Session 8: Haemoglobinopathies

Question 1

Normal hemoglobin structure

Answer 1

2 alpha-like globin chains, 2 beta-like globin chains, 4 heme molecules

Question 2

Each heme molecule ___ binds to ONE oxygen molecule

Answer 2

reversibly

Question 3

Erythrocyte shape and the benefit of the structure/shape

Answer 3

Biconcave disc of RBC allows them to have large surface area and deform and bend to squeeze through capillaries

Question 4

Function of RBC

Answer 4

Transport oxygen from the lungs to tissues

Question 5

Lifespan of RBC

Answer 5

~120 days

Question 6

Anemia

Answer 6

Decrease in hemoglobin level below the reference level for the age/sex of the individual

Male = 135 - 175 g/L, Female = 115 - 155 g/L

Question 7

Classification of anemia

Answer 7

Classified by Mean Corpuscle Volume (MCV) as low, medium or high

Question 8

The two NORMAL adult hemoglobin variants

Answer 8

HbA = a2b2 = 97%,
HbA2 = a2δ2 = 2%

Question 9

The one NORMAL fetal hemoglobin variant

Answer 9

HbF = a2γ2 = <1%

Question 10

Too little or too much globin chain synthesis (quantitative) leads to…

Answer 10

Thalassemia

Question 11

Synthesis of an abnormal gene product (qualitative) leading to abnormal structural variants of RBC leads to…

Answer 11

Sickle cell anemia

Question 12

In sickle cell Hb (HbS) - a hydrophilic ___ on the surface of the protein is mutated to a hydrophobic ___

Answer 12

In sickle cell Hb (HbS) - a hydrophilic glutamate on the surface of the protein is mutated to a hydrophobic valine

Question 13

In normal healthy hemoglobin, ___ alpha globin chain genes and 2 beta globin chain genes produce a balanced production of HbA (a2b2)

Answer 13

In normal healthy hemoglobin, four alpha globin chain genes and 2 beta globin chain genes produce a balanced production of HbA (a2b2)

Question 14

Alpha Thalassaemia inheritance pattern

Answer 14

Autosomal recessive

Question 15

Alpha Thalassaemia leads to the loss of ___ globin genes which leads to the excess production of ___ globin chains

Answer 15

Alpha Thalassaemia leads to the loss of alpha globin genes which leads to the excess production of beta globin chains

Question 16

Beta Thalassaemia leads to the loss of ___ globin genes which leads to the excess production of ___ globin chains

Answer 16

Beta Thalassaemia leads to the loss of beta globin genes which leads to the excess production of alpha globin chains

Question 17

Types of Alpha Thalassaemia a,a/a,-

Answer 17

1 gene missing - ‘Silent’ asymptomatic, Low MCV, Raised red cell count

Question 18

Types of Alpha Thalassaemia a,-/a,-

Answer 18

2 genes missing - Trait, Asymptomatic, Low MCV, Raised red cell count

Question 19

Types of Alpha Thalassaemia a,a/-,-

Answer 19

2 genes missing - Trait (far east), Asymptomatic, Low MCV, Raised red cell count

Question 20

Types of Alpha Thalassaemia a,-/-,-

Answer 20

3 genes missing - Hemoglobin H disease (HbH disease), Anaemia, Splenomegaly, Not transfusion-dependent

Question 21

Types of Alpha Thalassaemia -,-/-,-

Answer 21

All 4 genes missing - Hydrops fetalis, Incompatible with life

Question 22

Types of Beta Thalassaemia β/β+ or β/β0 Beta thal minor

Answer 22

• Asymptomatic, - Low MCV, - Mild anemia

Question 23

Types of Beta Thalassaemia β+/β0 (mild variants) or β+/β+

Answer 23

• Splenomegaly, - Anaemia, - Non-transfusion dependent, - Bony deformity, - Gallstones, - Iron overload

Question 24

Types of Beta Thalassaemia β+/β0 (severe variants) or β0/β0

Answer 24

• Asymptomatic at birth, - Splenomegaly, - Severe anaemia, - Developmental delay, - Growth retardation, - Extramedullary erythropoiesis, - Marrow expansion (skull/long bones), - Transfusion-dependent, - Iron overload

Question 25

Signs and symptoms of thalassemia

Answer 25

Pallor, Weakness, Fatigue, Jaundice, Facial bone deformities, Abdominal swelling (splenomegaly), Dark urine, Slow growth, Palpitations, Shortness of breath (dyspnea)

Question 26

Thalassemia patients who are transfusion-dependent may develop issues such as ___ iron in the body. This is caused by regular blood transfusions which are required to treat their anaemia.

