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MCD - haematology > Sickle Cell disease > Flashcards

Sickle Cell disease Flashcards

1
Q

What genetic mutation results in sickle cell disease? Why does sickle cell anaemia arise from this?

A

Missense mutation at codon 6 of the gene for b globin chain. Glutamic acid replaced by valine. Valine = non polar and insoluble compared to glutamine. DeoxyHbS is insoluble HbS polymerises to form tactics. Intertetrameric contacts stabilise structure.

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2
Q

What are the stages of sickling in red cells?

A

•Distortion

  • Polymerisation initially reversible with formation of oxyHbS
  • Subsequently irreversible
  • Dehydration
  • Increased adherence to vascular endothelium.

rigid, adherent, dehydrated.

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3
Q

What disorders are encompassed within the term ‘sickle cell disease’?

A

Sickle cell anaemia (SS) and compound

heterozygous states e.g. SC, Sbeta thalassaemia.

Autosomal recessive disorders but clinically very heterozygous.

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4
Q

Explain the pathogenesis of sickle cell disease.

A

•Shortened red cell lifespan - haemolysis - leading to

–Anaemia (partly due to low erythropoieticdrive as haemoglobin S is a low affinity haemoglobin)

–Gall Stones

–Aplastic Crisis (Parvovirus B19)

•Blockage to microvascularcirculation (vaso-occlusion)

–Tissue damage and necrosis (Infarction)

–Pain

–Dysfunction

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5
Q

What are the consequences of tissue infarction in the spleen, bones and skin?

A

•Spleen

  • hyposplenism

•Bones/Joints

  • dactylitis
  • avascular necrosis
  • osteomyelitis

•Skin

  • chronic/recurrent leg ulcers
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6
Q

Explain the pathogenesis of vaso-occlusion in SCD.

A

Due to deformed shape and increased adherence ability they block microvasculature which attracts neutrophils.

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7
Q

How is vasodilation inihibited in response to vaso-occlusion in SCD?

A

Cell-free haemoglobinlimits nitric oxide bioavailability

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8
Q

How is SCD and haemolysis related to pulmonary hypertension?

A

Free plasma Hb from intravascular haemolysis scavenges NO and inhibits its effect of vasodilation.

Associated with increased mortality.

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9
Q

Give some complications of SCD.

A

Lungs -

Acutechestsyndrome

Chronicdamage

Pulmonaryhypertension

Urinary tract -

Haematuria(papillary necrosis)

Impairedconcentration of urine (hyposthenuria)

Renal failure

Priapism

Brain -

Stroke

Cognitiveimpairment

Eyes -

Proliferativeretinopathy

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10
Q

When does SCD present clinically?

A

Switch from fetal to adult Hb synthesis. Symptoms rare before 3-6 months.

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11
Q

What are the early manifestations of SCD?

A

Dactylitis

Splenic sequestration

Infection-S. pneumoniae

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12
Q

What emergencies can arise from SCD?

A
  • Septic shock (BP <90/60)
  • Neurologicalsigns or symptoms
  • SpO2<92% on air
  • Symptoms/signs of anaemiawith Hb<5 or fall >3g/dl from baseline

Priapism>4 hours

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13
Q

What are the clinical features of acute chest syndrome?

A

Fever

Cough

Chest pain

Tachypnoea

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14
Q

In what forms of SCD is acute chest syndrome most common?

A

SS>SC>Sb+Thal

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15
Q

How does acute chest syndrome occur?

A

In context of vaso-occlusive crisis, e.g. surgery, pregnancy.

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16
Q

What bone complications can arise from SCD?

A

Avascular Necrosis of the Femoral Head

Osteomyelitis due to Salmonella Infection

17
Q

How common is stroke in SCD?

A

8% of SS individuals.

Most common in 2-9 year olds.

Involves major cerebral vessels.

18
Q

How does SCD relate to gallstone occurance? What effect does Gilbert syndrome have on this risk?

A

50% patients after 25 years.

Coinheritance increases risk.

19
Q

What are the laboratoy features of SCD?

A
  • Hb low (typically 6-8 g/dl)
  • Reticulocytes high (except in aplastic crisis)
  • Film

Sickled cells

Boat cells

Target cells

Howell Jolly bodies

20
Q

How can SCD be diagnosed with a solubility test?

A

In presence of a reducing agent oxyHb converted to deoxy Hb

Solubility decreases

Solution becomes turbid

Does not differentiate AS from SS

21
Q

How can a definitive diagnosis of SCD be made?

A

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

22
Q

What general measures are taken to manage SCD?

A

–Folic acid

–Penicillin

–Vaccination

–Monitor spleen size

–Blood transfusion for acute anaemic events, chest syndrome and stroke

–Pregnancy care

23
Q

How are painful SCD crises managed?

A

–Pain relief (opioids)

–Hydration

–Keep warm

–Oxygen if hypoxic

–Exclude infection:

  • Blood and urine cultures
  • CXR
24
Q

What can trigger a painful crisis?

A

Infection

Exertion

Dehydration

Hypoxia

Psychological stress

25
Q

How is pain managed in SCD?

A

Opioids - doses vary by person according to tolerance, diamorphine most widely used, children receive oral opioid.

Patient controlled analgesia.

Adjuvants - paracetamol, NSAIDs, Pregabalin/Gabapentin

26
Q

What more extreme measures can be taken to manage SCD?

A

•Exchange transfusion:

–Stroke

–Acute chest syndrome

•Haemopoietic stem cell transplantation

–<16yrwith severe disease

–Survival 90-95% Cure 85-90%

•Induction of HbF

–Hydroxyurea

–Butyrate

27
Q

What disease modifying therapies are currently used for SCD?

A
  • Transfusion
  • Hydroxycarbamide(Hydroxyurea)
  • Haemopoieticstem cell transplantation
28
Q

How does hydroxycarbamide help manage SCD?

A

Increases production of foetal Hb (HbF)

HbF inhibits polymerisation of HbS - reduced ‘stickiness’

Reduces WBC production

Improves RBC hydration

Gnerates NO which improves blood flow.

29
Q

How effective is hydroxycarbamide in reducing crisis rate, hospitalisation, acute chest syndrome, transfusion?

A

44%, 58%, 51%, 34%.

30
Q

When is HSCT considered?

A
  • CNS disease
  • Recurrent severe VOC*
  • Recurrent ACS*

* if hydroxycarbamide fails.

31
Q

What are the limitations of HSCT?

A

•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

–ChronicGvHD

–Organ toxicity

–Secondary malignancies

32
Q

What effect did the P-selectin inhibitor Crizanlizumab have on crisis rate during clinical trial?

A

45.3%

33
Q

What are the features of HbAS (sickle cell trait)

A
  • Normal life expectancy
  • Normal blood count
  • Usually asymptomatic
  • Rarely painless haematuria
  • Caution: anaesthetic, high altitude, extreme exertion
34
Q
A

MCD - haematology (6 decks)

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