Red Cells Flashcards
1
Q
what is anaemia?
A
the reduction in red cells or their haemoglobin content
2
Q
main causes of anaemia
A
blood loss
increased destruction
lack of production
defective production
3
Q
describe the development of red cells
A
see notes
4
Q
what substances are required for red cell production?
A
metals - iron, copper, cobalt, manganease
vitamina -B12, folic acid,thiamine, B6, C, E
amino acids
hormones - erythropoietin, GM-CSF, androgens, thyroxine, SCF
5
Q
normal life span of RBC
A
120 days
6
Q
where does red cell breakdown take place?
A
in macrophages of reticuloendothial system
7
Q
what happens to haem after red cell breakdown?
A
converted to biliverdin and bilirubin
8
Q
what happens to globin and iron after red cell breakdown?
A
reutilised
9
Q
describe the bilirubin cycle
A
see notes
10
Q
defects in what parts of RBCs cause congenital anaemia
A
membrane
enzymes
haemoglobin
11
Q
most congenital anemias result in what?
A
haemolysis
12
Q
what are skeletal proteins in RBCs responsible for?
A
maintaining red cell shape and deformability
13
Q
what can defects in the RBC cells membrane proteins caused?
A
increased cell destruction - haemolysis
14
Q
what proteins are most commonly mutated in red cell membranes?
A
ankyrin
band 3
spectrin
15
Q
draw a RBC membrane
A
see notes
16
Q
Hereditary spherocytosis: inheritance
A
autosomal dominant
17
Q
Hereditary spherocytosis: structural protein defects
A
ankyrin alpha spectrin beta spectrin band 3 protein 4.2
18
Q
Hereditary spherocytosis: shape of cells
A
spherical
19
Q
Hereditary spherocytosis: how are cells removed from circlulation?
A
haemolysis extravascular by spllen
20
Q
Hereditary spherocytosis: clinical presentation
A
anaemia
jaundice (neonatal)
splenomegaly
pigment gallstones
21
Q
Hereditary spherocytosis: treatment
A
folic acid
transfusion
splenectomy
22
Q
name 3 rare membrane disorders
A
hereditary elliptocytosis
hereditary pyropoikilocytosis
South East Asian Ovalocytosis
23
Q
name 2 cycles occuring in red cells. how are they linked?
A
gylcolysis
pentose phosphate shunt
glucose-6-phosphate dehydrogenase
24
Q
in RBCs what is the purpose of glycolysis?
A
provides energy
25
in RBCs what is the purpose of the pentose dehydrogenase shunt?
protects from oxidative damage
26
what protects red cell proteins from oxidative damage?
glucose 6 phosphate dehydrogenase (G6PD)
27
what does G6PD produce?
NADPH
28
what is NADPH vital for?
reduction of glutathione
29
what does reduced glutathion do?
scavenges and detoxifies reactive oxygen species
30
what is the commonest disease causing enzymopathy in the world?
G6PD deficiency
31
what does G6PD deficiency result in?
cells vulnerable to oxidative damage
32
where is G6PD most common and why?
malarial areas as confers protection against severe falciparum
33
inheritance in G6PDdeficiency
x linked
34
what characteristics are there of RBCs in G6PD deficiency?
blister and bite cells
35
where does haemolysis occur in G6PD deficiency, what is the problem with this?
intravascular
| haemoglobin can reach kidneys
36
clinical presentation of G6PD deficiency
neonatal jaundice
drug, broad bean or infection precipitated jaundice and anaemia
splenomegaly
pigment gall stones
37
triggers to haemolysis in G6PD deficiency
infection
acute illness e.g. DKA
broad beans "favism"
38
what drugs can cause G6PD deficiency?
```
o Antimalarials – primaquine, pamaquine
o Sulphonamides and sulphones – salazopyrin, dapson, seprtin
o Antibacterials – nitrofurantoin
o Analgesics – aspirin
o Antihelminths – B-naphthol
o Vitamin K analogues
o Probenecid
o Methylene blue
```
39
name a rare enzyme deficiency disorder and briefly describe it
o Reduced ATP
o Increased 2,3,-DPG
o Cells rigid
o Variable severity – anaemia, jaundice, gallstones
o More liable to haemolysis in circulation
40
in deoxyhaemoglobin what enzyme holds it in the tight binding structure?
