Haematology Flashcards
1
Q
What are T cells, B cells and NK cells derived from?
A
Lymphoid stem cells which are derived from pluripotent lymphoid stem cells
2
Q
What are granulocytes, erythroids and megakaryocytes derived from?
A
Multipotent myeloid stem cells which are derived from pluripotent myeloid stem cells
3
Q
How do stem cells produce mature progeny?
A
They divide to produce another stem cell and a cell capable of differentiating into mature progeny
4
Q
How do multipotent myeloid stem cells produce erythrocytes?
A
They differentiate into:
Proerythroblasts
Erythroblasts
Erythrocytes
5
Q
Where is erythropoietin synthesised?
A
Mainly by the kidneys in response to hypoxia
6
Q
How are erythrocytes removed from the circulation at the end of their life cycle?
A
By phagocytic cells of the spleen
7
Q
What is the first recognisable cell in white blood cell production?
A
Myoblasts
8
Q
How long does a neutrophil spend in the circulation before migrating into tissues?
A
7-10 hours
9
Q
What is the main function of an eosinophil?
A
Defence against parasites
10
Q
What is the main role of a basophil?
A
Involved in allergic responses
11
Q
How long do monocytes spend in the circulation? What are they when they migrate into tissues?
A
Spend several days in the circulation
Macrophages: Phagocytic and scavenging function. They also store and release iron
12
Q
How long do platelets spend in the circulation? What is their primary role?
A
10 days
Haemostasis
13
Q
What is anisocytosis?
A
Where red cells show more variation in size than normal
14
Q
What is poikilocytosis?
A
Where red cells show more variation in shape than normal
15
Q
What term is used to describe blood cells that are smaller than normal?
A
Microcytosis
Smaller than a lymphocyte nucleus
16
Q
What term is used to describe blood cells that are larger than normal?
A
Macrocytosis
Larger than a lymphocyte nucleus
17
Q
What are the different types of macrocyte?
A
- Round macrocytes
- Oval macrocytes
- Polychromatic macrocytes
18
Q
What is hypochromia?
A
Cells have a larger area of central pallor than normal, due to a lower haemoglobin content and concentration and a flatter cell
19
Q
What is hyperchromia?
A
Describes cells that lack central pallor. This can be because they are thicker than normal or because their shape is abnormal
20
Q
What are the two cell types in hyperchromia?
A
- Spherocytes
- Irregularly contracted cells
21
Q
What are spherocytes?
A
Red cells that are approximately round in shape, with a lack of central pallor
They result from the loss of cell membrane without the loss of an equivalent amount of cytoplasm so the cell is forced to round up
22
Q
What causes irregularly contracted cells?
A
They usually result from oxidant damage to the cell membrane and to the haemoglobin
23
Q
What is polyhromasia?
A
An increased blue tinge to the cytoplasm of a red cell- indicating that the red cell is young
24
Q
What stain is used in a reticulocyte stain?
A
Methylene blue
25
What are target cells? Where are they found?
Cells with an accumulation of haemoglobin in the area if central pallor
26
What are elliptocytes?
Red cells that are elliptical in shape. They occur in hereditary elliptocytosis and in iron deficiency
27
What causes the change in shape in sickle cell anaemia?
Results from the polymerisation of haemoglobin S when it is present in a high concentration
28
What are fragments?
Also known as schistocytes
| Small pieces of red cells indicating the red cell has fragmented
29
What is Rouleaux?
Stacks of red cells resembling a pile of coins resulting from alterations in plasma proteins
30
What are red cell agglutinates?
Irregular clumps of red cells usually resultant from antibody on the surface of the cells
31
What is a Howell-Jolly body?
A nuclear remnant in a red cell, commonly caused by a lack of splenic function
32
What terms describe too many or too few white cells?
Leucocytosis- too many
| Leucopenia- too few
33
What terms describe too many or too few neutrophils?
Neutrophilia- too many
| Neutropenia- too few
34
What terms describe too many lymphocytes?
Lymphocytopenia
35
What terms describe too many eosinophils?
Eosinophilia
36
What terms describe too many or too few platelets?
Thrombocytosis- too many
| Thrombocytopenia- too few
37
What terms describe too many red cells?
Erythrocytosis
38
What terms describe too many reticulocytes?
Reticulocytosis
39
What is "left shift"? What is it a sign of?
Where there is an increase in non-segmented neutrophils or where there are neutrophil precursors in the blood
Sign of a bacterial infection
40
How many lobes are there in a hypersegmented neutrophil? What is it usually caused by?
>5 lobes
| Usually due to a lack of vitamin B₁₂ or folic acid
41
What is mean cell haemoglobin?
The amount of haemoglobin in a given volume of blood divided by the number of red cells in the same volume
42
What is mean cell haemoglobin concentration?
The amount of haemoglobin in a given volume of blood divided by the proportion of the sample represented by the red cells
43
How do you interpret a blood count?
1) Leucocytes?
High or low number, which cell line is abnormal
2) Haemoglobin
3) Mean cell volume?
Blood count, large or small cells
4) Platelets
Thrombocytosis/thrombocytopenia, blood count
Look at the clinical history to point to the cause
44
What is polycythaemia? What are the potential causes?
```
Too many red cells in the circulation
Hb, RBC and PCV are all increased
Can present with splenomegaly, abdominal mass or cyanosis
Causes:
- blood doping
- medical negligence
- high levels of erythropoietin
• hypoxia
• illicit erythropoietin (sports)
• tumour
• polycythaemia vera (abnormal bone marrow function)
```
45
What is pseudopolycythaemia?
A decrease in plasma volume makes it look like patient has polycythaemia
When there is an increase in the number of circulating red cells there is a true polycythaemia
46
What is polycythaemia vera? How is it treated?
An intrinsic bone marrow disorder classified as a myeloproliferative neoplasm
Can lead to hyperviscoscity ("thick blood") which can cause vascular obstruction
Treatment
- venesection (remove blood)
- drugs (controlling the bone marrow production of blood cells)
47
What would you suspect as the cause of polycythaemia in a young healthy athlete?
Suspicious (doping)
48
What would you suspect as the cause of polycythaemia in a breathless cyanosed patient?
Probably due to hypoxia
| - an appropriate response
49
What would you suspect as the cause of polycythaemia in a patient with an abdominal mass?
Could be carcinoma of the kidney
50
What would you suspect as the cause of polycythaemia in a patient with splenomegaly?
A pointer to polycythaemia vera
51
What are the different possible mechanisms of anaemia? (4)
1) reduced production of red cells/haemoglobin in the bone marrow
2) Loss of blood from the body
3) Reduced survival of red cells in the circulation
4) Pooling of red cells in a very large spleen
52
What are the different classifications of anaemia based on size?
Microcytic
Normocytic
Macrocytic
53
What are the common causes of microcytic anaemia?
1) Defect in haem synthesis
- Iron deficiency
- Anaemia of chronic disease
2) Defect in globin synthesis (thalassaemia)
- Defect in α-chain synthesis (α thalassaemia)
- Defect in β-chain synthesis (β thalassaemia)
54
What causes macrocytic anaemia?
Abnormal haemopoiesis where red cell precursors continue to synthesise haemoglobin and other cellular proteins but they fail to divide normally. Results in cells that are larger than normal
OR
Premature release of cells from the bone marrow
55
What is megaloblastic erythropoiesis?
Delay in maturation of the nucleus while the cytoplasm continues to mature and the cell continues to grow
56
What is a megaloblast?
An abnormal bone marrow erythroblast
57
What are the common causes of macrocytic anaemia?
1) Lack of folic acid or vitamin B₁₂
2) Use of drugs interfering with DNA synthesis (e.g. chemotherapy)
3) Liver disease and ethanol toxicity
4) Recent major blood loss with adequate iron stores
5) Haemolytic anaemia
58
What are the mechanisms of normocytic normochromic anaemia?
- Recent blood loss
- Failure of production of red cells
- Pooling of red cells in the spleen
59
What are the possible causes of normocytic normochromic anaemia?
