Thalassaemia and Sickle Cell Disease

Question 1

What are haemoglobinopathies?

Answer 1

• Lack of normal globin chains due to absence of genes (seen in thalassaemias)
• Abnormal globin chains (seen in sickle cell)
• The severity of the disorder depends on the amount of abnormal haemoglobin, the type of abnormal haemoglobin and ameliorating factors.

Question 2

What are the genetics involved in normal haemoglobin?

Answer 2

• Beta globin gene cluster on chromosome 11. Responsable for productinf gamma globin (during pregnancy), delta globin (produced in very low levels) and finally the beta globin genes (produced from 3months+)
• Alpha globin gene cluster (contains zeta and 2 alpha globin genes)
• In total, 2 beta genes and 4 alpha genes

Question 3

What are thalassaemias?

Answer 3

Genetic disorder resulting in a relative lack of globin genes

Question 4

What are the different alpha gene permutations?

Answer 4

Alpha+ thal trait - Lacking 1 out of 4 alpha globin genes.
Homozygous alpha+ thal trait - Lacks 1 alpha gene from EACH parent (2 missing in total)
Alpha(o) thal trait - Inherits 2 non-working copies of alpha gene from the same parent.
HbH disease - Only inherits 1 working copy og the gene (3 non functioning)
Alpha thal major - No working copies, incompatible with life.

Question 5

What is the clinical significance of alpha thalassaemia?

Answer 5

Missing 1 gene - Mild microcytosis,
Missing 2 genes - Microcytosis and increase RBCs and asymptomatic anaemia (sometimes).
Missing 3 genes - Significant anaemia (HbH disease)
Missing 4 genes - Incompatible with life

Question 6

Describe clinical details of haemoglobin H disease (HbH)

Answer 6

Occurs when missing 3 alpha globin genes. The lack of alpha globin chains results in excess beta chains which join together to from haemoglobin H. Hb can vary between 65-76g/l
Patients can be relatively asymptomatic but do require blood transfusions in periods of stress

Question 7

What is beta thalassaemia major?

Answer 7

An autosomal recessive disease where both copies of the beta globin gene are missing. Also known as transfusion dependant thalassaemia. This results in the inability to make adult haemoglobin. It causes significant dyserythropoiesis which can result in boney changes.

Question 8

Describe the management of transfusion dependant thalassaemia (beta thalassaemia major)

Answer 8

• Blood transfusions (2-3units every 3 weeks). However need to carefully watch for iron overload as body cannot remove excess iron, this can be very dangerous.
• Iron chelation,
• Venous access can become a problem so some patietns given venous port.
• Monitor organs which can become affected by iron overload (liver, heard and endocrine)
• Consider bone marrow transplant in childhoods.
• Future considerations include gene therapy

Question 9

What is the pathogenesis of sickle cell disease?

Answer 9

Single amino acid substitution on Beta globin gene. Glutamine is substituted for valine. Resulting in the formation of Hb S

Question 10

Explain the polymerisation of Sickle haemoglobin

Answer 10

When Hb S is deoxygenated, it undergoes polymerisation, this is when it produces long polymers which result in the sickle shaped RBC.The rate of polymerisation depends on deoxygenation rate, Hb concentration and foetal haemoglobin

Question 11

What are the clinical effects of sickle cell haemoglobin

Answer 11

• Reduced RBC survival causing anaemia. Increased haemolysis and chronic endothelial dysfunction (which can cause inflammation and damage to local BVs causing chronic tissue damage).
• Vaso-occlusion (sickle shape is large and cannot bend through small capillaries) this results in tissue hypoxia and infraction causing pain and tissue damage.

Question 12

Explain some of the organ effects of sickle cell anaemia

Answer 12

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

Question 13

How can you prevent sickle cell anaemia crisis?

Answer 13

• Hydration, analgesia and early interventions.
• Prophylactic vaccinations and antibiotics,
• Folic acid,
• Hydroxycarbamide therapy which can increase HbF and reduce sickling.
• Regular red cell transfusion if high risk.

Question 14

What are the treatments for sickle cell anaemia?

Answer 14

• Prevention of crisis.
• Prompt management of crisis via oxygen, fluids, analgesia, antibiotics, specialist care and transfusion/red cell exchange.
• Some patients may get bone marrow transplant
• Future treatments may involve gene therapy.