2,3-DPG
41
function of haemoglobin
gas exchange
42
affinity of foetal haemoglobin (HbF) for oxygen compared to HbA
higher
43
describe the structure of normal adult haemoglobin
2 alpha chains
4 alpha genes, Chr16
2 beta chains
2 beta genes, Chr11
44
describe the composition of haemoglobin in a normal adult
HbA (aabb) - 97%
HbA2 (aadd) - 2%
HbF (aayy) - 1%
45
what are haemoglobinopathies?
inherited abnormalities of haemoglobin synthesis
46
what is thalassaemia?
reduced or absent globin chain production
47
give examples of mutations that lead to structurally abnormal globin chains
```
HbS (sickle)
HbC
HbD
HbE
HbO Arab
```
48
inheritance of haemoglobinopathies
autosomal recessive
49
structure of sickle haemoglobin
haem
2 alpha chains
2 beta (sickle) chains
50
what mutation leads to sickle beta chains
point mutation - glutamate to valine
51
describe the consequences of sickle cell
red cell injury, cation loss, dehydration
52
describe the process of vaso-occlusion in sickle cell
```
haemolysis
endothelial activation
promotion of inflammation
coagulation activation
dysregulation of vasomotor tone by vasodilator mediations (NO)
vaso occlusion
```
53
describe polymerisation in sickle cell
Some of the major complications of sickle cell disease (SCD) such as acute chest syndrome, stroke and pain episodes are attributed to vasoocclusive tissue damage. Cerebral vasculopathy is a major risk factor for stroke. The primary pathophysiologic mechanisms for lung disease are unknown. Pulmonary vasculopathy may be a risk factor for acute chest syndrome pulmonary hypertension. Both are leading causes of morbidity and mortality in adults with sickle cell disease.
54
sickle cell presentation
```
retinopathy
cardiomegaly - congestive HF
cholelithiasis
renal infarcts - haematuria
bone marrow hyperplasia
aseptic bone necrosis - osteomyelitis
ulcer
vaso-occlusion
infarcts of extremities
splenomegaly - splenic atrophy
pulmonary infarcts -pneumonia
cerebral infarcts - stroke - mental retardation
```
55
complications of sickle cell
```
• Painful vaso-occlusive crises
o Bone
• Chest crisis
• Stroke
• Increased infection risk
o Hyposplenism – splenic infarction and atrophy
• Chronic haemolytic anaemia
o Gallstones
o Aplastic crisis – eyrthrovirus
• Sequestration crises
o Spleen – children, pooling of RBCs and not getting out, enlarged spleen
o Liver – enlarged liver
• Life expectancy
o Males 42
o Females 48
o Childhood and perinatal mortality contribute to this reduction
```
56
treatment of a painful crisis in sickle cell
```
• Severe pain – often requires opiates
o Analgesia should be given within 30 mins of presentation
o Effective analgesia by 1 hour
o Avoid pethidine
• Hydration
• Oxygen
• Consider
• Antibiotics
• No routine role for transfusion
```
57
describe a chest crisis in sickle cell
* Life threatening
* Chest pain
* Fever
* Worsening hypoxia
* Infiltrates on CXR
* Respiratory support
* Antibiotics
* IV fluids
* Analgesia
* Transfusion – top up or exchange target HbS < 30%
* Incentive spirometry shown to reduce incidence
58
management of sickle cell
```
• Lifelong prophylaxis
o Vaccination
o Penicillin and malarial prophylaxis
o Folic acid
• Acute events
o Hydration
o Oxygenation
o Prompt treatment of infection
o Analgesia
Opiates
NSAIDs
• Blood transfusion
o Episodic and chronic
o Alloimmunisation
o Iron overload
• Disease modifying drugs
o Hydroxycarbamide
• Bone marrow
o Transplantation
o Severe
• Gene therapy
o Severe
```
59
thalassaemia can result from mutations/delections in
alpha genes
beta genes
also gamma and delta but less important
60
thalassaemia results in
chain imbalance - chronic haemolysis and anaemia
61
spectrum of thalassaemia from fatal to minor
homozygous alpha zero thalassaemia
thalassaemia major
thalassaemia intermedia
thalassaemia minor
62
what is homozygous alpha zero thalassaemia
no alpha chains
| hydrops fetalis - incompatible with life
63
what is beta thalassaemia major
no beta chains
| transfusion dependent anaemia
64
when may someone with thalassaemia intermedia require transfusions?