1) Peptic ulcer, oesophageal varices, trauma
2) Failure of production of red cells
- early stages of iron deficiency
- anaemia of chronic disease
- renal failure
- bone marrow failure or suppression
- bone marrow infiltration
3) Hypersplenism e.g. portal cirrhosis
60
What is haemolytic anaemia? What can it result from?
Anaemia resulting from shortened survival of red cells in the circulation
- Intrinsic abnormality of the red cells
- Extrinsic factors acting on normal red cells
61
What is the difference between inherited and acquired haemolytic anaemia?
Inherited- abnormalities in the cell membrane, the haemoglobin or the enzymes in the red cells
Acquired- extrinsic factors such as micro-organisms, chemicals or drugs that damage the red cell
62
What is the difference between intravascular and extravascular haemolysis?
Intravascular- occurs if there is very acute damage to the red cell
Extravascular- occurs when defective red cells are removed by the spleen
Often haemolysis is partly intravascular and partly extravascular
63
What are the possible defects in inherited haemolytic anaemia?
- Abnormal red cell membrane (e.g. hereditary spherocytosis)
- Abnormal Hb (e.g. sickle cell anaemia)
- Defect in glycolytic pathway (e.g. pyruvate kinase deficiency)
- Defect in enzymes of pentose shunt (e.g. G6PD deficiency)
64
What are the possible causes of acquired haemolytic anaemia?
- Damage to red cell membrane (e.g. AIHA or snake bite)
- Damage to whole red cell (e.g. MAHA)
- Oxidant exposure, damage to red cell membrane and Hb (e.g. dapsone or primaquine)
65
When would you suspect haemolytic anaemia?
- Otherwise unexplained anaemia, which is normochromic and usually normocytic/macrocytic
- Morphologically abnormal red cells (irregularly contracted cells, spherocytosis, sickle cell)
- Increased red cell breakdown (jaundice)
- Increased bone marrow activity
66
Give an example of a cause of haemolytic anaemia due to a membrane defect.
Hereditary spherocytosis
67
Give an example of a cause of haemolytic anaemia due to a haemoglobin defect.
Sickle cell anaemia
68
Give an example of a cause of haemolytic anaemia due to a glycolytic pathway defect.
Pyruvate kinase deficiency
69
Give an example of a cause of haemolytic anaemia due to a pentose shunt defect.
G6PD deficiency
70
What is hereditary spherocytosis? How do cells become spherocytic?
Red cells become less flexible and are removed prematurely by the spleen (extravascular spherocytosis)
After entering the circulation the cells lose their membrane in the spleen and become spherocytic
The bone marrow responds to haemolysis by increasing red cell output leading to polychromasia and reticulocytosis
Leads to increased bilirubin production, jaundice and gallstones
71
What is the treatment for hereditary spherocytosis
Only effective treatment is splenectomy but this has risks so only done in severe cases
Good diet is important so secondary folic acid deficiency does not occur
Alternatively one folic acid tablet to be taken daily
72
What is G6PD? Why is it important?
Glucose-6-phosphate dehydrogenase
Important enzyme in the pentose phosphate shunt
It is essential for the protection of the red cell from oxidant damage
73
How does a G6PD deficiency cause haemolysis?
```
Extrinsic oxidants (e.g. foodstuffs, chemicals or drugs) cause damage to red cells. G6PD is needed for protection against these oxidants.
A deficiency usually causes intermittent, severe intravascular haemolysis.
The gene for G6PD is on the X chromosome so affected individuals are usually hemizygous males (but occasionally homozygous females)
```
74
What cells would be seen in a blood smear from a patient with G6PD deficiency?
Considerable numbers of irregularly contracted cells
| Haemoglobin is denatured and forms round inclusions known as Heinz bodies (can be detected by a specific test)
75
What causes autoimmune haemolytic anaemia?
Production of autoantibodies directed at red cell antigens
The immunoglobulin bound to the red cell membrane is recognised by splenic macrophages, which remove parts of the red cell membrane, leading to spherocytosis
The combination of cell rigidity and recognition of antibody+complement on the red cell surface by splenic macrophages leads to removal of cells from the circulation by the spleen
76
How do you diagnose autoimmune haemolytic anaemia?
- Finding spherocytes and an increased reticulocyte count
- Immunoglobulin on the red cell surface
- Antibodies to red cell antigens or other autoantibodies in the plasma
77
How is autoimmune haemolytic anaemia treated?
Corticosteroids and other immunosuppressive agents
| Splenectomy for severe cases
78
A microcytic anaemia is likely to be due to:
1) Vitamin B₁₂ deficiency
2) Folic acid deficiency
3) Iron deficiency
4) Haemolysis
5) Acute blood loss
3) Iron deficiency
79
Polycythaemia in a patient seeing his GP because he has noticed his urine is red is most likely due to:
1) Chronic renal failure
2) Living at high altitude
3) Hypoxia from COPD
4) Haemolysis
5) Renal carcinoma
5) Renal carcinoma
80
How much iron is needed per day to produce red cells?
20mg per day (not including recycled iron)
Men- 1mg/day
Women- 2mg/day
81
What natural foods are a good source of iron?
Meat and fish (haem iron)
Vegetables
Whole grain cereal
Chocolate
82
Which type of iron can be absorbed and which type can't? What drinks aids absorption and prevents it?
Fe³⁺ cannot be absorbed
Fe²⁺ can be absorbed
Orange juice helps absorption, tea can prevent it
83
What factors affect absorption of iron?
```
Diet:
- increase in haem iron or ferrous iron
Intestine:
- acid (duodenum)
- ligand (meat)
Systemic:
- iron deficiency
- anaemia/hypoxia
- pregnancy
```
84
How does the gut cell alter iron absorption?
High iron = high hepidin = low ferroportin = low absorption
| ( hepcidin causes ferroportin to be internalised and degraded
85
Where is ferroportin found?
1) On enterocytes of the duodenum
2) On macrophages of the spleen which extract iron from old or damaged cells
3) On hepatocytes
86
How is iron transported in the plasma?
Carried by transferrin
87
What is the normal level of transferrin saturation?
20-40%
88
How does transferrin transport iron into cells?
Transferrin-iron complexes interact with the transferrin receptor and are internalised. As the pH drops iron is released and the transferrin receptors are recycled
89
What hormone is released in response to anaemia and tissue hypoxia?
Erythropoietin
90
What is anaemia of chronic disease?
Anaemia in patients who are unwell
| The present with no bleeding, no bone marrow infiltration and no iron, vitamin B₁₂ or folate deficiency
91
What are the laboratory signs of being ill?
1) C-reactive protein (acute phase protein associated with inflammation)
2) Erythrocyte sedimentation rate
3) Acute phase response: increases in
- ferritin
- FVIII
- fibrinogen
- immunoglobulins
92
What conditions are associated with anaemia of chronic disease?
1) Chronic infections (e.g. TB/HIV)
2) Chronic inflammation (e.g. RhA/SLE)
3) Malignancy
4) Miscellaneous (e.g. cardiac failure)
93
What is the pathogenesis of anaemia of chronic disease?
Cytokines prevent the usual flow of iron from the duodenum to red cells:
1) They stop erythropoietin increasing
2) They stop iron flowing out of cells
3) They increase the production of ferritin
4) Increase death of red cells
94
What cytokines are involved in the pathogenesis of anaemia of chronic disease?
TNF-α
| Interleukins
95
Is iron covalently bound to the globin protein chain in haemoglobin?
No
96
Where is iron mainly absorbed?
In the colon
97
In anaemia of chronic disease is ferritin elevated or reduced as part of the acute phase response to illness?
Elevated
98
What are the causes of iron deficiency?
1) Bleeding (e.g. menstrual/GI)
2) Increased use (e.g. growth/pregnancy)
3) Dietary deficiency (e.g. vegetarian)
4) Malabsorption (e.g. coeliac)
99
What investigations are conducted if someone presents with anaemia?
Coeliac screen- if negative:
- Upper GI endoscopy: oesophagus, stomach, duodenum
- take duodenal biopsy
- Colonoscopy
- Menstruating woman <40: if heavy periods/multiple pregnancies and no GI symptoms do nothing
- Urinary blood loss?
