Red Cells Flashcards
1
Q
Red blood cells are also known as
A
erythrocytes
2
Q
RBCs consist of
A
a membrane, enzymes and haemoglobin
3
Q
What are the substances required for RBC production?
A
Metals - iron, copper, cobalt, manganese
Vitamins - B12, folic acid, thiamine, vitamin B6, C, E
Amino acids
Hormones - erythropoietin, GM-CSF, androgens, thyroxine, SCF
4
Q
What is the normal lifespan of RBCs?
A
120 days
5
Q
Where does RBC breakdown occur?
A
In macrophages in the reticuloendothelial system
6
Q
What are globin and haem broken down to?
A
Globin
- amino acids, reutilised
Haem
- iron, reutilised
- heme -> biliverdin -> bilirubin
- bilirubin - bound to albumin
- unconjugated “indirect”
- conjugated in liver
7
Q
What is anaemia?
A
Reduction in red cells or their haemoglobin content
8
Q
How is the normal range derived?
A
Subjects without disease
Normal distribution
Mean +/- 2 standard deviations
Excludes 5%
9
Q
What factors affect normal range?
A
Age Sex Ethnic origin Time of day sample taken Time to analysis
10
Q
What is the normal range of Hb in males 12-70, males > 70, females 12-70 and females > 70?
A
Males 12-70 - 140-180
Male > 70 - 116-156
Female 12-70 - 120-160
Female > 70 - 108-143
11
Q
What sex is more physiologically anaemic?
A
Women
12
Q
What is the aetiology of anaemia?
A
Blood loss
Increased destruction
Lack of production
Defective production
13
Q
If anaemia arises from the bone marrow, what might be affected?
A
Cellularity
Stroma
Nutrients
14
Q
If anaemia arises from the RBCs, what might be affected?
A
Membrane
Haemoglobin
Enzymes
15
Q
If anaemia arises due to destruction or loss, what might this be due to?
A
Blood loss
Haemolysis
Hypersplenism
16
Q
What are the red cell indices?
A
Automated measurement of red cell size and haemoglobin count
MCV = mean cell volume
MCH = mean cell haemoglobin
Can give a morphological description of anaemia
17
Q
What are the morphological descriptions of anaemia?
A
Hypochromic microcytic
Normochromic normocytic
Macrocytic
18
Q
What are the general clinical features of anaemia?
A
Due to reduced oxygen delivery to tissues
- tiredness/pallor
- breathlessness
- swelling of ankles
- dizziness
- chest pain
Dependent on age and Hb level
19
Q
What are the clinical features of anaemia related to an underlying cause?
A
Evidence of bleeding - menorrhagia, dyspepsia, PR bleeding
Symptoms of malabsorption - diarrhoea, weight loss
Jaundice
Splenomegaly
Lymphadenopathy
20
Q
Why might people born with anaemia be able to tolerate this asymptomatically?
A
This is physiologically “normal” for them so may not cause symptoms
21
Q
When do symptoms of anaemia occur?
A
When there is a change in the internal environment or level of anaemia, will depend on the severity of anaemia, age etc.
22
Q
What is hypochromic microcytic anaemia most commonly due to?
A
Iron deficiency
23
Q
What test should you do for hypochromic microcytic anaemia and what would the results suggest?
A
Serum ferritin
- if low then iron deficiency
- if normal or increased then thalassaemia, secondary anaemia or sideroblastic anaemia
24
Q
What test should you do for normochromic normocytic anaemia and what would the results suggest?
A
Reticulocyte count
- if increased then acute blood loss or haemolysis
- if normal or low then secondary anaemia, hypoplasia or marrow infiltration
25
What test should you do for macrocytic anaemia and what would the results suggest?
B12 levels
Folate levels
Bone marrow biopsy
If B12 or folate deficient then megaloblastic anaemia
If due to myelodysplasia, marrow infiltration or drugs then non-megaloblastic anaemia
26
What is macrocytic anaemia most commonly due to?
