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I need to learen > Sickle Cell disease COPY > Flashcards

Sickle Cell disease COPY Flashcards

1
Q

What is the sickle gene

A

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

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2
Q

How does the sickle gene affect the overall cell

A

Glutamine (polar and soluble) ->
Valine (non polar insoluble)
Deoxyhaemoglobin S is therefore insoluble and polymerises to form tactoid fibres
Intertetrameric contact stabilise structure

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3
Q

What are the stages in the sickling of red cells

A

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

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4
Q

Describe the population genetics of sickle cell

A

Distribution matches that of endemic plasmodium falciparum malaria
Up to 25% africans and 10% Caribbeans carry the gene
Around 300,000 affected biths

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5
Q

Describe the epidemiology of sickle cell disease in the UK

A

70% reside in Greater London
250 new births per annum
12000-15000

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6
Q

What are sickle cell disorders

A

May be sickle cell anaemia or compound heterozygous states (SC, sickle beta thalassaemia)

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7
Q

Describe the pathogenesis of sickle cell disorders

A

Shortened red cell lifespan - haemolysis
Anaemia partly due to a reduced erythropoietic drive as HbS is low affinity
Blockage to microvascular circulation

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8
Q

What can haemolysis in sickle cell disorder cause

A 
Anaemia - removal of sickle cells that have a shorter lifespan of 20 days
Gall stones - accumulation of red cell breakdown products 
Aplastic crisis (parvovirus B19) - infects developing red cells in marrow to arrest development
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9
Q

What are the consequences of microvascular blockage

A

tissue damage and necrosis (infarction)
Pain
Dysfunction

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10
Q

What are the consequences of tissue infarction

A

Spleen - hyposplenism
Bones/joints - dactylitis, avascular necrosis, osteomyelitis
Skin - chronic/recurrent leg ulcers

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11
Q

How is pulmonary hypertension associated with haemolysis

A

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

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12
Q

What is the pathogenesis of sickle cell disease

A

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

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13
Q

Describe the early presentation of sickle cell disorders

A

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

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

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14
Q

Why does splenic sequestration occur in SCD

A

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

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15
Q

Describe the improvement in survival of SCD patients with diagnosis and prevention

A

Administration of antibiotics and parents were taught to look for enlarged spleens (sequestration)
Lowered death and infection rates
Life expectancy has improved, but 30 years lower than usual
1. national sickle cell act
2. preventative penicillin
3. hydroxycarbamide
4. transfusion for stroke prevention

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16
Q

What are some emergencies in sickle cell disease

A 
Septic shock (BP <90/60)  
Neurological signs or symptoms  
SpO2 <92% on air 
Symptoms/signs of anaemia with Hb <5 or fall >3g/dl from baseline 
Priapism >4 hours (prolonged erection)
17
Q

What is acute chest syndrome

A

New pulmonary infiltrate on chest X-rays with fever, cough, chest pain and tachypnoea
Incidence - SS>SC>Sb thal
Develops in context of vaso-occlusive crisis surgery pregnancy
Diagnosis often delayed
Mechanical ventilation 15%
Mortality > 18 yr 9%

18
Q

Describe stroke in sickle cell disease

A

Affects 8% SS
Most common 2-9 yrs
Involves major cerebral
vessels

19
Q

Describe gallstones in sickle cell disease

A

By 25 years prevalence of gallstones 50% in SS

Coinheritance of Gilbert syndrome(UGT 1A1 TA7/TA7 genotype) further increases risk

20
Q

What are the lab features of SCD

A

Hb is low (typically 6-8 g/dl)
Reticulocytes are high (except in aplastic crisis)
Film - sickled cells, boat cells, target cells, Howell jolly bodies

21
Q

How is SCD diagnosed

A

Solubility test:

  1. In the presence of a reducing agent, oxyHb -> deoxyHb
  2. Solubility decreases
  3. Solution becomes turbid
  4. does differentiate AS from SS

Definite:
Electrophoresis or high performance liquid chromatography (HLPC) separates proteins according to charge

22
Q

How is SCD managed generally

A 
Folic acid
Penicillin
Vaccination
Monitor spleen size
Blood transfusion for acute anaemic events, chest syndrome and stroke
Pregnancy care
23
Q

How is SCD managed in painful crisis

A 
Pain relief (opioids)
Hydration
Keep warm
Oxygen if hypoxic
Exclude infection:
	Blood and urine cultures
	CXR
24
Q

What can painful crises be triggered in SCD

A 
Infection
Exertion
Dehydration
Hypoxia
Psychological stress
25
Q

How is pain managed in SCD

A

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

26
Q

How is SCD managed in in more severe cases

A 
Exchange transfusion:
	Acute chest syndrome
	Stroke
Haemopoietic stem cell transplantation
	<16 yr with severe disease
	Survival 90-95% Cure 85-90%
Induction of HbF
	Hydroxyurea
	Butyrate
27
Q

What are the current disease modifying therapies for SCD

A

Transfusion
Hydroxycarbamide (Hydroxyurea)
Haemopoietic stem cell transplantation

28
Q

What is the significance of HbF in SCD

A

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

29
Q

Describe the use of hydroxyurea to treat SCD

A

Increases production of baby (fetal) haemoglobin (HbF)
Decreases ‘stickiness’ of sickle red blood cells
Reduces white blood cell production by the bone marrow
Improves hydration of red blood cells
Generates nitric oxide which improves blood flow

30
Q

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

A

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

*if hydroxyurea fails

31
Q

What are the limitations of HSCT

A 
Donor availability (only 18% have an unaffected sibling) 
Long treatment length (2 months in, 4 months out)
Transplant related mortality 
Long term:
	Infertility 
	Pubertal failure
	Chronic GvHD
	Organ toxicity 
	Secondary malignancy
32
Q

How is P-selectin inhibitor crizanlizumab used for SCD

A

Crizanlizumab is an inhibitor of P-selectin, which is one of adhesion molecules on RBC
Reduces vaso-occlusive crisis risk
Results in lower crisis rate

33
Q

What is sickle cell trait

A 
HbAS 
Normal life expectancy
Normal blood count
Usually asymptomatic
Rarely painless haematuria
Caution: anaesthetic, high altitude, extreme exertion

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