100
How do you confirm thalassaemia trait?
Haemoglobin electrophoresis
| - confirms an additional type of haemoglobin present
101
How can ferritin be used to differentiate between iron deficiency and chronic disease anaemia?
LOW in iron deficiency
| HIGH in chronic disease
102
How can transferrin be used to differentiate between iron deficiency and chronic disease anaemia?
Iron deficiency: transferrin goes UP
| Chronic disease: NORMAL or even LOW
103
How can transferrin saturation be used to differentiate between iron deficiency and chronic disease anaemia?
Iron deficiency: LOW saturation
| Chronic disease: NORMAL or HIGH
104
```
What changes would be seen in a blood test of a patient with classic iron deficiency?
Hb
MCV
Serum iron
Ferritin
Transferrin
Transferrin saturation
```
```
Hb: LOW
MCV: LOW
Serum iron: LOW
Ferritin: LOW
Transferrin: HIGH
Transferrin saturation: LOW
```
105
```
What changes would be seen in a blood test of a patient with anaemia of chronic disease?
Hb
MCV
Serum iron
Ferritin
Transferrin
Transferrin saturation
```
```
Hb: LOW
MCV: LOW or NORMAL
Serum iron: LOW
Ferritin: HIGH or NORMAL
Transferrin: NORMAL or LOW
Transferrin saturation: NORMAL
```
106
```
What is the diagnosis from this blood test result?
Hb: 10
MCV: 66
Serum iron: normal
Ferritin: normal
Transferrin: normal
Transferrin saturation: normal
```
Hb: LOW
MCV: LOW
Thalassaemia trait
107
```
What is the diagnosis from this blood test result?
Hb: 10
MCV: 78
Serum iron: low
Ferritin: normal
Transferrin: low
Transferrin saturation: normal
```
Hb: LOW
MCV: LOW
Rheumatoid arthritis with a bleeding ulcer
(Anaemia of chronic disease with iron deficiency)
108
If you see pencil cells in a blood film what is this indicative of?
Iron deficiency
109
What is the role of vitamin B₁₂?
Required for:
- DNA synthesis
- Integrity of the nervous system
110
What happens if deficient in vitamin B₁₂ and folate?
Absence leads to severe anaemia which can be fatal
111
What is folic acid required for?
- DNA synthesis
| - Homocysteine metabolism
112
What are the clinical features of a vitamin B₁₂ and folate deficiency?
```
All rapidly dividing cells are affected:
- Bone marrow
- Epithelial surfaces or mouth and gut
- Gonads
- Embryos
Anaemia (weak, tired, short of breath)
Jaundice
Glossitis and angular cheilosis
Weight loss
Change of bowel habit
Sterility
```
113
What type of anaemia occurs in a patient with a vitamin B₁₂ and folate deficiency?
Macrocytic and megaloblastic anaemia
| High MCV
114
What are the causes of macrocytic anaemia?
1) Vitamin B₁₂ or folate deficiency
2) Liver disease or alcohol
3) Hypothyroid
4) Drugs (e.g. azathioprine)
5) Haematological disorders
- Myelodysplasia
- Aplastic anaemia
- Reticulocytosis (e.g. chronic haemolytic anaemia)
115
What is normal red cell maturation?
Erythroblast
Normoblast: early / intermediate / late
Reticulocyte
Circulating red blood cell
116
What is megaloblastic anaemia?
Asynchronous maturation of the nucleus and cytoplasm in the erythroid series of development
Maturing red cells are seen in the bone marrow
117
What is seen in the peripheral blood of a patient with megaloblastic anaemia?
Anisocytosis (unequal sized red cells)
Large red cells
Hypersegmented neutrophils
Giant metamyelocytes
118
True or False?
| Thyroid disease can be a cause of megaloblastic red blood cells?
FALSE
| It can be a cause of macrocytic cells but not megaloblastic change
119
Give three tests that you would do if someone had a macrocytosis.
Check vitamin B₁₂ and folate
Liver function
Thyroxine
120
Name two possible underlying clinical disorders that could cause a hypersegmented neutrophil.
Vitamin B₁₂ or folate deficiency
121
What is a good source of dietary folate? How is this removed from foods?
Fresh leafy vegetables
| Destroyed by overcooking / canning / processing
122
What are the physiological causes for an increased folate demand?
- Pregnancy
- Adolescence
- Premature babies
123
What are the pathological causes for an increased folate demand?
- Malignancy
- Erythoderma
- Haemolytic anaemias
124
How is a laboratory diagnosis of a folate deficiency made?
Full blood count and film
| Folate levels in the blood
125
How is the cause of decreased folate assessed?
History (diet / alcohol / illness)
| Examination- skin disease / alcoholic liver disease
126
What are the consequences of a folate deficiency?
1) Megaloblastic, macrocytic anaemia
2) Neural tube defects in developing foetus
3) Increased risk of thrombosis in association with variant enzymes involved in homocysteine metabolism
127
What are the neural tube defects associated with folate deficiency?
- Spina bifida
| - Anencephaly
128
What dosage of folate are pregnant women advised to take? For how long?
0.4mg prior to conception and for the first 12 weeks
129
What are very high levels of homocysteine associated with?
- Atherosclerosis
| - Premature vascular disease
130
What are mildly high levels of homocysteine associated with?
- Cardiovascular disease
and potentially:
- Arterial thrombosis
- Venous thrombosis
131
What are the consequences of a vitamin B₁₂ deficiency?
Neurological problems
- Bilateral peripheral neuropathy
- Subacute combined degeneration of the cord
• Posterior and pyramidal tracts of the spinal cord
- Optic atrophy
- Dementia
132
What would present as an indication of a vitamin B₁₂ deficiency when taking the history and examining a patient?
```
History
- Paraesthesiae
- Muscle weakness
- Difficulty walking
- Visual impairment
- Psychiatric disturbance
Examination
- Absent reflexes
- Upgoing plantar responses
```
133
What are the possible causes of a vitamin B₁₂ deficiency?
1) Poor absorption
2) Reduced dietary intake
- Stores are large and last for 3-4 years
- Animal produce
- Vegans are at risk
3) Infections / infestations
- Abnormal bacterial flora (stagnant loops)
- Tropical sprue
- Fish tapeworm
134
Where is vitamin B₁₂ absorbed?
In the small intestine
135
How is vitamin B₁₂ excreted?
In the urine
136
How is vitamin B₁₂ absorbed?
B₁₂ combines with intrinsic factor
| B₁₂-IF binds to ileal receptors
137
What three things are needed for vitamin B₁₂ absorption?
1) Intact stomach
2) Intrinsic factor
3) Functioning small intestine
138
What can cause a reduction of intrinsic factor that would cause impaired vitamin B₁₂ absorption?
1) Post gastrectomy
2) gastric atrophy
3) Antibodies to intrinsic factor or parietal cells (PA)
139
What is pernicious anaemia? When is the most common age to get it?
Autoimmune condition associated with severe lack of intrinsic factor
(Antibodies to intrinsic factor or parietal cells)
Peak age: 60 years
140
What is the most common target of antibodies in pernicious anaemia?
90% of adults have antibodies to parietal cells
141
What diseases of the small bowel would cause impaired vitamin B₁₂ absorption?
1) Crohn's disease
2) Coeliac disease
3) Surgical resection
142
What infections are associated with impaired vitamin B₁₂ absorption?
H. pylori
Giardia
Fish tapeworm
Bacterial overgrowth
143
What drugs are associated with low vitamin B₁₂?
1) Metformin
2) Proton pump inhibitors (e.g. omeprazole)
3) Oral contraceptive pill
144
In patients with low vitamin B₁₂ what are the first investigations that are carried out to discover the cause?
Test:
1) Antibodies to parietal cells and intrinsic factor
2) Antibodies for coeliac disease
3) Breath-test for bacterial overgrowth
4) Stool for H. pylori
5) Test for Giardia
145
What is the Shilling Test?
