Session 19: Approach To Common Haematological Problems In Children

Question 1

Common childhood haematological diseases

Answer 1

RBC:
1. Fe deficiency anaemia (chronic blood loss, excessive menstruation, prolonged breastfeeding but without food supplement)
2. Thalassaemia
3. Hereditary spherocytosis
4. AIHA
5. Childhood TTP / HUS

Platelet:
1. ITP

WBC:
1. Acute lymphoblastic leukaemia
2. Acute myeloid leukaemia
3. Congenital neutropenia

Pancytopenia:
1. Aplastic anaemia (Causes: Idiopathic, Autoimmune, Congenital BM failure syndrome e.g. Fanconi anaemia (Autosomal recessive, involve abnormal Fanconi anaemia protein gene in DNA repair pathway))

Coagulation defect:
1. Haemophilia
2. Von Willebrand disease

Question 2

Management of β Thalassaemia major

Answer 2

Hypertransfusion regimen (completely inhibit RBC production by patient)
- Post-transfusion Hb target: 14 (stop endogenous haematopoiesis)
- Pre-transfusion Hb target: 9.5
- Every 4 weeks
—> Maintain adequate Hb level at always to ensure adequate function + growth
—> Amount: (14 - Pre-BT Hb) x BW x (4.2-4.7)
- Annual blood consumption: 250-350 ml/kg/yr (>300 ml/kg/yr —> Splenectomy (but now not done anymore)
- Stop Folic acid after receiving regular transfusion

Treatment complications:
1. Fe overloading (in heart, liver, endocrine organs, other tissues)
- Cardiomyopathy (1st cause of death (30s))
- Hormonal deficiency: Gonads, DM, Thyroid, Parathyroid, GH etc.
- Hepatic fibrosis and Cirrhosis
- Vascular stiffness

2. Infection
   - HCV, HBV, HIV
   - Yersinia, Klebsiella etc. (2nd cause of death) (Fe promote overgrowth of Gram -ve bacteria —> Gram -ve septicaemia)
   - Largely reduced by high standard of blood transfusion service

Question 3

Treatment of Fe overload

Answer 3

1. Avoid high Fe content diet (i.e. chocolate)
2. Fe chelators
   - single / combination of below:

Desferal (Deferoxamine):
- SC continuous infusion 10-12 hours home therapy during sleep
- Take Vit C during chelating therapy
SE:
- Local irritation, growth retardation, skeletal change
- Ferrophilic bacterial infection (Yersinia, Klebsiella)
- Visual and hearing impairment, trace elements deficiency

L1 (Deferiprone, Ferriprox)
- Oral 50-75 mg/kg/day TDS
- Better compliance than SC infusion
SE:
- Agranulocytosis, mild neutropenia —> Monitor CBC frequently
- Nausea + abdominal discomfort
- Arthralgia / Arthritis

ICL-670 (Deferasirox, Exjade)
- Oral 25-35 mg/kg/day
- Better compliance than SC infusion
SE:
- Skin rash
- Renal impairment —> Monitor RFT / reduce dose

When to start Chelation:
- ~2 yrs (when infant already started transfusion, give every 4 weeks), when Ferritin >2000 pmol/L
- Use Deferasirox in HK now till 6 yo

Question 4

Prognosis of β Thalassaemia major

Answer 4

• Life expectancy is much longer now (>38 yo median age in Italy)
• Minimal disfiguring skeletal change (e.g. Cooley’s facies) (∵ prevented massive expansion of BM spaces)
  —> Prominent frontal + parietal bone
  —> Collapsed nasal bridge
  —> Maxillary hyperplasia
• Seldom requires splenectomy
• Few cardiac / endocrine complications
• But short stature remains a potential problem
• Oral chelator increasingly used
• Combination therapy more standardised

HK: Good transfusion service + Good chelation regimen —> Good life expectancy

Question 5

Hereditary spherocytosis

Answer 5

• Autosomal dominant (boys + girls, across generations, but can have variations in phenotype across generations)
• RBC membrane defect

Key proteins in RBC membrane:
- Protein 3 (Band 3 protein)
- Ankyrin
- Spectrin
- Others

Mutation of one of key proteins in RBC membrane (Primary membrane defects)
—> ↑ Membrane instability
—> Membrane loss
—> ↓ Surface to volume ratio (Spherocytosis, not biconcave shape anymore) (Autosomal dominant)
—> ↓ Cellular deformability
—> Splenic trapping (i.e. trapped in Spleen)
—> Erythrostasis in spleen (↓ glucose, ↓ pH, ↑ Macrophage contact)
—> Extravascular haemolysis (via Phagocytosis, Osmotic lysis)
—> ATP depletion, Acid-induced damage, Macrophage processing
—> Membrane loss
—> Vicious cycle

