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Year 2 Collin > Haem 5 - Sickle Cell disease > Flashcards

Haem 5 - Sickle Cell disease Flashcards

1
Q

What causes sickle cell disease from a genetic perspective

A

Missense mutation at codon 6 for Beta-globin chain.

Glutamic acid replaced by valine

  • Valine is insoluble (unlike glutamine) —> so deoxyhaemoglobin S is insoluble —> HbS polymerises to form “tactoid” fibres —> distort shape of RBC —> distorted structure stabilised by intertetrameric contacts
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2
Q

Describe the stages in sickling of RBC

A
  1. Distortion - polymerisation occurs but initially reversible with formation of oxyHbS. Subsequently irreversible.
  2. Dehydration - further concentrates Hb in cell —> favours polymerisation
  3. Increased adherence to vascular endothelium

RIGID, ADHERENT, DEHYDRATED

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3
Q

Sickle cell anaemia is homozygous (SS) but may also involve compound heterozygous states e.g. SC, SB thalassaemia. escribe its genetic and clinical features

A

Genetically simple - autosomal recessive

Clinically heterogeneous

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4
Q

Sickle cell disease leads to shortened RBC lifespan due to haemolysis. What effects does this have

A
  1. Anaemia
  2. Gall stones
  3. Aplastic crisis due to Parvovirus B19 (blocks maturation of developing RBCs)

Anaemia is partly due to a reduced erythropoietic drive - HbS has lower affinity than HbA

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5
Q

Sickle cell disease can also cause microvascular blockage (vast-occlusion). This can cause?

A
  1. Tissue damage and necrosis (infarction)
  2. Pain
  3. Dysfunction
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6
Q

What are the consequences of tissue necrosis and infarction (as a result of SCD)

A
  1. Spleen - hyposplenism
  2. Bones/joints - dactylitis, avascular necrosis, osteomyelitis
  3. Skin - chronic, recurrent leg ulcers
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7
Q

How can SCD vasculopathy and NO cause pulmonary hypertension

A

Intravascular haemolysis releases free Hb into plasma —> this free Hb scavenges NO —> causing vasoconstriction

Pulmonary hypertension = quite common in SCD. Pulmonary hypertension correlates directly with severity of haemolysis

Associated with increased mortality

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8
Q

How can SCD affect lungs, urinary tract, brain and eyes?

A

Lungs - acute chest syndrome, chronic damage, pulmonary hypertension

Urinary tract - haematuria (papillary necrosis), impaired urine conc (hyposthenuria), renal failure, priapism

Brain - stroke, cognitive impairment

Eyes - proliferative retinopathy

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9
Q

SCD has a high variable and unpredictable course even within the same family

A

Y

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10
Q

The onset of SCD symptoms coincides with?

A

Switch from foetal to adult Hb synthesis

Symptoms rare before 3-6 months

Early manifestations include: dactylitis, splenic sequestration, infection (S. pneumoniae - can be fatal)

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11
Q

What are the SCD emergencies

A
  1. Septic shock / sepsis (BP < 90/60)
  2. Neurological signs/symptoms
  3. SpO2 < 92% on air
  4. Symptoms/signs of anaemia with Hb < 50 or fall >3g/dl from baseline
  5. Priapism > 4hrs
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12
Q

Describe acute chest syndrome

A

New pulmonary infiltrate on CXR
With: fever/chest pain/cough/tachypnoea

Incidence SS>SC>SB+ thalassaemia

Develops in context of vaso-occlusive crisis, surgery, pregnancy

Often a delayed diagnosis

Treated by emergency exchange transfusion

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13
Q

Where is a common site of avascular necrosis from SCD

A

Femoral head

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14
Q

Why might osteomyelitis occur from SCD

A

Osteomyelitis due to salmonella

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15
Q

Coinheritance of what syndrome further increases risk of gallstones?

A

Gilbert syndrome

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16
Q

What are the lab features of homozygous SCD

A
  1. Low Hb (typically 6-8g/dl)
  2. Reticulocytes high (except in aplastic crisis)
  3. Film shows sickled cells, boat cells target cells, Howell Jolly bodies
17
Q

How can SCD be diagnosed

A

Solubility test: incubate with reducing agent —> oxyHb converted to deoxyHb —> solubility decreases —> solution becomes turbid and opaque (if HbS present)

Solubility test doesn’t differentiate AS from SS

Definitive diagnosis = electrophoresis or HPLC used to separate proteins according to charge

18
Q

What are the general measures used to manage SCD

A
  1. Folic acid
  2. Penicillin
  3. Vaccination
  4. Monitor spleen size
  5. Blood transfusion - for acute anaemic events, chest syndrome and stroke
  6. Pregnancy care
19
Q

How are painful crises of SCD managed

A
  1. Pain relief - variation in response. Diamorphine most widely used. Kids get oral opioid. Adjuvants = paracetamol, NSAIDs, pregabalin/gabapentin
  2. Hydration
  3. Keep warm
  4. Oxygen if hypoxic
  5. Exclude infection - blood and urine cultures and CXR
20
Q

What are the triggers of painful crises

A
  1. Infection
  2. Exertion
  3. Dehydration
  4. Hypoxia
  5. Psychological stress
21
Q

When is an exchange transfusion used

A

In stroke or acute chest syndrome

22
Q

What are the current disease-modifying therapies for SCD?

A
  1. Transfusion
  2. Hydroxycarbamide (hydroxyurea)
  3. Haemopoietic stem cell transplantation
23
Q

Describe the use of haemopoietic stem cell transplantation

A
  1. Used in <16 y/o w/ severe disease, if hydroxyurea fails
  2. Disease free survival = 90-95%, cure 85-90%.

Limitations:

  1. Major limitation = low availability of HLA-matched donors
  2. Length of treatment - 2 months (inpatient) and 4 months (outpatient).
  3. Transplant related mortality
  4. Long term effects = infertility, pubertal failure, chronic GvHD, Organ toxicity, secondary malignancies
24
Q

What is used to induce HbF production

A
  1. Hydroxyurea

2. Butyrate

25
Q

Describe the use of hydroxyurea (hydroxycarbamide) for SCD treatment

A
  1. HbF inhibits HbS polymerisation - explains why infants with SCD don’t develop symptoms till > 3 months

Hydroxyurea - increases HbF production –> decreases stickiness of sickle RBCs —> reduces WBC production by bone marrow —> improves hydration of RBCs —> Generates NO —> improves blood flow

26
Q

What antibody can be given for SCD

A

P-selectin inhibitor - Crizanlizumab.

Antibody inhibitor - inhibits P-selectin - important for endothelial adhesion of sickle cels

27
Q

What are the features of Sickle cell trait? (HbAS)

A
  1. Normal life expectancy
  2. Normal blood count
  3. Usually asymptomatic

Must be careful with anaesthetic, high altitude, extreme exertion

Year 2 Collin (114 decks)

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