Haematology Flashcards
1
Q
When do you get anaemic?
A
When there is a decrease of haemoglobin in the blood before the reference for age/sex of an individual
2
Q
What 2 things may anaemia be due to?
A
- low red cell mass (RCM)
- increase plasma volume
3
Q
RBC lifespan?
A
120 days
4
Q
What can reduce a RBC’s lifespan?
A
- reduced production from marrow
- increased loss of RBC (by spleen, liver, marrow, blood loss)
5
Q
How do you test to see if the bone marrow production is the cause for anaemia?
A
Look at reticulocyte count (count of immature RBC in bone)
6
Q
What will the reticulocyte count be if the production of RBC is the issue?
A
Low
7
Q
What will the reticulocyte count be if the removal of RBC is the issue?
A
High
8
Q
How are various types of anaemia classified?
A
By mean corpuscular volume (MCV)
- average vol of RBCs
9
Q
Name the 3 major types of anaemia
A
- Hypochroic microcytic
- Normochromic normocytic
- Macrocytic
10
Q
What will a reduction in plasma volume lead to?
A
A falsely high haemoglobin (seen in dehydration)
11
Q
List the consequences of anaemia
A
- reduced O2 transport
- tissue hypoxia
12
Q
What are the compensatory changes for anaemia?
A
- increased tissue perfusion
- increased O2 transfer to tissues
- increased RBC production
13
Q
List the pathological consequences for anaemia?
A
- myocardial fatty change
- fatty change in liver
- aggravates angina
- skin & nail atrophic changes
- CNS cell death
14
Q
List the non-specific symptoms (clinical features) of anaemia
A
- fatigue / headaches / faintness
- dyspnea
- breathlessness
- anorexia
- palpitations
- intermittent claudication
15
Q
What clinical signs may anaemics show?
A
- pallor
- tachycardia
- systolic flow murmur
- cardiac failure
- may be absent in severe anaemia
16
Q
What are the main causes of microcytic anaemia?
A
- iron deficiency anaemia (most common cause world-wide)
- anaemia of chronic disease
- thalassemia
17
Q
Is microcytic anaemia high or low MCV?
A
Low
18
Q
What is the average daily intake of iron?
A
15-20mg
19
Q
What % of iron is normally absorbed and where?
A
10% - in the duodenum
20
Q
How are iron ions absorbed?
A
- actively transported into duodenal intestinal epithelial cells
21
Q
What transports iron ions into duodenal cells?
A
Intestinal haem transporter (HCP1)
22
Q
Where is HCP1 highly expressed?
A
In the duodenum
23
Q
What are some iron ions incorporated into?
A
Ferritin (acts as an intracellular store for iron)
24
Q
What happens to absorbed iron that doesn’t bind to ferritin?
A
- released into blood
- binds to transferrin
- circulates body
25
Describe the function of transferrin
Transports iron in blood plasma to bone marrow
26
What happens to iron that is transported to bone marrow?
Incorporated int new erythrocytes
27
What is the majority of iron incorporated into?
Haemoglobin
28
Where is the rest of the absorbed iron stored?
- reticuloendothelial cells
- hepatocytes
- skeletal muscle cells (as ferritin or haemosiderin)
29
What is the advantage of storing iron as ferritin?
- more easily mobilised than haemosiderin
| - for Hb formation
30
Where is ferritin found?
- plasma
| - most cells: liver, spleen, bone marrow
31
Where is haemosiderin found?
Found in macrophages: in bone marrow, liver, spleen
32
When does iron deficiency anaemia develop?
When there is an inadequate iron for Hb synthesis
33
What causes iron deficiency anaemia to develop?
- blood loss
- poor diet
- inc. demands (growth/pregnancy)
- malabsorption
34
Examples of blood loss events leading to iron deficient anaemia
- menorrhagia (severe menstruation)
- GI bleeding
- hookworm - leads to GI blood loss (leading cause of iron deficiency worldwide)
35
Examples of malabsorption
- poor intake (underdeveloped countries)
| - coeliac disease
36
What are the risk factors for iron deficient anaemia?
- undeveloped countries
- high vegetable diet
- premature infants
- introduction of mixed feeding delay
37
Pathophysiology of microcytic anaemia
- less iron available for haem synthesis
- crucial for haem production
- reduction ins iron = decrease in Hb
- smaller RBC
= microcytic anaemia
38
What are the clinical presentations of microcytic anaemia?
- brittle nails & hair
- spoon shaped nails
- atrophy of papillae of tongue
- angular stomatitis (ulceration of corners of the mouth)
39
Differential diagnoses of microcytic anaemia
- thalassaemia
- sideroblastic anaemia
- anaemia of chronic disease
40
How would you diagnose microcytic anaemia?