times of stress
65
what is thalassaemia minor?
carrier
hypochromic microcytic cells
asymptomatic
66
severe anaemia in beta thalassaemia major results in
o Expansion of ineffective bone marrow
o Bony deformities
o Splenomegaly
o Growth retardation
67
when does beta thalassaemia major present?
3-6months
68
treatment of beta thalassaemia major
chronic transfusion
iron chelation therapy
bone marrow transplant
69
how often do those with beta thalassaemia major require blood transfusions? what can this cause?
4-6 weekly
| iron overloading
70
consequences of iron overloading
death in 2nd/3rd decade due to heart/liver/endocrine failure if unteated
71
describe iron chelation therapy
s/c deferrioxamine infusions (Desferal)
Oral deferasirox (exjade)
If good adherence life expectancy >40
72
describe rare defects in haem synthesis
Defects in mitochondrial steps of haem synthesis result in sideroblastic anaemia. ALA synthase mutations. X linked inheritance. Acquired myelodysplasia. Defects in cytoplasmic steps result in porphyrias.
73
what factors influence normal haemoglobin?
```
age
sex
ethnic origin
time of day
time to analysis
```
74
normal haemoglobin: male 12-70
140-180
75
normal haemoglobin: male > 70
116-156
76
normal haemoglobin: female 12-70
120-160
77
normal haemoglobin: female >70
108-143
78
clinical features of acquired anaemia are due to?
reduced oxygen delivery to tissues
79
clinical features of acquired anaemia
```
tiredness/pallor
breathlessness
swelling of ankles
dizziness
chest pain
```
80
clinical features of acquired anaemia related to underlying cases
evidence of bleeding
symptoms of malabsorption - diarrhoea, weight loss
jaunice
splenomegaly/lymphadenopathy
81
potential causes of anaemia due to bleeding
menorrhagia
dyspepsia
PR bleeding
82
what further tests would you do in a hypochromic microcytic anaemia?
serum ferritin
83
what further tests would you do in a normochromic normocytic anaemia?
reticulocyte count
84
what further tests would you do in a macrocytic anaemia?
B12/folate
| bone marrow
85
most common cause of hypochromic microcytic anaemia?
iron deficiency
86
hypochromic microcytic anaemia, serum ferritin = low
iron deficiency
87
hypochromic microcytic anaemia, serum ferritin = normal/increased
secondary anaemia
thalassaemia
sideroblastic anaemia
88
describe iron metabolism
Transferrin can contain up to two atoms of iron. Transferrin delivers iron to tissues that have transferrin receptors, especially erythroblasts in the bone marrow which incorporate the iron into haemoglobin. At the end of the red cell life cycle, the red cells are broken down in the macrophages of the reticuloendothelial system and the iron is released from haemoglobin, enters the plasma and is reutilised to provide most of the iron on transferrin. Only a small proportion of plasma transferrin iron comes from dietary iron, which comes in via the duodenum and jejunum. Some iron is stored in the macrophages as ferritin and haemosiderin, which varies depending on overall body iron status. Iron is also present in the muscle as myoglobin and in most other cells of the body in iron-containing enzymes e.g. cytochromes, succinic dehydrogenase, catalase. Body has no way of getting rid or iron hence why it builds up in transfusions
Hepcidin goes up in menstruation, inflammation and renal impairment to stop utilising iron. Iron absorbed in duodenum - Fe2+ > Fe3+. Transported from enterocytes and. macrophages by ferroportin. Transported in plasma bound to transferrin. Stored in cells as ferritin. Hepcidin synthesised in hepatocytes in response to inflammation (also renal failure and ↑iron levels)– blocks ferroportin so reduces intestinal iron absorption and mobilisation from reticuloendothelial cells.