Before the test B₁₂ deficiency must be corrected
1) Patient drinks radiolabelled B₁₂
2) Measure excretion in the urine
(if there is no B₁₂ in the urine either they are not absorbing B₁₂ because have no IF or they have antibodies to IF/parietal cells OR the B₁₂ deficiency was not corrected before the test)
3) Repeat test with additional intrinsic factor (different radiolabel)
4) Measure excretion of B₁₂ in the urine
146
What is the treatment for a vitamin B₁₂ deficiency?
Injections of B₁₂ (1000μg) 3 times per week for 2 weeks
Thereafter every 2 months
IF NEUROLOGICAL INVOLVEMENT
- B₁₂ injections alternate days until no further improvement - up to 3 weeks
- Thereafter every 2 months
147
A 49 year old man with grey hair and blue eyes presents with anaemia. Hos blood count is as follows:
Hb: 90g/L
WBC: 4 x 10⁹/L
Platelets: 160 x 10⁹/L
MCV: 110fl
What would be an appropriate set of investigations?
Test:
Folate and vitamin B₁₂
Thyroid function test
Liver function test
148
What is the general process of haemostatic plug formation?
1) Vessel constriction
2) Formation of an unstable platelet plug
- platelet adhesion
- platelet aggregation
3) Stabilisation of the plug with fibrin
- blood coagulation
4) Dissolution of the clot and vessel repair
- fibrinolysis
149
What is synthesised by endothelial cells?
Prostacyclin (PGI₂): antiplatelet
Thrombomodulin: membrane glycoprotein
von Willebrand factor
Plasminogen activators
150
How are platelets produced?
Stem cell precursors undergo nuclear replication to form megakaryocytes and become multinucleate
Maturation with granulation
Each megakaryocyte produces ∼4000 platelets. Lifespan ∼10 days, ⅓ stored in the spleen
151
What is the action of ADP on platelets?
Amplifies platelet activation
152
What is the mechanism of platelet adhesion to collagen during formation of a haemostatic plug?
von Willebrand factor binds to exposed collagen and then captures platelets by binding to GlpIb (surface glycoprotein) on their surface
OR
Platelets bind directly to collagen using GlpIa
153
What is the next step in the formation of a haemostatic plug following platelets binding to exposed collagen?
A signal causes the platelets to be partially activated and initiates the release of ADP and thromboxane
This causes further activation of the platelets
154
What is the mechanism of platelet aggregation?
Fibrinogen and Ca²⁺ initiate platelet aggregation causing them to bind together through surface glycoproteins GlpIIb and GlpIIIa
Thrombin is released which causes coagulation activation, amplifying the response
155
What is the pathway of prostaglandin metabolism in endothelial cells? What does this produce?
```
Membrane phospholipid
↓ phospholipase
Arachidonic acid
↓ cyclo oxygenase
Endoperoxides (PGG₂, PGH₂)
↓ Prostacyclin synthetase
Prostacyclin (PGI₂)
PGI₂ is a potent inhibitor of platelet function
```
156
What is the pathway of prostaglandin metabolism in platelets? What does this produce?
```
Membrane phospholipid
↓ phospholipase
Arachidonic acid
↓ COX-1 (cyclo oxygenase)
Endoperoxides (PGG₂, PGH₂)
↓ Thromboxane synthetase
Thromboxane A₂
Endoperoxidases and thromboxane are potent inducers of platelet aggregation when secreted
```
157
How does aspirin affect platelet function?
Aspirin is a COX-1 antagonist so it inhibits the production of thromboxane which acts to induce platelet aggregation
158
What are the possible antiplatelet agents currently used as antithrombotic agents? How do they work?
ADP receptor antagonists: reduce the action of ADP which increases platelet activation
GPIIb/IIIa antagonists: Prevent agglutination of platelets by targeting the surface glycoproteins which crosslink
COX-1 antagonist: Inhibits the production of thromboxane which prevents further activation of platelets
159
Give an example of a COX-1 inhibitor.
Aspirin
160
Give examples of ADP receptor antagonists.
Clopidogrel
| Prasugrel
161
Give examples of GPIIb/IIIa antagonists.
Abciximab
Tirofiban
Eptifibatide
162
What tests are used to monitor platelets and their function?
Platelet count
Bleeding time
Platelet aggregation
163
What is the normal range for platelet count? What range is there bleeding with trauma? When is spontaneous bleeding common and when does it become severe?
Normal: 150-400 x 10⁹
Trauma: 40-100 x 10⁹
Spontaneous: 10-40 x 10⁹
Severe: <10 x 10⁹
164
What is a possible cause of a platelet count <40 x 10⁹?
Autoimmune thrombocytopenic purpura (Auto-ITP)
165
What could cause severe spontaneous bleeding?
Treatment for leukaemia
166
How is bleeding time measured? What does this test measure? What is a normal result?
Cuff placed on patient's arm with 40mmHg pressure. Standardised incision made. Bleeding time normally 3-8 minutes.
Used to check platelet-vessel wall interaction, when platelet count is normal, e.g. renal disease
Measures functional defect of platelets, e.g. vWF disease, inherited platelet defects
167
Where are clotting factors, fibrinolytic factors and inhibitors synthesised? Specify what is synthesised in each.
```
1) The liver
Most coagulation proteins
2) Endothelial cells
von Willebrand factor
3) Megakaryocytes
Factor V and von Willebrand factor
```
168
What is the intrinsic blood coagulation pathway?
```
XII→XIIa
↓
XI→XIa
↓
IX→IXa
↓ VIIIa
↓ PI
↓ Ca²⁺
X→Xa
```
169
What is the extrinsic blood coagulation pathway?
```
Tissue factor (vessel damage)
↓ VIIa ↓
↓ Ca²⁺ ↓
IX → IXa X → Xa
Tissue factor produces VIIa and Ca²⁺ which catalyse the production of IXa and Xa
```
170
What is the common blood coagulation pathway?
Xa
↓Va
↓Pl
↓Ca²⁺
Prothrombin → thrombin (IIa)
↓
Fibrinogen → Fibrin
↓ thrombin
↓ ↓
↓ XIIIa ← XIII
Crosslinked fibrin
171
What is the main driver of coagulation?
Tissue factor
172
What is the localisation phenomenon on the surface of platelets?
When activated phospholipids on the surface change shape so they attract coagulation factors. This catalyses the reaction between clotting factors as they are brought together in closer proximity so encourage the reaction to happen.
Factor VIIIa pulls factor IXa and X together to produce factor Xa
Factor Va then pulls factor Xa and II (thrombin) together to produce thrombin
This increases the production of thrombin 10,000 fold
173
What vitamin are clotting factors dependent on? Where are they produced?
Vitamin K dependent
| Produced in the liver
174
Why is Ca²⁺ needed for clotting?
Ca²⁺ enables clotting factors to bind to platelets by allowing residues to fold to bind to phospholipids
175
What is the mode of action of warfarin?
Warfarin inhibits Ca²⁺ thereby preventing the clotting factors from binding to phospholipids on the surface of platelets and ultimately producing fibrin
Warfarin also inhibits vitamin K, which is essential for synthesis of clotting factors in the liver
176
What is Heparin used for? How does it work?
Heparin binds to and accelerates the action of plasma inhibitor antithrombin
Heparin is used for immediate anticoagulation in venous thrombosis and pulmonary embolism
177
What is the mechanism of action of antithrombin?
Antithrombin inhibits the coagulation factors XIa, IXa, Xa and thrombin (IIa) by irreversibly binding to the factor. The complex is then cleared
178
How does heparin acceleerate the action of antithrombin?
Unfractionated heparin or low molecular weight heparin forms a bridge between the factor and antithrombin and pulls them together to allow antithrombin to inhibit the factor faster
179
What are the laboratory tests for blood coagulation?
APTT
PT
TCT / TT
180
What blood coagulation test measured the intrinsic pathway? How does it work?
APTT (Activated partial thromboplastin time)
| Initiates coagulation through FXII and detects abnoralities in the intrinsic and common pathways
181
What blood coagulation test measures the extrinsic pathway? How does it work?
PT (Prothrombin time)
| Initiates coagulation through tissue factor and detects abnormalities in extrinsic and common pathways
182
What blood coagulation test measured the common pathway? How does it work?
