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MCD Haematology > Sickle Cell Anaemia > Flashcards

Sickle Cell Anaemia Flashcards

1
Q

what amino acid is changed in the point mutation that caused Sickle Cell Diseases?

  • which amino acid
  • which chain does this happen on
A
  • glutamic acid (polar and soluble)
  • replaced by valine (non-polar and insoluble)
  • this happens on the beta globin chain

HbS is the sickle cell haemoglobin
HbA is the normal adult haemoglobin

they differ by a single amino acid

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2
Q

which particular chain does the point mutation occur HbS?

A

glutamate at codon 6 is replaced by valine

on the Beta chain

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3
Q

what is the impact of having an insoluble, non-polar valine in the beta globin structure?

A

Valine being a non polar amino acid reduced the solubility of deoxyghaemoglobin

HbS polymerises within RBC to form tactoids with inter-tetrameric contacts that stabilise structure–> sickle shape

The intracellular polymers give its stickiness to vascular endothelium

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4
Q

effects of sickling on RBCs

A

o Distortion -polymerisation initially reversible with formation of oxyHbS but is subsequently irreversible.

o Dehydration.

o Increased adherence to vascular endothelium.

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5
Q

genotypes in SCA

A

HbSS only

beta S and beta S

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6
Q

genotype in SCD

A

HbSS (anaemia) and HbSC

C is abnormal Hb gene

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7
Q

what is SCD

A

SCA plus all other conditions that lead to a disease syndrome due to the sickling of RBCs

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8
Q

pathogenesis of SCA

A
  • shorten red cell lifespan
  • blockage to microvascular circulation
  • lungs
  • urinary tract
  • brain
  • eyes
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9
Q

what is the impact of a shortened red cell lifespan

A

leads to haemolysis

  • anaemia: reduced erythropoietic drive as HbS is low affinity (good at releasing oxygen)
  • gallstone: increased risk with Gilbert syndrome co-inheritance
  • aplastic crisis
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10
Q

what is the impact of blockage to microvascular circulation?

A

o Infarction.
- Spleen – hyposplenism (leads to infection).
- Bones/joints – dactylitis (inflammation of bone), avascular necrosis and osteomyelitis (infection of bone).
- Skin – ulcerations.
o Pain and dysfunction.

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11
Q

what is the impact of the lungs being affected?

A

o Acute: Acute chest syndrome.
o Chronic: Pulmonary hypertension.
- Correlates with severity of haemolysis.
- Free plasma haemoglobin from haemolysis scavenges NO and causes vasoconstriction.

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12
Q

what is the impact of the urinary tract being affected?

A

o Haematuria – due to papillary necrosis.
o Renal failure and Hyposthenuria – impaired concentration of urine.
o Priapism.

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13
Q

what is the impact of the brain being impacted?

A

Stroke and cognitive impairment – affects 8% of SS, most common 2-9yrs.

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14
Q

what is the impact of the eyes being affected?

A

o Proliferative retinopathy.

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15
Q

when do SCA symptoms NOT appear?

A

before 3-6 months as the switch to adult HbA synthesis has not occurred at that stage

they are mainly HbF as this time period which contains no beta chains

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16
Q

early manifestations (effects of sickling)

A

o Dactylitis – most common in children.
o Splenic sequestration.
o Infection (pneumococcal normally).

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17
Q

what cause painful crises?

A 
infection
exertion
dehydration
hypoxia
psychological stress
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18
Q

management

A

o Folic acid – anaemia.
o Penicillin – splenic dysfunction.
o Vaccination – splenic dysfunction.
o Monitor spleen size – splenic dysfunction.
o Blood transfusion for acute anaemic events, chest syndrome and stroke.
o Pregnancy care.

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19
Q

what special consideration needs to be made with acute splenic sequestration?

A

Acute splenic sequestration can mean you get an enlarged spleen and often requires prophylactic therapy (against pneumococcal infection), transfusions to correct anaemia and maybe splenectomy.

