Sickle Cell Disease

Question 1

What mutation causes sick cell anaemia SCA

Answer 1

• Missense mutation at codon 6 of the gene for  globin chain
• Glutamic acid is replaced by valine

Question 2

What does mutation of SCA cause Hb to become and what does this form

Answer 2

• Deoxyhaemoglobin S is insoluble

- HbS polymerises to form fibres TACTOIDS

Question 3

Polarity / solubility of valine?

Answer 3

Non polar, insoluble

Question 4

Polarity / solubility of glutamic acid

Answer 4

Polar, soluble

Question 5

3 stages in sickling of RBC?

Answer 5

1. DISTORTION
2. DEHYDRATION
3. INCREASED ADHERENCE TO VASCULAR ENDOTHELIUM

Question 6

Pathogenesis of SCD? (3)

Answer 6

• Shortened red cell lifespan (as little as 5-7 days)
• Anaemia partly due to a reduced erythropoietic drive as HbS is a low affinity Hb
• Blockage to microvascular circulation (vaso-occlusion):

Question 7

What does haemolysis of SCs lead to (3)

Answer 7

Anaemia
Gallstones
Aplastic Crisis caused by Parvovirus B19

Question 8

What does blockage to the microvascular circulation by SCs cause (3)

Answer 8

Tissue damage and necrosis (infarction)
Pain
Dysfunction

Question 9

CONSEQUENCES OF TISSUE INFARCTION in the spleen

Answer 9

Hyposplenism

Question 10

CONSEQUENCES OF TISSUE INFARCTION in the bones/joints

Answer 10

Dactylitis, avascular necrosis, osteomyelitis (often due to salmonella

Question 11

CONSEQUENCES OF TISSUE INFARCTION in the skin

Answer 11

Chronic/recurrent leg ulcers

Question 12

Which haemoglobin polymerises to form fibre like structures that disports the shape of the RBC

Answer 12

HbS

Question 13

Cell-free haemoglobin limits XX bioavailability, disturbing Y

Answer 13

nitric oxide

vasoregulation

Question 14

Pathogenesis of SCD in the lungs

Answer 14

acute chest syndrome
Chronic damage
Pulmonary hypertension

Question 15

Pathogenesis of SCD in the urinary tract

Answer 15

Haematuria (papillary necrosis)
Impaired concentration of urine (hyposthenuria)
Renal failure
Priapism

Question 16

What is hyposthenuria

Answer 16

Impaired concentration of urine

Question 17

What is Impaired concentration of urine known as

Answer 17

hyposthenuria

Question 18

Pathogenesis of SCD in the brain

Answer 18

Stroke

Cognitive impairment

Question 19

Pathogenesis of SCD in the eyes

Answer 19

Proliferative retinopathy

Question 20

What does presentation of SCD symptoms coincide with

Answer 20

• Onset coincides with switch from foetal to adult haemoglobin synthesis

Question 21

Early manifestation of SCD? (3)

Answer 21

Dactylitis – middle finger is shorter
Splenic sequestration – acute enlargement of the spleen
Infection S. pneumoniae

Question 22

What does an SCD emergencies originate from?

Answer 22

• SEPTIC SHOCK (BP<90/60)

Question 23

Most common cause of death in adults with SCD is….

Answer 23

ACUTE CHEST SYNDROME

Question 24

Where does avascular necrosis occur in SCD commonly

Answer 24

THE FEMORAL HEAD

Question 25

Stroke in SCD involves ?major/minor? vessels

Answer 25

Major

Question 26

What are gallstones a consequence of in SCD

Answer 26

Haemolysis

Question 27

LABORATORY FEATURES OF SCD (blood film (4), Hb level)

Answer 27

- Hb low (anaemia) (typically 60-80g/L) - Reticulocytes high to try compensate for the low Hb (except in aplastic crisis)  Blood film Sickled cells, boat cells, holly leaf cells, Howell Jolly bodies

Question 28

DIAGNOSIS OF SCD 2 ways?

Answer 28

SOLUBILITY TEST and | ELECTROPHORESIS or HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC

Question 29

Problem with solubility test for diagnosis of SCD?

Answer 29

Doesn’t differentiate homozygous from heterozygous SCD

Question 30

General methods of management of SCD? (6)

Answer 30

- Folic acid supplements Adequate folate for blood cell production - Penicillin prophylaxis  Against pneumococcal infection - Vaccinations - Monitor spleen size - Blood transfusion for acute anaemic events, chest syndrome and stroke - Pregnancy care

Question 31

PAIN CRISIS management of SCD? (5+2)

Answer 31

- Pain relief (opioids) - Hydration - Keep warm - Oxygen if hypoxic - Exclude infection:  Blood and urine cultures  Chest X-Ray

Question 32

What is used in pain management of SCD? And what's given as an adjuvent?

Answer 32

``` Opioids - diamorphine Adjuvants: - Paracetamol - NSAIDs - Pregabalin/gabapentin ```

Question 33

Who is HAEMOPOIETIC STEM CELL TRANSPLANTATION used on

Answer 33

- Usually used on <16yr old with severe disease

Question 34

Cure for SCD?

Answer 34

Haemoietic stem cell transplant

Question 35

What can be used to treat SCD?

Answer 35

INDUCTION TO HbF (drugs that make you switch to making HbF) and EXCHANGE TRANSFUSION

Question 36

Drugs that induce change to HbF?

Answer 36

- Hydroxyurea | - Butyrate

Question 37

What do these drugs do? - Hydroxyurea - Butyrate

Answer 37

induce change to HbF

Question 38

What 3 disease modifying therapies for SCD are there

Answer 38

1. Transfusion 2. Hydroxycarbamide (hydroxyurea) 3. Haemopoietic stem cell transplantation

Question 39

How does hydroxyurea work

Answer 39

- Increases foetal haemoglobin production (HbF) - Decreases ‘stickiness’ of sickle RBCs - Reduces white cell production by bone marrow - Improves hydration of RBCs - Generates NO which improves blood flow

Question 40

Explain why infants with SCD don’t usually develop symptoms until >3months

Answer 40

- HbF inhibits polymerisation of HbS

Question 41

Indications for bone marrow transplantation in SCD? (3)

Answer 41

- CNS disease - Recurrent severe vaso-occlusive crises IF HYDROYUREA FAILS - Recurrent acute coronary syndromes (ACS) IF HYDROYUREA FAILS

Question 42

Limitations of HSCT in SCD?

Answer 42

Donor availability 1-2% of children with SCD qualify 6 months of treatment Infertility and other long term problems