- blood count & film
- serum ferritin
- serum iron
- serum soluble transferrin receptors
- low reticulocyte count
- investigate cause of blood loss
41
What will a blood count & film for microcytic anaemia?
- RBC are microcytic & hypochromic
| - poikilocytosis & anisocytosis
42
What is poikilocytosis?
Variation in RBC shape
43
What is anisocytosis?
Variation in RBC size
44
How will serum ferritin indicate microcytic anaemia?
Serum ferritin will be low
45
How will serum iron indicate microcytic anaemia?
- Will be low
| - total iron-binding capacity (TIBC) rises
46
When is iron deficiency present?
When transferrin saturation falls below 19%
47
How will serum soluble transferrin receptors indicate microcytic anaemia?
No. of transferrin receptors will INCREASE in iron deficiency
48
How would you treat microcytic anaemia?
- oral iron (ferrous sulphate / ferrous gluconate)
| - parenteral iron
49
What are the side effects of ferrous sulphate?
- nausea
- abdominal discomfort
- diarrhoea / constipation / black stools
(FERROUS GLUCONATE IF SIDE EFFECTS ARE BAD)
50
Examples of parenteral iron
- IV iron
| - deep intramuscular iron in extreme cases (severe malabsorption)
51
Describe anaemia of chronic disease
- if body is sick = bone marrow becomes sick
| - anaemia is secondary to chronic disease
52
Describe the appearance of RBCs in anaemia of chronic disease
- often normocytic
| - can be microcytic (in rheumatoid arthritis / Crohn's)
53
Name which chronic infections can lead to anaemia
- TB
- Crohn's
- Rheumatoid arthritis
- SLE
- Malignant disease
54
Pathophysiology of anaemia in chronic disease
- decreased iron release from bone marrow
- inadequate erythropoietin response
- decreased RBC survival
55
List the clinical presentations of anaemia in chronic disease
- fatigue / headaches / faintness
- dyspnea / breathlessness
- anorexia
- palpitations
- intermittent claudication
- angina (if coronary disease)
56
How would you diagnose anaemia in chronic disease?
- low serum iron / TIBC
- normal/raised serum ferritin due to inflammatory process
- normal serum soluble transferrin receptor level
- RBCs are normocytic/microcytic AND hypochromic
57
How would you treat anaemia in chronic disease?
- treat underlying chronic cause
| - erythropoietin = raises Hb level
58
When is erythropoietin used to treat anaemia?
- renal disease
| - inflammatory disease
59
List the side effects of using erythropoietin to treat anaemia
- flu like symptoms
- hypertension
- mild rise in platelet count
- thromboembolism
60
Describe normocytic anaemia
Normal MCV
61
List the main causes of normocytic anaemia
- acute blood loss
- anaemia of chronic disease
- endocrine disorders
- renal failure
- pregnancy
62
Suggest endocrine disorders that may lead to normocytic anaemia
- hypopituitarism
- hypothyroidism
- hypoadrenalinism
63
What would indicate a diagnosis normocytic anaemia?
- normal B12 & folate
- raised reticulocytes
- decreased Hb
- RBC's are normocytic
64
How would you treat normocytic anaemia?
- treat underlying cause
- improve diet (vitamins)
- erythropoietin injections
65
Describe macrocytic anaemia
High MCV
66
What can macrocytic anaemia be divided into?
1. Megaloblastic
| 2. Non-megaloblastic
67
Describe megaloblastic anaemia
- presence of erythroblasts
- delayed DNA synthesis = delayed nuclear maturation
- megaloblasts w/ large MCV & no nuclei
68
Describe non-megaloblastic anaemia
Erythroblasts are normal - normoblastic
69
What are the main causes of megaloblastic anaemia?
- vitamin B12 deficiency
| - folate deficiency
70
What are the main causes of non-megaloblastic anaemia?
- alcohol
- liver disease
- hypothyroidism
- haemolysis
- bone marrow failure / infiltration
- myeloma
- antimetabolite therapy
71
What deficiency does pernicious anaemia cause?
Vitamin B12 deficiency
72
What does B12 deficiency cause?
- impairs DNA synthesis
- delayed nuclear maturation
= larger RBC
= reduced RBC production in bone marrow
73
Why does low B12 affect DNA synthesis?
- B12 is essential for thymidine
| - thus important for DNA synthesis
74
What are the causes of B12 deficiency?
