022
— It is vital in fat metabolism.
— Helps maintain the antioxidant status by maintaining
glutathione in the reduced form.
— Nervous system (It is vital in synthesis of myelin sheath of
neurons).
— Cell replication. It is essential with THF in synthesis of
nucleic acids

Diagnosis of Vitamin B 12
1. Measurement of serum Vitamin B12
2. MMA level
3. Schilling Test

Question 28
— A 2 yr old boy presented to your clinic with pallor. Mother
reported drinking a lot of fresh “Goat Milk”. She said she
has been giving him this milk since he was 9 months of
age. You order CBC and WBC 6.7 x 109/L , Hb 8.1 g/dl,
MCV 107 fL, MCH 19 pg, MCHC 26 %. What test would
confirm the diagnosis for this condition:
A. Serum Folate
B. Iron Level
C. LDH
D. Ferritin
E. RBC Folate

Folate Deficiency
— Abdorbtion:
¡ Folate is absorbed in the jejunum by active and passive transport mechanisms across the
intestinal wall.
— Etiology:
¡ Malabsorption: Celiac disease, short bowel syndrome, Gastric Bypass
¡ Amyloidosis
¡ Hypothyroidism
¡ Goat Milk ?
¡ Drugs such as
÷ methotrexate
÷ phenytoin
÷ Sulfasalazine
÷ Trimethoprim
— Diagnosis:
÷ Serum Folate: <2 ng/mL are considered deficient, while levels > 4 ng/ml are considered as
normal
÷ RBC Folate: > 160 ng/mL is considered normal
— Treatment: oral folic acid (1 to 5 mg daily) typically for 1-3 months

Pediatric Oncology

Question 29
— A 2 yr old boy presented with incidentally found abdominal
mass. While he was being bathed, the mother felt a palpable
abdominal mass on the left side. CT abdomen showed a
homogenous abdominal mass, does not cross the midline, with
no calcification that has an area of necrosis and originate from
the left kidney. Patient has also the lesion shown on the photo.
What is the most likely diagnosis:
A. Wilms Tumor
B. Neuroblastoma
C. Rhabdomyosarcoma
D. Hepatolastoma
E. Adrenal Cell Carcinoma

Wilms Tumor
— Embryonal tumor develops from remnants of Immature
Kidney Tissue
— Survival has improved from 30% in the 1930’s to over 85%
currently
— Current management now emphasizes reducing morbidity of
treatment for low-risk patients
— More intensive treatment for selected high-risk patients for
whom survival remains poor.

n Wilms tumor was named after
German surgeon Max Wilms,
who published the first
comprehensive review of the
disease in 1899.
n The National Wilms Tumor Study
Group (NWTSG) established in
1969.
Wilms Tumor

Question 30
— A 6 year old girl presented with 6 weeks history of progressive pallor, fatigue and loss
of energy. She lost about 3 kg over the same period of time. CBC showed WBC 244.8
× 109/L , Hemoglobin 7.3 g/dl, Platelets of 34. She has petechial rash and significant
hepatosplenomegaly. Also was found to have Uric acid of 845 umol/L, K 7.6 mEq/L,
Phosphate of 2.9 mmol/L. Mg .051 mmol/L. Renal profile showed Creatinine of 256
umol//L, BUN of 15.7 mmol/L. Which of her conditions need immediate management?
A. Hyperuricemia, hyperkalemia, hyperphosphatemia
B. Renal failure (Dialysis)
C. Hyperleukocytosis (IV Fluids & Leukophresis)
D. Hypomagnesemia
E. A, B, and C

Laboratory Tumor Lysis Syndrome
Metabolite or electrolyte Criterion for diagnosis
Uric acid >475 umol/L or 25% increase from baseline
Potassium >6 mEq/L or 25% increase from baseline
Phosphorus > 6.5 mg/dL (children) or 25% increase from
baseline
Calcium

25% decrease from baseline

Cairo MS, Bishop M. Tumor lysis syndrome: New therapeutic strategies and classification. Br J Haematol 127: 3–11, 2004
Cairo-Bishop Definition of Laboratory Tumor Lysis syndrome

Cairo-Bishop Definition of Clinical Tumor Lysis Syndrome
— Clinical Tumor Lysis Syndrome: LTLS and one or more of:
1. Renal Insufficiency: ( Creatinine > 1.5 ULN)
2. Cardiac arrhythmia
3. Seizures
Cairo MS, Bishop M. Tumor lysis syndrome: New therapeutic strategies and classification. Br J Haematol 127: 3–11, 2004

Question 31
— A 9 mo old boy presented with diarrhea and on
examination he has an abdominal mass that crosses the
midline. Vital signs are normal. History of decreased
appetite and 10% weight loss. You ordered work up and
CT abdomen showed heterogenous, lobulated soft tissue
mass with calcification. The most likely Diagnosis:
A. Wilms Tumor
B. Neuroblastoma
C. Rhabdomyosarcoma
D. Hepatolastoma
E. Adrenal Cell Carcinoma

9 mo old boy with
abdominal mass

Neuroblastoma
— Malignancy of infants and young children
— Arise from neural crest cells that give rise to
sympathetic ganglia
— One of the Small Round Blue Cell Tumors (SRBCT)
— Wide variety of outcomes

