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2 Sickle cell Flashcards

1
Q

in which ethnicities is sickle cell disease most common?

A

african/caribbean

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2
Q

what is sickle cell disease

A

body produces unusually shaped RBCs that have short lifespans and can block blood vessels

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3
Q

what are the symptoms of sickle cell disease?

A

vision loss
strokes
bone crises
splenomegaly

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4
Q

what is the probability that a child has SCD if both parents have the gene?

A

1 in 4

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5
Q

describe treatments for SCD

A

drinking water to prevent dehydration
keeping warm
painkilers
daily antibiotics and regular vaccines to reduce infection risk
hydroxycarbamide
blood transfusions

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6
Q

is there a cure for sickle cell disease?

A

stem cell or bone marrow transplant
but rare due to high risk

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7
Q

What base substitution occurs in HbS?

A

Charged glutamic acid to uncharged valine at position 6

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8
Q

what are the 8 functional globin chains

A

zeta, alpha 1, alpha 2, epsilon, G gamma, A gamma, delta, beta

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9
Q

Describe the structure of haemoglobin.

A

protein component (4 globin chains) and 4 haem groups
many alpha helices
chains are arranged tetrahedrally
hydrophilic surface, hydrophobic core

haem gp consist of a porphyrin ring bound to a ferrous iron ion (Fe2+)
each haem gp can bind to one oxygen molecule
oxygen binds to Fe2+ in the haem gp

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10
Q

what are the types of haemoglobin?

A

4 global chains combine to form a tetramer

HbA: 2 alpha, 2 beta
HbA2: 2 alpha, 2 delta
HbF (fetal haemoglobin): 2 alpha, 2 gamma

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11
Q

What does deformation of erythrocyte lead to?

A

Vascular occlusion (blood can’t pass through vessel), leading to sickle cell anaemia

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12
Q

What genetic makeup causes sickle cell anaemia?

A

HbSS

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13
Q

What genetic makeup causes sickle cell trait?

A

HbAS - oxygen affinity is the same (asymptomatic)

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14
Q

What genotype gives symptomatic sickle cell?

A

HbSS - homozygous

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15
Q

What happens to the reticulocyte count in sickle cell disease?

A

It’s increased as a compensatory mechanism due to elevated levels of haemopoiesis.

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16
Q

what does a reticulocyte count measure?

A

the number of immature RBCs (reticulocytes) in your bone marrow

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17
Q

What is splenomegaly?

A

arises in patients with SCD (accumulation of degraded erythrocytes increases size of spleen)

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18
Q

How does sickle cell anaemia lead to vision loss?

A

sickle cells accumulate within the micro vessels in the retina, increasing the pressure and consequently damaging the vessels.

ischaemia causes chemokine release
angiogenesis causes collateral formation
collaterals are easily damaged and can grow across areas of vision

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19
Q

what is ischemia?

A

lack of oxygen

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20
Q

What is an ischaemic stroke?

A

cerebral artery is blocked resulting in oxygen deficiency

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21
Q

What can cause a sickle cell crisis?

A

cold weather
strenuous exercise
stress
dehydration

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22
Q

Why are sickle cells susceptible to damage?

A

Have a shorter lifespan due to rigid sickle structure

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23
Q

What does this blood film show:

https://www.notion.so/image/https%3A%2F%2Fs3-us-west-2.amazonaws.com%2Fsecure.notion-static.com%2F2f802ff9-2ab6-4ba9-8dee-3dfc7f85f137%2FUntitled.png?table=block&id=863707d2-b882-464f-a1c7-87a17a23c739&spaceId=c4020de8-c45c-4007-8148-86bf30a31035&width=450&userId=24f1b8d0-6103-4136-934e-6333a8f0b413&cache=v2

A

Howell-Jolly Bodies

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24
Q

List symptoms of sickle cell disease

A

Anaemia
Acute chest syndrome
Bone crises
Visual loss
Gall stones
Ischaemic/ haemorrhagic stroke
jaundice
Splenomegaly
Priapism
splenic sequestrian
kidney damage

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25
Q

What causes vision loss?

A

sickle cells accumulating within the microvessels in retina, increasing pressure and consequently damaging vessels.

Ischaemia releases chemokines → stimulate growth of collaterals via angiogenesis → maintain oxygen to retina. Collaterals easily damaged and grow across areas of vision

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26
Q

What causes an ischaemic stroke?

A

Cerebral artery blocked due to sickling resulting in oxygen deficiency

sickle cells block blood vessels
lack of blood supply –> ischaemia and infarction
silent strokes are asymptomatic

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27
Q

What causes a haemorrhagic stroke?

A

Occurs due to angiogenesis

Collaterals are easily broken

causing blood to leak out into tissues

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28
Q

what is angiogenesis?

A

development of new blood vessels

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29
Q

what is a collateral?