- dietary (vegans)
- malabsorption (lack of intrinsic factor / terminal ileum removal)
- pernicious anaemia (most common cause)
75
Describe pernicious anaemia
- autoimmune disorder
- parietal cells attacked
- results in atrophic gastritis
- loss of intrinsic factor production
= B12 malabsorption
76
List the risk factors for pernicious anaemia
- elderly (over 60)
- female
- fair haired / blue eyes
- blood group A
- thyroid / Addison's disease
77
What % of patients are intrinsic factor antibodies found in?
50% - SPECIFIC FOR DIAGNOSIS
78
What and how does autoimmune gastritis affect?
- the fundus
| - with plasma cell & lymphoid infiltration
79
What are parietal and chief cells replaced by?
Mucin-secreting cells
80
What happens to the acid production in pernicious anaemia?
Reduced HCl production - Achlorhydria
81
What are the clinical presentations of pernicious anaemia?
- fatigue/headache
- pallor
- dyspnea
- anorexia
- palpitations/tachycardia
- yellow skin
- red sore tongue
- angular stomatitis
- neurological features
82
Why might patients with pernicious anaemia appear yellow?
- due to pallor & mild jaundice
| due to excessive breakdown of Hb - as body tries to get rid of defective RBC
83
When might neurological features present in pernicious anaemia?
When B12 levels are very low
84
What type of neurological features may present in pernicious anaemia?
- symmetrical parenthesis (burning/prickling pain) in toes / fingers
- early loss of vibration/proprioception
- progressive weakness / ataxia
- paraplegia
- dementia / hallucinations / delusions / psychiatric problems
- optic atrophy
85
What are the differential diagnoses of pernicious anaemia?
- differentiate from other cause of megaloblastic anaemia
- differentiate from other causes of B12 deficiency
- terminal ileum disease
- bacterial overgrowth in small bowel
- gastrectomy
86
What would suggest a diagnosis of pernicious anaemia?
- RBCs are macrocytic
- raised serum bilirubin
- low serum B12
- low Hb
- low reticulocyte
- intrinsic factor antibodies (not present in all patients)
87
What would a peripheral blood film of pernicious anaemia show?
- oval macrocytes
WITH
- hypersegmented neutrophil polymorphs
- 6< lobes in nucleus
88
Why might serum bilirubin be raised in pernicious anaemia?
- ineffective erythropoiesis
| - increased RBC breakdown
89
How would you treat anaemia if it is not pernicious?
Treat underlying cause
90
How would you treat low B12 due to malabsorption?
Injections
91
How would you treat low B12 due to dietary causes?
Oral B12
92
How can you replenish B12 levels?
Intra muscular hydroxocobalamin (injectable form of B12)
93
What type of anaemia is folate deficiency?
Megaloblastic
94
What is folate found in?
- spinach
- broccoli
- nuts
- yeast
- liver
95
How long can you live with low stores of folate for?
4 months
96
When might folate deficiency develop rapidly?
- patients w poor intake + excess utilisation
| E.G patients in ICU
97
Where is folate absorbed?
Duodenum / proximal jejunum
98
What does folate deficiency impair?
- DNA synthesis (same as B12)
| - fetal development (results in neural tube defects)
99
List the causes of folate deficiency
- poor intake
- increase demand
- malabsorption (Crohn's coeliac's)
- antifolate drugs
100
When might there be an increased demand for folate?
- pregnancy
| - increased cell turnover (haemolysis, malignancies, inflammatory disease, renal dialysis)
101
Examples of antifolate drugs
- methotrexate
| - trimethoprim
102
Clinical presentations of folate deficiency
- patients may be asymptomatic
- symptoms similar to anaemia
- glossitis
- no neuropathy (WILL HELP TO DISTINGUISH BETWEEN B12)
103
How would you diagnose folate deficiency?
- macrocytic RBC in blood film
- oval macrocytes in peripheral film
- low serum & RBC folate
- GI investigation
- raised serum bilirubin
104
How would you treat folate deficiency?
- treat underlying cause
| - folic acid tablets
105
How long would you prescribe folic acid tablets for?
Daily for 4 months
| - ALWAYS WITH B12 (unless patient has normal B12)
106
Describe haemolytic anaemia
- RBCs can be normocytic
- if many young RBCs due to excessive destruction of old RBCs
- if so, then RBCs are macrocytic
- premature breakdown of RBCs
107
Name the 2 sites where premature RBC breakdown in haemolytic anaemic occurs?
1. Circulation - intravascular
| 2. Reticuloendothelial system & bone marrow
108
Describe what happens when RBC are prematurely broken down in the circulation
- Hb is liberated
- binds to haptoglobulin
- these become saturated
- excess free Hb filtered in glomerulus
- enters urine
- Hb broken down in renal tubular cells
- deposited in the cells as haemosiderin
109
Why does decreased RBC survival not always lead to anaemia?
There is a compensatory increase in RBC production in bone marrow
110
How many times can bone marrow increase its RBC output by?
