1
Q
What is anaemia?
A
A Hb concentration lower than the normal range
-not a diagnosis, but manifestation of an underlying disease state
(Normal range varies with age,sex,ethnicity, location)
2
Q
What are the signs and symptoms of anaemia?
A
Symptoms
- breathlessness
- palpitations
- headaches
- claudication (cramping pain in legs during exercise)
- lethargy/weakness
- angina
- confusion
Signs
- pallor (pale)
- tachycardia
- tachypnoea (fast breathing rate)
- hypotension
- systolic flow mumur
3
Q
What are specific signs for severe anaemia?
A
- nails look spoon shaped (Koilonychia-due to iron deficiency)
- swollen, shiny tongue (Glossitis- vit B12 deficiency)
- haemopoiesis in bone not expected e.g. facial bones-thalassaemia, rare in recent times due to early diagnosis
- inflammation of corners of the mouth (Angular stomatitis- iron deficiency)
Don’t see these due to screening now.
4
Q
How may anaemia develop?
A
In bone marrow:
- reduced/dysfunctional erythropoiesis
- abnormal haem synthesis
- abnormal globin chain synthesis
Peripheral RBC’s:
- abnormal structure
- mechanical damage to membrane
- abnormal metabolic pathway
- excessive bleeding (e.g. bowel cancer)
- increased activity of removal by RES
5
Q
What is the negative feedback loop involving erythropoietin (EPO)?
A
- low oxygen in blood
- pericytes in kidney sense hypoxia, and produce EPO
- EPO binds to receptors on erythroblasts (have nucleus, come before reticulocyte) in bone marrow stimulating RBC production
- increased number of RBC’s > high blood oxygen
- negative feedback to pericytes in kidney
6
Q
How might defects in Hb synthesis develop?
A
- mutations in globin chain proteins (alpha/beta thalassaemia, sickle cell)
- sideroblastic anaemia (defects in haem synthesis)
- insufficient iron (leads to iron deficiency anaemia)
- anaemia of chronic disease (sufficient iron in body but not available for erythropoiesis)
7
Q
How do abnormal structure/mechanical damage to blood cells lead to haemolytic anaemia ?
A
-damaged/abnormal RBC’s get removed quickly
Inherited
-mutations in genes coding for proteins involved in interactions b/w plasma membrane and cytoskeleton
-cause cells to become less flexible/more easily damaged
-break up in circulation/removed more quickly by RES
E.g. hereditary spherocytosis
Acquired damage
- osmotic damage
- heat damage
- microangiopathic haemolytic anaemias result from mechanical damage (stress as cells pass through defective heart valve,cells snagging on fibrin strands in small vessels where clotting cascade has occured)
8
Q
What are some metabolic abnormalities causing anaemia?
A
G6PDH deficiency
- limits amount of NADPH
- NADPH required for conversion of oxidised glutathione back to reduced glutathione
- therefore oxidative defence mechanism not working
- lipid peroxidation to cell membrane, protein damage causing aggregates of cross linked Hb
- formation of heinz bodies
- causing haemolysis (removed by spleen)
Pyruvate kinase deficiency
- final enzyme in glycolysis
- can’t undergo glycolysis and make energy properly
- RBC’s rely on glycolysis due to lack of mitochondria
- causes RBC’s to become rapidly deficient in ATP, so they undergo haemolysis
9
Q
How can excessive bleeding cause anaemia?
A
Acute blood loss
- injury
- surgery
- childbirth
- ruptured blood vessel
Chronic bleeding (small amount of bleeding continuing over a long time)
- heavy menstrual bleeding
- GI tract bleeding (blood lost in stool)
- repeated nosebleeds
- haemorroids
- kidney/bladder tumours (blood lost in urine)
10
Q
Why does splenomegaly arise?
A
Due to haemolytic anaemias, as the spleen is doing extra work.
11
Q
What is myelofibrosis?
A
Reactive bone marrow fibrosis from proliferation of mutated haematopoietic stem cells, so no space for bone marrow/growth of RBC’s
-mutated progenitor cells can colonise liver/spleen leading to extramedullary haemopoiesis (showing enlarged liver and spleen)
12
Q
What is thalassaemia?
A
- inhertied disorder resulting in absent/decreased beta globin chain development
- microcytic hypohromic red cells
- splenomegaly
13
Q
What would you see an increase in if the patient is anaemic?
A
Reticulocytes
(If bone marrow is working)
(MCV is larger as reticulocytes are bigger than RBC’s)
14
Q
What are the 2 key factors that help you work out the cause of anaemia?
A
- RBC size (microcytic-small, macrocytic-big, normocytic-normal)
- increase in reticulocyte count (yes= Bone marrow working)
15
Q
If the bone marrow is functioning, what is the next sign to look for after presence of reticulocytes?
