7. Haemoglobin & Sickle Cell Anaemia Flashcards Preview

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Flashcards in 7. Haemoglobin & Sickle Cell Anaemia Deck (20)
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1
Q

haemoglobin facts

A

average adult contains 5000 million rbcs per ml of blood
each rbc has 280 mill Hb
average adult has 5L blood

2
Q

haemoglobin structure

A

comprised of 4 chains - two alpha and two beta

cooperation between globin chains optimises the oxygen delivery profile

3
Q

genetics of haemoglobin

A

beta globin gene is produced from chromosome 11
alpha globin gene is on chromosome 16
on the chromosome 11 we have:
-epsilon globin gene produced during embryonic development
-gamma globin gene takes over during fetal growth where HbF is produced
-delta
-beta globin
on chromosome 16 it is 2 zeta and 2 alpha, we inherit one beta globin gene from each parent and two alpha globin genes from each parent so total of 4 alpha globins

4
Q

haemoglobin development

A

genetic defects of haemoglobin are the most common genetics defects in the world
different genes are activated or suppressed depending on the stage of development

5
Q

normal adult haemoglobins

A

less than 1 % of HbF in adults chromosome 11
haemoglobin A
- normal haemoglobin that exists after birth
- a tetramer with two alpha chains and two beta chains α2β2
haemoglobin A2
a minor component of the haemoglobin found in red cells after birth
consists of 2 alpha chains and 2 delta chains α2δ2
less than 3% of the total red cell haemoglobin
haemoglobin F
predominant haemoglobin during fetal development
a tetramer of two alpha chains and two gamma chains α2γ2

6
Q

haemoglobin in circulation

A

at the peripheral tissues there is a low (acidic) pH so a high pCO2 and a low pO2. mainly deoxyhaemoglobin present here as oxygen needs to be given up to respiring tissues
in the lungs there is a high pH and a low conc of pCO2, high pO2. this is where we have oxyhaemoglobin subunit as oxygen taken up

7
Q

thalassaemias and haemoglobinopathies

A

disorders affecting haemoglobin synthesis or function leading to anaemia as rbc shape deformed and recognised as dysfunctional so broken down prematurely
thalassaemia: decreased synthesis of wild type haemoglobin, normal globin structure. quantitative
haemoglobinopathies: synthesis of mutant haemoglobin chains (eg sickle cell anaemia). qualitative (quality of hb is affected
classification not straightforward: some abnormal globins are synthesised at a reduced rate

8
Q

sickle cell anaemia

A

a haemoglobinopathy
incidence: West African, Afro- carribean have higher incidences
when the sickle haemoglobin loses its oxygen (deoxy state) it forms long rods in the red cell and changes its shape) so not biconcave disc

9
Q

inheritance of sickle cell anaemia

A

if you only inherit one sickle cell gene from one parent u can pass it on but not suffer any symptoms, - sickle cell trait (heterozygous) carrier
sickle cell disease - red blood cells inherit 80% HbS, you will have inherited one gene from each parent

10
Q

sickle cell anaemia - biochemical analysis

A

abnormal haemoglobin structure , Pauling discovered the allelic change occurs in a single gene. first demonstration that a genetic mutation can produce a physically different protein
- caused by point mutation in the beta globin gene from A to T so changes to valine
this had a dramatic effect on the haemoglobin tetramer in the deoxy state, hb wants to lose its oxygen

11
Q

sickle cells in circulation

A

HbS is insoluble and forms crystal when it is exposed to low oxygen tension (pressure)
deoxygenated sickle haemoglobin polymerises into long fibres
will take up O2 in the lungs but will give it up as it travels thorugh the body, but forms crystals as lower pO2 towards tissues and hb cant revert back to oxygenated form, gradual process

12
Q

pathophysiology of sickle cell anaemia

A

deoxygenation to the polymerisation of Hb to the sickling of rbc toendothelial activation/ damage which means blood cant flow freely through vessels. activation triggers clotting/ can cause damage as elements are exposed to things in circulation like rbc wbc and these will stick to blood vessel lining ie the endothelium. neutrophils can release things and cause further damage
sickle cells get stuck in blood vessels and cause vascular occlusion, liits blood flow so less to organs. oxygen ischaemia and organ damage

13
Q

complications from sickle cell disease

A

sickle cells become trapped and destroyed in the spleen causing splenic sequestration
- shortage of red blood cells or anaemia
- pain episodes
- stroke or brain damage
kidney failure
- pneumonia or chest syndrome (respiratory, occlusions in pulmonary vasculature)
- chronic damage to liver
- osteomyelitis, reduced blood supply to bones

14
Q

sickle cell anaemia - crises

A

vasoocclusive
-most common
-sickle cells adhere to neutrophils and endothelial cells
-can affect the bones, lungs, spleen, brain and spinal cord
visceral
-sickling within organ occurs and pooling of blood
-can make the anaemia worse
haemolytic
-increase rate of haemolysis (destruction of rbc due to abnormal shape)
-fall in haemoglobin

15
Q

sickle cell anaemia diagnosis

A

Low haemoglobin (6-9 g/dL)
Sickle cells and target cells in blood
Blood is deoxygenated and tests for sickling are positive
Electrophoresis – no HbA is detected, HbF levels vary between 5-15% (when we see HbF conc rising we can see sickle cell anaemia)

16
Q

sickle cell anaemia testing

A

In pregnancy samples obtained by chorionic villus biopsy
Amniotic fluid cells can be used
PCR used to amplify DNA
can determine if mutation present

17
Q

sickle cell anaemia treatment

A
  • prophylactic ie preventative
  • folic acid (5mg once a week) to prevent folate deficiency
  • good general nutrition and hygiene
  • vaccinations reduce infection rates
  • treat crises by rest, rehydration, oral fluids, intravenous saline (3L in 24h) and antibiotics if infection present
  • transfusions, suppresses HbS production over several months/years
  • hydroxyurea can increase Hb levels and improve outcome
18
Q

recent research ideas on treating sickle cell anaemia

A
Scientists have used the CRISPR-Cas9 gene-editing technique to rewrite the genetic mutation in blood cells that causes sickle cell disease. Once these treated hematopoietic progenitors, which had been harvested from patients, were given to mice, the cells began to produce healthy haemoglobin.
Published results (October 12 2016) in the journal Science Translational Medicine
19
Q

sickle cell trait

A

Sickle cell trait (carrier of sickle haemoglobin gene)
One sickle cell haemoglobin gene (HbS) and one normal haemoglobin gene (HbA)
Carrier has sufficient normal haemoglobin in red blood cells to keep cells flexible and so don’t have symptoms of sickle cell disorders
No anaemia
Red blood cells look normal

20
Q

clinically significant variant haemoglobins

A

Most structural Hb variants are a result of a single amino acid substitution in globin chain

Haemoglobin S
Sickle cell disease
Alpha chain is normal
Disease-producing mutation exists in the beta chain giving the molecule the structure, a2bS2

Haemoglobin C
Haemoglobin D
Haemoglobin E
Haemoglobin H