B12 or folate deficiency, followed by a problem with RBC production in bone marrow
27
What are reticulocytes?
Immature RBCs - measuring can determine whether bone marrow if functioning properly
28
Normally, the dietary intake of iron is balanced by
loss e.g. shedding of skin/hair cells, urine
29
What carries iron around the circulation?
Transferrin
30
To what tissues does transferrin deliver iron?
Tissues that have transferrin receptors
31
How many iron atoms can transferrin contain?
2
32
What incorporates iron into haemoglobin?
Erythroblasts in the bone marrow
33
Where are RBCs broken down?
In macrophages in the reticuloendothelial system
34
What happens to the iron in RBCs when they are broken down?
Iron is released from haemoglobin, enters the plasma and is reutilised to provide most of the iron on transferrin
This recycling is where most of the body's iron is
35
Where does dietary iron enter the body?
Via duodenum and jejunum
36
What is the function of ferroportin?
Carries iron into transport protein (hepcidin) in order to get iron across cell membranes into circulation and hepatocytes and storage areas
37
Some iron is stored in the macrophages as
ferritin and haemosiderin - varies depending on overall body iron status
38
Iron is present in the muscle as
myoglobin
39
Iron is present in most other cells of the body in
iron-containing enzymes e.g. cytochromes, succinic dehydrogenase, catalase
40
What is the role of hepcidin?
Binds and blocks ferroportin so reduces intestinal iron absorption and mobilisation from reticuloendothelial cells
Will bind when sufficient iron to stop mobilisation of iron into the circulation from the hepatocytes if there is already sufficient iron in the circulation
41
What transports iron from the macrophages and enterocytes?
Ferroportin
42
How is iron stored in cells?
As ferritin
43
Where is hepcidin synthesised?
In the hepatocytes in response to inflammation (and increased iron levels)
44
Why does chronic inflammation lead to anaemia?
Hepcidin will prevent iron from being mobilised so it cannot be used to make blood
45
What is the commonest cause of anaemia worldwide?
Iron deficiency anaemia
46
What are the important features of the history in a patient with iron deficiency anaemia?
```
Dyspepsia
GI bleeding
Other bleeding e.g. menorrhagia
Diet
Increased requirement e.g. pregnancy
```
47
What are the important features of the examination of a patient with iron deficiency anaemia?
Signs of iron deficiency - pallor, conjunctival pallor
| Abdominal and rectal examination for GI causes
48
What are the clinical features of iron deficiency anaemia?
Pencil/rod cells, hypochromic microcytic red cells
Koilonychia
Atrophic tongue
Angular cheilitis
49
What are the common causes of iron deficiency anaemia?
GI blood loss
Menorrhagia
Malabsorption
50
What are the investigations for iron deficiency anaemia?
Establish cause from history
Endoscopy
Barium studies
51
What is the management of iron-deficiency anaemia?
Correct underlying cause
- diet
- ulcer therapy
- surgery if active bleeding
Correct anaemia
- iron, oral usually adequate
- transfusion
52
Structure of haemoglobin
Tetramer consisting of two dimers that bind to oxygen
Globular protein with quaternary structure
Four polypeptide subunits - 2 alpha chains and 2 beta chains
53
Functions of haemoglobin
Gas exchange - O2 to tissues, CO2 to lungs
Oxygen dissociation curve
- shift as compensatory mechanism
- Bohr effect; acidosis, hyperthermia, hypercapnia
- HpF - higher O2 affinity than HbA
54
What is normal adult haemoglobin composed of?
```
Haem molecule
2 alpha chains
4 alpha genes (chromosome 16)
2 beta chains
2 beta genes (chromosome 11)
```
55
What percentage of adult haemoglobin is HbA, HbA1 and HbF?
HbA 97% (alpha-alpha-beta-beta)
HbA2 2% (alpha-alpha-delta-delta)
HbF 1% (alpha-alpha-gamma-gamma)
56
What are haemglobinopathies?