6-8 times
111
How does bone marrow increase RBC output?
- increases proportion of cells that produce RBC
| - expands volume of active marrow
112
What are the consequences of haemolysis?
- bone marrow increases output
| - premature release of reticulocytes
113
What are reticulocytes? What is their appearance?
Immature RBC
- larger than mature cells
- macrocytic
114
How and what do reticulocytes stain?
- stain with light blue tinge
| - on peripheral blood film
115
What are the main causes of haemolytic anaemia?
1. RBC membrane defect
2. Enzyme defect
3. Haemoglobinopathies
4. Autoimmune haemolytic anaemia
116
Name an example of RBC membrane defect that leads to haemolytic anaemia
Hereditary spherocytosis
117
Name an example of enzyme defect that leads to haemolytic anaemia
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
118
Name 3 examples of haemoglobinopathies that lead to haemolytic anaemia
1. B thalassaemia
2. A thalassaemia
3. Sickle cell
119
List the features of haemolytic anaemia
- high serum unconjugated bilirubin
- high urinary urobilinogen
- high faecal stercobilinogen
- splenomegaly
- bone marrow expansion
- reticulocytosis
120
What is hereditary spherocytosis? (HS)
- defect of structural membrane proteins in RBC
| - deficiency in spectrin (structural protein)
121
What is the abnormal cell membrane functionally associated with?
- increased Na+ permeability
| - requires inc. rate of active transport of Na+ OUT of cells
122
What happens to the RBC due to increased outward Na+ transport?
- decreased SA:V ratio
| - cells become SPHEROCYTIC (spheres)
123
Describe properties of spherocytes
- more rigid
- less deformable than normal RBC
- unable to pass through splenic microcirculation
124
Why do spherocytes become trapped in the spleen?
- more rigid & less deformable
| - can't pass through splenic microcirculation
125
What happens due to spherocytes becoming trapped in the spleen?
- shorted lifespan
| - destroyed via extravascular haemolysis
126
Epidemiology of HS
- autosomal dominant
- most common cause of inherited haemolytic anaemia
- can spontaneously occur 25% (even if neither parent is affected)
127
List the clinical presentations of HS
- jaundice at birth (may be delayed onset)
- haemolytic anaemia
- splenomegaly
- ulcers on the leg
- chronic haemolysis = gall stones
128
What might interrupt the course of HS?
- aplastic anaemia
| - megaloblastic anaemia
129
What is aplastic anaemia? When might it occur?
- sudden stop in RBC production
| - after infection (erythrovirus etc.)
130
What is megaloblastic anaemia caused by ?
- folate depletion
| - because of hyperactivity of bone marrow
131
How would you diagnose HS?
- blood film
- blood count
- haemolysis
- direct antiglobulin test (Coombs')
132
What would a blood film show in confirmed HS?
- spherocytes
| - reticulocytes
133
What would a blood count show in confirmed HS?
- low Hb (anaemia)
| - increased reticulocytes
134
What would suggest haemolysis is occurring for HS diagnosis?
- increased serum bilirubin
| - increased urinary urobilinogen
135
How would the Coombs' test confirm HS?
- would be negative
| - ruling out autoimmune haemolytic anaemia
136
How would you treat HS?
SPLENECTOMY
- relieves symptoms
- after childhood (due to infection risk post-op)
- immunisations & life long penicillin prophylaxis after op
137
Epidemiology of G6PD deficiency
- heterogenous X-linked - more males affected
- present with haemolytic anaemia
- heterozygous females can also have clinical problems
138
Which parts of the world is G6PD deficiency more common?
- Africa
- Mediterranean
- Middle East
- SE Asia
139
How many different structural types of G6PD are there?
Over 400
140
Which type of mutation are most G6PD types?
- single amino acid substitutions (MIS-SENSE POINT MUTATIONS)
141
How / what is G6PD essential for?
- provides NADPH
- NADPH is used with glutathione
- which protects RBC from oxidative damage from compounds (e.g hydrogen peroxide)
142
How does G6PD deficiency affect RBC?
- reduces lifespan
| - because they can't be protected against oxidative damage
143
Where is the gene for G6PD localised?
- chromosome Xq28
| - near factor VIII gene
144
Why might patients with G6PD deficiency experience an oxidative crisis?
Because of reduced glutathione production
145
What is reduced glutathione production precipitated by?
ACUTE DRUG INDUCED HAEMOLYSIS (dose related):
- aspirin
- antimalarials
- antibacterials
- dapsone
- quinidine
146
What are the clinical presentations of G6PD deficiency?
