IPFC 1 - Childhood Anemia

What is anemia

Hemoglobin level too low to maintain cellular oxygen demands.

Practical definition: Hemoglobin level > 2 SD lower than mean value for age, sex and race.

4 main types of globins

Protein subunits that make up Hgb

Alpha

Beta

Delta

Gamma

Hemoglobin type is determined by...

The combination of globin chains

- HbA can also be written as “α2ß2”

- HbS can also be written as “α2ßS2”

Hemoglobin type by age

< 0 months

- Hb F start to decrease around the second trimester

0-6 months

- HbF > HbA,HbA2

2-3 months:

- β globin production begins

- γ globin continues to decrease

> 6 months

- Hb A continues to increase and becomes the dominant Hb

Which chromosomes are the globin genes are arranged on ?

chromosomes 11 and 16 in the order they are expressed.

T/F Globin genes are permanently either activated (hypomethylated) or suppressed (hypermethylated)

False, Globin genes are activated (hypomethylated) or suppressed (hypermethylated) at different stages in life

T/F Globins are synthesized independently

True! and they combine with each other to produce the various hemoglobins.

Hemoglobin at birth is ~___________

150-200 g/L.

Progressive decline during first 2-3 months

the smaller or more premature the infant, the ___________ and __________ the hemoglobin nadir.

earlier and lower

T/F Hemoglobin and MCV values are unrelated to age, sex, pubertal stage, ethnicity, altitude and heredity

False, they are related to age, sex, pubertal stage, ethnicity, altitude and heredity

T/F Iron deficiency is unusual before 6 months of age

true

Diets consistent with anemia

Cow's milk (iron), goat's milk (folate), vegan/vegetarian (B12), favism, pica (iron deficiency)

Symptoms consistent with anemia

Pallor, exercise intolerance, headache, excessive sleeping, poor feeding, syncope

Can anemia result in developmental delays?

Yes, Delays due to chronic anemia/nutritional deficiencies

Medications that can cause anemia

Anti-folates (SMX-TMP, phenytoin, antimetabolites, AZT, alcohol), oxidant stress (nitrofurantoin, anti-malarials), immune hemolysis (penicillin)

Evaluating anemia: physical findings

MOUTH: bruises, gum swelling, glossitis, angular stomatitis, pharyngitis (infection)

SKIN: petechiae, purpura, pallor, jaundice, café au lait macules

NECK: lymphadenopathy, thyroid

ABDOMEN: HSM, tenderness, masses

Three most important tests when evaluating anemia:

CBC - Hemoglobin, MCV, RBC, WBC, Platelets

Reticulocyte count – indicator of bone marrow response

Peripheral blood smear - morphological clues

Optional tests when indicated:

- Examine stool and urine for blood loss

IDA: serum iron, transferrin/TIBC, ferritin, soluble transferrin receptor

Thalassemia or SCD: sickle screen, hemoglobin analysis, hemoglobin H prep

Megaloblastic anemia: RBC folate, serum B12, homocysteine, MMA

Hemolysis: LDH, haptoglobin, bilirubin, DAT, G6PD assay, pyruvate kinase activity

- If spherocytes, consider osmotic fragility test for hereditary spherocytosis

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4 different approaches to classifying anemia

- Morphology (size, shape and colour)

- Etiology (cause of the anemia)

- Pathophysiology

- Reticulocyte response

Causes of iron deficiency

1. Inadequate iron stores at birth (e.g. prematurity, maternal iron deficiency)

2. Inadequate dietary absorption

➢ Poor bioavailability (cow’s milk, high gastric pH, inhibitors of absorption)

➢ Loss/dysfunction of absorptive surface (duodenectomy, short gut syndrome, Celiac disease)

3. Blood loss

➢ GI tract (cow’s milk, Meckel's, polyps, ulcer, H. pylori, IBD, parasitic infection, varices)

➢ Epistaxis, menorrhagia, rarely pulmonary or renal losses

4. Malabsorption of iron

➢ Celiac disease, antacids, giardiasis, iron-refractory IDA (IRIDA)

Treatment for 17 month old boy with IDA

Ferrous sulfate for 3 months

3-6 mg/kg/day elemental Fe

Oral Iron Challenge

Fasting serum iron level before and 2 hours after 1 mg/kg dose of oral iron

- Can help detect malabsorption

Iron-refractory Iron Deficiency Anemia (IRIDA)

abnormal oral iron challenge

Treated with IV iron with normalization of CBC and iron indices.