Inherited abnormalities of haemoglobin synthesis
57
What does reduced or absent globin chain result in?
Thalassaemia
58
What do mutations leading to structurally abnormally globin chains result in?
```
HbS (sickle cells)
HbC
HbD
HbE
HbO Arab
```
59
What is the inheritance of haemoglobinopathies?
Autosomal recessive
1/4 chance of having an affected child
1/2 chance of being a carrier
60
What are the components of sickle haemoglobin?
Haem molecule
2 alpha chains
2 beta sickle chains
Rigid sickle-like RBCs
61
What are the consequences of HbS polymerisation?
Red cell injury, cation loss, dehydration
Haemolysis
- endothelial activation, promotion of inflammation, coagulation activation, dysregulation of vasomotor tone by vasodilator mediators
- vaso-occlusion
62
Cerebral vasculopathy is a major risk factor for
stroke
63
What are the clinical presentations of sickle cell disease?
```
Painful vaso-occlusive crises - bone
Chest crisis
Stroke, cerebral infarcts, mental retardation
Increased infection risk - hyposplenism
Chronic haemolytic anaemia - gallstones, aplastic crisis
Sequestration crises - spleen, liver
Retinopathy
Pulmonary infarcts, pneumonia
Splenomegaly, splenic atrophy
Infarcts of extremities
Vaso-occlusion
Ulcers
Bone marrow hyperplasia, aseptic bone necrosis, osteomyelitis
Renal infarcts, haematuria
Cholelithiasis
Cardiomegaly, congestive heart failure
```
64
What is the life expectancy of patients with sickle cell disease?
Median age at death in US is 42 for males and 48 for females
Survival to 18 years increasing;
- 85% in 2004
- 96% in 2010
65
What is the management of sickle cell painful crisis?
```
Severe pain - often requires opiates
Analgesia should be given within 30 mins of presentation
Effective analgesia by 1 hour
Avoid pethidine
Hydration
Oxygen
Consider antibiotics
No routine role for transfusion
```
66
What is the clinical presentation of sickle cell chest crisis?
Chest pain
Fever
Worsening hypoxia
Infiltrates on CXR
67
What is the management of sickle cell chest crisis?
```
Respiratory support
Antibiotics
IV fluids
Analgesia
Transfusion - top up or exchange target HbS < 30%
```
68
What is the management of sickle cell disease?
Lifelong prophylaxis
- vaccination
- penicillin prophylaxis
- folic acid
Acute events
- hydration
- oxygenation
- prompt treatment of infection
- analgesia - opiates, NSAIDs
Blood transfusion
- episodic and chronic
- alloimmunisation
- iron overload
Disease modifying drugs
- hydroxycarbamide
Bone marrow transplantation
69
What is the cause of thalassaemia?
Reduced or absent globin chain production
Mutations or deletions in alpha genes (alpha thalassaemia) or beta genes (beta thalassaemia) - there are also gamma and delta thalassaemias but alpha and beta are the most important
70
What is the spectrum of clinical severity of thalassaemia?
Homozygous alpha zero thalassamia
- no alpha chains
- hydrops fetalis, incompatible with life
Thalassaemia major
- beta thalassameia major
- no beta chains
- transfusion-dependent anaemia
Thalassaemia intermedia
- non-transfusion dependent
Thalassaemia minor
- trait or carrier state
- hypochromic microcytic red cells indices
71
What is the presentation of beta thalassaemia major?
```
Severe anaemia
Presents at 3-6 months of age
Expansion of ineffective bone marrow
Bony deformities
Splenomegaly
Growth retardation
```
72
What is the life expectancy of beta thalassaemia major when untreated or with irregular transfusions?
< 10 years
73
What is the treatment of beta thalassaemia major?
Chronic transfusion support - 4-6 weekly
Normal growth and development but iron overloading
Death in 2nd or 3rd decade due to heart, liver or endocrine failure if iron overloading is untreated
Iron chelation therapy
- subcutaneous desferrioxamine infusions
- oral desferasirox
74
What is the curative treatment of beta thalassaemia major?