TCT (Thrombin clotting time)
| Add thrombin and shows abnormalities in the fibrinogen to fibrin conversion
183
What coagulation tests are used to screen for causes of bleeding disorders?
APTT and PT
184
What coagulation test is used to monitor heparin therapy in thrombosis?
APTT
185
What coagulation test is used to monitor Warfarin therapy?
PT
186
What is the process of fibrinolysis?
In the presence of a fibrin clot plasminogen is converted to plasmin, converted by tissue plasminogen activator (t, PA)
Plasmin then breaks dow the fibrin clot to produce fibrin degradation products (FDP)
187
In what condition do you see elevated levels of FDP?
DIC (disseminated intravascular coagulation)
188
Why does blood not clot completely whenever clotting is initiated by vessel injury?
Coagulation inhibitory mechanisms prevent this.
1) Antithrombin
2) The protein C anticoagulant pathway (with protein C and protein S)
189
What is the mechanism by which protein C inhibits coagulation?
Protein C becomes activated by thrombomodulin (produced from thrombin) and is the proteolytic component of the complex. Proteins S is the binding protein essential for the formation of the anticoagulant complex on cell surfaces made up of protein C and factor VIIIa or Va
190
What are the possible causes of abnormal haemostasis?
1) Lack of a specific factor
- failure of production: congenital or acquired
- increased consumption/clearance
2) Defective function of a specific factor
- genetic defect
- acquired defect: drugs, synthetic defect, inhibition
191
What is primary haemostasis?
Platelet adhesion an platelet aggregation
192
What are the possible causes of disorders of primary haemostasis?
1) Platelets
- Low numbers: Thrombocytopenia
- Impaired function
2) Von Willebrand Factor
- Von Willebrand disease
3) The vessel wall
193
What are the possible causes of thrombocytopenia?
- Bone marrow failure
e. g. leukaemia, B₁₂ deficiency
- Accelerated clearance
e. g. immune (ITP), DIC
- Failure of platelet production
- Shortened half-life of platelets
- Increased pooling of platelets in an enlarged spleen (hypersplenism) and shortened half-life
194
What is auto-ITP?
Auto-immune Thrombocytopenic Purpura
| Antiplatelet autoantibodies sensitise platelets by binding to antigen on surface leading to clearance by macrophages
195
What are the possible causes of impaired platelet function that affect primary haemostasis?
- Hereditary absence of glycoproteins or storage granules
| - Acquired due to drugs: aspirin, NSAIDs, clopidogrel
196
Give examples of hereditary platelet defects in primary haemostasis.
1) Glanzmann's thrombasthenia
2) Bernard Soulier syndrome
3) Storage Pool disease
197
What are the causes of von Willebrand disease?
1) Hereditary decrease of quantity and/or function (common)
| 2) Acquired due to antibody (rare)
198
What is the function of von Willebrand factor in haemostasis?
1) Binding to collagen and capturing platelets
| 2) Stabilising factor VIII (FVIII may be low if VWF is very low)
199
What are the different types of VWD?
Deficiency of VWF (type 1 or 3)
| VWF with abnormal function (type 2)
200
What disorders of the vessel wall can affect primary haemostasis?
1) Inherited (rare) Hereditary haemorrhagic telangiectasia, Ehlers-Danlos syndrome and other connective tissue disorders
2) Acquired: Scurvy, steroid therapy, ageing (senile purpura), vasculitis
201
What bleeding disorders occur in primary haemostasis?
1) Typical primary haemostasis bleeding:
- Immediate
- Prolonged bleeding from cuts
- Epistaxes
- Gum bleeding
- Menorrhagia
- Easy bruising
- Prolonged bleeding after trauma or surgery
2) Thrombocytopenia - Petechiae
3) Severe VWD - haemophilia-like bleeding
202
What tests are performed to check for disorders of primary haemostasis?
Platelet count
Bleeding time (PAF100 in lab)
Assays on VWF
Clinical observation
203
What is secondary haemostasis?
Stabilisation of the platelet plug with fibrin
204
What is the role of the coagulation cascade?
To generate a burst of thrombin which will convert fibrinogen to fibrin
205
What are the possible causes for disorders of coagulation?
1) Deficiency of coagulation factor production
- Hereditary (haemophilia)
- Acquired
2) Increased consumption
- Acquired
206
What effect would a factor VIII and IX deficiency have?
Haemophilia
- Severe but compatible with life
- Spontaneous joint and muscle bleeding
207
What effect would a factor II deficiency have?
Prothrombin deficiency
| - LETHAL
208
What effect would a factor XI deficiency have?
Bleed after trauma but not spontaneously
209
What effect would a factor XII deficiency have?
Would show very abnormal coagulation tests but no excess bleeding at all
210
What are the acquired causes of coagulation factor deficiencies would cause disorders in coagulation?
1) Liver disease
2) Dilution
3) Anticoagulant drugs
e. g. Warfarin
211
How can dilutions lead to factor deficiencies which would cause disorders in coagulation?
Red cell transfusions no longer contain plasma
| Major transfusions require plasma as well as red blood cells and platelets
212
What are the acquired causes of increased consumption which would lead to disorders of coagulation?
1) Disseminated intravascular coagulation (DIC)
| 2) Immune- autoantibodies
213
How does Disseminated Intravascular Coagulation cause increased consumption and in turn a coagulation disorder?
Generalised activation of coagulation by exposed tissue factor by coming into contact with factor VII
Associated with sepsis, major tissue damage and inflammation
Consumes and depleted coagulation factors
Platelets are consumed
Activation of fibrinolysis depletes fibrinogen
Deposition of fibrin in vessels causes organ failure
214
What sort of bleeding occurs in coagulation disorders?
Superficial cuts do not bleed (platelet plug is sufficient)
Bruising is common, nosebleeds are rare
Spontaneous bleeding is deep, into muscles and joints
Bleeding after trauma may be delayed and prolonged
Frequently restarts after stopping
215
What sort of bleeding occurs in platelet disorders?
Superficial bleeding into skin and mucosal membranes
| Immediate bleeding after injury
216
What tests are performed for coagulation disorders?
```
Screening tests
- Prothrombin time (PT)
- Activated partial thromboplastin time (APTT)
- Full blood count (platelets)
Factor assays (for factor VIII etc)
Tests for inhibitors
```
217
What bleeding disorders are not detected by routine clotting tests?
- Mild factor deficiencies
- von Willebrand disease
- Factor XIII deficiency (cross-linking)
- Platelet disorders
- Excessive fibrinolysis
- Vessel wall disorders
- Metabolic disorders (e.g. uraemia)
- Thrombotic disorders
218
What are the possible cuases of disorders of fibrinolysis?
1) Hereditary
- antiplasmin deficiency
2) Acquired
- drugs such as tPA
- dissemnated intravascular coagulation
219
What is the inheritance pattern of haemophilia?
It is a sex-linked recessive disorder
220
What is the inheritance pattern of von Willebrand disease?
Type 2 and type 1 are autosomal dominant disorders
| Type 3 is autosomal recessive
221
What is the treatment of abnormal haemostasis caused by failure of production or function of factors or platelets?
Replace missing factor/platelets
- Prophylaxis
- Therapeutic
Stop drugs
222
What is the treatment of abnormal haemostasis caused by immune destruction?
Immunosuppression (e.g. prednisolone)
| Splenectomy for ITP
223
What is the treatment of abnormal haemostasis caused by increased consumption?
Treat cause
| Replace as necessary
224
What are the possible options for factor replacement therapy?
1) Plasma
Contains all coagulation factors
2) Cryoprecipitate
Rich in fibrinogen, FVIII, VWF and FXIII
3) Factor concentrates
Concentrates available for all factors except factor V
4) Recombinant forms of FVIII and IX are available
225
What treatment is used for platelet repacement therapy?
Pooled plasma concentrations
226
What alternative treatments are used for haemostasis disorders other than factor replacement and immune suppression?
DDAVP
Tranexamic acid
Fibrin glue/spray
227
How does DDAVP boost haemostatis in individuals with a disorder?
Desmopressin a vasopressin derivative, causes endothelial cells to release their endogenous stores of VWF
Only useful in mild disorders
228
How does tranexamic acid boost haemostasis in individuals with haemostatic disorders?