A

side branch of a blood vessel
very easily damages and can grow over area of vision

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30
Q

What is a microvascular occlusion?

A

reduced flow to the bone marrow

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31
Q

What are some patient triggers of a vaso-occlusive crisis?

A

Cold weather

Strenuous exercise

Dehydration

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32
Q

what is myoglobin?

A

an oxygen binding protein found in muscle

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33
Q

https://occipital-sociology-d6d.notion.site/image/https%3A%2F%2Fs3-us-west-2.amazonaws.com%2Fsecure.notion-static.com%2F833cc332-5301-4f30-ba23-667614d85b01%2FScreenshot_2021-11-02_at_23.00.40.png?table=block&id=109b160a-4823-47f0-903e-9aa247b201bd&spaceId=d6d0a69f-1810-4a9a-b42a-675e0b93173c&width=1490&userId=&cache=v2

A
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34
Q

what is the partial pressure of oxygen in the lungs vs tissues?

A

lungs = around 100 torr
so Hb is highly saturated w oxygen (98%)

tissues = around 20 torr
so Hb releases 66% of its oxygen

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35
Q

what is positive cooperacy?

A

once an oxygen molecule binds to one haem gp it causes a conformational shape change which makes it easier for oxygen to bind to the next haem group
reflected by the sigmoidal shape of the oxygen dissociation curve for Hb

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36
Q

what gene editing is being used to tackle. SCD?

A

CRISPR-Cas9

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37
Q

what does the Cas9 enzyme do?

A

targets and repairs the faulty beta-goblin gene using a guide RNA

incorrect T. base is replaced with A

beta goblin gene repaired and norma RBCs produced

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38
Q

how does Cas9 promote the production of fetal haemoglobin?

A

by breaking a gene that encode a repressor such as BCL11A

fetal production. no longer blocked and sickling of red blood cells prevented

39
Q

what’s the inheritance pattern of sickle cell disease?

A

autosomal recessive

normal = AA
carriers = AS
sufferers= SS

40
Q

what does 2,3-BPG do?

A

binding of 2,3-BPG to Hb modifies the binding of oxygen to Hb

it’s an allosteric effector that binds to a site in deoxyhaemoglobin, distant from. the haem groups, and stabilises the structure, decreasing the affinity of Hb for oxygen

41
Q

what happens to Hb in the absence of 2,3-BPG?

A

doesn’t have the sigmoidal shaped oxygen dissociation curve

42
Q

how is 2,3-BPG generated?

A

Rapport-Luebering shuttle

some of the 1,3-BPG produced in glycolysis is convertedd to 2,3-DPG by movement of a phosphate group

43
Q

what do rapidly respiring cells do?

A

rapidly decarboxylate pyruvate to form acetyl CoA. forms Co2 so partial pressure of co2 inc

rapidly convert pyruvate –> lactate so pH dec (H+ conc inc)

44
Q

what is the role of H+ and CO2 as allosteric effectors?

A

bind to sites in Hb distant from haem gps
dec affinity of Hb for O2

so more O2 released by Hb when RBCs enter these tissues

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45
Q

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A
46
Q

which gene is more negatively charged?

A

normal Hb (A) ran further towards. the positive electrode (bottom of Gell) than sickle Hb (S)

so HbA more negative than HbS

47
Q

what causes the difference in charge between HbS and HbA?

A

point mutation

glutamate is replaced by valine

48
Q

give characteristics of valine and glutamate

A

glutamate (HbA)- hydrophilic, negative charge, polar, soluble

valine (HbS)- hydrophobic, uncharged, non-polar, insoluble

49
Q

what causes symptoms of HbSS?

A

not the low Hb conc

50
Q

which has the higher affinity for. oxygen, HbS or HbA?

A

HbA
so HbS releases oxygen more readily
sickle cell have lower baseline Hb conc

51
Q

give symptoms of a low Hb count in someone with HbA

A

tiredness, breathlessness, heart palpitations

52
Q

what is the geneotype for sickle cell trait?

A

HbAS

53
Q

explain the chemistry of sickle celll

A

during deoxygenation, HbS has a conformational shape change
hydrophobic valine protrudes from surface
causes hydrophobic interactions between HbS molecules
fibres form

rigid fibres distort the shape of the RBC

54
Q

why do sickle cell sufferers have higher mean cell volume?

A

inc reticulocyte count
reticulocytes larger than RBCs

55
Q

do HbSS patients have same hbF as normal?

A

no, have elevated HbF as a compensatory mechanism

56
Q

what is the sickle solubility test?

A

in presence of a reducing agent, oxyHb is converted to deoxy Hb

57
Q

how does conversion of oxygen Hb too deoxy hb affect ssolubility?