Biochemical end results:
- ↑ Unconjugated bilirubin
- ↑ Urine urobilinogen (colourless, no change in urine colour)
- ↑ Expired CO + HbCO

Question 6

Diagnosis of Hereditary spherocytosis

Answer 6

NO genetic tests available

1. RBC morphology in peripheral blood smear + Positive family history (AD)
2. Flow cytometry: Eosin-5-maleimide (EMA) binding test
   - EMA binds to Band 3 protein (disrupted in HS)
   —> ↓ Fluorescence compared with normal
   - Sensitivity 92.7%, Specificity of 99.1%
3. Osmotic fragility test (OF) (Phased out)
   - Measures the increased sensitivity of spherocytes to lysis in a gradient of NaCl concentrations compared with normal RBC
   - Sensitivity is improved by incubating at 37oC for 24 hours
   - Non-specific + Time-consuming
   - ~20% of mild HS cases will be missed —> no longer recommended

Question 7

Management of Hereditary spherocytosis

Answer 7

1. Supportive with Folic acid supplement
   - For RBC production
2. Screen for pigmented gallstone
3. Splenectomy / Splenic artery embolisation
   - Consider in >4 yo / symptomatic anaemia (sever enough to affecting daily activity / growth)
   - Anaemia will resolve upon splenectomy
   - Should have prior vaccination (against Hib, Pneumococcus, Meningococcus)
   - PenVK prophylaxis
   —> Penicillin G: 250mg oral BD (<5 yo, 125mg oral BD)
   —> Duration undetermined
   - Patients who are most likely to benefit from prophylaxis are:
   —> Children <16 yo
   —> Underlying immunodeficiency

Question 8

Haemolytic anaemia + Thrombocytopenia

Answer 8

1. Evan’s syndrome (rare in children)
   - AIHA (AutoAb against RBC) + Thrombocytopenia
   - Coomb’s +ve
   - Associated with autoimmune diseases
   - Treatment: Prednisolone, RBC transfusion

Microangiopathic haemolytic anaemia (MAHA):
2. Low grade DIC
- D-dimer elevated, fibrinogen low, WBC normal / low
- Microangiopathic pictures

3. TTP / HUS (O157 E. coli, Pneumococcus)
   - Mechanical damage to RBC —> Fragmented RBC
   - Pentad: Fever, Neurological signs, Impaired renal function (Uraemia), Red cell fragmentation, Thrombocytopenia
   - D-dimer normal, fibrinogen normal, WBC normal
   - Microangiopathic pictures
   - Associated with autoimmune diseases / infections
   - Can be familial besides acquired (Relapsing TTP)
   - Low ADAMTS13 (Metalloproteinase)

Haemolytic uraemic syndrome (HUS):
- Typical: O157:H7 E. coli, Pneumococcus —> Shiga toxin —> ADAMTS13 inhibition (web)
- Atypical: Defect in complement system (genetic-related) —> over-activation of complement, treated by Eculizumab (counteract complement activation)

Question 9

Paediatric ITP

Answer 9

• Commonest in children, present acutely, usually triggered by viral infection
• AutoAb (Anti-platelet Ab) bind to platelet
• Peripheral destruction of normal platelet due to autoimmune dysregulation
• 85-90% resolved within 6 months in children
• Usually affect 2 to 8 year of age
• Older children tend to have Chronic ITP (~5%)

Current concept:
- Use immune instead of idiopathic, to emphasise immune-mediated mechanism
—> Primary (no specific cause identified)
—> Secondary (associated with other autoimmune diseases)
- Delete “purpura” (because some may be asymptomatic), Retain acronym ITP: Immune thrombocytopenia
- Subclassified into:
—> Newly diagnosed: resolved within 3 months of diagnosis (formerly known as Acute ITP)
—> Persistent: between 3-12 months from diagnosis (formerly known as Chronic ITP)
—> Chronic: lasting >12 months
—> Severe: with bleeding + requires treatment
- Defined thrombocytopenia as platelet <100
- Normal healthy adults can have platelet count 100–150

Clinical features:
- Preceding infectious illness
- Mucocutaneous bleeding
—> Petechiae / Purpura / Bruises (appear quickly) (>80%)
—> Epistaxis
—> Haematuria
- Intracranial bleeding (0.5%)
- Platelet often very low (<10), with RBC + WBC normal
- Peripheral blood smear: No blast cells, large platelets

