Thalassaemia and Sickle Cell Disease

Question 1

What are the different types of thalassaemia?

Answer 1

Alpha thalassaemia - defects in alpha globin,
Beta thalassaemia - defects in beta globin

Question 2

What is the pathophysiology of alpha thalassaemia?

Answer 2

There are two alpha globin genes located on each chromosome 16. Disease is autosomal recessive. Severity of disease depends on how many genes affect.

Question 3

What is the clinical severity of alpha thalassaemia?

Answer 3

If 1 or 2 genes affected then its called alpha-thal train. This results in normal Hb but hypochromic, microcytic RBCs.
3 alpha globulin alleles affect results in Haemoglobin H disease.
4 alpha alleles affected results in alpha thalassaemia major.

Question 4

What are the clinical features of haemoglobin H disease?

Answer 4

Microcytic anaemia,
Haemolysis,
Splenomegaly,
Normal survival

Question 5

What are the clinical features of alpha thalassaemia major?

Answer 5

Also called hydrops fetalis. Lack of alpha globin causes excess gamma chains which creates Hb barts (poor carries of oxygen)

Question 6

What is the management for alpha thalassaemia/haemoglobin H disease?

Answer 6

Blood transfusions,
Stem cell transplant,
Splenectomy.

Question 7

What is the pathophysiology of beta thalassaemia?

Answer 7

AR disease. One non functioning copy - beta thalassaemia trait. Two non functioning copies of the beta globin gene causes beta thalassaemia major.

Question 8

What are the features of beta thalassaemia trait?

Answer 8

Tend to be asymptomatic. Can have a mild hypochromic, microcytic anaemia (microcytosis usually disproportionate to anaemia)
Raised HbA2

Question 9

What are the features of beta thalassaemia major?

Answer 9

Tends to present with severe anaemia aged 3-9 months, failure to thrive and hepatosplenomegaly.
There will be raised HbA2 and HbF and absent HbA.
Ineffective haematopoiesis results in frontal bossing (hair on end appearance on skull XR) and maxillary overgrowth and prominent frontal/parietal bones.

Question 10

What are the investigations for Beta thalassaemia minor?

Answer 10

Bloods: Isolated microcytosis and mild anaemia (less severe than expected for low microcytosis).
Blood film: target cells and basophil stippling.
Hb electrophoresis (raised HbA2)

Question 11

What are the investigations for Beta thalassaemia major?

Answer 11

Bloods: Profound microcytic anaemia, increased reticulocytes.
Film: Anisopoikilocytosis, targets cells, nucleated RBCs.
Methyl blue stains,
Electrophoresis - Minly shows HbF.
HbA2 elevated
Haemolysis

Question 12

What is the management of beta thalassaemia major?

Answer 12

Regular blood transfusions - risk of iron overload toxicity so give iron chelating agents.
Hydroxycarbamide (boosts HbF)
Allogenic bone marrow transplant (can be curative)

Question 13

What are some iron chelating agents?

Answer 13

Desferrioxamine,
Deferiprone

Question 14

What is Anisopoikilocytosis?

Answer 14

Where RBCs are different shapes and sizes

Question 15

What are the complications of beta thalassaemia?

Answer 15

Cardiomyopathy, arrythmias or failure.
Acute sepsis,
Liver cirrhosis , portal hypertension and acute decompensation,
Endocrine dysfunction,
Diabetes
As they often develop secondary haemochromatosis

Question 16

What is the pathogenesis of sickle cell disease?

Answer 16

Single amino acid substitution on Beta globin gene. Glutamine is substituted for valine. Resulting in the formation of Hb S. When HbS is deoxygenated it undergoes polymerisation which causes sickle shape of RBC. More severe if patient is homozygous (HbSS)

Question 17

What is the mechanism of hyposplenism in sickle cell disease?

Answer 17

Sickled red cells seqester in the spleen where they are then phagocytosed. This leads to extravascular haemolysis which is followed by splenic infarct.

Question 18

What are the signs and symptoms of sickle cell disease?

Answer 18

1. Vaso-occlusive crisis (microvascular obstruction caused by RBC sickling, may be triggered by local hypoxia)
2. Acute chest crisis (tachypnoea, wheeze, cough, hypoxia and pulmonary infiltrates on CXR)
3. Splenic infarct,
4. Sequestration crisis,
5. Osteomyelitis/osteonecrosis,
6. Stroke,
7. Dactylitis,
8. CKD,
9. Gallstones, retinal disorder, priaprism, pulmonary fibrosis

Question 19

Describe features of priaprism?

Answer 19

Can occur due to vaso-occlusive crisis. It causes painful persistent erection. Treated by aspirating blood from penis

Question 20

What are the investigations for sickle cell anaemia?

Answer 20

Definitive diagnosis - Haemoglobin electrophoresis +/- genetic testing
FBC - Microcytic anaemia + haemolysis
Blood film: Sickle cells, target cells, reticulocytes, hyposplenism (howell-Jolly bodies)

Question 21

What is the management of an acute sickle crisis?

Answer 21

High flow oxygen,
IV fluids and analgesia,
Top up transfusions

Question 22

What is the treatment for chronic sickle cell disease?

Answer 22

Hydroxycarbamide (increases foetal HB),
Regular transfusions,
Vaccinations.
Crizanlizumab (targets P-selectin which prevents vaso-occlusive crisis)
Bone marrow transplant and gene-editing are possibly curative

Question 23

What are the clinical features of sickle cell anaemia?

Answer 23

Brain - Stroke/moya moya (formation of weak spindly vessels),
Lungs - Acute chest syndrome/ pulmonary hypertension.
Bones - Dactilysis (infarction of growing bones) or osteonecrosis in adults.
Spleen - Hyposplenic,
Kidneys - Loss of concentration/infarction.
Urogenical - Priapism (sustained erection)
Eyes - Vascular retinopathy,
Placenta - Growth retardation or foetal loss