Sickle-Cell Anaemia

Question 0

What is the consequence of the mutation in the beta-globin gene?

Answer 0

Sticky hydrophobic pocket created by valine substitutions

Hb polymerises when in the T form (aggregation —> sickled cells)

Question 1

What is the genetic mutation leading to sickle-cell anaemia?

Answer 1

Single Base Substitution: A —> T

Glutamate (charged, hydrophilic) —> Valine (uncharged, hydrophobic)

Mutation in beta-globin gene

Question 2

How does the HbS O2 saturation curve differ to normal Hb?

Answer 2

Shift to the right (lower O2 affinity)

Therefore lower saturation of Hb

More O2 released at same pO2

Question 3

What is the inheritance pattern of sickle-cell?

Answer 3

Autosomal recessive

Carrier = sickle-cell trait

Question 4

Why is sickle-cell anaemia so common, despite being a recessive mutation?

Answer 4

Carrier status confers protection against malaria

Therefore selective advantage for allele in malaria-ridden areas e.g. Africa

Question 5

In what parts of the body will you find sickled cells?

Answer 5

Low pO2 e.g. tissue blood flow (T form predominates)

Question 6

Why does anaemia result from sickle-cell disease?

Answer 6

Premature lysis of deformed/weakened sickled cells by spleen —> decrease in Hb

(haemolytic anaemia)

Question 7

What is the lifespan of the sickled RBCs compared to normal RBCs?

Answer 7

Normal = 120 days

Sickled = 10-20 days

Question 8

How can the body adapt to chronic anaemia?

Answer 8

• increase in tissue blood flow

- lower O2 binding affinity of HbS means that tissues are still well-supplied with O2

Question 9

Why does sickle-cell disease cause jaundice?

Answer 9

Haemolytic anaemia —> haem broken down —> increased bilirubin

Bilirubin > renal threshold —> spills into bloodstream

Question 10

Why does sickle-cell disease cause gallstone formation?

Answer 10

Increased bilirubin produced —> increased bilirubin in bile —> pigment gallstones —> biliary colic (pain due to obstruction of bile duct)

Question 11

What are the complications of frequent occlusion of blood vessels?

Answer 11

Decreased blood flow to skin —> leg ulcers (open sore caused by break in skin/mucous membrane)

Bleeding in retinal veins/retinal detachment —> blindness

Question 12

What are some other chronic effects of sickle-cell disease apart from gallstones and frequent occlusion-related conditions?

Answer 12

Priapism (persistent erection —> impotence)

Splenic crisis

Acute chest syndrome

Question 13

Where is the spleen located anatomically? What are its functions?

Answer 13

Superolateral left upper quadrant

• lymphocyte proliferation
• immune surveillance & response
• lysis of old RBCs (recycling of haem)

Question 14

What is an acute sickle-cell crisis?

Answer 14

Increased T form of RBCs —> more sickling in tissue capillaries —> occlusion —> infarction (ischaemia due to inadequate oxygen & nutrient supply -> PAIN) —> necrosis (tissue death) —> scar tissue formation

note: restore blood flow quickly to attempt to reverse

Question 15

What are some common areas of occlusion during an acute sickle cell crisis? What can this lead to?

Answer 15

• bone
• pleura
• brain —> STROKE
• kidney —> KIDNEY FAILURE
• spleen —> SPLENIC CRISIS

Question 16

What is a splenic crisis?

Answer 16

(spleen sequesteration)

ACUTE:
Sickled cells pool in spleen —> vaso-occlusion of blood vessels in spleen (blood not circulating in spleen)
Splenomegaly to try and compensate

Sudden, severe anaemia and drop in heart rate

CHRONIC:
Damaged spleen —> fibrosis
Auto-splenectomy (body removes non-functional spleen) —> decreased lymphocyte production —> increased risk of infection

Question 17

What is acute chest syndrome?

Answer 17

Sickling in lung capillaries —> fever, pain, violent wheezing cough —> pulmonary hypertension —> heart failure

Question 18

What are some of the factors which can precipitate an acute sickle-cell crisis?

Answer 18

• hypoxia (low pO2 —> more T form RBCs —> more sickled cells which block vessels)
• dehydration (increased polymerisation of T form)
• infection (stresses body reserves; can cause hypoxia and dehydration)
• low environmental temp. (vasoconstriction - occlusion - increased O2 binding affinity)
• low pH —> increased [H+] —> increased T form

Question 19

What is the prevention (conservative) management of sickle-cell disease?

Answer 19

Avoid factors precipitating a crisis

Prophylactic antibiotics & vaccinations (especially with spleen dysfunction & removal)

Frequent eye exams (screen for retinopathy)

Folic acid (prevent severe anaemia)

Direct line to hospital

Question 20

What is the therapeutic (medical) treatment for sickle-cell disease?

Answer 20

Blood transfusion for anaemia (to reduce risk of stroke by increasing [HbA]:[HbS]) —> chelation therapy if this leads to iron overload

Crisis treatment:

• analgesia (opioids, anti-inflammatories, vasodilators e.g. NO)
• oxygenate & hydrate (to increase R:T)
• antibiotics if cause is infection
• blood transfusion

Question 21

What is the surgical treatment for sickle-cell disease?

Answer 21

Splenectomy for splenic crisis

Chemotherapy (destroy bone marrow and replace with stem cell transplant for normal RBC production) (children only)