Disorders of hemoglobin

Question 1

Hb H:

• What is it?
• How to visualize Hb H inclusions?

Answer 1

• B4

- Supravital stain (Brilliant Cresyl blue): golf balls

Question 2

Thalassemia major: surveillance recommended

Answer 2

• CBC at least yearly, before each transfusion
• Bone scan yearly (starting 10 y.o.)
• Monitoring of liver iron with T2* MRI yearly
• LFT and albumin yearly
• Ferritin yearly
• Monitoring of cardiac iron with T2* MRI yearly (starting 10 y.o.)
• HIV and hepatitis serologies for transfused pts
• Fasting glucose yearly (starting 10 y.o.)
• Endocrine panel 1 yearly (starting at 6 y.o.): TSH/T4, PTH, 25-OH-vit D, 1,25-OH2-vit D
• Endocrine panel 2 yearly (starting at 10 y.o.): FSH/LH, testosterone, estradiol

Question 3

Indications for iron chelation (3)

Answer 3

1. Transfusion of >100-200 ml/kg RBC
2. Liver iron concentration > 5-7 mg/g dry weight
3. Ferritin > 1500-2000 ng/mL

Question 4

Sickle solubility test:
False (-)ve
Falve (+)ve

Answer 4

False negative: severe anemia, elevated Hb F, HPFH, Hb S < 10%, co-inheritance of alpha-thal trait

False positive: some Hb variants (Hb Barts, Hb Jamaica I, …), increased blood viscosity (e.g. polycythemia, hyperlipidemia, elevated serum proteins)

Question 5

Iron chelation: which agents can be given PO?

Which agent requires parenteral administration?

Answer 5

Deferasirox (Exjade), desferiprone

Desferoxamine (IV or SC)

Question 6

What are the most common side effects of deferasirox (Exjade)?
What side effect is specific to desferiprone?

Answer 6

GI upset, transaminitis, elevation in creatinine (reversible), ocular and auditory toxicity
Agranulocytosis

Question 7

Thalassemia:

Indications for HSCT

Answer 7

Should be offered to all patients with severe phenotype, especially in the presence of a matched sibling donor

Question 8

Thalassemia: how is prenatal diagnosis possible?

3 methods

Answer 8

• Chorionic villus sampling (10th week)
• Amniocentesis (18th week)
• Fetal DNA in maternal blood (not widely available)

Question 9

HSCT for thalassemia: name 3 risk factors associated with poor outcome

Answer 9

1. Hepatomegaly
2. Inadequate therapy for iron overload
3. Portal fibrosis

Question 10

Name 7 manifestations of iron overload

Answer 10

• Skin hyperpigmentation
• Fatigue
• Arthropathy
• Arrythmias, heart failure
• Liver disease
• Diabetes mellitus
• Hypogonadism
• Growth delay
• Iron deposits usually in skin, joints, liver, heart and endocrine organs predominantly.

Question 11

Mechanisms of action of hydroxyurea (4)

Answer 11

1) Increase in Hgb F
2) Increase in RBC deformability (higher RBC volume, increased hydration)
3) Decrease in retics and neutrophils adhesiveness
4) Decrease in neutrophil count (inhibition of ribunucleotide reductase)

Question 12

Treatment Diamond-Blackfan anemia

Answer 12

• Steroids (prednisone), started at 2 mg/kg/day (usually after 6 months) and tapered to lowest required dose; to be given with PCP prophylaxis
• RBC transfusion if steroid-resistant of younger than 6-12 months
• HSCT for selected cases

Question 13

Indications of HSCT in patient with Blackfan-Diamong anemia

Answer 13

• Steroid-resistant patients, especially if MSD
• Progression to SAA
• Progression to MDS/AML

Question 14

What did show the study BABY-HUG?

Answer 14

Hydroxyurea in infants with SCD led to:

• Reduction of pain episodes
• Reduction of dactylitis
• Reduction of acute chest syndrome
• Reduction of transfusion

Question 15

What did show the study MSH?

Answer 15

Hydroxyurea in adults with SCD (replicated after with teenagers and older children) led to:

• Reduction of pain episodes
• Reduction in acute chest syndrome
• Reduction in admissions to hospital
• Reduction in transfusions

Question 16

Indications of HSCT in sickle cell disease

Answer 16

• Stroke or central nervous system event lasting longer than 24 h
• Impaired neuropsychological function with abnormal brain MRI and angiography
• Recurrent acute chest syndrome
• Stage I or II sickle lung disease
• Recurrent vaso-occlusive painful episodes or recurrent priapism
• Sickle nephropathy (GFR 30%–50% of predicted normal)

Question 17

Indications of HSCT in thalassemia

Answer 17

Severe phenotype, transfusion dependent

Individualized, taking int account availability of a MSD and family and physician’s preferences

Question 18

Thalassemia: main predictor or survival in TDT?

Answer 18

Compliance with iron chelation

Question 19

What is the Pesaro classification?

Answer 19

Risk stratification of thalassemia patient undergoing transplant, based on 3 RF
- Hepatic fibrosis
- Inadequate iron chelation pre-transplant
- Degree of hepatomegaly
Class I: no RF, TFS: 94%
Class II: 1-2 RF, TFS: 77%
Class III: 3 RF, TFS 53%

Question 20

What is the mutation in sickle cell disease?

Answer 20

Point mutation A>T at chr 11p15.5 leading to glutamic acid being substituted by valine

Question 21

What bacterial pathogen is encountered with thalassemia?

Answer 21

Yersinia

Question 22

What possible diagnoses can give a “FS” pattern on newborn screening for sickle cell disease?

Answer 22

• Hgb SS
• Hgb S-B0thal
• Compound heterozygosity for Hgb S and HFPH
• Hgb S-B+thal (produce low levels of A but sometimes below level of detection at birth)