Sickle cell disease and haemoglobinopathies Flashcards
What is normal adult haemoglobin
HbA
describe what chains the haemoglobin is made out of
2 alpha
2 beta
How many molecules of haem are in an adult haemoglobin
4 haem molecules
define haemoglobinopathies
Abnormalities
affecting the globin chains
What are the two main groups of haemoglobinopathies
- Sickling syndromes
- Thalassaemias
What is sickle cell disease charactersied by
- the presence of HbS
What happens in sickle cell disease
- vaso-occlusion/infarction - abnormal shape red blood cell blocks the normal circulation and causes vascular occulsion
- haemolysis - abnormal red cells are easily destroyed by the epithelial system
Describe the precipitating factors of sickle cell disease
◦ Hypoxia
◦ HbS Concentration / dehydration
◦ Acidosis
What does the presence of haemoglobin S do
- causes polymerisation - causes the red cell to sickle - this is reversible
what are the characteristics of sickle cell disease
- Painful crises
- Systemic vasculopathy
- End organ damage
- Reduced life expectancy
What mutation causes HbS
- point mutation
- substitution of glutamate by valine in position 6 in the Beta globin chain
How is sickle cell anaemia passed on
- autosomal recessive - two people both have to have it to give someone a chance of getting it
- carriers are asymptomatic
How do you diagnose sickle cell disease
Clinical
- family history
- recurrent pain
Lab
- anaemia
- haemolysis - high bilirubin, high LDH, raised reticulocytes and undetectable haptoglobin
- blood film - sickle cells
- haemoglobin electrophoreiss/sickle solubility test
How does the sickle solubility test work
- Place the red cells in an acidic medium
- Negative - if you can see the lines behind the tube
- Positive if you cannot see lines behind the tube
What are the emergency presentations of sickle cell disease
- Pain/acute painful crisis
- acute deterioration of anaemia
- sequestration
- aplastic crisis
- overwhelming sepsis
- acute chest sydnrome
- stroke
- fat embolism sydnrome/multi organ failure
- renal impairment
- priapism
- acute visual loss
What is the most common cause for patients presenting to hospital with sickle cell anaemia
- acute painful crisis
what are the precipitating factors of an acute painful crisis
- infections
- skin cooling
- dehydration
- deoxygenation
- stress
- in up to 50% there is no obvious precipitator
How do people present with acute painful crisis in sickle cell anaemia in hospital
• Rapid onset of bone pain; bone marrow infarction
• Variable severity and duration; hours to weeks
• Fever, bone tenderness +/- swelling, hypertension, tachycardia,
tachypnoea
How do you manage acute acute painful crisis in sickle cell anaemia
- deliver an analgesia within 30 minutes from presentation
- parental opiate analgesia often required
- re-assess and repeat as necessary
anticipate and treat pre-emptively
- nausea/vomiting = anti emetics
- pruritus = anti histamines
- constipation = laxatives
When a patient presents with acute painful crisis in sickle cell anaemia what should you investigate
- temperature
- vital signs
- fluid intake
- analegesia
- sedation/urinary retention/restlessness
- FBC and reticulocytes
- U and E and liver function test
- LDH
- CRP
- blood cultures
- CXR
- always look for precipitating factors
What is acute chest syndrome in painful crisis in sickle cell anaemia
All ages; commonest cause of death in adults (25% of all deaths)
- 2nd most common cause of hospitalisation
How do you define acute chest syndrome
- Acute illness associated with respiratory symptoms and a new infiltrate on a CXR
What are the precipitating factors on acute chest syndrome (sickle cell disease)
- Surgery/anaesthesia
- pregnancy
What can acute chest syndrome increase
- increased risk of chronic lung disease
- increased risk of death
describe the pathophysiology of acute chest syndrome (sickle cell disease)
increase in
- infection
- asthma
- hypoventialtion
This causes hypoxia, inflammation and acidosis
which casues vasooclusion within the pulmonary microvasculature which causes hypoxia, inflammation and acidosis and so on
- fat embolism and pulmonary thrombi can also cause vasoocclusiion within the pulmonary microvasculature
What is the acute management for acute chest syndrome (sickle cell disease)
- adequate analgesia
- incentive spirometry
- reduces ACS in patients admitted with VOC (5% v 42%)
- oxygen therapy
- value of NIV even in the absence of severe hypoxia
Fluid management
Antibiotics
Transfusion
- value of TUT in mild ACS
- Exchange Transfusion (ExTx) gen recommended for moderate/severe ACS
- if ExTx cannot be readily offered give a transfer to a place where they can do it
What is an exchange transfusion
remove the patients own blood and replace it with normal
patients who are homozoygous HbSS tend to …
- splenic auto-infarction from a very young age = leads to functional asplenia
by what age do people who have sickle cell anaemia homozygously are asplenia (sickle cell disease)
Majority <3 years
What does not having a spleen put you at risk of (sickle cell disease)
Pneumococcal, Meningococcal & Haemophilus influenzae
what symptoms can asplenia present with (sickle cell disease)
- febrile
- coma
- altered sensorium
- seizures
How can you treat patients with asplenia (sickle cell disease)
- antibiotic treatment
- prophylactic penicillin V
- vaccination
What is splenic sequestration (sickle cell disease)