In attacks:
- rapid anaemia
- jaundice
General:
- chronic haemolytic anaemia
- neonatal jaundice
- haemoglobinuria
147
What are the clinical features of G6PD deficiency due to?
- rapid intravascular haemolysis
148
How would you diagnose G6PD deficiency?
- blood count (normal between attacks)
- blood film during attacks
- G6PD enzyme levels (LOW)
149
What will a blood film of G6PD show during an attack?
- irregularly contracted cells
- bite cells (have indentation in the membrane)
- reticulocytosis (inc. reticulocytes)
150
Why might there be falsely high G6PD enzyme levels after an attack?
- oldest RBCs w/ least G6PD activity are destroyed selectively
151
How would you treat G6PD deficiency?
- stop any drugs causing it
- blood transfusion
(splenectomy is not usually helpful)
152
Describe structure of normal Hb (HbA)
- haem
- 2 alpha chains
- 2 beta chains
153
Describe structure of foetal Hb (HbF)
- haem
- 2 alpha chains
- 2 gamma chains
154
Describe structure of Hb delta (HbA2)
- haem
- 2 alpha chains
- 2 delta chains
155
What is the percentage of HbA in an adult?
97%
156
What is the percentage of HbF in an adult?
1%
157
What is the percentage of HbA2 in an adult?
2%
158
What is the balanced production of alpha & beta chains?
1:1
159
Describe the thalassaemias
- genetic disease
- unbalanced Hb synthesis
- under production (no production) of one globin chain
160
What does an imbalance of globin chains in RBC precursors result in?
- cell damage
- death of precursors in bone marrow
- INEFFECTIVE ERYTHROPOIESIS
- in mature cells = haemolysis
161
What is beta thalassaemia?
- reduced beta chain synthesis
| - excess alpha chains
162
What happens to with the excess alpha chains produced in B thalassaemia?
- combine with delta/gamma chains
| - results in increased HbA2, HbF
163
What mutation causes B thalassaemia?
- point mutations
164
What do mutations in B thalassaemia lead to?
Defects in:
- transcription
- RNA splicing
- modification
- translation (via fram shifts / nonsense codons)
165
What do frame shifts/ nonsense codons in B thalassaemia lead to?
- production of highly UNSTABLE b-globin
| - can't be utilised
166
Pathophysiology of heterozygous B-thalassemia
- asymptomatic microcytosis
| - with or without mild anaemia
167
List the clinical presentations of B-thalassaemia minor (carrier)
- asymptomatic
| - hypochromic & microcytic RBCs ( low MCV)
168
What does a Hb electrophoresis of B-thalassaemia show?
- raised HbA2
| - raised HbF
169
How can B-thalassaemia be distinguished from iron deficiency?
- serum ferritin & iron stores are normal
170
Clinical presentations of B-thalassaemia intermedia
- splenomegaly
- bone deformities
- recurrent leg ulcers
- gallstones
- infections
171
Clinical presentations of B-thalassaemia major
- severe anaemia at age 3-6 months
- extra medullary haematopoiesis
- life long transfusion dependent
- hypertrophy of ineffective bone marrow
- normal serum ferritin
172
What does extra medullary haematopoiesis result in?
- hepatosplenomegaly (due to haemolysis)
| - bone expansion
173
What would a skull X-ray of B-thalassaemia major show?
- "hair on end" due to increased marrow activity
174
What would blood results of B-thalassaemia major show?
- v low MCV - microcytic
175
What would blood film of B-thalassaemia major show?
Large and small irregular hypochromic RBCs
176
What would be the diagnostic indicators B-thalassaemia major?
- hypochromic, microcytic anaemia
- raised reticulocyte count
- nucleated RBC in peripheral circulation
177
What would haemoglobin electrophoresis of B-thalassaemia major show?
- increased HbF
| - absent/fewer HbA (normal)
178
How would you treat B-thalassaemia major?
- regular life-long transfusions
- iron-chelating agents
- large doses of ascorbic acid
- splenectomy
- bone marrow transplant
- long term folic acid
179
How frequent would transfusions have to be in B-thalassaemia major?
Every 2-4 weeks
180
Transfusions help to keep the Hb level above what? (B-Thalassaemia)
90g/L
181
How do transfusions help B-thalassaemia major?
- suppress ineffective extramedullary haematopoiesis
| - allows normal growth
182
Examples of iron-chelating agents
- oral deferiprone
| - subcutaneous desderrioxamine
183
How do iron chelating agents help B-thalassaemia major?
- prevent iron overload
| esp. during infusions
184
What are the side effects of iron-chelating agents?
- pain
- deafness
- cataracts
- retinal damage
185
How does ascorbic acid help B-thalassaemia major?
Increases urinary excretion of iron
186
What are the complication of transfusions for B-thalassaemia major?
