Paediatric Anaemia

Take home points

• Iron deficiency is uncommon in first 6 months of term infants
  • Common in those >6mo who prolong breastfeeding without iron supplementation, excessive dependence on cow’s milk or if food sources are restricted
• Sickle cell disease is unlikely to present as anaemia under 4mo
• HUS typically affects those under 4yo
• TTP affects children >10 yo
• Iron deficiency is common in adolescent females
• G6PD deficiency occurs mainly in males
  • Typically uncooked broad beans precipitate haemolysis

• Recent infection may precipitate autoimmune haemolytic anaemia, non-immune haemolytic anaemia, HUS and TTP
• Hyperbilirubinaemia due to haemolysis leads to jaundice, cholelithiasis, cholecystitis and dark urine
• Normal MCV = 84 + 0.6fL/year of age up to 96 (normal adult MCV)

DDx

• Microcytic
  • Iron deficiency, thalassaemia, hereditary spherocytosis, lead toxicity, chronic illness
• Normocytic
  • Acute bleeding, hypersplenism, haemolytic, marrow failure, chronic renal/liver disease, anaemia of chronic disease, sideroblastic anaemia
• Macrocytic
  • B12/folate deficiency
  • Alcohol
  • Liver disease
  • Reticulocytosis

Investigations

• Reticulocyte count
  • Low in reduced RBC production
  • High in haemolysis or bleeding (unless marrow failure)
• Bilirubin – Elevated unconjugated suggests haemolysis
• Urea/creatinine – Elevated in HUS/TTP
• Iron studies
• Coombs’ test – Immune-mediated haemolysis
• Hb electrophoresis

• RBC morphology on film
  • Schistocytes – Erythrocyte fragmentation syndromes
  • Sickle cells – SCD
  • Spherocytes – Immune-mediated haemolytic anaemia, hereditary spherocytosis
  • Blister or bite cells with poikilocytosis – G6PD deficiency

Neonatal anaemia

• Hb 159-191g/L at birth and rises in first 24 hours
• Falls to nadir of 90-114 between 8-12 weeks of age (physiological anaemia of infancy)
• Immune-related anaemia
  • Most common cause of anaemia in neonate
  • Rhesus/ABO
• Neonatal infection
  • May inhibit erythropoiesis or cause haemolysis
  • Consider CMV, rubella, toxoplasmosis, parvovirus, vertical malaria transmission, HIV and congenital syphilis

• Haemoglobinopathies and enzymopathies
  • G6PD deficiency
  • Thalassaemias and SCD tend to present later once foetal Hb declines
• Blood loss
  • Twin-twin transfusion/obstetric procedures or delivery
  • Consider underlying coagulopathy or Vitamin K deficiency
  • Vit K deficiency can be exacerbated by absent newborn dosing, prolonged breastfeeding, maternal warfarin/isoniazid/phenytoin/rifampicin, malabsorption, chronic diarrhoea or prolonged use of oral antibiotics
  • Haemophilia rarely presents in the neonatal period

Anaemias of childhood

• Iron deficiency
• Haemolytic anaemia
  • Acquired – Autoimmune haemolytic anaemia
  • Non-immune – Macro/microangiopathic HA, HUS, TTP
  • Hereditary – G6PD
• Thalassaemia
• Sickle cell disease

Iron deficiency anaemia

• Iron deficiency found in 20% of Australian infants in second 6 months of life with anaemia in 3%
  • 35% and 9% in 2^nd year of life
• Found in up to 9% of adolescent females
• Stages
  • Stage 1 – Low serum ferritin
  • Stage 2 – Impaired erythropoiesis with microcytes, elevated erythrocyte protoporphyrin level and serum iron falls
  • Stage 3 – Microcytic hypochromic anaemia

• Causes
  • Prolonged breastfeeding beyond 6 months without supplementation
  • Cow’s milk only diet (poor iron content, GI irritation and low appetite for other foods)
• Complications
  • If <24mo: Cognitive and psychomotor impairment
  • May affect neutrophil and lymphocyte function leading to recurrent infection

• Diagnosis
  • Microcytic hypochromic anaemia, low serum iron, low serum ferritin, high TIBC and low transferrin
  • Dx confirmed by reticulocytosis 2 weeks after iron supplementation initiated and rise in Hb over 2-4 weeks
• Treatment
  • Ferrous iron 2-3mg/kg/day (6mg/kg/day if severe anaemia)
  • Medication must be stored safely due to risk of toxicity