Bone marrow transplantation
75
What is the life expectance of beta thalassaemia major with good adherence to chelation therapy?
> 40 years, requires regular monitoring
76
What do defects in mitochondrial steps of haem synthesis result in?
Sideroblastic anaemia
- ALA synthase mutations
- Hereditary (x-linked)
- acquired - myelodysplasia
77
What do defects in cytoplasmic steps of haem synthesis result in?
Porphyrias
78
When is haem converted to bilirubin?
When RBCs are broken down, as haem is released from haemoglobin it is converted to bilirubin
79
What do direct and indirect bilirubin measure?
Direct bilirubin is the measurement of conjugated bilirubin in the blood
Indirect bilirubin is the measurement of unconjugated bilirubin in the blood
80
What are the features of the direct antiglobulin test/Coombs test?
Detects antibody or complement on red cell membrane
Reagent contains either; anti-human IgG or anti-complement
Reagent binds to antibody (or complement) on red cell surface and causes agglutination in vitro
Implies immune basis/component of haemolysis
Only tells you if antibodies are present on surface of cells, does not tell you why they are there
81
In haemolytic anaemia, what does it mean when the direct antiglobulin test is positive and what does it mean when negative?
If positive - immune mediated
| If negative - non-immune mediated
82
```
In immune haemolysis, what does the presence of;
warm auto-antibody
cold auto-antibody
alloantibody
mean?
```
Warm auto-antibody - autoimmune, drugs or CLL
Cold auto-antibody - CHAD, infection or lymphoma
Alloantibody - transfusion reaction
83
What are the histological features of extravascular immune haemolysis?
Spherocytes on film
Agglutination in cold
AIHA
84
What are the histological features of intravascular immune haemolysis?
Red cell fragments - schistocytes
85
Genetic defects leading to congenital anaemias are described in terms of
red cell membrane
metabolic pathways
haemoglobin
86
What are the features of red cell membrane disorders?
Skeletal proteins responsible for maintaining red cell shape and deformability
Defects in skeletal proteins can lead to increased cell destruction
87
What is the most common form of hereditary spherocytosis?
Autosomal dominant
88
In hereditary spherocytosis, defects in what 5 structural proteins are described?
```
Ankyrin
Alpha spectrin
Beta spectrin
Band 3
Protein 4.2
```
89
What are the features of the abnormal RBCs in hereditary spherocytosis?
Spherical in shape and removed from circulation by spleen
90
What is the clinical presentation of hereditary spherocytosis?
```
Variable
Anaemia
Jaundice
Splenomegaly
Pigment gallstones
```
91
What is the treatment of hereditary spherocytosis?
Folic acid - increased requirements
Transfusion
Splenectomy
92
What are the other rare membrane disorders?
Hereditary elliptocytosis
Hereditary pyropoikilocytosis
South East Asian ovalocytosis
93
What is the commonest disease causing enzymopathy in the world?
G6DP deficiency
94
What are the features of G6DP deficiency?
```
Cells vulnerable to oxidative damage
Many genetic variants
Confers protection against malaria
X-linked, affects males with female carriers
Blister cells and bite cells seen
```
95
What is the clinical presentation of G6DP deficiency?
```
Variable
Neonatal jaundice
Drug, broad bean or infection precipitated jaundice and anaemia
- intravascular haemolysis
- haemoglobinuria
Splenomegaly
Pigment gallstones
```
96
What are the triggers to haemolysis in G6DP deficiency?
Infection
Acute illness e.g. DKA
Broad beans
Drugs
97
What drugs can trigger haemolysis in G6DP deficiency?
Antimalarials - primaquine, pamaquine
Sulphonamides and sulphones - salazopyrin, dapsone, septrin
Antibacterials - nitrofurantoin
Analgesics - aspirin
Anti-helminthics - B naphthol
Miscellaneous - vitamin K analogues, probenecid, methylene blue
98
What are the features of pyruvate kinase deficiency?