- progressive increase in body iron load
- liver cirrhosis & fibrosis
- diabetes
- hypothyroidism
- hypocalcaemia
- premature death
187
Where is iron deposited as a result of transfusions?
- liver
- spleen
- endocrine glands
- heart
188
What is alpha thalassaemia?
- gene for alpha globin chains is duplicated on both chromosomes 16
- deletion might be of one or both alpha chain genes on chromosome 16
189
What type of mutation causes alpha thalassaemia?
Gene deletions
190
What is 4 gene deletion in A-thalassaemia?
- deletion of both genes on both chromosomes
191
Describe 4 gene deletion
- no alpha chain synthesis
| - only Hb barts (4 gamma chains) present
192
Why is Hb Barts bad?
- they cannot carry O2
| - incompatible with life
193
Clinical presentations of 4 gene deletion
- infants are stillborn / die soon after birth
- pale
- oedematous
- v large livers & spleens (HYDROPS FETALIS)
194
Describe 3 gene deletion
- severe reduction in A chain synthesis
- results in HbH disease
- HbH has 4 beta chains
195
Clinical presentations of 3 gene deletion
- moderate anaemia
- splenomegaly
- patient not usually transfusion dependent
196
Describe 2 gene deletion
(A-thalassaemia carrier)
- microcytosis
- with or without mild anaemia
197
Describe 1 gene deletion
Usually a normal blood picture
198
What is sickle cell anaemia?
- production of abnormal beta globin chains
| - autosomal recessive
199
What are the probabilities for sickle cell anaemia?
- 25% chance of disease
- 50% carrier
- 25% disease free
200
What type of mutation causes sickle cell haemoglobin? (HbS)
SINGLE BASE MUTATION
| - of adenine to thymine
201
What does HbS mutation cause?
- produces substitution of valine for glutamic acid
| - at 6th codon of beta globin chain
202
At what stage does the sickle cell manifest, and why?
- at 6 months of age
| - HbF synthesis is normal - so only manifests until HbF decreases to adult levels
203
Pathophysiology of sickle cell anaemia
- HbS is insoluble & polymerises when deoxygenated
- cell flexibility decreases
- become rigid = sickle
204
Is sickling of cells reversible?
Only INITIALLY
205
What happens with repeated sickling?
- cells lose membrane flexibility
- become irreversibly sickled
- irreversible cells are dehydrated & dense
(don't return to normal even when oxygenated)
206
What does sickling result in?
- shortened RBC survival = leads to haemolysis
- impaired passage of cells through microcirculation
- leads to obstruction of small vessels & tissue infarct = pain
207
What is sickling precipitated by?
- infection
- dehydration
- cold
- acidosis
- hypoxia
208
Why do patients still feel well despite being anaemic? (sickle cell)
HbS releases O2 into tissues more readily than normal RBCs
209
What are the clinical presentations of heterozygous sickle cell?
- symptom free except in hypoxia
| - protection against falciparum malaria
210
What are the clinical presentations of homozygous sickle cell?
- vaso-occlusive crises
- acute chest syndrome
- pulmonary hypertension
- anaemia
211
Describe vaso-occlusive crises
- acute pain in hands & feet
- pain in long bones
- possible CNS infarcts in children = stroke, seiners, cognitive defects
212
What causes acute pain in the hands, feet & long bones in sickle cell anaemia?
- Vaso-occlusion of small vessels
| - avascular necrosis of bone marrow in children
213
What is acute chest syndrome?
Vaso-occlusive crises of pulmonary vasculature
214
Name the most common cause of deaths in adults with sickle cell?
- pulmonary hypertension
| - chronic lung disease
215
Causes of acute chest syndrome
- infection (chlamydia, strep. pneumonia etc)
- fat embolism from necrotic bone marrow
- pulmonary infarction due to sickle cells (cells get trapped in pulmonary vasculature)
216
What is the definition of pulmonary hypertension?
Mean pulmonary artery pressure greater than 25mmHg by right heart catheterisation
217
What percentage of sickle cell patients suffer from PT?
10%
218
What causes pulmonary hypertension in sickle cell?
- damage from repeated chest crises
- repeated thromboembolism
- intravascular haemolysis
219
What does PT increase the risk of?
- hypoxaemia
| - worsening sickle cell crises
220
How does chronic haemolysis affect Hb levels?
Stabilises Hb levels
221
What can cause an acute fall in Hb level?
1. Splenic sequestration
| 2. Bone marrow aplasia
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What is splenic sequestration?
When sickle cells get trapped in the spleen due to their shape
223
What does splenic sequestration lead to?