Inhibits fibrinolysis
| Widely distributed- crosses the placenta, low concentration found in breast milk
229
What is contained in one haemoglobin molecule?
- Four globin protein chains (2+2)
- Four haem groups
- Four iron molecules
- Up to four oxygen molecules
230
Where is haem synthesised?
In mitochondria
231
Where is globin synthesised?
In ribosomes
232
What is the normal concentration of haemoglobin in adults?
120-165g/L
233
How much haemoglobin is produced and destroyed in the body every day?
90mg/kg
234
How much Fe per gram of Hb?
3.4mg
235
When is haemoglobin synthesised?
65% in erythroblast stage
| 35% in reticulocyte stage
236
What enzyme is important in the production of haem (commits substrates to production of haem)?
ALAS
237
What is the structure of haem?
Protoporphyrin ring with a central iron atom
| Iron usually in ferrous iron form (Fe²⁺)
238
What are the ratios of haem and globin produced?
Produced in proportionate amounts, so no excess haem or globin
239
What are the different types of globin chain?
α and β chains
240
When does HbF production decrease?
6 months of age
241
What are the normal amounts of haemoglobin in adults?
Hb A (α₂β₂) 96-98%
Hb A₂ (α₂δ₂) 1.5-3.2%
HbF (α₂γ₂) 0.5-0.8%
242
What is the predominant haemoglobin in adults?
HbA
243
What is the primary, secondary and tertiary structure of globin?
Primary: α 141 AA, non-α 146 AA
Secondary: 75% α and β chains, helical arrangement
Tertiary: ∼sphere, hydrophilic surface (charged polar side chains), hydrophobic core with haem pocket
244
What are the dimers that make up haemaglobin? What bonds bind them?
(α₁ and β₂) OR (β₁ and α₂) form a dimer.
| The two globin chains in a dimer are bound with covalent bonds, but two dimers have weaker hydrogen bonds between them
245
What effect does 2,3-DPG have on haemoglobin?
Allows oxygen to bind less strongly to the haemoglobin, so it is given up more readily to the tissues.
It is produced in metabolising cells
246
What shape is the oxygen dissociation curve?
Sigmoid shape
247
What kind of binding does oxygen have to haemoglobin?
Cooperative binding (binding of one oxygen increases the binding affinity of a second then a third etc)
248
What causes a leftward shift of the oxygen dissociation curve? What is this beneficial for?
```
Foetal haemoglobin (HbF)
Decreased 2,3-DPG
Increased pH
Low CO₂
Beneficial for picking up oxygen in the lungs or picking up oxygen from the maternal circulation
```
249
What causes a rightward shift of the oxygen dissociation curve?
```
Sickle haemoglobin (HbS)
Increased 2,3-DPG
Decreased pH
High CO₂
Binds oxygen at a lower affinity but delivers it more readily to the tissue
```
250
What is thalassaemia?
A genetic defect characterised by a defect in globin chain synthesis
251
What are the different severities of thaassaemia?
- minor "trait" (carrier)
- intermedia
- major (absence of a globin protein)
252
How many α and β genes do we have? Where are they located?
α: 4 genes (α₁ and α₂) located on chromosome 16
| β: 2 genes located on chromosomes 11
253
What is β-thalassaemia?
Deletion or mutation in β globin gene(s) causing reduced or absent production of β-globin
254
How is thalassaemia diagnosed in a laboratory?
FBC
- Microcytic hypochromic indices
- Increased RBCs relative to Hb
Film
- Target cells, poikilocytosis but no anisocytosis
Hb
- EPS / HPLC
- α-thal: Normal HbA₂ and HbF, +/- HbH
- β-thal: Raised HbA₂ and raised HbF
Globin chain synthesis/DNA studies
- Genetic analysis for β-thalassaemia mutations and Xmnl polymorphism
255
What is β-thalassaemia trait?
Carrier status for β-thalassaemia
May be asymptomatic or have slightly reduces haemoglobin
Can have raised HbA₂ fraction
256
What is thalassamia major?
2 abnormal copies of β-globin gene
Severe anaemia, incompatible with life without regular blood transfusions
Clinical presentation ∼4-6 months of life when HbF production stops
257
What is the clinical presentation of thalassaemia major?
- Severe anaemia usually presenting after 4 months
- Hepatosplenomegaly
- Blood film shows gross hypochromia, poikilocytosis and many nucleated RBCs
- Bone marrow: erythroid hyperplasia
- Extra-meduallary haematopoiesis
258
What are the clinical features of β-thalassaemia?
- Chronic fatigue
- Failure to thrive
- Jaundice
- Delay in growth and puberty
- Skeletal deformity
- Splenomegaly
- Iron overload
259
What are the major causes of death in β-thalassaemia?
```
1960-1984
- Cardiac disease 71%
- Infections 12%
- Liver disease 6%
- Other 11%
1999-2008
- Cardiac 54%
```
260
What is the treatment of thalassaemia major?
- REGULAR BLOOD TRANSFUSIONS
- IRON CHELATION THERAPY
- Splenectomy
- Supportive medical care
- Hormone therapy
- Hydroxyurea to boost HbF
- Bone marrow transplant (only cure)
261
How frequently do thalassaemia major patients require transfusion and when is it required? What treatment is used if this is unsuccessful?
Pre-transfusion Hb 95-100g/L
Transfusion 2-4 weekly
If higher requirement than this consider splenectomy
262
What infections are prevalent in thalassaemia major patients? How is infection managed in thalassaemia major patients?
- Yersinia (iron-loving bacteria)
- Other gram negative species
- Prophylaxis in splenectomised patients- immunisation and antibiotics
263
When is iron chelation therapy used in thalassaemia major patients? What tests must be done beforehand?
Start after 10-2 transfusions or when serum ferratin >1000mcg/L
Audiology and ophthalmology screening prior to starting
264
What are the three currently available iron chelators?
Desferrioxamine (I.V.)
Deferiprone (oral)
Deferasirox (oral)
265
How is iron overload monitored?
1) Serum ferritin
- >2500 = increased complications
- acute phase protein
- check 3 monthly is transfused otherwise annually
2) Liver biopsy
- rarely performed
3) T2* cardiac and hepatic MRI
- <20ms: increased risk of impaired LF function
- Check anually or 3-6 monthly if cardiac dysfunction
3) Ferriscan - R2 MRI
- non-invasive quantitation of LIC
- not affected by inflammation or cirrhosis
- <3mg/g normal
- >15mg/g associated with cardiac disease
- check annually or 6 monthly is result >20
266
What is sickle β thalassaemia?
When sickle cell is co-inherited with β-thalassaemia
267
What is HbE β-thalassaemia?
Very common combination in South East Asia
| Clinically variable in expression can be as severe as β-thalassaemia major
268
What is α-thalassaemia?
- Deletion or mutation in α-globin gene
- Reduced or absent production of α-globin chains
- Affects both foetus and adult
- Excess β and γ chains form tetramers or HbH and Hb Barts respectively
269
What determines the severity of α-thalassaemia?
Depends on the number of α-globin genes affected
270
What are the problems associated with treatment of thalassaemia in developing countries?
- Lack of awareness
- Lack of experience in healthcare
- Availablity of safe blood
- Cost and compliance with iron chelation therapy
- Availability of and high cost of bone marrow transplant
271
How would a person inherit β-thalassaemia intermedia?
There are two different types of carrier a person can be:
- carrier with whole β-globin gene deletion on one chromosome
- carrier with a small deletion or frame shift mutation
Inheriting both of these genes would result in β-thalassaemia intermedia
272
How many units of blood are used per day?
9000 units per day in the UK
273
What is the shelf life of 1 unit of red cells? How are they stored?
5 weeks
| Stored in a fridge at 4°C
274
What structure causes the differing blood groups?
Red cells have a common glycoprotein and fructose stem on their membrane
O has no additional sugar
A has added galnac (N-Acetylgalactosamine)
B has added gal (Galactose)
275
What is the inheritance pattern of ABO blood groups?