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20
Q

how do you treat the painful crises?

A

o Pain relief – opioids.
o Hydration.
o Keep warm.
o Oxygen if hypoxic.

excludes treatment of infection

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21
Q

what is an exchange transfusion given for?

A

stroke

acute chest syndrome

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22
Q

what is the effect of hydroxyurea/ hydroxycarbimide in treating SCA?

what else can be used?

A

a chemotherapy agent that can reduce the occurrence of SCD symptoms
by inducing expression of HbF – up to 20% more HbF.

butyrate can also be used

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23
Q

lab features of SCA

A 
	Hb is low – 6-8g/dL.
	Reticulocytes (immature RBCs) high – except in aplastic crisis where it is low
	Film 
o	Sickled cells.
o	Boat cells.
o	Target cells.
o	Howell-Jolly bodies (hyposplenism)
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24
Q

how is SCA diagnosed?

A

sickle cell solubility test:
OxyHb is converted to deoxyHb in the presence of a reducing agent
solubility decreases and solution becomes turbid

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25
Q

what is the problem with using the solubility test for diagnosis?

A

doesn’t differentiate AS from SS therefore the test only checks for one or more sickle traits

does not confirm anaemia

26
Q

how can HPLC be used to diagnose?

A

Separates proteins according to charge.
 homozygous sickle patients have NO HbA and only HbS and a little HbA2.
Heterozygous sickle patients have both HbS and HbA.

27
Q

HbAS (sickle cell trait)

A

 Normal life expectancy.
 Normal blood count.
 Asymptomatic usually – rarely painless haematuria.
 Caution taken with – anaesthetic, high altitude and extreme exertion.

28
Q

haemoglobinopathies that show sickle cells

A 
these are all sickle cell diseases
Hb SS
Hb SC
HB S/beta thalassaemia
Hb SD-Punjab
Hb SO-Arab
29
Q

what are the genes in sickle cell anaemia?

A

two beta HbS genes (HbSS)

  • they are no normal beta genes
  • can’t produce normal beta chains
  • they can’t produce HbA (2alpha2beta)
30
Q

what is the difference between sickle cell disease and sickle cell anaemia?

A

sickle cell disease is a general term for diseases causing the sickled shaped red cell

e. g. HbSC
- C is a beta chain variant
e. g. beta thal. trait

31
Q

why is the sickle beta globin gene (betaS) common in Africa, the Middle East and Asia?

A

carrier state is protective against malaria

32
Q

beta genes in sickle cell anaemia

A

beta S beta S

produce HbS

33
Q

beta genes in haemoglobin C disease (a sickle cell DISEASE)

A

beta S beta C

produce HbS and HbC

34
Q

beta genes in sickle cell trait

A

beta S and beta A

produce HbA (normal) and HbS (sickle cell haemoglobin)

35
Q

beta genes in normal

A

beta A and beta A

produce HbA

36
Q

why can only adults (i.e. non-foetus) be affected by sickle cell disease

A

adults can only have beta chains (in HbA made of 2 alpha 2 beta)

foetus’ make HbF (2 alpha 2 gamma)

beta chain needs to be present for sickle disease
for beta chains to be present you need to be at least 4 months old when HbF starts to fall and HbA rises

37
Q

what vascular effects do sickle cells have?

A
  • become trapped in small vessels
  • impair circulation
  • damage multiple organs
  • cause infarcts (in children) of small bones (hands and feet)
  • painful dactylitis (hand-foot syndrome) –> shortening of digits
  • general pain in adults due to oxygen deprivation of tissue and avascular necrosis of bone marrow
38
Q

what causes pain in adults with sickle cell disease (having sickle cells) ?

A

oxygen deprivation of tissue and avascular necrosis of bone marrow

39
Q

what are the organs effects by sickling of cells?