A

solubility dec
solution becomes turgid

58
Q

give a limitation of the sickle solubility test

A

doesn’t differentiate AS from SS

59
Q

what can haemolysis/reduced roc survival cause?

A

anaemia
jaundice
gallstones

60
Q

where can vaso-occlusion occur?

A

bone, kidney, cerebral, retina, lung, spleen

61
Q

what is haemolysis?

A

Repeated sickling weakens the cell membrane.
sickle cells live for 20 days
reduced abc survival –> anaemia

62
Q

how is jaundice and gallstones caused?

A

release of bilirubin into the blood

63
Q

what is vast-occlusion?

A

the blockage of the micro-circulation, including capillaries.

64
Q

what problems can vas-occlusion cause?

A

vision loss
stroke
bone crisess
hyposplenism
splenic sequestrations
kidney damage

65
Q

what causes a bone crisis?

A

blockage of blood flow to marrow

66
Q

how is stroke caused?

A

Blockage of blood flow to brain tissue, leading to ischaemic stroke.

Collateral vessels form to circumvent blockage. These collateral vessels are very fragile, and so are more likely to rupture is there is blockage in the collaterals, leading to haemorrhagic stroke.

67
Q

what causes vision loss?

A

Blood blockage in microvessels in retina. This damages these vessels, leading to formation of collateral vessels. Collateral vessels are weaker and could rupture, leading to haemmorhage.

Collateral rupture and initial blockage to vessels could both result in vision loss.

68
Q

what are Triggers of Vaso-Occlusive Crises

A
  • Exercise –> Hb deoxygenation
  • Cold temperature –> vasoconstriction
  • Dehydration –> increased blood viscosity
69
Q

what does a blood transfusion do?

A

supplies functioning erythrocytes

70
Q

adverse effect of blood transfusion

A

requires iron chelation therapy to remove excess iron (Hemosiderosis)

71
Q

how does hydroxycarbaamide work?

A

stimulates synthesis of fetal haemoglobin

surpresses reticulocyte and neutrophil production

72
Q

problem of hydroxycarbamide

A

increased risk of infection was reduced no neutrophils

73
Q

how does gene therapy work

A

viral vectors insert functional gene into haematopoietic stem cell

74
Q

how does cas9 work?

A

repairs mutation in the beta global chain
swaps T for A
normal RBCs produced

75
Q

where is the mutation in sickle haemoglobin?

A

beta globin (HBB) gene
non-conservative mutation
6th amino acid (glutamate) is swapped with valine

76
Q

is valine hydrophobic or hydrophilic?

A

hydrophobic
promotes binding of individual Hb molecules together

77
Q

what type of mutation causes HbS?

A

non-conservative missence mutation
glutamate swapped for valine

78
Q

is sickle cell aa mutation in the alpha or beta globin chains?

A

beta

79
Q

how does deoxygenated sickle haemoglobin function?

A

when oxygenated its fine
when deoxygenated, beta globin chains change shape, Hb molecules clump together

80
Q

give a factor that affects sickle cell anaemia

A

acidosis
low o2 conc
small radius vessels

81
Q

what is electrophoresis?

A

technique used to separate molecules based on their charge and mass

82
Q

what is the charge of glutamate and valine?

A

glutamate = negative
valine = neutral

83
Q

why do two bands appear for sickle cel trait mutation?

A

because its autosomal recessive

84
Q

why do sickle cell patients have a higher than normal reticulocyte count?

A

defective cells don’t carry oxygen very well
bone marrow has to produce more rbcs
reticulocytes are immature but can carry oxygen
problem: they don’t have the fexibility of mature rbcs

85
Q

what do target cells look like?

A

darker patch in middle
area of decreased density in middle
Hb spread out to side

86
Q

why do you see more target cells in sickle haemoglobin?

A

polymerisation of sickle cell Hb

87
Q

which 4 types of cell would you expect to see on a sickle cell anaemia blood film?

A

target cells
normal RBCs
sickle cells
reticulocytes

88
Q

what do chemokines do following ischaemia?

A

promote angiogenesis. (blood vessels quickly produced to deliver blood to part of body where it’s lacking)

89
Q

what causes a bone crises?

A

reduced flow to bone marrow due to microvascular occlusion
prolonged ischaemia –> infarction
ischaemia exacerbates sickling

90
Q

how do you diagnose sickle cell anaemia?

A

electrophoresis
screening
sickle solubility test

91
Q

how do you carry out a sickle solubility test?

A

blood is taken
sodium dithionite is added as a reducing agent
Hb released
HbA dissolves easily in blood plasma
HbS is less soluble, causing the solution to become turbid

92
Q

give management plans for sickle cell

A

blood transfusions
pain kilers
hydroxycarbamide
gene therapy
antibiotics

93
Q

how does gene therapy work?

A

viral vectors insert functional gene into haematopoiettic stem cell

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