Sickle Cell Disease

Question 1

What is the sickle gene

Answer 1

missense mutation at codon 6 of the gene for beta globin chains (glutamic acid -> valine)

Question 2

How does the sickle gene affect the overall cell

Answer 2

Glutamine (polar and soluble) ->
Valine (non polar insoluble)
HbS polymerises to form tactoid fibres
deoxyHbS Is insoluble
Distortion of cells

Question 3

Describe the structure of sickle cells

Answer 3

Rigid
Adherent
Dehydrated

Question 4

What are the stages in the sickling of red cells

Answer 4

Distortion (polymerisation is initially reversible with formation of oxyHbS, then irreversible)
Dehydration
Increased adherence to the vascular endothelium

Question 5

Distinguish between sickle cell anaemia, sickle cell disease, and sickle cells trait

Answer 5

Sickle Cell Anaemia = homozygous state (SS)

Sickle Cell Disease = anything that causes disease due to sickling (generic)

trait = HbAS (almost normal)

Question 6

Describe the sickle cell trait

Answer 6

Normal life expectancy and blood count
Usually Asymptomatic

Under conditions of hypoxia they may have some complications due to sickling cells e.g. anaesthesia, high altitude, extreme exertion

Question 7

Summarise the pathogenesis of sickle cell disorders

Answer 7

Shortened lifespan (20 days) -> haemolysis

Question 8

What are the consequences of sickle cell disease

Answer 8

Anaemia
Gallstones
Aplastic crisis

Question 9

Explain how sickle cell disease causes anaemia

Answer 9

Removal of short-lifespan RBCs

Reduced erythropoietic drive as haemoglobin S has a low affinity for oxygen so it delivers oxygen
more effectively to tissues
So hypoxia doesn’t stimulate the erythropoietin release from the kidneys as much.

Question 10

Explain how sickle cell disease causes gallstones

Answer 10

Increased haemolysis means an increase in the release of bilirubin and other red cell breakdown products
Excretion through the gallbladder

Question 11

Explain how sickle cell disease causes an aplastic crisis

Answer 11

Parvovirus B19 - infects developing red cells in marrow to arrest development

Parvovirus switches off RBC production until the virus clears, and won’t have an effect in healthy people (120days)
Due to the 20 day life span of sickled cells, a parvovirus infection can lead to a steep drop in haemoglobin (ANAEMIA)

Question 12

What are the consequences of microvascular blockage

Answer 12

tissue damage and necrosis (infarction)
Pain
Dysfunction

Question 13

What are the consequences of tissue infarction

Answer 13

Spleen - hyposplenism

Bones/joints - dactylitis, avascular necrosis, osteomyelitis

Skin - chronic/recurrent leg ulcers

Question 14

How is pulmonary hypertension associated with haemolysis

Answer 14

Correlates with severity of haemolysis
Free plasma Hb resulting from intravascular haemolysis scavenges NO and causes vasoconstriction
Associated with increased mortality

Question 15

Describe the early presentation of sickle cell disorders

Answer 15

Symptoms rare before 3-6 months
onset coincides with the switch from HbF to HbA

Dactylitis (digit inflammation)
Splenic sequestration
Infection - S. pneumoniae

Question 16

Why does splenic sequestration occur in SCD

Answer 16

Spleen holds onto RBC, gets bigger and damaged and doesn’t protect from infection

Could be aplastic crisis.
Look for reticulocytes, if none found = aplastic crisis

Question 17

How is SCD diagnosed

Answer 17

Films and GBC

Solubility test and electrophoresis

Question 18

What are the hematological features of SCD

Answer 18

Low Hb 6-8g/dL
Reticulocytes
Sickled cells
Boat cells
Target cells
Howell Jolly Bodies

Question 19

Describe the solubility test and explain why it should be used with other diagnostic methods

Answer 19

1. In the presence of a reducing agent, oxyHb -> deoxyHb
2. Solubility decreases
3. Solution becomes turbid

Does not differentiate sickle cell trait from sickle cell disease

Question 20

Describe electrophoresis

Answer 20

Separates proteins according to charge
Glutamate is positively charged and valine is not charge
Therefore, the normal A chains will travel further towards the negative pole
Sickle cell trait - two bars and somebody
Sickle cell disease - one bar lower down

Question 21

What is the clinical presentation of sickle cell disease

Answer 21

Dactylitis
Splenic sequestration
Pneumococcal infection
Painful crisis

Question 22

What is the most common clinical manifestation of sickle cell disease

Answer 22

Vaso-occlusive crisis
Occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain
Pain crises constitute the most distinguishing clinical feature of SCD

Question 23

What may a painful crisis in sickle cell disease be triggered by

Answer 23

Infection
Exertion
Dehydration
Hypoxia
Psychological stress

Question 24

How is SCD managed generally

Answer 24

Folic acid
Penicillin
Vaccination
Hydroxycabimade (hydroxyurea)
Monitor spleen size
Blood transfusion
Pregnancy care
Haemapoietic stem cell transplant

Question 25

What is the treatment for a SCD painful crisis

Answer 25

Opioids
Hydration
Keep Warm
Oxygen

Question 26

What is the significance of HbF in SCD

Answer 26

HbF inhibits polymerisation of HbS
Infants with SCD do not usually develop symptoms until > 3 months
Patients with higher HbF levels have fewer complications and improved survival

Question 27

Why may hydroxycabimade be used for SCD management

Answer 27

increases HbF to prevent painful crises, acute chest syndrome and need for transfusions
(CI when planning a family/pregnant)

Question 28

What are the indications to have a haematopoietic stem cell transplant (HSCT) for SCD

Answer 28

CNS disease
Recurrent severe vaso-occlusive crisis*
Recurrent ACS*

*if hydroxyurea fails