Haematopoiesis and anaemias Flashcards
(185 cards)
1
Q
types of blood cells?
A
Red cells, Platelets, White cells
2
Q
where and when does haematopeisis occur?
A
After birth, and during early childhood, hematopoiesis occurs in the red marrow of the bone. With age, hematopoiesis becomes restricted to the skull, sternum, ribs, vertebrae, and pelvis.
3
Q
regulation of haematopoeisis
A
Regulated by variety of glycoprotein hormones, including stem cell factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin and IL-3.
4
Q
in normal peripheral blood, role of... -platelets - red cells - white cells
A
clotting
O2 transport
immunity + infection response
5
Q
How do platelets work?
A
have no nucleus
The granules secrete substances which control clotting and the breakdown of blood clot
6
Q
what do platelets form part of?
A
blood clot
7
Q
What is a platelet’s life span
A
8-12 days, then removed by macrophages (WBC type) in the spleen and liver
8
Q
What do low levels of platelets lead to
and what is it a side effect of?
A
Easy bruising and haemorrhage
chemotherpay/disease
9
Q
types of white cells (leucocytes)
A
lymphoid cells (lymphocytes)
- T cells
- B cells
- NK cells
myeloid cells
- monocytes
- granulocytes
- eosinophils
- basophils
- neutrophils !!
10
Q
What are granulocytes involved in
A
Innate immunity
11
Q
How do neutrophils kill bacteria?
A
phagocytosis
engulf and destroy
granules contain lysosyme + myeloperoxidase.
ppl with too few neutrophils die of bac infection if not treated w antibiotics
12
Q
where do neutrophils (type of granulocytes) live?
A
in blood for few hrs then migrate to tissues - cna live for 4-5 days
short. replaced
13
Q
What do eosinophils do?
A
used in parasite infections (not phagocytic)
14
Q
What do basophils do?
A
release histamine and heparin
15
Q
hoe are eosinophils + basophils similar?
A
allergy/ atropy
16
Q
What can monocytes do?
A
Migrate from blood into tissues and become macrophages
role in innate immnuity
17
Q
how are monocytes similar to macrophages?
A
phagocytic
engulf+destroy dead cells, bacteria, protozoa, fungi
18
Q
Where do T cells develop?
what are they and role?
A
T hymus
early progenitor for bone marrow but migrate and develop in thymus
19
Q
what fo T cells exit thymus as?
A
naive cells - not yet exposed to antigen
20
Q
where is thymus , role?
A
(gland behind sternum, in lungs - part of lymphatic system produces mature T cells)
21
Q
what are (NK) lymphocytes?
A
small cells w low granularity (7-10 microM) by microscope
22
Q
Where do B cells develop
A
Bone marrow
exit as naive cells
23
Q
Where do Natural killer cells develop
A
bone marrow
24
Q
what do T cells drive?
A
cell mediated immunity
25
what are dendritic cells
antigen presenting cells
work alongside T and B cells
26
What are mast cells
Cells that contain histamine, causes inflammation. Produced in the bone marrow but mature in tissues
allergy response
27
What is too few blood cells lead to?
Cytopenia
28
What is too many blood cells lead to?
Cytosis
29
normal values in blood of...
- red cells
- platelets
- neutrophils
- lymphocytes
red cells: 4.5-6.5 x 1012/L in M (lower in F)
... Hb more important 125 / 165 g/L
platelets: 150-400 x 109/L
neutrophils: 2.5-7.5 x 109/L
lymphocytes: 1.5-3.5 x 109/L
30
Describe the myeloid cells involvement in immunity.
granulocytes and monocytes
- neutrophils
live in blood for a few hours then migrate to tissues and live for 4-5 days
engulf and destroy bacteria (phagocytic)
granules contain lysosome and myeloperoxidase
- eosinophils and basophils
both for allergy
eosinophils for parasite infections
less abundant
- monocytes
migrate from blood into tissues and become macrophages
phagocytic; engulf and destory dead cells, bacteria, protozoa, fungi
31
Describe the two types of adaptive immunity.
humoral immunity: B cells = antigen specific antibodies
| cell mediated immunity: T and NK cells = non specific
32
What is the lifespan of red cells, platelets, neutrophils and lymphocytes?
red cells: 120 days
neutrophils: <48 hours
platelets: 8-12 days
lymphocytes: years
33
whys chemotherapy done every 3 weeks?
as platelets and neutrophils are back at normal levels
lifespans:
neutrophils: <48 hours
platelets: 8-12 days
34
How long do eyrthrocyte transfusions, platelet transfusions and heamatopoietic stem cells last?
eyrthrocyte transfusions: 1 month - treatment of anaemia
platelet transfusions: few days
heamatopoietic stem cells: life long
35
What is haematopoiesis?
| and When does haematopoiesis start?
blood cell production
starts 17 days after fertilisation and continues throughout life
regulated
36
What is leukaemia?
malignancies of haematopoietic cells arise in marrow and spread to involve blood/lymph nodes/spleen
37
4 types of haematologiccal malignancies?
leukaemias
lymphomas
myelomas
myeloproliferative disease + myelodysplasia
38
What is a lymphoma?
malignancies of lymphoid cells arise in lymph nodes/spleen and spread to involve blood and marrow
39
What is a myeloma?
malignancy of plasma cells (mature B lymphocytes) in marrow
| can have multiple myeloma- multiple sites
40
What is myeloproliferative disease and myelodysplasia?
neoplastic chronic abnormal myeloid proliferation
41
maturation arrest causes what?
acute leukaemia
e.g. acute myeloid leukaemia (AML)
affects stem cells
proliferation of mature cells
42
when no maturation arrest -->?
over production of mature cells
e.g. chronic myeloid leukaemia (CML)
43
Classification of leukaemias
Lineage (Myeloid or lymphoid)
Maturation arrest or not: (acute or chronic)
Myeloid (AML or CML)
Lymphoid (ALL or CLL)
44
whys CLL (chronic lymphocytis leuk) different to all other leukaemias?
arises form mature cell (B lymphocytes)
45
What is a stem cell
cell that can differentiate and become any type of human cell
46
What are haemotopoietic stem cells (HSC)?
| what about embryonic SC?