Neuroblastoma
— A spectrum of Neuroblastic Tumors:
¡ Ganglioneuromas
¡ Ganglioneuroblastomas
¡ Neuroblastoma

Epidemiology of Neuroblastoma
Incidence
— 65 per million in infants <1 yr of age
— 30 per million in second yr of life
— 9 per million in children < 15 yr of age
— 90 % of all cases occur before 10 yrs of age
— Neuroblastoma is the most common cancer occurring in the first yr of life
Ries et al SEER1994

Neuroblastoma
— Neuroblastomas account for 97% of all neuroblastic tumors
— They are heterogeneous, varying in terms of:
¡ location
¡ histopathologic appearance
¡ biologic characteristics
— Broad spectrum of clinical behavior, which can range from:
¡ Spontaneous regression
¡ Maturation to a benign ganglioneuroma
¡ Aggressive disease with metastatic dissemination leading to
death

Neuroblastoma Clinical Course
Two distinct entities:
— Infant:
1. Possibility of spontaneous regression (apoptosis or differentiation
into ganglioneuroblastoma)
2. Chemosensitive
3. Chemocurable
— Older
¡ Aggressive tumor
¡ Chemoresistant

Neuroblastoma; Clinical Presentation
— Abdominal mass (retroperitoneal or hepatic)
— Abdominal pain or constipation
— Rib Cage Pain/ Back Pain (Paraspinal location / posterior
mediastinum)
— Proptosis
— Periorbital ecchymoses ("raccoon eyes", from periorbital
ecchymosis caused by orbital metastases)
— Horner syndrome (miosis, ptosis, anhidrosis)
— Localized back pain, weakness (from spinal cord compression)
— Scoliosis, bladder dysfunction
— Palpable nontender subcutaneous nodules

A. Subcutaneous Noduels B. Racoon Eyes
August 12, 2022

Neuroblastoma
— Management:
¡ Surgery
¡ Chemotherapy
¡ Radiation Therapy
— Prognosis:
¡ Age:
÷ Age younger than 1 year: 90%.
÷ Age 1 to 4 years: 68%.
÷ Age 5 to 9 years: 52%.
÷ Age 10 to 14 years: 66%
¡ MYCN Amplication

Question 32
— A 6 year old girl previously healthy presented to ER with history of pallor, bone pain
and lately fevers. On physical examination, she looks pale and tired. T 39.2, HR 125,
BP 110/65. RR 14 and O2 Sats 99% on R/A. She had multiple significant cervical
lymphadenopathy. Also Spleen was 6 cm BCM and liver 5 cm BCM. CBC showed
WBC of 66.4 × 109/L , Hemoglobin of 7.8, Platelets count of 76. LDH 1855 IU/L. ALT
77 IU/L, AST 92 IU/L. Urea 3.5 mg/ml and Creatinine 45 μmol/L. Chest X-Ray
showed a mediastinal mass. What is the most likely diagnosis ?
A. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL)
B. T-Cell Acute Lymphoblastic Leukemia (T-Cell ALL)
C. Acute Myeloid Leukemia (AML)
D. Chronic Lymphoblastic Leukemia (CML)
E. Juvenile Myelomonocytic Leukemia (JMML)

— ALL is the most common cancer diagnosed in children
— About 25%-40% of “cancer diagnoses” among children <15 years.
— Higher in KSA .. Why ??
— ALL occurs at an annual rate of approximately 30 to 40 per million.
— 2,400 children and adolescents < 20 years diagnosed with ALL /yr
— Gradual increase in the incidence of ALL in the past 25 years
— harp peak in ALL incidence is observed among children aged 2 to 3 y
Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, Feb 2, 2012
Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer 97 (7): 1009-12, 2007
Pediatric Acute Lymphoblastic Leukemia

— The incidence of ALL among children aged 2 to 3 years:
¡ >90 cases per 1 million per year
¡ Fourfold greater than that for infants
¡ Tenfold greater than that for adolescents who are 19 years old.
— ALL is substantially higher in white children than in black children
— Incidence is substantially higher in white children than in black children
Pediatric Acute Lymphoblastic Leukemia

} Signs & Symptoms: reflect bone marrow infiltration and/or extramedullary
disease.
} When leukemic blasts replace the bone marrow, patients present with signs of ??
} Bone pain, arthritis, and limping may be presenting symptoms and in 5% of
patients are the only symptoms
} Fevers are common at presentation, but despite neutropenia, sepsis is rarely
seen.
} Other common clinical manifestations include fatigue, pallor, petechiae, and
bleeding.
} Leukemic spread may manifest as lymphadenopathy and hepatosplenomegaly.
Clinical Presentation

Clinical Presentation
— Mature-B ALL : extramedullary masses in the abdomen or head and neck and
CNS involvement.
— In patients with T-lineage ALL, Respiratory distress ? renal failure. Why ??
— Symptoms of CNS involvement (headaches, vomiting, lethargy, and nuchal
rigidity: rare in B-Cell ALL
— More common in T-lineage and mature B cell ALL
— Testicular involvement at diagnosis is also rare; if present, it appears as
unilateral painless testicular enlargement. Genital exam in boys is a MUST
Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. Mar 22 2008;371(9617):1030-43.