- acute, painful spleen enlargement
- acute fall in Hb
- fibrotic, non-functioning spleen
224
When does bone marrow aplasia occur?
- most commonly after infection (erythrovirus B19)
225
How does bone marrow aplasia affect the body?
- rapid fall in Hb levels
- no reticulocytes in peripheral blood
- failure of erythropoiesis in marrow = APLASTIC CRISIS
226
What can sickle cell affect in the long term?
1. Growth & development
2. Bones
3. Infection in bones, lungs, kidneys
4. Heart
5. Brain
6. Liver
7. Renal
8. Eye
9. Pregnancy
227
How can sickle cell affect growth and development?
- young children are short - regain height in adulthood
- below normal weight
- delayed sexual maturation
228
How can sickle cell affect bones?
- avascular necrosis of hips & shoulders
- compression of vertebrae
- shortening of bones in hands / feet
- osteomyelitis (due to staph. aureus / pneumonia, salmonella)
229
What are bones, lungs & kidneys most susceptible to in sickle cell?
Vaso-occlusive crisis
230
How can sickle cell affect the heart?
- cariomegaly
- arrhythmias
- iron overload cardiomyopathy
- MI
231
How can sickle cell affect the brain?
- TIA
- fits
- cerebral infarction
- coma
- occurs in 25% of patients
232
How can sickle cell affect the liver?
- chronic hepatomegaly
| - liver dysfunction (due to trapping of sickle cells)
233
How can sickle cell affect the kidneys?
Chronic tubulointerstitial nephritis
234
How can sickle cell affect the eyes?
- retinopathy
- vitreous haemorrhage
- retinal detachments
235
How can sickle cell affect pregnancy?
Impaired placental blood flow - results in spontaneous abortion
236
How would you diagnose sickle cell?
- blood count
- blood film
- sickle solubility test
- Hb electrophoresis
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What will a blood count of sickle cell show?
- level of Hb in the range of 60-80 g/L
| - raised reticulocyte count
238
What will blood films of sickle cell show?
Sickled erythrocytes
239
How will a sickle solubility test confirm sickle cell?
Test will be positive
240
What will Hb electrophoresis of sickle cell show?
- 80-95% HbS
- absent HbA
- diagnose at birth (cord blood) - aids prompt pneumococcal prophylaxis
241
How and what would you treat to treat sickle cell?
- treat precipitating factors ASAP
- folic acid to ALL
- acute painful attacks
- anaemia
242
List some precipitating factors of sickle cell?
- infection
- cold
- dehydration
243
How would you treat acute painful attacks?
- IV fluids
- analgesic (morphine, codeine, paracetamol, NSAIDS)
- O2 & antibiotics
244
How would you treat anaemia in sickle cell?
- blood transfusions
- oral hydroxycarbamide
- stem cell transplant
245
What is blood transfusion given for?
- acute chest syndrome
- acute anaemia due to splenic sequestration
- aplastic crisis
- stroke
- heart failure
246
What does oral hydroxycarbamide do?
Increases HbF conc
247
Describe the epidemiology of aplastic anaemia due to bone marrow failure?
- rare stem cell disorder
- pancocytopenia
- hypocellularity (aplasia) of bone marrow
248
What is pancocytopenia?
Reduction in all major cell lines; RBC, RBC, platelets
249
What is hypocellularity of the bone marrow?
Marrow stops making cells
250
Is aplastic anaemia due to bone marrow failure acquired or inherited?
- mainly acquired
| - may be inherited
251
What are the main causes of aplastic anaemia due to bone marrow failure?
- idiopathic acquired
- benze, toluene, glue sniffing
- chemotherapeutic drugs
- antibiotics (chloramphenicol, carbamazepine, azathioprine)
- infections (EBV, HIV, TB)
252
Describe the pathophysiology of bone marrow failure?
- reduction in no. of pluripotent stem cells
- fault in remaining stem cells / immune reaction against them
- unable to repopulate bone marrow
253
List the clinical presentations of bone marrow failure
BC OF RBC, WBC, PLATELET DEFICIENCY;
- anaemia
- increased susceptibility to infection
- bleeding
- bleeding gums/bruising with minimal trauma
- blood blisters in mouth
254
List the differential diagnoses of bone marrow failure
(Differentiated from other causes of pancocytopenia)
- drugs
- Hodgkin's AND non-Hodgkin's lymphoma
- myeloma
- SLE
255
How do you diagnose bone marrow failure?
- blood count
| - bone marrow examination
256
What will a blood count test show for bone marrow failure?
Pancocytopenia with low reticulocyte count
257
What will a bone marrow examination show to diagnose bone marrow failure?
- hypocellular marrow
| - increased fat spaces
258
How would you treat bone marrow failure?