Answer 26

Thalassemia patients who are transfusion-dependent may develop issues such as excess iron in the body. This is caused by regular blood transfusions which are required to treat their anaemia.

Question 27

Iron overload affects two organs particularly. Which organs are these?

Answer 27

Heart, Liver

Question 28

Management of thalassaemia

Answer 28

Question 29

In thalassemia, regular transfusions may be needed to keep blood Hb >___g/L

Answer 29

Hb >100g/L

Question 30

Sickle cell disease is caused by the homozygous sickle cell mutation (Hb SS). This is due to a ___ of a single amino acid. Hydrophilic glutamate is replaced which hydrophobic ___.

Answer 30

Sickle cell disease is caused by the homozygous sickle cell mutation (Hb SS). This is due to a substitution of a single amino acid. Hydrophilic glutamate is replaced which hydrophobic valine.

Question 31

The replacement of hydrophilic glutamate with hydrophobic valine in Sickle Cell Disease makes HbS ___ soluble and more prone to ___ in its deoxygenated state

Answer 31

The replacement of hydrophilic glutamate with hydrophobic valine in Sickle Cell Disease makes HbS less soluble and more prone to polymerisation in its deoxygenated state

Question 32

Sickled RBC (SCD) have less ___ ___ compared to the normal bioconcave shape of RBCs. This leads to less oxygen carrying capacity

Answer 32

Surface area

Question 33

What are the five types of sickle cell crises?

Answer 33

1) Vaso-occlusive crises, 2) Acute chest syndrome, 3) Bone marrow aplasia, 4) Splenic sequestration, 5) Hemolysis

Question 34

Vaso-occlusive crises in SCD

Answer 34

Occlusion of small or large vessels by sickled cells leading to ischemia

Question 35

Acute chest syndrome crises in SCD

Answer 35

Vaso-occlusion within the pulmonary vasculature of patients with sickle cell disease.

Question 36

Bone marrow aplasia crises in SCD

Answer 36

Temporary cessation of erythropoiesis causing severe anaemia

Question 37

Hemolysis crises in SCD

Answer 37

Excessive hemolysis - uncommon

Question 38

Sickle Cell Anemia presentation

Answer 38

Chronic pain (25%), Early multiple strokes, Osteonecrosis, Ulcers, Pulmonary hypertension, Sepsis (autosplenectomy), Proliferative retinopathy, Priapism, Dactylitis

Question 39

Management of Sickle Cell Anaemia during ACUTE CRISIS

Answer 39

Pain relief (analgesia), IV fluids, Oxygen, Antibiotics for infections, Exchange transfusion

Question 40

Management of Sickle Cell Anaemia LONG-TERM

Answer 40

Penicillin V prophylaxis, Vaccination, Folic acid, Hydroxycarbamide, Preventative transfusions, Stem cell transplantation

Question 41

Name a drug which is used in the long-term management of Sickle Cell Anaemia which REDUCES the sickling of RBCs

Answer 41

Hydroxycarbamide

Question 42

Sickle cell trait

Answer 42

Symptoms shown by those possessing a heterozygous genotype for sickle cell anemia: 2 alpha chains, 1 mutated B chain, 1 normal B chain, 4 heme

Question 43

Sickle cell trait confers a resistance to what disease in 30-40% of sub-Saharan Africa?

Answer 43

Malaria

Question 44

Patients with haemoglobinopathies are particularly vulnerable to iron overload. Why is this?

Answer 44

Regular transfusions, Excess iron from transfusions and body has no mechanism for excreting excess iron loads, Iron overload can be fatal for = heart, liver and endocrine glands

Question 45

Managing iron overload - name three iron chelator oral and subcutaneous medications that can be given to patients with iron overload

Answer 45

- Deferoxamine, - Deferiprone, - Deferasirox

Question 46

Caution of prescribing iron chelating drugs to patient with iron overload

Answer 46

1) Require long-term compliance to be effective, 2) Have their own toxicities/risks

Question 47

Pre-natal screening program in the UK for haemoglobinopathies

Answer 47

Family Origin Questionnaire (FOQ) - Screens women at risk and offers pre-natal diagnosis of the fetus

Question 48

Screening for haemoglobinopathies in newborns

Answer 48

Newborn blood spot test - 10 days post-birth - Diagnosing many conditions such as sickle cell, CF, PKU