Haem 5 - Sickle cell disease

Question 1

Describe the mutation of genes to produce the sickle gene?

Answer 1

Missense mutation (single nucleotide change) at codon 6 for the beta globin chain
Glutamic acid replaced by Valine
Glu Valine
Polar Non polar
Soluble Insoluble
Deoxyhaemoglobin S is insoluble
HbS polymerises to form fibres - “tactoids”

Question 2

What does the polymerisation of HbS cause?

Answer 2

Polymerising to form tactoids - these distort the shape of the RBC. Sickle cell shape means they are unable to traverse the microvascular circulation because they become trapped.

Question 3

What are the stages of sickling in RBCs?

Answer 3

Stages in sickling of red cells
Distortion
     - Polymerisation initially 
     reversible with formation 
     of oxyHbS
      - Subsequently irreversible
Dehydration
Increased adherence to 
       vascular endothelium

RIGID ADHERENT DEHYDRATED

Question 4

Describe the population genetics of the sickle gene?

Answer 4

Distribution matches that of endemic plasmodium falciparum malaria

Question 5

Define sickle cell disease?

Answer 5

Incorporates sickle cell anaemia and all other conditions that can lead to a disease syndrome due to sickling.

Although sickle cell anaemia (SS) and compound heterozygous states e.g SC, Sbeta thalassaemia are genetically simple (autosomal recessive), they are clinically heterozygous.

Lots of different clinical presentations - Clinical course is variable and unpredictable even within the same family

Question 6

Describe pathogenesis 1 of SC disease

Answer 6

Shortened red cell lifespan- haemolysis. Usually 120 days but can be as short as 5-7 days due to sickle cell

• Anaemia - due to haemolysis
• Gall Stones
• Aplastic Crisis (Parvovirus B19) - infect developing erythrocytes in the bone marrow and arrests their differential maturation. This can be life threatening for those with sickle cell anaemia.

Anaemia is also partly due to a reduced erythropoietic drive as haemoglobin S is a low affinity haemoglobin. HbS gives up oxygen more readily in tissues therefore there is less erythropoietic drive.

Question 7

Describe pathogenesis 2 of SC disease

Answer 7

Blockage to microvascular circulation (vaso-occlusion)

Tissue damage and necrosis (Infarction)
Pain (acute pain - in bones)
Dysfunction (organ dysfunction)

Question 8

What are the consequences of tissue infarction?

Answer 8

Spleen		
    - hyposplenism
Bones/Joints 
    - dactylitis (pain crisis)
    - avascular necrosis (chronic damage - hip and shoulder joints)
    - osteomyelitis (could be due to salmonella)
Skin		
    - chronic/recurrent leg ulcers

Question 9

Summarise the pathogenesis of vaso-occlusion in sickle cell disease

Answer 9

HbS polymerises forming complex structures that distort the shape of the RBC
The shapes become sickle shaped
These become entrapped in the microvascular circulation particular the post capillary venules.

Question 10

In terms of haemolysis and NO describe what happens?

Answer 10

Intravascular haemolysis releases Hb into the plasma and enables it to bind to NO produced in the endothelium. Cell-free haemoglobin limits NO bioavailability in sickle cell disease = SC vasculopathy

Pulmonary hypertension - The likely mechanism is that the free plasma haemoglobin resulting from intravascular haemolysis scavenges NO and causes vasoconstriction
Associated with increased mortality

Question 11

What other problems can arise form sickle cell disease?

Answer 11

Lungs:
Acute chest syndrome
Chronic damage
Pulmonary hypertension

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

Brain:
Stroke
Cognitive impairment

Eyes:
Proliferative retinopathy

Question 12

What are the early presentations of sickle cell disorders?