A and B genes are co-dominant
| O gene is recessive
276
What Ig class is present in the plasma against antigens not found on the surface of red cells?
IgM
277
What is the inheritance pattern of RhD blood groups?
D (Rh +) codes for antigen on red cell membrane
| d (Rh -) is recessive
278
Do Rh negative people have anti-D antibodies?
They can make anti-D antibodies after exposure to the antigen either by transfusion of RhD positive blood or a woman being pregnant with a RhD positive foetus
279
What antibody class are anti-D antibodies?
IgG
280
What causes haemolytic disease of the newborn?
If a RhD negative mother is exposed to Rh-D they produce anti-D antibodies. If the next pregnancy is RhD positive the mother's IgG antibodies can cross the placenta which causes haemolysis of foetal red cells.
If severe causes hydrops fetalis and death.
281
Other than ABO and RhD what other antigens are present on the surface or red cells?
C, c, E, e, Kell, Duffy, Kidd
282
What anticoagulant is found in blood packs? How does it prevent coagulation?
Citrate
| Depletes Ca²⁺ necessary for clotting factors to bind to the platelet membrane and prevents coagulation
283
What componenets are taken from one unit of blood?
Red cells
Platelets
Plasma
284
What is the shelf life of fresh frozen plasma and cryoprecipitate? How is it stored?
Shelf life 2 years
| Stored at -30°C (frozen within 6 hours to preserve coagulation factors
285
When would fresh frozen plasma be required?
1) If bleeding + abnormal coagulation test results (PT, APTT)
- Monitor response clinically + coagulation tests
2) Reversal of Warfarin
e. g. for urgent surgery (if PCC not available)
3) Other conditions occasionally
286
What does cryoprecipitate contain?
Fibrinogen
| Factor VIII
287
What is cryoprecipitate used for?
1) If massive bleeding and fibrinogen is very low
| 2) Rarely hypofibrinogenaemia
288
What is the shelf life of platelets? How are they stored?
Shelf life of 5 days
| Stored at 22°C (room temperature) and constantly agitated
289
When are platelets used?
1) Mostly haematology patients with bone marrow failure (if platelets are <10 x 10⁹/L
2) Massive bleeding or acute DIC
3) If very low platelets and patient needs surgery
4) For cardiac bypass when patient on anti-platelet drugs
290
If a patient is bleeding post surgery, what components does he need is his platelet count is normal and his coagulation test are prolonged?
FFP
291
If a patient is bleeding post surgery, what components does he need is his PT and APTT are long and his fibrinogen is very low?
Cryoprecipitate
292
What factors are taken from fractionated plasma?
1) Factor VIII and IX
2) Immunoglobulins
3) Albumin
293
When are factor VIII and IX given?
1) For haemophilia A and B respectively
| 2) Factor VIII for von Willebrand's disease
294
When are immunoglobulins given?
IM: Specific- tetanus, anti-D, rabies
IM: Normal globulin- broad mix in population (e.g. HAV)
IVIg- pre-op in patients with ITP or AIHA
295
What dilution of albumin is used in burns or plasma exchange patients?
4.5%
296
What dilution of plasma is used in severe liver and kidney conditions?
20%
297
What percentage of Caribbeans and Africans carry the sickly gene?
10% Caribbeans
| 25% Africans
298
What is βs?
```
The sickle gene
A point mutation at codon 6 of the gene for β globin
Glutamic acid (polar) is replaced by valine (non-polar)
```
299
What causes the distortion of red blood cells in sickle cell disease?
Deoxyhaemoglobin S is insoluble
1) Distortion
Polymerisation initially reversible with formation of oxyHbS
Subsequently irreversible
2) Dehydration
3) Increased adherence to vascular endothelium
300
What is the inheritance pattern of sickle cell disorders?
Recessive
301
What is the life span of a sickle cell?
5-7 days
302
What are the clinical consequences of haemolysis in sickle cell disorders?
Anaemia
Gall stones
Aplastic crisis (Parvovirus B19)
303
What can increased the incidence of gall stones by 3-5 times in sickle cell?
Gilbert syndrome
304
What are the clinical consequences of blockage to the microvascular circulation in sickle cell disorders?
Tissue damage and necrosis (infarction)
Pain
Dysfunction
305
What are the consequences of tissue infarction in sickle cell disorders?
```
1) Spleen:
hyposplenism (infection)
2) Bones/Joints:
a) dactylitis (inflammation of a digit)
b) avascular necrosis
c) osteomyelitis
3) Skin
Ulceration
```
306
How can the lungs be affected in sickle cell disorders?
- Acute chest syndrome
| - Chronic damage- pulmonary hypertension
307
How can the urinary tract be affected in sickle cell disorders?
- Haematuria (papillary necrosis
- Imparied concentration or urine (hyposthenuria)
- Renal failure
- Priapism (painful erection)
308
How can the brain be affected in sickle cell disorders?
- Stoke
| - Cognitive impairment
309
How can the eyes be affected in sickle cell disorders?
- Proliferative retinopathy
310
Why does pulmonary hypertension occur in sickle cell disorders?
Pulmonary hypertension correlates with the severity of haemolysis
Likely that the free plasma haemoglobin resulting from intravascular haemolysis scavenges NO and causes vasoconstriction
Associated with increased mortality
311
What are the triggers of pain crisis in sickle cell disorders?
```
Infection
Exertion
Dehydration
Hypoxia
Psychological stress
```
312
What is the general management measures of sickle cell disorders?
```
Folic acid
Penicillin
Vaccination
Monitor spleen size
Blood transfusion for acute anaemic events, chest syndrome and stroke
Pregnancy care
```
313
What is the management of painful crisis in sickle cell disorders?
```
Pain relief (opioids)
Hydration
Keep warm
Oxygen if hypoxic
Exclude infection:
- Blood and urine cultures
- CXR
```
314
What is the only possible cure for sickle cell disorders?
Haematopoietic stem cell transplantation
315
What drugs are used to induce HbF production in sickle cell disorders?
Hydroxyurea (hydroxycarbamide)
| Butyrate
316
What are the laboratory features of a patient with a sickle cell disorder?
```
Hb low (typically 6-8g/dl)
Reticulocytes high (except in aplastic crisis)
Film
- Sickled cell
- Boat cell
- Target cells
- Howell Jolly bodies
```
317
How is a diagnosis of sickle cell disorders made?
1) Solubility test:
- In presence of a reducing agent oxyHb converted to deoxyHb
- Solubility decreases
- Solution becomes turbid
- Does not differentiate AS from SS
2) Electrophoresis or high performance liquid chromatography separated proteins according to charge
318
What risks are there for individuals with sickle cell trait?
Can experience sickling:
Anaesthetic
High altitude
Extreme exertion
319
True of false?
| Sickle cell anaemia includes both HbSS and HbSC?
False
320
True of false?
| Sickling is due to a change in the α globin chain?
False
321
True of false?
| The molecular alteration in sickle cell disorder is a deletion which protects against malaria?
False
| Point mutation
322
True of false?
| Sickle Hb makes red cells less deformable?
True
323
True of false?
| Clinical manefestations may start in utero because β-globin is part of foetal HB?
False
324
True of false?
| Osteomyelitis is the name given to inflammation of a digit?
False
325
True of false?
| Women with HbSS have a normal life expectancy?
False
326
True of false?
| Chest crises may be fatal?
True
327
True of false?
| Solubility tests are used to confirm sickle cell anaemia is screening tests are positive?
False
328
True of false?
| If a lady with HbAS has a partner with HbSS she should be offered genetic counselling?
True
329
What is anisocytosis?
When red blood cells are all different sizes on a blood film
330
What is poikilocytosis?
When red blood cells are all different shapes on a blood film
331
What happens if low vitamin B₁₂ is left untreated?
Paralysis
Blindness
Dementia
Soreness of mouth and tongue
332
If a patient has macrocytic anaemia and a low vitamin B₁₂ what would be the next diagnostic steps?
Test gastric parietal cell antibodies
Test IF antibodies
Shilling test
333
What is the commonest cause of hypochromic microcytic anaemia?
Iron deficiency
334
What specific results on a FBC confirm inflammation?