A
Evidence of haemolysis (high bilirubin/LDH)
16
Q
What are the causes of macrocytic anaemia?
A
Megaloblastic anaemias
- DNA synthesis gone wrong in RBC’s, nucleus can’t mature at same rate as cytoplasm
- cell division is delayed, so cell gets larger while maturation occurs
- formation of megaloblasts
e. g.vit B12/folate deficiency, drugs interfering with DNA synthesis/erythroid leukaemias where DNA synthesis is retarded
Macronormoblastic
- cells just larger (no difference in maturation of nucleus/cytoplasm)
- erythroblasts are larger than normal so give rise to larger RBC’s
e. g.liver disease, alcohol toxicity
Stress erythrpoiesis (macrocytic cells)
- high reticulocyte count- reticulocytes are larger than RBC’s
- high level of erythropoietin leads to accelerated erythropoiesis
e. g. blood loss/haemolytic anaemia recovery
17
Q
What is folate?
A
- synthesised by bacteria and plants
- present often in animal/veg food (often green leafy) or liver in pate
- absorbed mainly by duodenum/jejunum
- converted to tetrahydrofolate by intestinal cells
- taken up by liver acting as a store (3-4 months of store)
- provides carbons for other reactions
-important in reactions that involve DNA/RNA synthesis, as it is used in base formation
18
Q
Causes of folate deficiency?
A
- poor diet
- increased requirement (more stress on bone marrow) e.g. pregnancy, haemolytic anaemia due to increased erythropoiesis, severe skin disease-losing folic acid via shed skin
- diseases of duodenum/jejunum (Coeliac/Crohn’s)
- drugs that inhibit dihydrofolate reductase (Methotrexate)
- alcoholism (damage to intestinal cells)
- urinary loss of folate in liver disease & heart failure
19
Q
What are some symptoms of folate deficiency?
A
- diarrhoea
- those related to anaemia
- sense of taste loss
- numbness/tingling in feet/hands
- depression
- muscle weakness
20
Q
Why is folate so important in pregnancy?
A
- folate used for formation of neural tube
- can lead to spina bifida
21
Q
What is the function of vit B12?
A
- water soluable
- essential co factor for DNA synthesis/erythropoiesis/normal functioning of CNS
- produced by bacteria (in animals-commensal bacteria)
22
Q
How is vit B12 absorbed?
A
- B12 released from food proteins by proteolysis in stomach
- binds to haptocorrin in stomach stopping it from being digested
- enters small intestine
- digested by pancreatic proteases, splitting B12 from haptocorrin
- B12 binds to intrinsic factor in small intestine (intrinsic factor produced by gastric parietal cells)
- B12/intrinsic factor complex binds to cubam receptor initiating receptor mediated endocytosis into enterocytes
- B12 released into intestinal cell via lysosomal release
- B12 exits via basolateral membrane (orientated away from lumen) via MDR1
- B12 binds to transcobalamin in blood and transported around blood
- stored in liver (3-6 years storage)
23
Q
Causes of B12 deficiency:
A
- dietary deficiency
- lack of intrinsic factor (pernicious anaemia)
- diseases of ileum (this is where B12 intrinsic factor complex is absorbed)
- lack of transcobalamin
- chemical inactivation of B12 (nitrous oxide gas)
- drugs can chelate intrinsic factors
- parasitic infections (tapeworm in fish can trap B12)
24
Q
What is pernicious anaemia?
A
-lack of intrinsic factor
-exhaustion of B12 reverse
-autoimmune disease: cells damage cells in stomach so they can’t produce intrinsic factor
E.g.blocking/binding Ab
25
Symptoms of B12 deficiency:
- glossitis + mouth ulcers
- those related to anaemia
- paraesthesia
- diarrhoea
- disturbed vision
- irritability
26
What is subacute combined desegregation of the chord caused by and symptoms?
-deficiency in B12/folate
Folate: in pregnancy- neural tube defects
B12: associated with focal demyelination (often reversible but can result in SCDC- irreversible)
-degeneration of posterior/lateral columns of spinal chord
Symptoms
- gradual onset weakness
- numbness/tingling in arms/trunk which worsens
- changes to mental state
27
How is B12/folate linked?
- combination of uracil instead of thymine
- both required for creation of thymine
- absence of thymine means uracil incorporated instead
Causes megaloblastic anaemia as B12/folate are necessary for nuclear maturation/division- open chromatin
28
What are megaloblastic features in blood film?
- tear drops
- hypersegmented neutrophils
- macrocytic red cells
- ovalocytes
- anisopoikilocytosis (variance in size and shape)
29
What is the treatment of B12/folate deficiency?