Refer to Hematology if:

- Iron deficiency with poor response to a therapeutic trial of oral iron

- Anemia with additional cytopenia

- Evidence of acute or chronic hemolysis

- Any unexplained normocytic anemia

Hemoglobinopathies

"Diseases of hemoglobin"

Qualitative vs quantitative hemoglobinopathy

Quantitative = reduced or absent globin synthesis

- Thalassemia syndromes

Qualitative = structural hemoglobin variants

-Sickle cell disease (HbC, HbS)

- Methaemoglobinemia (metHb)

- G6PD deficiency, etc.

Canada is seeing more patients with hemoglobinopathies due to _____________

immigration

Sickle cell disease (SCD)

A group of hemoglobin disorders caused by a mutation in the ß globin (HBB) gene (p.Glu6Val) i.e. ßS

Autosomal recessive

The only risk factor for SCD is ancestry from:

- Sub-Saharan Africa

- Caribbean

- Central and South America

- India

- Mediterranean basin

- Middle East

T/F Sickle cell trait (HbAS) is a risk factor for malaria

False! Sickle cell trait (HbAS) confers protection to malaria

Pathophysiology of sickle cell disease

When HbS is deoxygenated, α2βs2 can polymerize which causes the RBC’s membrane to deform sickle shape.

Effects of SCD

1. Vaso-occlusion occurs when RBC get trapped in blood vessels causing infarcts

2. Intravascular hemolysis promotes inflammation and redox instability and leads to vasculopathy

RBC lifespan: sickled vs normal

Normal RBC: 110 to 120 days

Sickled RBC : 10 to 20 days

Bloodwork consistent with chronic hemolysis/anemia

high LDH

high Bilirubin

low Hgb

SCD subtypes

Autosomal recessive

Homozygous

HBSS (main type in the USA)

Heterozygous

HbSB0

HbSO-Arab

newborn screening ontario (NSO)

- Consider screening patients who are were born prior to screening

- Some people may not be aware of their genetic status

- Earlier diagnosis = Reduction of childhood infections / complications

Sickle-cell crisis

AKA vaso-occlusive crisis (VOC), sickling crisis

Presentation:

- Chest pain

- Dyspnea

- Low PO2

- Pulmonary infiltrates on CXR

Acute sickle chest syndrome (ACS)

is a common cause of death (~25%)

Sickle-cell crisis treatment

Analgesics: opioids, ketamine, NSAIDS

Bronchodilators, O2

Hydration

Transfusions?

Risk factors for Sickle-cell crisis

- Dehydration

- Anoxia

- Infections

- Venous stasis

- Acidosis

- Deoxygenation (e.g. high altitudes, operations, obstetric delivery)

- Vigorous exercise

Treatment options for SCD

Hydroxyurea

Supportive care

- Antimicrobial prophylaxis / immunizations

- Blood transfusions (HbS ≤ 30%)

- Splenectomy

- Supplementation

Hydroxyurea (Hydrea®) mechanism

Induces production of fetal hemoglobin (primary mechanism)

• Inhibition of ribonucleotide reductase (RR) = blocks DNA synthesis in the S-phase

• Decreased adhesion and improve rheology of circulation neutrophils and reticulocytes

• Increased hydration of RBC→improved flexibility

Baby hug trial

Showed that hydroxyurea 20mg/kg daily resulted in:

• Lower rates of initial and recurrent episodes of pain

• Lowest episodes of dactylitis

• Fewer acute chest syndromes

• Lower hospitalization

• Fewer transfusions requirements

• Mild-to-moderate neutropenia in the hydroxyurea group but no increase in # of infections

Hydroxyurea indications

- HbSS or HbSB0: start at 9 mo. (BABY HUG trial)

- HbSC or HbSB + with a history of ≥3 crises/year

Hydroxyurea dosing

Once daily

- Children: start at 20 mg/kg, up to 35 mg/kg (or as tolerated)

- Adults: start at 1000 mg daily and increase as tolerated

Renally cleared → adjust dose if CrCl < 60 ml/min

Supportive care for SCD

Antibiotic prophylaxis (PROPS 1 and II trials)

- Penicillin (or amoxicillin) PO until age ~6

Splenectomy

Folic acid (1 daily or 5mg weekly)

- increases RBC turnover

T/F SCD patients with painful episodes will present with vital sign abnormalities.

False, most will have normal vitals

T/F Opioid dependence is uncommon in patients with SCD

true

Individuals with SCD do not have a higher pain tolerance.

True, SCD-related pain should be treated aggressively and adequately.