- treat cause
- red cell transfusion & platelets
- bone marrow transplant
- immunosuppressive therapy (in those over 40 & below 40 with severe disease, transfusion dependent)
259
Criteria for bone marrow donor
- from HLA identical sibling
| - donor treatment of choice under 40
260
Why should bone / platelet transfusion be used cautiously?
To avoid sensitisation
261
What is the immunosuppressive therapy given for bone marrow failure?
- antithymocyte globulin (ATG)
| - ciclosporin
262
What is polycythaemia?
Any increase in RBC
263
What can polycythaemia also be referred as?
Erythrocytosis - increase in RBC mass
264
What is polycythaemia defined as?
- increase in Hb
- increase in packed cell volume (PCV) - known as haematocrit
- increased RBC count
(ALL dependent on plasma volume & RBC mass)
265
Which is a more reliable indicatory of polycythaemia - Hb or PCV?
PCV
| - Hb may be disproportionally low in iron deficiency
266
What can polycythaemia be divided into?
1. Absolute
| 2. Relative
267
What is absolute polycythaemia due to?
Increase in RBC mass
268
What can absolute polycythaemia be divided into?
1. Primary
| 2. Secondary
269
What can primary absolute polycythaemia be due to?
- polycythaemia vera (PV)
- mutations in erythropoietin receptor
- high O2 affinity Hb
270
What can secondary absolute polycythaemia be due to?
- hypoxia
| - inappropriately high erythropoietin secretion
271
When might someone be hypoxic?
- high altitude
- chronic lung disease
- cyanotic congenital heart disease
- heavy smoking
272
When might someone have inappropriately high erythropoietin secretion?
- renal carcinoma
| - hepatocellular carcinoma
273
What is relative polycythaemia due to?
Decreased plasma volume
| - normal RBC mass
274
What is relative polycythaemia split into?
1. Apparent polycythaemia
| 2. Dehydration
275
What is apparent relative polycythaemia?
- chronic form of polycythaemia
276
What is apparent relative polycythaemia associated with?
- obesity
- hypertension
- high alcohol / tobacco intake
277
What is dehydration relative polycythaemia?
Acute
| - due to dehydration (alcohol / diuretics)
278
Epidemiology of polycythaemia vera
- 95% of patients have acquired mutations of gene JAK2
279
What is gene JAK2?
- Janus kinase 2
- cytoplasmic tyrosine kinase
- transducer signals - triggered by haemopoietic growth factors (erythropoietin)
280
What type of mutation leads to polycythaemia vera? (PV)
Point mutation
- substitutes phenylalanine with valine
- at position 617
281
Pathophysiology of PV
- clonal stem cell disorder
| - results in malignant proliferation of clone derived from one pluripotent marrow stem cell
282
Why are erythroid progenitor offspring unusual?
Don't need erythropoietin to avoid apoptosis
283
What does PV result in?
- excess proliferation of RBCs, WBCs & platelets
| - causes raised haematocrit
284
What does raised haematocrit result in?
- hyper viscosity
| - thrombosis
285
List the clinical presentations of PV
- may be asymptomatic
- over 60
- severe itching when patient is hot
- erythromelalgia
- gout
- HT
- angina
- intermittent claudication
- plethoric complexion
- hepatosplenomegaly
- risk of thrombosis / haemorrhage
286
List the vague symptoms of PV due to hyper viscosity
- tiredness
- dizziness
- headaches
- itching
- tinitus
- visual disturbance
287
What is erythromelalgia?
Burning sensation in fingers / toes
288
What is plethoric complexion?
Congested / swollen with blood in facial skin
289
What is hepatosplenomegaly in PV due to?
Extramedullary haemopoiesis
| - distinguishes PV from secondary causes
290
How do you detect asymptomatic PV?
With FBC
291
How do you diagnose PV?
- blood count - raised WBC count / platelets
- raised HB
- presence of JAK2 mutation
- bone marrow biopsy
- low serum erythropoietin
292
What will a bone marrow biopsy of PV show?
Prominent erythroid, granulocytic & megakaryocytic proliferation
293
How do you treat PV?
NO CURE - treat to maintain blood count
- venesection
- chemo
- low dose aspirin (along with others)
- radioactive phosphorus
- allopurinol
294
What is the purpose of venesection?
- to treat PV
- lowers PCV & platelets count
- roves 400-500mL of blood weekly - relieves symptoms
295
Which chemotherapy agents would you give for PV?
- hydroxycarbamide
| - low dose busulfan
296
Under what conditions would you administer radioactive phosphorus for PV patients?
- over 70
| - due to increased risk of acute leukaemia
297
What does allopurinol do?
- blocks uric acid production
| - reduces gout
