Sickle Cell Disease

Question 1

What causes sickle cell disease?

Answer 1

#A single amino acid difference in the beta-chain of haemoglobin distinguishes HbA from HbS.
beta- S is a point mutation (missense)at codon-6 of the gene for b-globin

Glutamic acid (polar and soluble) is replaced by Valine (non-polar and insoluble)

As b-S is therefore insoluble (HbS), HbS polymerises to form fibres called “tactoids” with inter-tetrameric contacts stabilising the structure

Question 2

What are the stages of sickling of RBCs?

Answer 2

Distortion – polymerisation initially reversible with formation of oxyHbS but is subsequently irreversible

Dehydration

Increased adherence to vascular endothelium

Question 3

What is sickle cell disease?

Answer 3

sickle cell anaemia and all the other conditions that lead to a disease syndrome due to sickling of RBCs.

Question 4

What are the effects of shortened red cell life span?

Answer 4

leads to haemolysis

Anaemia – partly due to reduced erythropoietin drive as HbS is a low affinity Hb.

Gallstones – co-inheritance of Gilbert syndrome further increases risk.

Aplastic crisis – Parvovirus B19

Question 5

What is the consequence of tissue infarction?

Answer 5

Spleen – hyposplenism (leads to infection)

Bones/joints – dactylitis (inflammation of bone), avascular necrosis and osteomyelitis (infection of bone)

Skin – ulcerations

*Pain and dysfunction

Question 6

What are the complications of sickle cell disese in differnt organs?

Answer 6

Lungs:
- Acute: Acute chest syndrome
- Chronic: Pulmonary hypertension
> Correlates with severity of haemolysis
> Free plasma haemoglobin from haemolysis scavenges NO and causes vasoconstriction

Urinary tract:

• Haematuria – due to papillary necrosis
• Renal failure and Hyposthenuria – impaired concentration of urine
• Priapism

Brain:
- Stroke and cognitive impairment – affects 8% of SS, most common 2-9yrs

Eyes:
- Proliferative retinopathy

Question 7

How does sickle cell disease present?

Answer 7

Symptoms are rare before 3-6 months (as the switch to adult HbA synthesis hasn’t occurred yet)

Early manifestations are:

• Dactylitis – most common in children
• Splenic sequestration.
• Infection (pneumococcal normally)

Painful crises can also be triggered by – infection, exertion, dehydration, hypoxia and psychological stress

Mortality:

• Females – 48 years
• Males – 42 years
• 21% from painful crises and 14 % from chest syndromes

Question 8

How is sickle cell disease managed?

Answer 8

Generally:
- Folic acid – anaemia
- Penicillin – splenic dysfunction
- Vaccination – splenic dysfunction
- Monitor spleen size – splenic dysfunction
> Acute splenic sequestration can mean you get an enlarged spleen and often requires prophylactic therapy (against pneumococcal infection), transfusions to correct anaemia and maybe splenectomy
- Blood transfusion for acute anaemic events, chest syndrome and stroke
- Pregnancy care

Painful crisis – must exclude infection as cause with blood/urine cultures and chest x-ray

• Pain relief – opioids
• Hydration
• Keep warm
• Oxygen if hypoxic

Exchange transfusion:

• Stroke
• Acute chest syndrome

Haematopoietic stem cell transplantation – from sibling HLA or other haplo-identical donors:

• <16 years with SCD
• Survival rate is 90-95% with a cure in 85-90% of cases

Induction of HbF:
- Hydroxyurea/Hydroxycarbimide – a chemotherapy agent that can reduce the occurrence of SCD symptoms
> Induces expression of HbF – up to 20% more HbF
- Butyrate

Question 9

What happens in a sickle cell emergency?

Answer 9

septic shock (BP<90/60)

neurological signs and symptoms

SpO2 <92% on air

symptoms/signs of anaemia with Hb<5 or fall >3g/dl from baseline

priapism >4 hours

Question 10

What are the laboratory features of sickle cell disease?

Answer 10

Hb is low – 6-8g/dL

Reticulocytes (immature RBCs) high – except in aplastic crisis

Film (shown on left bottom):

• Sickled cells
• Boat cells
• Target cells
• Howell-Jolly bodies

Question 11

How does the solubility test he with diagnosis?

Answer 11

In presence of reducing agent, oxyHb is converted to deoxyHb

Solubility decreases and solution becomes turbid

• Doesn’t differentiate AS from SS though – so only checks to see if you have one or more sickle traits

Question 12

What can give a definitive diagnosis?

Answer 12

Electrophoresis (HPLC):

• Separates proteins according to charge.
• You can see homozygous sickle patients have NO HbA and only HbS and a little HbA2.
• Heterozygous sickle patients have both HbS and HbA