Question 33
— You are a senior resident on the pediatric ward at KFAFH.
At 2 am, a nurse called you and told you Sarah, the 3 year
old girl with ALL in induction, has spiked a fever and she is
also neutropenic. What would predict the worst outcome:
A.Degree of Neutropenia
B.Duration of Neutropenia
C.Fever 39.6
D.Presence of cough
E.Presence of diarrhea

Febrile Neutropenia
— Definition: ANC Calculation
— Why do we care ?
— Because infections in FN is rapidly fatal if not managed
properly
§ Mortality rate in the 1960’s was ~ 50%
§ With proper management < 5% today
Sung L, Phillips R, Lehrnbecher T: Time for paediatric febrile neutropenia guidelines: Children are not little adults. Eur J Cancer 47:811-813, 2011

Assessment of FN Pediatric Oncology Patient
— Good history and physical exam
§ Be aware that with ¯ ANC may not have inflammation -
so redness, swelling and infiltrates may not be seen
§ Mouth, pharynx, lower esophagus, lung, skin, anus and
perineum are often sites of infection
— Blood work - CBC, Creat, BUN, liver profile, CRP
— Culture
§ blood cultures (include central line if present)
§ Urine / CSF / other cultures as indicated clinically
§ Chest X-Ray If Resp Symptoms present
Thomas Lehrnbecher, Paula Robinson, Sarah Alexander, and Lillian Sung et al, Guideline for the Management of Fever and Neutropenia in Children With Cancer and
Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update, Journal of Clinical Oncology 2017 35:18, 2082-2094

August 12, 2022

Question 34
August 12, 2022
— Which of the following is not an anterior mediastinal tumor?
A. Thymoma
B. Lymphoma
C. Neurogenic Tumor
D. Teratoma
E. Thyroid Cancer

August 12, 2022

Most common types of
mediastinal tumors in children
Pediatric Board Review Hematology
Oncology
August 12, 2022
DDx of Mediastinal Mass in Children
— Anterior
¡ Non-Hodgkin’s lymphoma
¡ Hodgkin’s disease
¡ Teratoma
— Middle
¡ Lymphoma
— Posterior
¡ Neuroblastoma
¡ Schannoma

Question 35
— A 3 yr old girl who was known case of Acute Lymphoblasti
Leukemia (ALL Standard Risk) in Consolidation phase who was
brought by her parents to the emergency room with blurred
vision, difficulty in walking, headache, jaw pain and
numbness/tingling in fingers and toes. She is also constipated and
did not pass stools for the last 5 days. Which of the following
medications is most likely responsible for her symtpoms:
A. Doxorubicin
B. Methotrexate
C. Vincristine
D. PEG-Asparginase
E. Cytarabine

Chemotherapy Agents
— Chemotherapy (also known as chemo) is a therapy in
which toxic drugs are given to the cancer patient to
interfere with the growth of the cancer cells.
— The goal of chemotherapy is to:
¡ Cure
¡ Control Disease
¡ Provide palliative care

Chemotherapy Agents
— Cell-Cycle Specific Agents:
¡ work by targeting the microtubules which form spindle fibers thus
interfering with cell division and resulting in cell death.
— Cell-Cycle Nonspecific Agents:
¡ damage the DNA by causing the DNA double-helix to break and/or
interfere with the DNA repair mechanism.

Chemotherapy Agents
— Alkylating agents
— Platinums
— Antitumor antibiotics
— Antimetabolites
— Plant alkaloids

Common Chemotherapy Drugs Adverse Effects
August 12, 2022
Chemotherapy Agent Common Side Effects
Cyclophosphamide (Cytoxan) • Myelosuppression
• Hair Loss
• Nausea, Vomiting
• Abdominal Pain
• Hemorrhagic Cystitis
Vincristine (Oncovin) • Peripheral Neuropathy
• Numbness or tingling in the fingers or toes
• Drop Foot
• Jaw Pain
• Hyporeflexia
• Constipation
• Abdominal pain
Doxorubicin (Adriamycin) • Nausea
• Vomiting
• Cardiac Toxicity (Dose Dependant)
• Hyperpigmentation esp irr areas
• Myelosuppresion (Anemia, Low Plts , Nueutropenia)
Methotrexate • Dizziness
• Drowsiness
• Headache.
• swollen, tender gums
• Decreased appetite.
• Hair loss

Summary & Conclusion
— Pediatric Hematology topics:
• Sickle Cell Disease
• Thalassemia
• ITP
• Autoimmune Hemolytic Anemia
• HDN
• HrDN
• Hemophilia A & B
— Pediatric Oncology Topics:
§ ALL and AML, Lymphoma
§ Common pediatric solid tumors (Neuroblastoma, Wilm’s Tumor etc.)
§ Oncologic emergencies (TLS, SVCS, Febrile Neutropenia etc. )

Thank you !
Any Questions ???
All the best to all of you J

Pediatric Hematology Oncology Board Review August 12

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