Session 8: Haemoglobinopathies NEW

Normal hemoglobin structure

2 alpha-like globin chains

2 beta-like globin chains

4 heme molecules

Each heme molecule ___ binds to ONE oxygen molecule

reversibly

Erythrocyte shape and the benefit of the structure/shape

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

Function of RBC

Transport oxygen from the lungs to tissues

Lifespan of RBC

~120 days

Anemia

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

Classification of anemia

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

The two NORMAL adult hemoglobin variants

HbA = a2b2 = 97%

HbA2 = a2δ2 = 2%

The one NORMAL fetal hemoglobin variant

HbF = a2γ2 = <1%

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

Thalassemia

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

Sickle cell anemia

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

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

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

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

Alpha Thalassaemia inheritance pattern

Autosomal recessive

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

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

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

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

Types of Alpha Thalassaemia

a,a/a,-

1 gene missing

- 'Silent' asymptomatic

- Low MCV

- Raised red cell count

Types of Alpha Thalassaemia

a,-/a,-

2 genes missing

- Trait

- Asymptomatic

- Low MCV

- Raised red cell count

Types of Alpha Thalassaemia

a,a/-,-

2 genes missing

- Trait (far east)

- Asymptomatic

- Low MCV

- Raised red cell count

Types of Alpha Thalassaemia

a,-/-,-

3 genes missing

- Hemoglobin H disease (HbH disease)

- Anaemia

- Splenomegaly

- Not transfusion-dependent

Types of Alpha Thalassaemia

-,-/-,-

All 4 genes missing

- Hydrops fetalis

- Incompatible with life

Types of Beta Thalassaemia

β/β+ or β/β0 Beta thal minor

- Asymptomatic

- Low MCV

- Mild anemia

Types of Beta Thalassaemia

β+/β0 (mild variants) or β+/β+

- Splenomegaly

- Anaemia

- Non-transfusion dependent

- Bony deformity

- Gallstones

- Iron overload

Types of Beta Thalassaemia

β+/β0 (severe variants) or β0/β0

- Asymptomatic at birth

- Splenomegaly

- Severe anaemia

- Developmental delay

- Growth retardation

- Extramedullary erythropoiesis

- Marrow expansion (skull/long bones)

- Transfusion-dependent

- Iron overload

Signs and symptoms of thalassemia

Pallor

Weakness

Fatigue

Jaundice

Facial bone deformities

Abdominal swelling (splenomegaly)

Dark urine

Slow growth

Palpitations

Shortness of breath (dyspnea)

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.

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.

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

Heart

Liver

Management of thalassaemia

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

Hb >100g/L

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 ___.

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.

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

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

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

Surface area

What are the five types of sickle cell crises?

1) Vaso-occlusive crises

2) Acute chest syndrome

3) Bone marrow aplasia

4) Splenic sequestration

5) Hemolysis

Vaso-occlusive crises in SCD

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

Acute chest syndrome crises in SCD

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

Bone marrow aplasia crises in SCD

Temporary cessation of erythropoiesis causing severe anaemia

Hemolysis crises in SCD

Excessive hemolysis - uncommon

Sickle Cell Anemia presentation

Chronic pain (25%)

Early multiple strokes

Osteonecrosis

Ulcers

Pulmonary hypertension

Sepsis (autosplenectomy)

Proliferative retinopathy

Priapism

Dactylitis

Management of Sickle Cell Anaemia during ACUTE CRISIS

Pain relief (analgesia)

IV fluids

Oxygen

Antibiotics for infections

Exchange transfusion

Management of Sickle Cell Anaemia LONG-TERM

Penicillin V prophylaxis

Vaccination

Folic acid

Hydroxycarbamide

Preventative transfusions

Stem cell transplantation

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

Hydroxycarbamide

Sickle cell trait

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

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

Malaria

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

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

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

- Deferoxamine

- Deferiprone

- Deferasirox

Caution of prescribing iron chelating drugs to patient with iron overload

1) Require long-term compliance to be effective

2) Have their own toxicities/risks

Pre-natal screening program in the UK for haemoglobinopathies

Family Origin Questionnaire (FOQ)

Screens women at risk and offers pre-natal diagnosis of the fetus

Screening for haemoglobinopathies in newborns

Newborn blood spot test

- 10 days post-birth

- Diagnosing many conditions such as sickle cell, CF, PKU