- A sudden painful enlargement of the spleen and drop in haemoglobin to less than 2g/L (high reticulocyte level)
Who experiences splenic sequestration (sickle cell disease)
Children; 78% in the first events - less than 2 years
what is the mortality and recurrence for splenic sequestration (sickle cell disease)
- Mortality 12%
- Recurrence ~50%
What is the management of splenic sequestration (sickle cell disease)
- Early detection
- Parental education
- Urgent blood transfusion;
- Splenectomy
What is an aplastic criss (sickle cell disease)
- this is an infection with HPV B19
- sudden drop in haemoglobin
what happens in an aplastic crisis (sickle cell disease)
- infection of red cell precursors in bone marrow - leads to pure red cell aplasai and low reticulocytes
How long does aplastic crisis last for
- the normal lifespan of a red cell is about 3 months
- if you shut down production for 2 or 3 weeks you might feel a bit under the weather and then the bone marrow picks up again
- if you have any blood disease and the red blood cell life is shortened then you rely on the bone marrow to work overtime to help produce haemoglobin therefore it can result in a sudden drop and deterioration of anaemia
What is another word for aplastic crisis
- Slapped cheek disease
what should you watch out for in aplastic crisis
= ask about siblings - HPVB19 can spread and result in multiple losses
What is the management of aplastic crisis
urgent blood transfusion
What is thalasaemia
- This is a reduction and absent production of beta or alpha chains
- leads to an imbalance and ineffective erythropoiesis
What do you need to watch out for when transfusion of patients with thalassaemia
- effects of iron overload in transfused patients
out of the beta thalassaemias which ones are transfusion dependent
Transfusion dependent thalassaemia - beta thalassaemia major
transfusion +/- dependnet - beta thalassaemia intermedia
Non transfusion dependent thalassaemia - beta thalassaemia trait
describe what beta thalassaemia major looks like
Severe Anaemia
◦ Growth failure
Plasma volume expansion
◦ Worsening of anaemia
◦ Heart failure
Bone marrow expansion ◦ “Thalassaemic facies” ◦ Poor dentition ◦ Bone disease ◦ Extramedullary haemopoiesis
if you dont get a transfusion when do you die with beta thalassaemia major
- death in 1st - 2nd decade without transfusion
How do you treat beta thalassaemia major
- regular transfusion from ealry life to maintain haemoglobin greater than 10g/dl with chelation to prevent iron overload
What happens if you have iron overload
Pituitary
- impaired growth, infertility
Thyroid
- hypoparathyrodism
Heart
- cardiomyopathy, cardiac failure
Liver
- hepatic cirrhosis
Pancreas
- diabetes melititus
Gonads
- hypogonadism
- death in teens or early 20s typically due to severe CF or sudden death due to arrhythmia
How do you assess iron status
Liver biopsy
Serrum ferritin
cardiac/liver MRI
what is the gold standard for assessing iron status
Cardiac/Liver MRI
what is the advantages of liver and serum ferritin
Liver biopsy
- invasive
- risk
Serum ferritin
- quick, cheap, readily available
- acute phase protein - non-specific
How does a cardiac liver MRI measure the iron status
- the time taken for the heart/liver MRI to darken is the level of iron present in the body
describe the measurements of cardiac/liver MRI
Liver (mg/g dry weight)
- Normal: less than 2
- Mild: 2-6.9
- Moderate: 7-14.9
- Severe: greater than 15
Cardiac (msec)
- Normal: less than 20
- moderate: 10-20
- Severe: less than 10
- Very severe: less than 6 (50% risk of symptomatic heart failure at 12 months)
Name the available chelating agents
- Desferoxamine (continous infusion)
- deferiprone (oral)
- deferassirox (oral)
- combination of them
what combinations of alpha thalassaemia are there
- alpha + thalassaemia trait - each chromosome has one alpha gene
- Alpha 0 thalassaemia trait - one chromosome has no alpha genes whereas the other one as both alpha genes
- Haemoglobin H - Beta tetramer - no function
- Haemoglobin barts - gamma tetramer
What happens in alpha thalassaemia to beta chains
- reduced production of alpha chains therefore there is an excess of free beta chains (beta chains are less toxic then the alpha chains)
What puts you at high risk of alpha thalassaemia 0
- China
- SE Asia
- eastern mediterranean
- middle east
What is the alpha thalassaemia trait look like
- asymptomatic
- low MCV/MCH with no evidence of iron deficiency
- definitive diagnosis by genetic testing
What happens if you have alpha thalassaemia 0 (no alpha chains)
- incompatible with life
- hydrops fetalis
Describe haemoglobin H disease
- only one alpha chain
- microcytic/hypochromic anaemia of variable severity
- HbH inclusion body
- tendency for iron overload
What is the purpose of antenatal screening
To identify all pregnancies at risk of a clinical significant haemoglobinopathy
- offer partner screening and genetic counselling to affected couples
why should you identify all children with sickle cell disease
◦ Penicillin prophylaxis
◦ Immunisation
◦ Parent education
What is the long term management of sickle cell disease
- Hydroxyurea – increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
- Receive the pneumoccoal polysaccharide vaccine every 5 years
What is the difference in sickle cell anaemia in the blood between a aplastic crisis and a sequestration
Aplastic crisis has reduced reticulocytes, whereas sequestration crisis has increased reticulocytes