Answer 12

Symptoms rare before 3-6 months
Onset coincides with switch from fetal(alpha and gamma Hb) to adult (alpha and beta) Hb synthesis

Early manifestations
Dactylitis
Splenic sequestration - acute enlargement of the spleen due to sickle RBC being trapped in the spleen; can be characterised by a shortened digit (consequence of infarction of growing bone during childhood). Symptoms include anaemia and hypervolaemia
Infection-S. pneumoniae (common cause of mortality)

Question 13

Describe the signs of sickle emergencies

Answer 13

Septic shock (BP <90/60) - sepsis
Neurological signs or symptoms
SpO2 <92% on air - signs of acute chest syndrome
Symptoms/signs of anaemia with Hb <50 or fall >30g/l from baseline - managed with transfusions
Priapism >4 hours

Question 14

Define Acute chest syndrome

Answer 14

Defined as new pulmonary infiltrate on chest X-ray often with:

• Fever
• Cough
• Chest pain
• Tachypnoea

Mechanical ventilation often required

Commonly develops in context of a vaso-occlusive crisis, post-operatively and during pregnancy.

Question 15

Describe the incidence of acute chest syndrome with different types of sickle cell disease?

Answer 15

SS>SC>Sbeta+ Thal

Question 16

What are the laboratory features of sickle cell disease?

Answer 16

Hb low (typically 60-80 g/l)
Reticulocytes high (except in aplastic crisis - bone marrow is shut down). The bone marrow is producing a lot of reticulocytes to make up for the low Hb

Film

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

Question 17

What test is used to diagnose sickle cell disease?

Answer 17

Solubility test:
In presence of a reducing agent oxyHb converted to deoxy Hb
Solubility decreases
Solution becomes turbid (in the presence of HbS)

Does not differentiate AS from SS

Definitive diagnosis - Electrophoresis or high performance liquid Chromatography (HPLC) separates proteins according to charge

Question 18

Describe the management 1 of sickle cell disease (general measures)

Answer 18

Folic acid - for the production of new RBCs
Penicillin prophylaxis
Vaccination
Monitor spleen size (detect splenic squestration)
Blood transfusion for acute anaemic events, chest syndrome and stroke
Pregnancy care

Question 19

Describe the management 2 of sickle cell disease (managing painful crisis)

Answer 19

Pain relief (opioids)
Hydration
Keep warm
Oxygen if hypoxic
Exclude infection: 
Blood and urine cultures
CXR

Question 20

What are the pain crisis triggered by?

Answer 20

Infection
Exertion
Dehydration
Hypoxia
Psychological stress

Question 21

Describe the different methods of pain management?

Answer 21

Opioids
- Marked individual variation in response
- Diamorphine most widely used
- Most children receive oral opioid
Individual analgesia protocols
Patient controlled analgesia
Adjuvants – paracetamol, NSAIDs, Pregabalin/Gabapentin

Question 22

Describe the management 3 of sickle cell disease

Answer 22

Exchange transfusion: The aim is to remove some of the patients blood volume and replace it with donors containing HbA to bring the HbS percentage down below 30%.

• Stroke
• Acute chest syndrome

Haemopoietic stem cell transplantation

• <16 yr with severe disease
• Survival 90-95% Cure 85-90%

Induction of HbF - these stimulate the production of foetal Hb

• Hydroxyurea
• Butyrate

The current disease-modifying therapies

• Transfusion
• Hydroxycarbamide (Hydroxyurea) (stimulates HbF production, decreases stickiness of S RBC, reduces WBC production, improves hydration of RBC & generates NO = improves blood flow)
• Haemopoietic stem cell transplantation (very good treatment for children) Indications for the transplant include CNS disease, recurrent severe VOC and recurrent ACS (if hydroxyurea fails)

Question 23

What are the limitations of HSCT?

Answer 23

Donor availability

• 18% have unaffected sibling donor
• 1-2% of children with SCD qualify

Length of Treatment:

• 2 months as an inpatient
• 4 months as outpatient

Transplant Related Mortality

Long Term Effects:

• Infertility
• Pubertal failure
• Chronic GvHD
• Organ toxicity
• Secondary malignancies