What is the management for sickle cell disease?
1. Early aggressive treatment for infections with prophylactic antibiotics and appropriate vaccinations
2. Folate supplement
3. Hydroxyurea: to increase HbF concentration
4. Long-term follow-up
>> Transcranial doppler: stroke risk assessement
>> Starting at 10 years of age: Annual fundoscopy
>> Biannual screening for pulmonary hypertension
>> Biannual urinalysis
5. Chronic transfusion
What are the 3 underlying pathophysiological causes of physiological anemia of infancy?
1. HbF has 2/3rd of the half-life of HbA
2. Increased oxygen outside the uterus and the increased oxygen affinity of HbF render less RBCs/Hb necessary after birth
3. Rapid expansion of plasma volume in a newborn
>> Hb 18g/dL at birth of a term infant
>> Hb 8-11g/dL at 2 months of a term infant
>> Reticulocyte count at birth: 5%
Reticulocyte count at 1 week of life: 1%
What are the complications of Hemophilia A?
- Anti-FVIII antibodies: "inhibitors" -- present in 5-20% of patients
- Transfusion-related complications
>> Line infection
>> Symptoms of iron overload
:: Liver cirrhosis
:: Diabetes (pancreatic deposition)
:: Testicular failure
:: Slate grey discoloration of the skin
- Problems with vascular access for transfusion
What is the treatment for B-thalassemia major?
- Life-long regular transfusion with Fe chelation +/- folate supplements
>> Signs of iron overload
:: Liver cirrhosis
:: Cardiac myopathy
:: Diabetes mellitus from pancreatic deposition
:: Infertility (testicular failure) and delayed growth from pituitary deposition
:: Hyperpigmentation of the skin
>> Chelating agents
:: Deferoxamine (SC infusion)
:: Deferasirox (PO)
- Hydroxyurea (in thalassemia intermedia): to increase HbF levels
- Bone Marrow Transplant
What are the long-term complications of sickle cell disease?
- Growth delay
- Bone abnormalities, eg. AVN
- Restrictive lung diseases
- Cardiomyopathy with pulmonary hypertension
What can DDAVP be used to treat?
- Central diabetes insipidus
- Nocturnal enuresis
- Hemophilia A
- vWF disease
- Uremic platelet dysfunction
>> DDAVP helps release vWF and thus factor VIII
What are the reference numbers of anemia in childhood?
3 months: ~8-10g/dL
Adult female: ~12-16g/dL
Adule male: ~14-18g/dL
What are the CBC reference ranges for neonates?
WBC: 10-25 x 10^9/L
PLT: 150-400 x 10^9/L
Therefore, Hb and WBC levels are elevated in normal neonates, while the PLT levels should be similar to those of normal adults.
What is the typical age at presentation of iron deficiency?
6 months - 3 years
>> Iron stores last ~6 months in term infants
>> Iron stores last ~2-3 months in preterm infants
What is usually the first sign of vaso-occlusive crisis in sickle cell disease?
What are the features of lead poisoning?
L: Lead lines on gingivae and epiphyses of big long bones on X-ray
E: Encephalopathy; Erythrocyte basophilic stippling
A: Anemia (microcytic); Abdominal colic
D: Drops of the wrist and foot
What is the Mentzer index?
= MCV/RBC count
- Thalassemia: <13
- Iron-deficiency anemia: >13
What are the three types of crises in sickle cell disease?
- Vaso-occlusive crisis
- Aplastic crisis
- Acute splenic sequestration
What are the possible causes of bleeding tendencies in children?
>> Increased consumption
:: Giant hemangioma
>> Increased destruction
>> Decreased production
:: Aplastic anemia
:: Marrow infiltration
:: Glanzmann's thromboasthenia
:: Drugs (ASA, NSAIDs, alcohol)
von Willebrand disease
Coagulation pathway problem
>> Hemophila A
>> Hemophilia B
>> Vit K deficiency -- hemorrhagic disease of newborn
>> Liver disease
>> DIC Vascular problem
>> Connective tissue disorders
:: Ehlers-Danlos syndrome
:: Marfan syndrome
>> Osler-Weber-Rendu syndrome
>> Henoch-Schonlein Purpura
>> Cushing's syndrome
>> Purpura simplex
What are the drugs to avoid in a G6PD patient?
Hemolysis IS PAIN.
What is the peak age of onset for immune thrombocytopnic purpura (ITP)?
2-6 years (2-10 years)
What is the most common cause of thrombocytopenia in childhood?
Immune thrombocytopenic purpura
What are the presenting features of ITP?
Usually 1-3 weeks after viral illnesses (URTI, chickenpox)
- Sudden onset of petechiae, purpura and epistaxis
- Otherwise well
- No lymphadenopathy
- No hepatosplenomegaly
- PLT low
- Hb normal
- WBC normal
What are the possible complications of ITP?
- GI bleeding
- Intracranial hemorrhage (<10 PLT) --- Chance: <0.5%
What are the indications for a bone marrow aspirate in ITP?
- >1 cell line abnormal
- Hepatosplenomegaly present
- Before steroid treatment
>> Steroid treatment can mask the features of ALL and thus further delay diagnosis and treatment
What is the management for ITP?
- Spontaneous recovery in >70% within 3 months
- Avoid contact sports and NSAIDs
2. Medical: usually gum bleeding/PLT <20
- IV prednisone
- Anti-D antibodies
3. Surgical: for life-threatening bleeding
- Additional platelet transfusion
- Emergency splenectomy
What is the definition of chronic ITP?