A

1) Bones:
- dactylitis
- osteomyelitis
- avascular necrosis of the hip
2) Kidneys:
- haematuria
- failure to concentrate urine
- papillary necrosis
3) Brain: stroke
4) Lungs: “chest crisis”
5) Spleen:
- splenic sequestration/hyposplenism
6) Skin: skin ulcers

40
Q

infarct

A

death of tissue due to loss of blood suppy

41
Q

dactylitis

A

inflammation of a digit due to infarction of the bone

especially in children

42
Q

avascular necrosis

A

death of tissue due to lack of blood supply

especially in adults

43
Q

osteomyelitis

A

infection of bone

dead tissues are susceptible to bacterial infection

44
Q

splenic sequestration

A

pooling of large numbers of red cells in the spleen

45
Q

hyposplenism

A

reduced function of the spleen

in the case of sickle cell disease, the recurrent interruption of blood supply leading to splenic tissue damage

46
Q

“chest crisis” in the lungs

A

hypoxia due to lung tissue death

47
Q

what is the consequence of sickle cell fragility?

A

shorted lifespan due to haemolysis

results in anaemia

(SCD comes before SCA)

48
Q

how does the affinity for oxygen in HbS compare to HbA?

A

HbS has a lower affinity for oxygen therefore released it readily

this makes anaemia tolerable

49
Q

why can folic acid supply become low due to anaemia?

A

to compensate for the short lifespan of the sickle cells, there is an increased turnover of the cells which uses up folic acid

50
Q

what infection does the shortened life span of red cells in SCD make someone someone susceptible to?

A

parvovirus B19

infected RBC precursors and stop RBC production for upto a week
low reticulocyte numbers
this leads to a dramatic fall in Hb levels –> aplastic crisis

51
Q

what is an aplastic crisis?

A

due to dramatic drop in Hb as a result of halted RBC production (paravovirus B19)

there will be a REDUCTION in reituculocytes

52
Q

what is splenic sequestration crisis?

A

children:
abdominal pain, pallor, shock, enlarged spleen and low Hb
raised reticulocytes

53
Q

blood count in SCD

A
  • shows low Hb

- raised reticulocytes (not in aplastic crisis)

54
Q

blood film in SCD

A
  • sickled cells
  • Howell-Jolly Bodies (hyposplenism- nuclear remnants removed in spleen)
  • target cells
55
Q

what does the screening test for SCD depend on?

A

the decreased solubility of the HbS when oxygen tension is low

the sickle solubility test: reducing agent added to diluted blood leading to formation of sickle cells (in trait and anaemia) making the blood go turbid

positive result goes into electrophoresis (definitive diagnosis)

56
Q

What affect does an alkaline pH have on electrophoresis?

what can skew the results?

A

HbS separates readily from the HbA and HbF

non-sickling Hb like HbD and HbG can also run with HbS so a solubility test needs to be done first

57
Q

what Hbs are detected in sickle cell anaemia?

A
  • no HbA
  • HbS
  • variable HbF
  • small amount HbA2
58
Q

what Hbs are detected in sickle cell anaemia?

A
  • HbS
  • no HbA
  • small amount of HbA2 and HbF
59
Q

how is a painful crisis managed?

A
  • first avoid factors that precipitate them
  • analgesia
  • rehydration
  • warmth
  • additional oxygen
    these are for the precipitating factors
  • antibiotics if infections has been detected
60
Q

how should SCD be managed?

A
  • folic acid 5mg/day
  • vaccination (against pneumococcal infection)
  • prophylactic penicillin (prevent infections caused by hyposplenism)
  • blood transfusion
  • stem cell transplantation (considered in small children)
61
Q

what are the blood transfusions used?

A
  • top up: in aplastic and sequestration crises

- exchange blood transfusion: life threatening/severe disease e.g. stroke so to reduce HbS levels

62
Q

what can promote sickling in sickle cell trait people?

A
  • anaesthesia (should be screened before surgery if BetaS)
  • high altitude
  • air travel in unpressurised plane

MCD Haematology (11 decks)

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