```
Reduced ATP
Increased 2,3-DPG
Cells rigid
Variable severity
- anaemia
- jaundice
- gallstones
```
99
What are the features of haemolytic anaemia?
Accelerated red cell destruction (reduced haemoglobin)
Compensated by bone marrow (increased retics)
Level of Hb = increased production/rate of destruction
Haemolysis can be extravascular e.g. within macrophages or intravascular (or both)
100
What is the difference between intravascular and extravascular haemolysis?
Extravascular haemolysis is a normal physiological process
Intravascular haemolysis is what happens when damage occurs to the RBCs within the circulation e.g. toxic damage, leaky heart valve causing turbulent flow, and is a pathological process rather than a normal physiological process
101
What are the congenital causes of haemolytic anaemia?
Hereditary spherocytosis
Enzyme deficiency
Haemoglobinopathy
102
What are the acquired causes of haemolytic anaemia?
Auto-immune haemolytic anaemia (extravascular)
Mechanical e.g. artificial valve (intravascular)
Severe infection (intravascular)
Drugs (intravascular)
Acquired immune haemolytic anaemia is mostly extravascular
Acquired non-immune haemolytic anaemia is mostly intravascular
103
What investigations should you do to determine whether a patient is haemolysing?
FBC, reticulocyte count (high), blood film (differentiate between serocytes, membrane disorder, sickle cell disease etc.)
Serum bilirubin (direct/indirect), LDH (high in haemolysis)
Serum haptoglobin - binds free Hb, level low if haemolysis (bilirubin high)
104
How can you determine the mechanism of haemolysis?
History and examination
Blood film
Direct antiglobulin test (Coombs test)
Urine for haemosiderin (free Hb coming out in urine)/urobilinogen
105
What is the management of haemolytic anaemia?
Support marrow function - folic acid
Correct cause
- immunosuppression if autoimmune, treat trigger e.g. CLL, lymphoma
- remove site of red cell destruction - splenectomy
- treat underlying cause e.g. sepsis, leaky prosthetic valve, malignancy etc. if intravascular
Consider transfusion
106
What are are the features of secondary anaemia?
70% normochromic normocytic
30% hypochromic microcytic
Defective iron utilisation
- increased hepcidin in inflammation
- ferritin often elevated
Identifiable underlying disease
Treatment is to treat underlying disease
107
What are the causes of megaloblastic anaemia?
B12/folate deficiency
108
What are the causes of vitamin B12 deficiency?
Pernicious anaemia
| Gastric/ileal disease
109
What are the causes of folate deficiency?
Dietary
Increased requirements
GI pathology
110
What is the typical presentation of megaloblastic anaemia due to folate deficiency?
Lemon yellow tinge to skin
111
Why can vitamin B12 deficiency take years to present?
Due to stores
112
What does dietary vitamin B12 bind to?
Intrinsic factor, secreted by gastric parietal cells
| Vitamin B12 cannot be absorbed unless bound to intrinsic factor
113
What is vitamin B12 bound by in the portal circulation?
Transcobalamin
114
What is the commonest cause of vitamin B12 deficiency in western populations?
Pernicious anaemia
115
What are the features of pernicious anaemia?
Autoimmune disease
Antibodies against intrinsic factor
Malabsorption of dietary B12
Symptoms/signs take 1-2 years to develop
116
What is the treatment of megaloblastic anaemia?
Replace vitamin
B12 deficiency
- B12 IM injection, loading dose then 3 monthly maintenance
Folate deficiency
- oral folate replacement, ensure B12 normal if neuropathic symptoms
If in doubt, give both B12 and folate which waiting for full test results (especially if neuropathic symptoms)
117
What are the other causes of macrocytosis?
```
Alcohol
Drugs - methotrexate, antiretrovirals, hydroxycarbamide
Disordered liver function
Hypothyroidism
Myelodysplasia
```