WBC count raised
| ESR (erythrocyte sedimentation rate) raised
335
What is the MCV in anaemia of chronic disease?
Normal-low
336
What are the four mechanisms of anaemia of chronic disease?
1) Ineffective iron utilisation
2) Reduced erythropoietin
3) Reduced erythropoietin sensitivity
4) Reduced RBC survival
337
What are the three most common causes of jaundice?
Hepatitis
Haemolysis
Obstructive jaundice
338
What toxin causes haemolysis of red cells leading to jaundice?
E. coli toxin
339
What is the most common cause of acute renal failure in children?
Haemolytic Uraemic Syndrome
340
What type of anaemia had slightly low haemoglobin and very low mean cell volume?
Hypochromic microcytic anaemia
341
How do you test for thalassaemia trait?
Haemoglobin electrophoresis
342
What is haemopoiesis?
Production of blood cells in the bone marrow.
| Normally it is polyclonal, healthy and reactive
343
What are types of malignant haemopoiesis?
Leukaemia (lymphoid, myeloid)
Myelodysplasia
Myeloproliferative
344
In what situations would you see myeloblasts, prohyelocytes, myelocytes, metamyelocytes and neutrophils?
In patients undergoing chemotherapy and patients being treated with G-CSF
345
Give examples of bone marrow failures that cause decreased WBC count.
- Aplastic anaemia
- Post chemotherapy
- Metastatic cancer
- Haematological cancer
346
What are the causes of reactive eosinophilia?
Caused by normal haemopoiesis:
1) Inflammation
2) Infection
3) Increased cytokine production
- Distant tumour
- Haemopoietic or non haemopoietic
347
What are the causes of primary eosinophilia?
Caused from abnormal haemopoiesis:
1) Cancers of haemopoietic cells
2) Leukaemia
- Myeloid or lymphoid
- Chronic or acute
3) Myeloproliferative disorders
348
What causes the increase in production of cells in malignant haematopoiesis?
DNA damage
349
What are the steps in investigating a raised WBC count?
1) History and examination
2) Haemoglobin and platelet count
3) Automated differential
4) Examine blood film
5) Abnormality white cells only or all 3 lineages
6) 1 type of white cell or all lineages
7) Mature cells only or mature + immature cells?
350
In a reactive raised WCC how many types of WBC are raised?
Normally more than one
351
Immature neutrophils present in a raised WCC are suggestive of what?
Neoplastic cause
352
Mature neutrophils present in a raised WCC are suggestive of what?
Infection
353
Mature lymphocytes present in a raised WCC are suggestive of what?
Not suggestive. They can still occur in neoplastic processes
354
What do blasts occur in the presence of?
Low Hb and low platelets
355
What percentage of neutrophils are marginated?
50%
356
What causes neutrophilia that develops in minutes?
Demargination
357
What causes neutrophilia that develops in hours?
Early release from bone marrow
358
What causes neutrophilia that develops in days?
Increased production
359
How much does neutrophil production increase by during infection?
Three times
360
What is toxic granulation?
An abnormal distribution of granules in neutrophils
361
What are the causes of neutrophilia?
1) Infection
2) Tissue inflammation
(e. g. colitis, pancreatitis)
3) Physical stress, adrenaline, corticosteroids
4) Underlying neoplasia
5) Malignant neutrophilia
- Myeloproliferative disorders
- CML
362
What infections do not produce a neutrophilia?
- Brucella
- Typhoid
- Many viral infections
363
What causes reactive eosinophilia?
- Parasitic infestation
- Allergic diseases (e.g. asthma, rheumatoid, polyarteritis, pulmonary eosinophilia)
- Neoplasms (esp. Hidgkin's, T-cell NHL)
- Hypereosinophilic syndrome
364
A mutation in what gene causes Malignant Chronic Eosinophilic Leukaemia?
PDGFR fusion gene
| Platelet Derived Growth Factor Receptor
365
In what conditions is monocytosis seen?
- TB, bruella, typhoid
- Viral: CMV, varicella zoster
- Sarcoidosis
- Chronic Myelomonocytic Leukaemia (MDS)
366
What types of infection, inflammation and neoplasia can cause an elevated neutrophil count?
Infection: Bacterial
Inflammation: Auto-immune; tissue necrosis
Neoplasia: All types
367
What types of infection, inflammation and neoplasia can cause an elevated eosinophil count?
Infection: Parasitic
Inflammation: Allergic (asthma, atopy, drug reactions)
Neoplasia: Hodgkin's NHL
368
What types of infection can cause an elevated basophil count?
Infection: Pox viruses
369
What types of infection can cause an elevated monocyte count?
Infection: Chronic (TB, brucella)
370
What diagnosis would be given in a patient with lymphocytosis if mature cells are present?
- Chronic lymphocytic leukaemia
| - Autoimmune/inflammatory disease
371
What diagnosis would be given in a patient with lymphocytosis if immature cells are present?
Acute lymphoblastic leukaemia
372
What do immature lymphoblasts look like?
Large immature nucleus with visible cytoplasm
373
How do you know if lymphocytosis is primary or reactive? Give an example of each
Primary: monoclonal lymphoid proliferation
e.g. CLL
Secondary (reactive): polyclonal response to infection
e.g. chronic inflammation or underlying malignancy
374
What are the possible causes of reactive lymphocytosis?
1) Infection
- EBV, CMV, toxoplasma
- infectious hepatitis, rubella, herpes infections
2) Autoimmune disorders
3) Neoplasia
4) Sarcoidosis
375
What cell is characteristic of mononucleosis syndrome?
Atypical lymphocytes
376
What is mononucleosis syndrome typically misdiagnosed as? Why?
Leukaemia as lymphocytes resemble blasts
377
What causes glandular fever?
- EBV infection of B-lymphocytes via CD21 receptor
- Infected B-cell proliferates and expresses EBV associated antigens
- Cytotoxic T-lymphocyte response
- Acute infection resolved resulting in lifelong sub-clinical infection
378
Who is Chronic Lymphocytic Leukaemia particularly common in?
People over the age of 70
379
Pleomorphic lymphocytes are characteristic of what type of lymphocytosis?
Reactive
380
Monoclonal lymphocytes are characteristic of what type of lymphocytosis?
Neoplastic
381
What is an immunophenotype?
Shows the antigen expressed on the surface of the lymphocytes to differentiate between polyclonal and monoclonal
382
What light chains are found on polyclonal B cells?
Kappa and lambda
383
What light chains are found on monoclonal B cells?
Kappa only
OR
Lambda only
384
What method of analysis is used to detect identical Ig or TCR configuration in lymphocytosis?
Southern Blot analysis
385
If you have a patient with a high WCC, normal neutrophils, slightly high eosinophils and very high lymphocytes with normal looking cells in the blood film how would you make a diagnosis?
Could still be leukaemia (chronic lymphocytic leukaemia)
Cells all look the same (monoclonal) so perform immunophenotying
If B cells are all the same (kappa or lambda) other than CD5 it is a sign of CLL
386
What diagnosis would be made with a patient with low Hb who is thrombocytopenic and neutropenic?
Acute leukaemia (all cell types are low)
387
What diagnosis would be made with a patient who has raised platelets, raised WBC count (mostly neutrophils), slightly raised eosinophils and both mature and immature cells present?
Chronic myeloid leukaemia
388
What causes a prolonged APTT?
APTT tests the intrinsic clotting pathway (Factors XII, XI, IX and VIII). Factor XII would not cause
389
What causes Haemophilia A?
Factor VIII deficiency
390
What causes Haemophilia B?
Factor IX deficiency
391
Which type of haemophilia is most common?
Haemophilia A
392
What type of jaundice causes dark urine and pale stools? Why?
Obstructive jaundice
| Causes fat malabsorption and malabsorption of fat soluble vitamins (K, A, D, E)
393
What are the possible causes of multiple clotting factor deficiencies?
- Vitamin K deficiency
| - Liver disease
394
In what type of jaundice do you see unconjugated bilirubin?
Pre-hepatic jaundice
395
In what type of jaundice do you see conjugated bilirubin?
Obstructive jaundice