-oral folic acid
-oral B12
-intramuscular hydroxycobalamine for pernicious anaemia NOT ORAL
(beware of hypokalaemia at beginning of treating pernicious anaemia due to increased requirement of K+ as erythropoiesis increases back to normal)
30
Difference between signs and symptoms?
Symptoms: what the patient feels
Signs: what you can see
31
Is anaemia alone a diagnosis?
No, it shows a manifestation of an underlying disease, so it is important to establish the cause of anaemia.
32
What are pericytes?
Cells that wrap around endothelial cells that line capillaries.
33
How may anaemia develop from low erythropoiesis?
- kidney stops making erythropoietin
- bone marrow being unable to respond to EPO
- if marrow is infiltrated by cancer cells/fibrous tissue, number of normal haemopoietic cells is reduced
- anaemia of chronic disease: iron not available to make RBC’s
- myelodysplastic syndromes (abnormal clones of marrow stem cells limit capacity to make blood cells)
34
How do autoimmune haemolytic anaemias work?
Autoantibodies bind to red cell membrane proteins causing them to be recognised by macrophages in spleen and destroyed.
35
What is intravascular/extravascular anaemia?
Intra: damage occurs within the blood vessels
Extra: within RES system
36
What are reticulocytes?
- immature RBC's
- larger than RBC's so increase in reticulocyte number, increase MCV
- no nucleus & eliminate remaining mitochondria
- 1 day to mature to RBC
37
How would you evaluate anaemia?
```
1) increased reticulocyte count?
NO= problem in bone marrow
2)RBC size? Micro:TAILS/macro:vit B12, folate deficiency, liver disease,alcohol/normo:bone marrow failure
YES= bone marrow functioning normally
2)evidence of haemolysis?
YES= autoimmune, enzyme/membrane defects
NO=blood loss, splenic sequestration
```
38
Why can anaemia arise from chronic kidney disease?
Kidney stops producing erythropoietin
39
How can anaemia develop from parovirus/chemotherapy?
Marrow is unable to respond to EPO
40
How does myelofibrosis/cancer cause anaemia?
Marrow is infiltrated by cancer cells or fibrous tissue, so number of normal haemopoietic cells is reduced
41
What are myelodysplastic syndromes/
Blood cancer
| -cause abnormal clones of marrow stem cells which limit capacity to make red and white blood cells
42
What does presence of schistocytes indicate?
Form of pathology is present
43
What is haemolysis?
Rupture/destruction of RBC's
44
Why does chronic NSAID usage lead to anaemia?
(Aspirin, Ibuprofen, Naproxen)
Induce GI injury/bleeding via:
-direct cytotoxic effects on epithelium
45
What are reticulocytes?
Immature RBC's- just been released from marrow to blood
- no nucleus & they eliminate mitochondria
- 1 day to mature to erythrocytes
46
What is dihydrofolate reductase?
Enzyme which converts folate to tetrahydrofolate
47
What are some good sources of b12?
```
Meat
Fish
Milk
Cheese
Eggs
Marmite
```
48
What is pernicious anaemia?
- decreased/absent intrinsic factor
- exhaustion of B12 reserves
- autoimmune disease
49
Types of antibody involved in pernicious anaemia?
- blocking antibody (blocks binding of B12 to IF)
| - binding antibody (prevents receptor mediated endocytosis)
50
What are gastric parietal cells?
Epithelial cells that secrete HCl and intrinsic factor
| -in stomach
51
What does thymine deficiency cause and what is it caused by?
Caused by folate/B12 deficiency
Causes
-uracil combined into DNA instead of thymine
-DNA repair enzymes detect errors and repair
-results in asynchronous maturation b/w nucleus and cytoplasm
52
What can develop as B12/folate deficiency progresses?
Pancytopenia
| -low platelets and neutrophils as well
53
What is hydroxycobalamine/cyanocobalamine?
A form of vitamin B12 (cyanocobalamine is man made)
54
What can blood transfusion in patients with severe anaemia caused by vitamin 12 deficiency cause?
High output cardiac failure (so if required transfuse a smaller volume with care)
MEH
flashcards
Decks in class (22)
# Cards
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Lecture 451
-
Lecture 2145
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Lecture 1918
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Lecture 1741
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Lecture 1555
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Lecture 1347
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Lecture 1253
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Lecture 1135
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Lecture 1050
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Lecture 952
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Lecture 842
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Lecture 754
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Lecture 550
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Lecture 352
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Lecture 1430
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Lecture 641
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Lecture 1635
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Lecture 1840
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Lecture 2058
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Lecture 2246
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Lecture 1 (Alcohol metabolism & Oxidative stress)44
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Lecture 2 (Protein & AA metabolism)7