Investigations:
- Blood film
- BM exam (rule out leukaemia)

When to treat?
- Mucosal bleeding (Epistaxis, Gum bleeding, Haematuria, Subconjunctival haemorrhage, Retinal haemorrhage)
- GI bleeding
- Intracranial bleeding
- Low platelet count

Treatment:
Acute
1. Steroid (1st line, 2 mg/kg of Prednisolone (high dose) for 2 weeks, reduce dose after 2 weeks)
2. IVIG (1 g/kg, quick onset of action) (Rhogam (Rho(D) immune globulin))
NB: Never give platelet unless there is life threatening bleeding (∵ there is still many AutoAb in circulation in body —> not respond well to platelet transfusion)

Chronic (self notes):
1. Rituximab (may recur when B cell recover after Rituximab effect wore off after 6 months)
2. Eltrombopag, Romiplostim
3. Splenectomy

Prognosis:
- >60% resolve spontaneously after 5 years

Question 10

Haemophilia A (Factor 8 deficiency)

Answer 10

• X-linked recessive
• Majority present at ~1 yo (when baby become ambulatory)
• Moderate: Factor 8 level >1%
• Severe: Factor 8 level <1%
• Look for affected individuals in maternal side e.g. maternal uncle

Clinical features:
1. Spontaneous joint and muscle haemorrhage most common
- Target joint phenomenon: tend to bleed into same joint over and over again
- Tend to bleed into weight bearing lower limb joints (more exposed to trauma in children)
- Recurrent bleeding in joint can cause synovial proliferation —> chronic synovitis —> damage joint

2. CNS bleeding (Uncommon 3%)
3. Post-surgical hemorrhage (Life threatening)

NB: Haematuria / Gum bleeding requires different approach

Management:
1. DDAVP for minor bleeding in mild haemophilia only
- Elevate Factor 8 level

2. Prophylactic treatment with Factor 8 (aka AHG (Antihaemophilic globulin))
   - Primary Prophylaxis
   - Salvage / Secondary prophylaxis (1-3 times / week)
   - Early treatment with AHG for suspected bleeding, if in doubt, treat!!
   - Some may develop inhibitor to Factor 8 (render Factor 8 replacement ineffective) (occurs in around 11% of Haemophilia A in HK) —> Novoseven (Recombinant factor 7a, short t1/2) / Hemlibra (Emicizumab, long t1/2)
3. Anti-fibrinolytic agents (e.g. Tranxamin) for gum / nasal bleeding

Question 11

Von Willebrand disease

Answer 11

VWF:
- Serves as a binding protein to Factor 8
- Slow down Factor 8 catabolism
—> without VWF: t1/2 <2 hr
—> with VWF: 12-20 hr

• Prevalence ~1:100 (as high as 10% in some part of Sweden)
• Autosomal dominant
• Symptomatic in around 1 per million population
• In some VWD, Factor 8 can decrease to <10% (e.g. type 3 (homozygous))

Clinical features (Mild to Severe):
Mucosal bleeding pattern (∵ Platelet adhesion defect) (If severe also cause Deep-seated bleeding (self notes))
1. Epistaxis in children
2. Menorrhagia in women

Investigations:
1. VWF antigen (VWF:Ag)
2. Ristocetin cofactor test (VWF:RiCo) (test for function of VWF)
3. Factor 8 level

Type 1 VWD:
- ↓ VWF:Ag
- ↓ VWF:RiCo
- Normal / ↓ Factor 8 level
- Normal VWF structure
- Less amount of circulating VWF affects binding of platelet + increase bleeding tendency

Type 2A VWD:
- ↓ VWF:Ag
- ↓↓ VWF:RiCo
- Normal / ↓ Factor 8 level
- VWF cleaving protease cleaved VWF (mainly at site 182) into various sizes of fragments in ER, only fragments of VWF are released into circulation

Type 3 VWD:
- Absent VWF:Ag
- Absent VWF:RiCo
- ↓↓ Factor 8

Management:
- Based on VWD subtypes
- DDAVP
—> Induce release of both pre-stored VWF + Factor 8 from endothelial cells
—> VWD1: Usually respond
—> VWD2A: Rarely respond
—> VWD2B: Contraindicated
—> VWD2M: Rarely respond
—> VWD2N: Occasionally respond
—> VWD3: Ineffective