Haemaglobinopathies

Question 1

What are the three different forms of haemoglobin?

Answer 1

HbA - most common in adults (2 alpha and 2 beta chains)

HbA2 - raised = diagnostic of B thalassaemia (2 alpha and 2 delta chains)

HbF - fetal haemoglobin (2 alpha and 2 gamma chains)

Question 2

describe the genetic control of globin formation

Answer 2

2 Alpha-like genes per chromosome on chromosome 16
1 beta-like gene per chromosom on chromosome 11

during the first months of life HbF becomes HbA as gamma chains change to beta chains

Question 3

What are the two different types of haemoglobinopathies?

Answer 3

Thalassaemia: decreased rate of globin chain production
Structural: structurally abnormal globin chains e.g. HbS

Question 4

What are the two main types of thalassaemia? what does this ultimately lead to?

Answer 4

Alpha thalassaema: alpha chains affected (microcytic, hypochromic anaemia)
Beta thalassaemia: beta chains affected (inadequate Hb production)

imbalance accumalation of globin chains = ineffectiv erythropoeisis and haemolysis

Question 5

What does α vs α+ vs α0 stand for? what causes this?

Answer 5

α - normal alpha chain synthesis
α+ - reduced alpha chain synthesis: caused by deletion of 1 alpha gene
α0 - absent alpha chain synthesis: caused by deletion of both alpha genes

Question 6

What are the 4 different types of alpha thalassaemia?

Answer 6

Silent α thalassaemia trait
α thalassaemia trait
Haemoglobin H disease (HbH)
Hb barts hydrops fetalis

Question 7

what is silent α thal. trait? what genes do they have?

Answer 7

silent carriers of alpha thalassaemia, only one gene affected:
- α/α α = α+/α

Question 8

what is α thalassaemia trait? what gene types could they have? what is seen clinically? what type of anaemia is seen? with special stains what type of cells are seen? what can this be easily mistaken for? what treatment is needed?

Answer 8

2 alpha genes affected:
- -/α α = α0/α
or
- α/- α = α+/α+

Clinically asymptomatic

Microcytic, hypochromic RBC’s, mild anaemia

Golf ball cells can be seen with special stains (red cell inclusions AKA HbH)

easily mistaken for iron deficiency but normal ferritin

no treatment is needed

Question 9

HbH disease:

• by which pattern is this inherited?
• what is the gene pattern?
• where is this most common?
• what is HbH

Answer 9

• autosomal recessive: have to have one parent with α0 and the other with α+
• –/-α = α0/α+
• most common in s.e asia/middle east/meditteranean
• There are excess B chains which form tetramers B4 = HbH

Question 10

HbH disease clinical features 6

Answer 10

• wide variation (can be asymptomatic to transfusion dependant)
• splenomegaly (extramedullary haematopoeisis)
• Jaundice (haemolysis/ineffective eythropoesis)
• gallstones
• iron overload
• growth retardation

Question 11

What is the management of HbH disease:

• mild
• severe

Answer 11

Mild: transfusion only needed at times of illness

Severe: case transfusion dependant
-splenectomy may reduce transfusion need if severe

Folic acid supplements as there is an increase in RBC turnover so there’s an increased demand

Question 12

what is Hb barts hydrops fetalis?

Answer 12

• no alpha genes inherited from either parent - HbA cannot be produced
• small amount of embryonic Hb present at birth but the majority of Hb at birth is HbBarts (γ4) or HbH (β4)

Question 13

What are the 5 clinical features of Hb barts hydrops fetalis? what is done to prevent this?

Answer 13

• pallor/oedema
• heart failure
• skeletal vascular abnormalities
• most die in-utero or die shortly after birth
• growth retardation
• hepatosplenomegaly

Prevention:
ν Antenatal screening to identify parents at high risk (ie both possible α0 carriers) now standard in Scotland
ν Family Origin Questionnaire and FBC
ν Further testing if from high-risk area or abnormal RBC indices
ν Couples at risk should be counselled
ν Prenatal diagnosis with selective termination of pregnancy considered

Question 14

how is alpha thalassaemia diagnosed:

• blood film
• HPLC
• molecular testing

Answer 14

-alpha thalassaemia trait suspected from RBC indices and ethnicity of patient

Blood film:

• target cells
• anispoikilocytosis

High performance liquid chromatography:

• identifies abnormal Hb
• Quantifies HbA, HbA2, HbF
• Excludes β thalassaemia

Molecular testing:
-needed to confirm α thal. trait and determine mutation via PCR

Question 15

Beta Thalassaemia:

-what different types of β thalassaemia exist?

