Haemaglobinopathies

Question 1

Major forms of Haemoglobins

Answer 1

HbA (two alpha chains and two beta chains, α2β2 )
HbA2  (two alpha and two delta, α2δ2)
HbF (two alpha  and two gamma, α2γ2)
In adults HbA is the major form present;
HbA 97%
HbA2  2.5%
HbF  0.5%

Question 2

which chromosomes are alpha and beta haemoglobin genes on?

Answer 2

Alpha like genes are on chromosome 16
Two alpha genes per chromosome (4 per cell)

Beta like genes are on chromosome 11
One beta gene per chromosome (2 per cell)

Question 3

list the classifications of alpha thalassaemia

Answer 3

α thalassaemia minima. Silent α thal trait; one gene affected (-α/αα)

α thalassaemia minor. α thal trait; two affected genes (–/αα or -α/-α)

HbH disease; usually 3 genes affected (–/-α )

Hb Barts hydrops fetalis; no functional α genes (–/–)

Question 4

How could Alpha thalassaemia trait be distinguished from iron deficiency anaemia?

What might be seen with special stain

Answer 4

but normal ferritin, raised red cell count

Microcytic, hypochromic red cells with mild anaemia

Red cell inclusions (HbH bodies) can sometimes be seen with special stains

Question 5

What is pathophysiology of HbH disease

Answer 5

Only 1 working α gene per cell (–/-α )

α chain production

Question 6

Clinical features of HbH?

Answer 6

Wide variation; nearly asymptomatic to transfusion dependant
Splenomegaly due to extramedullary haematopoiesis
Jaundice due to;
- Haemolysis
- Ineffective erythropoiesis
Other problems such as growth retardation, gallstones and iron overload can occur

Question 7

Management of HbH

Answer 7

Mild: transfusion only needed at times of intercurrent illness
Severe cases transfusion dependent
Splenectomy may reduce transfusion need in severe cases (NB vaccinations)
Folic acid supplementation (↑ RBC turnover so ↑demand)

Question 8

what’s the pathophysiology of Hb Bart’s Hydrops Foetalis?

Answer 8

Severest form of α thalassaemia
Occurs when no α genes inherited from either parent (–/–)
Minimal or no α chain production →HbA can’t be produced
Hb Barts (γ4), HbH (β4) majority of Hb at birth
Small amounts of embryonic Hb present

Question 9

what is the screening of Bart’s Hydrops featalis

Answer 9

Family Origin Questionnaire and FBC

Question 10

How is alpha thal diagnosed

Answer 10

α thal trait usually suspected from red cell indices and ethnic origin (exclude iron deficiency first)
Blood film; target cells, anisopoikilocytosis
High performance liquid chromatography (HPLC) or haemoglobin electrophoresis ;
Quantifies HbA, HbA2, HbF
Identify abnormal haemoglobins eg HbH
Excludes beta thal trait etc
Molecular testing needed to confirm α thal trait and determine mutation involved
PCR used to screen for common mutations, guided by patients’ ethnic background

Question 11

Where are alpha thal and B thal most prevalent

Answer 11

alpha thal- S.E. Asia, Middle East and the Mediterranean

beta thal- S.E. Asia, Cyprus and Sardinia

Question 12

how are thalessaemias inherited

Answer 12

autosomal recessive

Question 13

what are the different calssifications of b Thal

How would B thal trait be diagnosed?

Answer 13

β thalassaemia trait (usually β+ /β or β0/ β);
Asymptomatic
Low MCV/MCH
Raised HbA2 is diagnostic
β thalassaemia intermedia (usually β+ /β+ or β0 /β+);
Moderate severity requiring occasional transfusion
β thalassaemia major;
Severe, lifelong transfusion dependency

Question 14

what are the lab features of b thal

Answer 14

Moderate to severe anaemia (Hb 30-90g/l)
Very low MCV/MCH
Reticulocytosis
Film; anisopoikilocytosis and target cells 
HPLC: 
mainly HbF present
small amounts of HbA
HbA2 often elevated

Question 15

what are the clinical features of beta thal

Answer 15

Presents aged 6-24 months 
 Failure to thrive
 Pallor
 Extramedullary haematopoiesis causing;
Hepatosplenomegaly
Skeletal changes 
Organ damage

Question 16

treatment of B thal major

Answer 16

Regular transfusion programme to maintain Hb above 95-105g/l to;
Suppress ineffective erythropoiesis
Inhibit gut over-absorption of iron
Allows for relatively normal growth and development
Iron overload from transfusion then becomes the main cause of mortality
Bone marrow transplant may be an option if carried out before complications develop

Question 17

what are the issues with iron overload

Answer 17

Endocrine dysfunction
Impaired growth and pubertal development
Diabetes
Osteoporosis

Cardiac disease
Cardiomyopathy
Arrhythmias

Liver disease
Cirrhosis
Hepatocellular cancer

Question 18

what is the management of iron overload?

Answer 18

250mg of iron per unit of red cells
Chronic anaemia → increased absorption of Fe from gut
Venesection not feasible
Iron chelating drugs such as Desferrioxamine necessary
Chelators bind to iron, complexes formed are excreted in urine or stool

Question 19

what are the clinical signs of sickle cell anaemia?

Answer 19

Tissue infarction due to vascular occlusion
Symptoms depend on site and severity
Digits (dactylitis), bone marrow, spleen, CNS, lung, renal
Leg ulcers
Pain may be extremely severe
‏ Chronic haemolysis
Sequestration of sickled RBCs in liver and spleen

Question 20

what are the precipitants of a sickle cell crisis?

Answer 20

Hypoxia ‏
Dehydration
Infection
Cold exposure
Stress/fatigue

Question 21

What is the treatment of a painful crisis?

Answer 21

Opiate analgesia 
Hydration 
Rest
Oxygen 
Antibiotics if evidence of infection 
Red cell exchange transfusion in severe crises eg chest crisis or neurological symptoms

Question 22

what is the long term treatment of sickle cell anaemia?

Answer 22

Education/lifestyle to avoid precipitants
Reduce risk of infection;
Prophylactic penicillin
Vaccination; pneumococcus, meningococcus, haemophilus
Folic acid supplementation

Hydroxycarbamide can reduce severity of disease by inducing HbF production