PLT remains low 6 months after diagnosis
Management for persistent bleeding affecting daily life:
- TPO factors
- Screening for SLE
How do we classify hemophilia severity?
Mild: 5-40% of normal factor VIII levels
Moderate: 1-5% of normal factor VIII levels
Severe: <1% of normal factor VIII levels
What is the mode of inheritance of hemophilia A/B?
What is the management of hemophilia A?
- Recombinant FVIII concentrate
>> Aim for 30% in minor bleeds
>> Aim for 100% for major OT or life-threatening bleeds
:: Maintain at 30-50% for 2 weeks
:: Regular infusion of factor concentrate (8-12 hourly)
Prophylaxis for severe hemophilia
- Aim for baseline >2%
- Regular recombinant factor concentrate infusion
- 2-3 times per week, starting at 2-3 years of age
- DDAVP: promotes release of VIII-Ag
How can we manage inhibitors to FVIII concentrates in Hemophila A patients?
- Very high doses of FVIII recombinant concentrates
- Activated FVII recombinant concentrate
What are the causes of anemia in children?
- Red cell aplasia
:: Aplastic anemia
:: Diamond-Blackfan syndrome
:: Fanconi's anemia
:: Parvovirus B19 infection
:: Acquired aplastic aenmia
:: Transient erythroblastosis of childhood
- Ineffective erythropoiesis
>> Iron deficiency
>> B9/B12 deficiency
>> Chronic inflammation: JIA, IBD
>> Chronic renal failure
>> Lead poisoning
- RBC enzyme defect: G6PD deficiency
- RBC membrane defect: hereditary spherocytosis/elliptocytosis
- Hemoglobulinopathy: thalassemia, sickle-cell disease
- Fetomaternal bleeding
- Chronic GI blood loss
- Inherited coagulopathies
>> vWF disease
>> PLT dysfunction
>> Coagulation dysfunction
How does one approach anemia in children?
- Iron deficiency
- Anemia of chronic disease
- Sideroblastic anemia
- Lead poisoning
- High reticulocyte count (destruction problem)
:: Enzyme defect: G6PD deficiency
:: Membrane defect: spherocytosis
:: Other hemogloblinopathies: sickle cell
:: Immune causes
~ Infection: B19, malaria
:: Microangiopathic anemia
- Low reticulocyte count (production problem)
:: Aplastic anemia
:: Myelodysplastic syndromes
:: Bone marrow-suppressive drugs: chemotherapy
>> Isolated anemia
:: Anemia of chronic disease
:: Renal disease (decreased EPO production)
:: Liver disease
>> B12 deficiency
>> Folate deficiency
>> Liver disease
What is the chronological order of response to iron supplement in iron-deficiency anemia?
- Increased reticulocyte count in 2-3 days
- Increased hemoglobin levels in 4-30 days
- Iron store repletion in 1-3 months
What are the complications of iron deficiency?
- Developmental delay if untreated
- Angular cheilitis
Which inflammatory mediator is involved in anemia of chronic disease?
IL-6 with increased hepcidin
What are the causes of sideroblastic anemia?
- X-linked hereditary
- Treat with high-dose vitamin B6
- Idiopathic: preleukemic phenomenon (10% to AML)
What are the causes of basophilic stippling in RBCs on a peripheral blood smear?
A: Anemia of chronic disease
I: Iron deficiency
L: Lead poisoning
What are the causes for target cells on a peripheral blood smear?
H: HbC disease, sickle cell disease
L: Liver disease
What are the causes for aplastic anemia in children?
- Fanconi's anemia
- Schwachman-Diamond syndrome
- Post-viral infection
>> Parvovirus B19
>> HBV, HDV, HEV
- Ionizing radiation
>> Graft-versus-host disease
What are the laboratory findings in hemolytic anemia?
- Increased reticulocyte count
- Decreased haptoglobin
- Increased unconjugated bilirubin
- Increased LDH
- Increased urobilinogen
What are the clinical features of B-thalassemia major?
Onset at 6-12 months >> HbF to HbA at 3-6 months
- Severe anemia and jaundice
- Maxillary overgrowth
- Frontal bossing
- Gross hepatosplenomegaly
- Skull X-ray: hair-on-end/crew-cut appearance
- Pathological fractures common
- Pigmented gallstones
What is the mode of inheritance of thalassemia?
What are the complications of iron overload?
- Cardiac failure
- Liver failure/cirrhosis
- Growth failure
- Skin pigmentation
How many b-chain genes do we have?
2 on chromosome 11
How many a-chain genes do we have?
4 on chromosome 16
What are the different types of a-thalassemia?
1 defective gene: clinically silent (trait)
2 defective genes: normal Hb, decreased MCV (trait)
3 defective genes: HbH (b4) disease
4 defective genes: Hb Barts (gamma4) disease - hydrops fetalis;
incompatible with life
What is a specific investigation for vW disease?
Ristocetin-induced platelet aggregation test: decreased in von Willebrand disease
What is the mode of inheritance of von Willebrand disease?
Mostly autosomal dominant
What is the management for von Willebrand disease?
- Tranexamic acid
- High-purity FVIII concentrate
- Conjugated estrogens to increase vWF levels
What are the common presenting features of hemophilia A?
- Head hemorrhage
What are the types of vW disease?
Type I: mild quantitative disease (~75%)
Type II: qualitative disease (~20-25%)
Type III: severe quantitative disease (rare)