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2 Sickle cell Flashcards

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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
What causes vision loss?
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
26
What causes an ischaemic stroke?
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
27
What causes a haemorrhagic stroke?
Occurs due to angiogenesis Collaterals are easily broken causing blood to leak out into tissues
28
what is angiogenesis?
development of new blood vessels
29
what is a collateral?
side branch of a blood vessel very easily damages and can grow over area of vision
30
What is a microvascular occlusion?
reduced flow to the bone marrow
31
What are some patient triggers of a vaso-occlusive crisis?
Cold weather Strenuous exercise Dehydration
32
what is myoglobin?
an oxygen binding protein found in muscle
33
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34
what is the partial pressure of oxygen in the lungs vs tissues?
lungs = around 100 torr so Hb is highly saturated w oxygen (98%) tissues = around 20 torr so Hb releases 66% of its oxygen
35
what is positive cooperacy?
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
36
what gene editing is being used to tackle. SCD?
CRISPR-Cas9
37
what does the Cas9 enzyme do?
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
38
how does Cas9 promote the production of fetal haemoglobin?
by breaking a gene that encode a repressor such as BCL11A fetal production. no longer blocked and sickling of red blood cells prevented
39
what's the inheritance pattern of sickle cell disease?
autosomal recessive normal = AA carriers = AS sufferers= SS
40
what does 2,3-BPG do?
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
what happens to Hb in the absence of 2,3-BPG?
doesn't have the sigmoidal shaped oxygen dissociation curve
42
how is 2,3-BPG generated?
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
what do rapidly respiring cells do?
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
what is the role of H+ and CO2 as allosteric effectors?
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 https://occipital-sociology-d6d.notion.site/image/https%3A%2F%2Fs3-us-west-2.amazonaws.com%2Fsecure.notion-static.com%2Fc78f4d05-fdc3-44c4-bb54-52b96f302ebe%2FScreenshot_2021-11-02_at_23.31.20.png?table=block&id=5c1a6f09-ee22-4cf5-b430-346b7cb2b734&spaceId=d6d0a69f-1810-4a9a-b42a-675e0b93173c&width=1490&userId=&cache=v2
45
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46
which gene is more negatively charged?
normal Hb (A) ran further towards. the positive electrode (bottom of Gell) than sickle Hb (S) so HbA more negative than HbS
47
what causes the difference in charge between HbS and HbA?
point mutation glutamate is replaced by valine
48
give characteristics of valine and glutamate
glutamate (HbA)- hydrophilic, negative charge, polar, soluble valine (HbS)- hydrophobic, uncharged, non-polar, insoluble
49
what causes symptoms of HbSS?
not the low Hb conc
50
which has the higher affinity for. oxygen, HbS or HbA?
HbA so HbS releases oxygen more readily sickle cell have lower baseline Hb conc
51
give symptoms of a low Hb count in someone with HbA
tiredness, breathlessness, heart palpitations
52
what is the geneotype for sickle cell trait?
HbAS
53
explain the chemistry of sickle celll
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
why do sickle cell sufferers have higher mean cell volume?
inc reticulocyte count reticulocytes larger than RBCs
55
do HbSS patients have same hbF as normal?
no, have elevated HbF as a compensatory mechanism
56
what is the sickle solubility test?
in presence of a reducing agent, oxyHb is converted to deoxy Hb
57
how does conversion of oxygen Hb too deoxy hb affect ssolubility?
solubility dec solution becomes turgid
58
give a limitation of the sickle solubility test
doesn't differentiate AS from SS
59
what can haemolysis/reduced roc survival cause?
anaemia jaundice gallstones
60
where can vaso-occlusion occur?
bone, kidney, cerebral, retina, lung, spleen
61
what is haemolysis?
Repeated sickling weakens the cell membrane. sickle cells live for 20 days reduced abc survival --> anaemia
62
how is jaundice and gallstones caused?
release of bilirubin into the blood
63
what is vast-occlusion?
the blockage of the micro-circulation, including capillaries.
64
what problems can vas-occlusion cause?
vision loss stroke bone crisess hyposplenism splenic sequestrations kidney damage
65
what causes a bone crisis?
blockage of blood flow to marrow
66
how is stroke caused?
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
what causes vision loss?
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
what are Triggers of Vaso-Occlusive Crises
- Exercise --> Hb deoxygenation - Cold temperature --> vasoconstriction - Dehydration --> increased blood viscosity
69
what does a blood transfusion do?
supplies functioning erythrocytes
70
adverse effect of blood transfusion
requires iron chelation therapy to remove excess iron (Hemosiderosis)
71
how does hydroxycarbaamide work?
stimulates synthesis of fetal haemoglobin surpresses reticulocyte and neutrophil production
72
problem of hydroxycarbamide
increased risk of infection was reduced no neutrophils
73
how does gene therapy work
viral vectors insert functional gene into haematopoietic stem cell
74
how does cas9 work?
repairs mutation in the beta global chain swaps T for A normal RBCs produced
75
where is the mutation in sickle haemoglobin?
beta globin (HBB) gene non-conservative mutation 6th amino acid (glutamate) is swapped with valine
76
is valine hydrophobic or hydrophilic?
hydrophobic promotes binding of individual Hb molecules together
77
what type of mutation causes HbS?
non-conservative missence mutation glutamate swapped for valine
78
is sickle cell aa mutation in the alpha or beta globin chains?
beta
79
how does deoxygenated sickle haemoglobin function?
when oxygenated its fine when deoxygenated, beta globin chains change shape, Hb molecules clump together
80
give a factor that affects sickle cell anaemia
acidosis low o2 conc small radius vessels
81
what is electrophoresis?
technique used to separate molecules based on their charge and mass
82
what is the charge of glutamate and valine?
glutamate = negative valine = neutral
83
why do two bands appear for sickle cel trait mutation?
because its autosomal recessive
84
why do sickle cell patients have a higher than normal reticulocyte count?
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
what do target cells look like?
darker patch in middle area of decreased density in middle Hb spread out to side
86
why do you see more target cells in sickle haemoglobin?
polymerisation of sickle cell Hb
87
which 4 types of cell would you expect to see on a sickle cell anaemia blood film?
target cells normal RBCs sickle cells reticulocytes
88
what do chemokines do following ischaemia?
promote angiogenesis. (blood vessels quickly produced to deliver blood to part of body where it's lacking)
89
what causes a bone crises?
reduced flow to bone marrow due to microvascular occlusion prolonged ischaemia --> infarction ischaemia exacerbates sickling
90
how do you diagnose sickle cell anaemia?
electrophoresis screening sickle solubility test
91
how do you carry out a sickle solubility test?
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
give management plans for sickle cell
blood transfusions pain kilers hydroxycarbamide gene therapy antibiotics
93
how does gene therapy work?
viral vectors insert functional gene into haematopoiettic stem cell

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