Haemolytic anaemia

• Normally 1% of RBC population removed by haemolysis and replaced each day
• In adults, any increase in haemolysis can often be compensated for by increased marrow erythropoiesis and subsequent reticulocytosis
• In neonates/infants, erythropoiesis is maximal and cannot compensate for pathological haemolysis

Autoimmune haemolytic anaemia

• Autoantibodies as a result of:
  • Infection – EBV, CMV, mumps, mycoplasma, TB
  • Systemic illness – SLE, RA, thyrotoxicosis, ulcerative colitis, malignancy and immunodeficiency syndromes
  • Idiopathic
• Intravascular haemolysis with subsequent positive Coombs’ test (detects coating of Ig or complement on RBC surface
• Reduced haptoglobin (mops up free haemoglobin)
• RBC fragmentation, spherocytosis and tear-shaped cells seen as a result of splenic macrophage attack on red cell membrane
• LDH raised

• Typically acute severe anaemia with resolution within 3 months
• Slower onset is more likely to be chronic and relapsing with guarded prognosis
• Associated immune thrombocytopaenia in 1/3
• Hyperbilirubinaemia
• Free antibodies may be detectable
  • Cold (maximally active between 0 and 30; IgM) or warm (maximally active at 37; IgG) agglutinins

• Treatment
  • Steroids if IgG (warm)
  • Plasmapheresis if IgM (cold)
  • IVIG 1g/kg may help both
  • Splenectomy is last resort for IgG-induced AIHA

Non-immune haemolytic anaemia

• Causes
  • Infections – Malaria, Gram-positive or negative sepsis
  • Madications – Salicylates, sulfasalazine, nitrofurantoin
  • Chemicals – Naphthalene
• Coombs’ negative

Erythrocyte fragmentation syndromes

• Haemolytic anaemia due to direct physical or mechanical damage
• Characterised by
  • Red cell fragmentation
  • Schistocytes
  • Spherocytes
  • Features of intravascular haemolysis i.e. reduced haptoglobin, raised bilirubin

• Macroangiopathic
  • Associated with cardiac and large vessel disease often post-surgical
  • Must consider graft failure if occurs distinct from surgical period
  • Due to shearing forces and usually mild
• Microangiopathic
  • Usually acute and severe with associated thrombocytopaenia
  • Most commonly HUS if under 4 and TTP if over 10
  • Also connective tissue disease, haemangiomas and severe burns

Haemolytic uraemic syndrome

• Most common cause of acute renal failure in children
• Classical triad: Microangiopathic haemolytic anaemia, thrombocytopaenia and uraemia
• More than 90% of affected children are under 4yo
• Can occur following E. coli (verocytotoxin), Shigella, Salmonella, Yersinia, Campylobacter, S. pneumoniae, echovirus, Coxsackie and varicella
• Also seen with OCP, cyclosporin and SLE due to endothelial injury
• May be complicated by thrombocytopaenia, bleeding, cardiomyopathy, brain infarcts/haemorrhage, bowel perforation or diabetes

• Treatment
  • Dialysis if indicated
  • Transfusion
  • Platelets only if bleeding
• Prognosis
  • 90% survival in acute phase
  • Chronic complications may arise decades later
  • Atypical HUS following URTI causes severe hypertension and renal failure with poor prognosis

Thrombotic thrombocytopaenic purpura (TTP)

• HUS + Neurological deficit
• Confusion, seizure, coma, CN deficits may be seen
• Renal failure not as severe
• Thrombocytopaenia more severe
• Usually children >10 yo

• Triggers
  • Mycoplasma, viral infections, HIV, subacute bacterial endocarditis
• Treatment
  • Supportive therapy
  • Exchange transfusion +- plasmapheresis

G6PD deficiency

• Renders RBC vulnerable to haemolysis when exposed to oxidant
• X-linked recessive condition
• Homozygous females are rare
• Multiple different variants and severities
• Triggers
  • Viral and bacterial infections can trigger acute haemolysis, especially in children <3yo
  • Naphthalene, sulphonamides, antimalarials, nitrofurantoin, diazoxide, dapsone
  • Favism following broad/fava been intake or inhalation of their pollen (can also be passed to infant through breastmilk)
• Anaemia presents within 3-36 hours of exposure and lasts 2-6 days
• Prevention is crucial and treatment is supportive

