Sickle Cell Anaemia Flashcards
what amino acid is changed in the point mutation that caused Sickle Cell Diseases?
- which amino acid
- which chain does this happen on
- 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
which particular chain does the point mutation occur HbS?
glutamate at codon 6 is replaced by valine
on the Beta chain
what is the impact of having an insoluble, non-polar valine in the beta globin structure?
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
effects of sickling on RBCs
o Distortion -polymerisation initially reversible with formation of oxyHbS but is subsequently irreversible.
o Dehydration.
o Increased adherence to vascular endothelium.
genotypes in SCA
HbSS only
beta S and beta S
genotype in SCD
HbSS (anaemia) and HbSC
C is abnormal Hb gene
what is SCD
SCA plus all other conditions that lead to a disease syndrome due to the sickling of RBCs
pathogenesis of SCA
- shorten red cell lifespan
- blockage to microvascular circulation
- lungs
- urinary tract
- brain
- eyes
what is the impact of a shortened red cell lifespan
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
what is the impact of blockage to microvascular circulation?
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.
what is the impact of the lungs being affected?
o Acute: Acute chest syndrome.
o Chronic: Pulmonary hypertension.
- Correlates with severity of haemolysis.
- Free plasma haemoglobin from haemolysis scavenges NO and causes vasoconstriction.
what is the impact of the urinary tract being affected?
o Haematuria – due to papillary necrosis.
o Renal failure and Hyposthenuria – impaired concentration of urine.
o Priapism.
what is the impact of the brain being impacted?
Stroke and cognitive impairment – affects 8% of SS, most common 2-9yrs.
what is the impact of the eyes being affected?
o Proliferative retinopathy.
when do SCA symptoms NOT appear?
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
early manifestations (effects of sickling)
o Dactylitis – most common in children.
o Splenic sequestration.
o Infection (pneumococcal normally).
what cause painful crises?
infection exertion dehydration hypoxia psychological stress
management
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.
what special consideration needs to be made with acute splenic sequestration?
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.
how do you treat the painful crises?
o Pain relief – opioids.
o Hydration.
o Keep warm.
o Oxygen if hypoxic.
excludes treatment of infection
what is an exchange transfusion given for?
stroke
acute chest syndrome
what is the effect of hydroxyurea/ hydroxycarbimide in treating SCA?
what else can be used?
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
lab features of SCA
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)
how is SCA diagnosed?
sickle cell solubility test:
OxyHb is converted to deoxyHb in the presence of a reducing agent
solubility decreases and solution becomes turbid
what is the problem with using the solubility test for diagnosis?
doesn’t differentiate AS from SS therefore the test only checks for one or more sickle traits
does not confirm anaemia
how can HPLC be used to diagnose?
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.
HbAS (sickle cell trait)
Normal life expectancy.
Normal blood count.
Asymptomatic usually – rarely painless haematuria.
Caution taken with – anaesthetic, high altitude and extreme exertion.
haemoglobinopathies that show sickle cells
these are all sickle cell diseases Hb SS Hb SC HB S/beta thalassaemia Hb SD-Punjab Hb SO-Arab
what are the genes in sickle cell anaemia?
two beta HbS genes (HbSS)
- they are no normal beta genes
- can’t produce normal beta chains
- they can’t produce HbA (2alpha2beta)
what is the difference between sickle cell disease and sickle cell anaemia?
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
why is the sickle beta globin gene (betaS) common in Africa, the Middle East and Asia?
carrier state is protective against malaria
beta genes in sickle cell anaemia
beta S beta S
produce HbS
beta genes in haemoglobin C disease (a sickle cell DISEASE)
beta S beta C
produce HbS and HbC
beta genes in sickle cell trait
beta S and beta A
produce HbA (normal) and HbS (sickle cell haemoglobin)
beta genes in normal
beta A and beta A
produce HbA
why can only adults (i.e. non-foetus) be affected by sickle cell disease
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
what vascular effects do sickle cells have?
- 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
what causes pain in adults with sickle cell disease (having sickle cells) ?
oxygen deprivation of tissue and avascular necrosis of bone marrow
what are the organs effects by sickling of cells?
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
infarct
death of tissue due to loss of blood suppy
dactylitis
inflammation of a digit due to infarction of the bone
especially in children
avascular necrosis
death of tissue due to lack of blood supply
especially in adults
osteomyelitis
infection of bone
dead tissues are susceptible to bacterial infection
splenic sequestration
pooling of large numbers of red cells in the spleen
hyposplenism
reduced function of the spleen
in the case of sickle cell disease, the recurrent interruption of blood supply leading to splenic tissue damage
“chest crisis” in the lungs
hypoxia due to lung tissue death
what is the consequence of sickle cell fragility?
shorted lifespan due to haemolysis
results in anaemia
(SCD comes before SCA)
how does the affinity for oxygen in HbS compare to HbA?
HbS has a lower affinity for oxygen therefore released it readily
this makes anaemia tolerable
why can folic acid supply become low due to anaemia?
to compensate for the short lifespan of the sickle cells, there is an increased turnover of the cells which uses up folic acid
what infection does the shortened life span of red cells in SCD make someone someone susceptible to?
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
what is an aplastic crisis?
due to dramatic drop in Hb as a result of halted RBC production (paravovirus B19)
there will be a REDUCTION in reituculocytes
what is splenic sequestration crisis?
children:
abdominal pain, pallor, shock, enlarged spleen and low Hb
raised reticulocytes
blood count in SCD
- shows low Hb
- raised reticulocytes (not in aplastic crisis)
blood film in SCD
- sickled cells
- Howell-Jolly Bodies (hyposplenism- nuclear remnants removed in spleen)
- target cells
what does the screening test for SCD depend on?
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)
What affect does an alkaline pH have on electrophoresis?
what can skew the results?
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
what Hbs are detected in sickle cell anaemia?
- no HbA
- HbS
- variable HbF
- small amount HbA2
what Hbs are detected in sickle cell anaemia?
- HbS
- no HbA
- small amount of HbA2 and HbF
how is a painful crisis managed?
- first avoid factors that precipitate them
- analgesia
- rehydration
- warmth
- additional oxygen
these are for the precipitating factors - antibiotics if infections has been detected
how should SCD be managed?
- folic acid 5mg/day
- vaccination (against pneumococcal infection)
- prophylactic penicillin (prevent infections caused by hyposplenism)
- blood transfusion
- stem cell transplantation (considered in small children)
what are the blood transfusions used?
- top up: in aplastic and sequestration crises
- exchange blood transfusion: life threatening/severe disease e.g. stroke so to reduce HbS levels
what can promote sickling in sickle cell trait people?
- anaesthesia (should be screened before surgery if BetaS)
- high altitude
- air travel in unpressurised plane
