Sickle cell anaemia

Question 1

What ethnicities are most affected by sickle cell anaemia?

Answer 1

10% of Caribbeans carry the sickle gene

25% of Africans carry

Question 2

What does sickle cell match the distribution of?

Answer 2

Malaria

Question 3

What is the beta s?

Answer 3

Point mutation at codon 6 of the gene for beta globin

Question 4

What is sickle haemoglobin like compared to normal haemoglobin?

Answer 4

Sickle haemoglobin has two normal alpha chains and two variant beta chains

Question 5

What is the difference in the beta chains compared to normal?

Answer 5

Glutamic acid is replaced by valine at position 6

Question 6

What are the differences in character between glutamic acid and valine?

Answer 6

Glutamic acid- Polar and soluble

Valine- Non polar and insoluble

Question 7

What effect do the characteristics of valine have on the haemoglobin?

Answer 7

The deoxyhaemoglobin is insoluble

HbS polymerises to form fibres called tactoids

Question 8

What are the three stages in sickling of red cells?

Answer 8

Distortion- polymerisation
Dehydration
Increased adherence to vascular endothelium
(Also changes in red cell membrane)

Question 9

What are the three typical characteristics of sickle cells?

Answer 9

Rigid
Adherent
Dehydrated

Question 10

What accounts for the increased transit time of red blood cells which leads to the increased sickling?

Answer 10

The cells are more adherent so stick to vessel wall and increases transit time hence allows more time for the polymerisation to occur

Question 11

What is the definition of sickle cell disease?

Answer 11

Generic term that encompasses sickle anaemia and all other conditions that can lead to a disease syndrome due to sickling

Question 12

What is the most common and severe sickle cell disorder?

Answer 12

Sickle cell anaemia - homozygous SS

Question 13

What happens when a red cell distorts?

Answer 13

It is removed from the body

Question 14

What is the lifespan of a sickle cell?

Answer 14

20 days

Question 15

The decreased lifespan leads to increased haemolysis, what are the effects of this?

Answer 15

Anaemia- partly due to a reduced erythropoietic drive as haemoglobin S has a low affinity for oxygen so is more effective
Gallstones- increased bilirubin
Aplastic crisis (parvovirus B19)
Blockage of microvascular circulation
Tissue damage and necrosis
Pain
Dysfunction

Question 16

What is parvovirus B19?

Answer 16

Common respiratory virus

Question 17

Why does parvovirus B19 cause an aplastic crisis in sickle cell anaemia?

Answer 17

It infects the developing red cells in the bone marrow and block production, it isn’t a problem normally because erythrocytes last 120 days so it’ll just switch it off for a few days whilst the infection lasts but sickle cells have a shorter lifespan so it can cause severe anaemia

Question 18

How do you treat gallstones?

Answer 18

Cholecystectomy

Question 19

What is a genetic modifier that increases the incidence of gallstones in people with hereditary haemolytic anaemia?

Answer 19

Coinheritance of Gilbert’s syndrome- reduced activity of UGT (uridine glucuronyl transferase)

Question 20

What are the majority of individuals with Gilbert’s homozygous for?

Answer 20

Variant in the promoter of the gene within the TATA block- normally has six TA repeats but in Gilbert’s, homozygous for variant allele that has an extra TA dinucleotide on each chromosome

Question 21

What is the effect of this different TATA block?

Answer 21

Increased risk of having gallstones 3-5 fold

Question 22

What is one of the first organs to be affected by tissue infarction?

Answer 22

Spleen

Question 23

What does damage to/loss of splenic function predispose individuals to?

Answer 23

Life-threatening infection from capsulated bacteria (mainly pneumococcal)

Question 24

What is the most common site of tissue infarction in terms of clinical presentation?

Answer 24

Bones and joints

Question 25

How do the bones and jones characteristically present?

Answer 25

Dactylitis- inflammation of a finger or toe caused by bone infection- painful

Question 26

In terms of bones and joints, what can chronic ischaemic damage lead to over time?

Answer 26

Avascular necrosis | Osteomyelitis

Question 27

What is avascular necrosis?

Answer 27

Death of bone tissue due to lack of blood supply

Question 28

What is osteomyelitis?

Answer 28

Inflammation of bone due to infection

Question 29

Where else is a common site that is affected by tissue infarction?

Answer 29

Skin- causing chronic ulcers

Question 30

What is the commonest cause of death in adults with sickle cell disease?

Answer 30

Acute chest syndrome

Question 31

What is acute chest syndrome?

Answer 31

Vaso-occlusive crisis of the pulmonary vasculature

Question 32

What are the long term effects of tissue infarction on lungs?

Answer 32

Pulmonary hypertension | Chronic sickle cell lung disease

Question 33

What effect does tissue infarction have on urinary tract?

Answer 33

Haematuria Impaired concentration of urine Renal failure Priapism

Question 34

What is priapism?

Answer 34

Persistent and usually painful erection of penis that requires urgent decompression

Question 35

What effect does tissue infarction have on the brain?

Answer 35

Stroke | Cognitive impairment

Question 36

What effect does tissue infarction have on the eyes?

Answer 36

Proliferative retinopathy

Question 37

What correlates with how severe pulmonary hypertension is?

Answer 37

Severity of haemolysis

Question 38

How is pulmonary hypertension caused by tissue infarction?

Answer 38

Free plasma haemoglobin from intravascular haemolysis scavenges nitric oxide and depletes it, this takes away the vasodilatory effect hence causing vasoconstriction of certain vascular beds

Question 39

What percentage of patients with sickle cell disease are affected by strokes?

Answer 39

8%

Question 40

When does sickle cell disease present?

Answer 40

Symptoms are rare before 3-6 months when you get a switch to adult haemoglobin

Question 41

What are the early manifestations of sickle cell disease?

Answer 41

Dactylitis Splenic sequestration- pooling of blood in spleen Infection (pneumococcal)

Question 42

What triggers painful crises in sickle cell disease?

Answer 42

``` Infection Exertion Dehydration Hypoxia Psychological stress ```

Question 43

What are the median survival ages for females and males with SCD?

Answer 43

Female- 48 | Male- 42

Question 44

What is the general management of SCD?

Answer 44

Folic acid supplementation- high RBC production Penicillin- reduce risk of pneumococcal infection Vaccination- protect due to hyposplenism Monitor spleen size- sequestration can cause death Blood transfusion for acute anaemic events, acute chest syndrome and stroke Pregnancy care Painful crisis management- pain relief, hydration, keep warm, oxygen if hypoxic Exchange transfusions Haematopoietic stem cell transplantation- good in young Induction to HbF- hydroxyurea

Question 45

What are the laboratory features of sickle cell disease?

Answer 45

``` Hb low (6-8g/dL) Reticulocytes high (except aplastic crisis) Blood film: Sickle cells Boat cells Target cells Howell-Jolly bodies ```

Question 46

How can you diagnose sickle cell disease?

Answer 46

Solubility test | Electrophoresis/high performance liquid chromatography

Question 47

What is the solubility test?

Answer 47

In presence of reducing agent, oxyhemoglobin can be converted to deoxyhaemoglobin and solubility decreases In presence of deoxyhaemoglobin S the solution becomes turbid instead

Question 48

What does the solubility test not differentiate between?

Answer 48

AS and SS

Question 49

What is someone with sickle cell trait like?

Answer 49

Normal life expectancy Normal blood count Usually symptomatic Rarely painless haematuria