Answer 15

β thal trait
β thal intermedia
β thal major

Question 16

what is β vs β+ vs β0

Answer 16

β - normal beta chain synthesis
β+ - reduced beta chain synthesis
β0 - absent beta chain synthesis

Question 17

What type of Hb is affected? how is this inherited?

Answer 17

• only HbA is affected

- autosomal recessive inheritance

Question 18

β thal trait: what genotypes exist? symptoms? what type of anaemia is seen? what is diagnostic of this?

Answer 18

β+/β or β0/β

• asymptomatic
• microcytic anaemia, low MCH (mean cell haemoglobin)
• raised HbA2 is diagnostic

Question 19

β thal intermedia: what genotypes exist? what is needed?

Answer 19

β+/β+ β0/β+
moderate severity
occasional transfusions needed

Question 20

β thal major: management?

Answer 20

severe and needs lifelong transfusions

Question 21

β thal major:
What is seen on FBC?
blood film?
HPLC?

Answer 21

V low MCV/MCH

Blood film: reticulocytosis, anisopoikilocytosis, target cells (lack central pallor)

HPLC: mainly HbF, small amounts HbA, HbA2 elevated

Question 22

β thalassaemia major:

• age of presentation
• clinical features 4?

Answer 22

Present 6-24months

• failure to thrive
• pallor
• extramedullary haemapoeisis: hepatosplenomegaly, increase in bone size, organ damage

Question 23

what is the management of β thal major?

Answer 23

-Regular blood transfusions to maintain Hb above 95-105g/l to suppress ineffective erythropoeisis and inhibit gut overabsorption of iron
=relatively normal growth and development

bone marrow transplant if carried out before complications develop

Question 24

What is the main cause of mortality in β thal major?

Answer 24

overload of iron from blood transfusions:

• liver disease: cirrhosis/hepatocellular cancer
• Cardiac: arrythmias/myopathies
• Endocrine dysfunction: impaired growth and pubertal development/diabetes/osteoporosis

Question 25

What is the pathophysiology of sickle cell anaemia?

Answer 25

• autosomal recessive disease
• causes beta chain = βs = HbS
• HbS polymerises when exposed to low oxygen levels = distorting the cell as the RBC membrane is damaged

Question 26

What is sickle cell trait? Blood film? HPLC

Answer 26

• one abnormal β gene: β/βs
• only sickle in severe hypoxia (high altitude or under anaesthesia)

Blood film: normal or mildly reduced MCV/MCH

HPLC: mainly HbA, <50% HbA

Question 27

What is sickle cell disease? HPLC? what does this cause?

Answer 27

• 2 abnormal β genes: βs/βs
• HbS > 80%, no HbA, HbF variable

results in:

• tissue infarction due to vascular occlusion (dactylitis/bone marrow/spleen/CNS/lung/renal/leg ulcers/severe pain)
• chronic haemolysis
• pooling of sickled RBCs in liver and spleen (sequestration)

Question 28

What causes a sickle crisis 5

Answer 28

• hypoxia
• dehydration
• infection
• cold exposure
• stress/fatigue

Question 29

what is the treatment for sickle cell crisis 5

Answer 29

• opiate analgesia
• hydration/rest
• oxygen
• abiotics if indicated
• red cell exchange transfusion in severe crisis e.g. chest or neuro crisis (venesect - transfuse - venesect)

Question 30

what 4 long term affects can sickle cell disease cause?

Answer 30

• poor growth
• infections (hyposplenism from repreated infarcts)
• organ damage (pulm. hypertension, renal disease, avascular necrosis)
• psychosexual

Question 31

What is the long term treatment of sickle cell disease?

Answer 31

• education/lifestyle to avoid precipitants
• reduce infection risk: prophylactic penicillin/vaccination
• folic acid supplements
• hydroxycarbamide: reduces the severity by inducing HbF