89
causes of iron deficiency
```
dyspepsia, GI bleeding
menorrhagia
diet
increased requirement e.g. pregnancy
malabsorption
```
90
what may cause malabsorption of iron?
gastrectomy
| coeliac disease
91
principles of management in iron deficiency
correct the deficiency
| correct the cause
92
how to correct iron deficiency
oral iron
IV if intolerant of oral
transfusion rarely indicated
93
how to correct the cause of iron deficiency
diet
ulcer therapy
gynae interventions
surgery
94
nomochromic normocytic anaemia, reticulocyte count = increased
blood loss
| haemolysis
95
nomochromic normocytic anaemia, reticulocyte count = normal/low
secondary anaemia
hypoplasia
marrow infiltration
96
results of haemolytic anaemia
accelerated red cell destruction - decreased haemoglobin
| compensated by bone marrow - increased reticulocytes
97
causes of haemolytic anaemia: congenital
hereditary spherocytosis
enzyme deficiency G6PD def
haemoglobinopathy - sickle cell
98
causes of haemolytic anaemia: acquired
autoimmune haemolytic anaemia
mechanical e.g. artificial valve
sever infections/DIC
PET/HUS/TTP
99
extra vs intravascular. acquired haemolytic anaemia - immune related
extravascular
100
extra vs intravascular. acquired haemolytic anaemia - non-immune related
intravascular
101
in haemolytic anaemia what does it mean if DAGT is positive?
immune related
102
causes of acquired immune haemolysis + warm auto antibody
auto immune
drugs
CLL
103
causes of acquired immune haemolysis +cold autoantibody
CHAD
infections
lymphoma
104
causes of acquired immune haemolysis + alloantibody
transfusion reaction
105
how do you determine if a patient is haemolysing?
o FBC, reticulocyte count, blood film
o Serum bilirubin (direct/indirect), LDH
o Serum haptoglobin
106
how do you determine the cause of haemolysis?
o History and examination
o Blood film
o Direct antiglobulin test (Coombs’ test)
o Urine for haemosiderin/urobilinogen -intravascular haemolysis
107
management of haemolytic anaemia
```
• Support marrow function
o Folic acid
• Correct cause
o Immunosuppression if autoimmune
Treat trigger e.g. CLL , lymphoma
o Remove site of red cell destruction
Splenectomy
o Treat sepsis, leaky prosthetic valve, malignancy etc if intravascular
• Consider transfusion
```
108
secondary anaemia aka
anaemia of chronic disease
109
secondary anaemia is mostly what type?
normochromic normocytic
110
what causes secondary anaemia?
Defective iron utilisation as a result of increased hepcidin in inflammation. Ferritin is often elevated. Identifiable underlying disease – infection, inflammation, malignancy.
111
causes of megalblastic macrocytic anaemia
B12/folate deficiency
112
causes of non-megaloblastic macrocytc anaemia
myelodysplasia
marrow infiltration
drugs
113
causes of B12 deficiency
pernicious anaemia
| gastric/ileal disease
114
causes of folate deficienc
dietary
increased requirements e.g. haemolysis
GI pathology e.g. coeliac
115
how is B12 absorped?
dietary B12 binds to intrinsic factor, secreted by gastric parietal cells. B12-IF complex attaches to specific IF receptors in distal ileum. Vit B12 bound by transcobalamin II in portal circulation for transport to marrow and other tissues
116
mechanism of pernicious anaemia
It is an autoimmune disease. Antibodies against intrinsic factor (diagnostic) and gastric parietal cells. There is malabsorption of dietary B12, but the signs and symptoms take around 1-2 years to develop.
117
causes of non-megaloblastic macrocytosis
```
• Alcohol
• Drugs
o Methotrexate, antiretrovirals, hydroxycarbamide
• Disordered liver function
• Hypothyroidism
• Myelodysplasia
```