Thalassaemia

Beta-Thalassaemia major

• Homozygous with no beta-chains produced
• Presents in first month of life as HbF falls
• Excess alpha chains aggregate to form unstable tetramer and inactive
• Haemolysis increases and anaemia results
• Extramedullary haematopoiesis leads to hepatosplenomegaly, functional hypersplenism, frontal bossing
• Microcytic, hypochromic anaemia with poikilocytosis, target cells and reticulocytosis
• Eventually get iron overload due to increased GI absorption in response to anaemia
• Treatment
  • Lifelong blood transfusions
  • Iron chelation
  • HLA-matched bone marrow transplant has been curative

Beta-thalassaemia minor

• Heterozygote; Sth East Asian, Mediterranean and Arabic families
• Enough beta-chain production to avoid symptomatic anaemia
• Lifespan of RBC’s only slightly decreased
• Microcytic, hypochromic anaemia with target cells and elliptocytes
• HbA2 increased >3.5% (as long as sufficient iron in diet)
• Hyperplastic bone marrow

Alpha-thalassaemia

• Two genes and 4 alleles; Sth East Asian, African Arabic
• Deletion of one allele is asymptomatic
• Deletion of two alleles causes mild anaemia
• Deletion of three alleles causes HbH disease
  • Beta-chain aggregations lead to unstable haemoglobin/haemolytic anaemia
  • Chronic haemolytic anaemia, jaundice, cholelithiasis, hepatomegaly and leg ulcers
• Deletion of four alleles causes intrauterine death (foetal hydrops)

Sickle cell disease

• Autosomal recessive condition
• In homozygote with HbSS, haemoglobin is unstable in deoxygenated state
  • Precipitates in RBC causing sickle shape (reversible)
  • Sickle cells have reduced lifespan of 10-20 days (instead of 120) and occlude microvasculature, leading to end-organ ischaemia
• Precipitants for sickling
  • Tissue hypoxia
  • Tissue acidosis
  • Dehydration
  • Vascular stasis
  • Increased 2,3-DPG levels in RBC

• Diagnosis
  • Haemoglobin electrophoresis and sickle prep test (sodium metabisulphite applied to RBC’s, which extract oxygen to cause sickling)
• Clinical features
  • Baseline Hb 60-90 with reticulocytosis 5-15%
  • Functional asplenism by 5yo and abnormal complement function
  • Fever must be managed as a medical emergency due to high risk of bacterial infection
  • Dactylitis occurs in 50% of children by 2yo
    • Symmetric painful swelling of hands/feet (DDx: Osteomyelitis)
  • Vaso-occlusive and aplastic crises
  • Acute splenic sequestration

• Vaso-occlusive crises
  • Acute severe pain from tissue infarction due to vessel occlusion by sickled RBC’s
  • Bones, lungs, liver, spleen, brain and penis most commonly involved
  • Treatment – Analgesia, IV fluids if dehydrated, hydroxyurea if recurrent
• Aplastic crises
  • Reticulocytosis falls to <1% and Hct may fall 10-15% per day
  • Usually post-infectious
  • Spotnaneous recovery is usual but may require transfusions in interim

• Acute splenic sequestration
  • Life-threatening complication in 7-30% of homozygous sickle cell disease patients under 2yo
  • Acute pallor, weakness, abdominal pain and distension with hypovolaemic shock
  • Usually intercurrent infection with massive tender spleen and shock
  • Hct <50% of baseline at this point
  • Only affects those with functional spleen still (i.e. before autosplenectomy)
  • Hepatic sequestration of RBC’s can also occur but is less severe due to less volume due to tight hepatic capsule
  • Treatment
    • IV fluids, prevention of sickling of remaining RBC’s (i.e. oxygen, acidosis, fluids) and prompt treatment of infective precipitant
  • Recurrent in 50% of cases
    • Splenectomy is the only treatment for recurrent cases

Sickle cell trait

• Heterozygous state
• FBC normal
• HbS:HbA = 40:60 on electrophoresis
• RBC’s have normal life span
• Complications
  • Sudden death in rigorous exercise
  • Splenic infarcts at high altitude
  • Haematuria
  • Bacteriuria
  • Normal lifespan

Last Updated on November 20, 2021 by Andrew Crofton