Multipotent
ESC = pluripotent can change to ANY cell in body
47
benefits of stem cell being able to divide indefinateky?
- can replenish itself
| - give rise to specialised, differentiated cells
48
Where is the site of haematopoiesis in Infants
bone marrow
| virtually all bones
49
Where is the site of haematopoiesis in adults
Bone marrow - axial skeleton
50
How to identify haemotopoetic cells
Cell markers
51
how is haematopiesis evaluated?
bone marrow biopsy - use local anaesthetci
hip bone surgery
in kids: sternum used
52
Name a condition in which monocyte cells will be elevated.
Allergy or Parasitic infection (Eosinophil).
53
What would a blood smear look like if theres no haematopoiesis?
hypocellular e.g. aplastic anaemia
no blood cells just fatty tissue
(trephine histology - best for cellularity)
54
How can you identify haematopoietic cells?
cell markers
| CD (cluster of differentiation). standardised nomencalture (mainly leukocyte markers)
55
what does each hematopoietic cell have?
unique profile of markers (most names as CD)
| diff functions - lineage / maturation/ function/ activation
56
whats immunophenotyping?
diff cells idnetified by diff monoclonal antibodies to cell markers
(usually by flow cytometry detecting fluorescent antibodies)
57
What do stem cells turn into?
mature blood cells
58
Where is the site of haematopoiesis in adults
Bone marrow - axial skeleton- skull + trunk
59
How can these haemotopiectic cells be identified
Monoclonal antibodies (immunophenotyping)
60
stem cells life
self renewal
or commitment...
maturation-> progenitor -> precursor -> mature
61
how is stem cell/ progenitor identified by?
functional assay
62
how is stem cell: precursor/ mature cell identified by?
routine marrow staining
63
how is stem cell at any stage of maturation identified ?
immunophenotyping
64
whats critical for haematopeiesis?
transcription factors
| = proteins that control which genes turned on/off by binding to DNA + promoting/ blocking gene transcription
65
What effects do growth factors/cytokines have in hematopoiesis?
```
glycoproteins acting on specific receptors on haematopoeitic cells
have multiple (pleiotropic) effects depending on cells
```
66
How can glycoproteins (G-CSF, a growth factor) affect haematopoesis
```
Proliferation
Maturation
Functional
Activation
Suppression of apoptosis
```
67
What are the key hormones in RBC and platelet production?
G-CSF
EPO
TPO (thrombopoeitin- platelet prodn)
68
whats EPO?
Erythropoetin (EPO)
| HORMONE THAT STIMULATES RBC'S PRODUCTION
69
Growth factor in clinical use: G-CSF (2)
(recombinant SC injections) used for
- primary/ secondary preventions of infections in neutropenic patients (chemotherapy, congenital neutropenia)
- and to mobilise stem cells into periperal blood for stem cell harvest for stem cell transplants
70
whats is meant by
CSF
IL
colony stimulating factor
| interleukin
71
How is erythropoiesis a negative feedback loop?
RBCs -> blood O2 content in lungs..
pO2 -> HIF-2 in kidney... EPO to erythroid precursors.
inc EPO = dec blood O2 content...
i.e. tissue oxygenation controls Epo production and Epo controls red blood cell (RBC) production, provides homeostasis in oxygen delivery to body tissues.
72
what in liver controls ion stores. and is inhibited by erythroferrone in epo loop?
hepcidin
73
What does a reticulocyte have and do?
has extruded nucleus but still has RNA.
can still make Hb (not possible in erythrocyte)
used to analsye causes of anemia
74
Growth factor in clinical use: EPO
(recombinant SC injections) used for imporvement of anaemia so transfusions not needed
mainly for end stage renal disease (endogenous epo low)
75
in what 3 particular cases is Growth factor in clinical use: EPO used?
some cases of myelodysplasia: low blood count
(when endogenous epo not increased)
patients getting chemotherapy
Jehovas witness (blood loss)- dont have blood transfusion
76
monocytes maturation stages by marrow staining...
monoblast -> promonocyte -> monocyte
77
whats neutropenia a side effect of and how treated?
chemotherapy,
| prevented using recombinant G-CSF SC innjections
78
plateelts arise from what?
cytoplasm of megakaryocytes in bone marrow
| 2-3000 per megakaryocyte
79
platelet prodn is regulated by what?
TPO (thrombopoeitin)- hormone mainly produced by liver
80
Growth factor in clinical use: TPO .. receptor agonists
1. romiplostim ( SC injections)
2. eltrombopag (oral)
licensed for refractory immune thrombocytopenia (ITP) 2nd line
potential uses:
- thrombocytopenia in myelopdysplasia/post chemotherapy
- asplastic anaemia
81
what does blood consist of?
55% plasma (proteins, electrolytes, hormones, nutrients)
45% platelets, white cells + red cells
82
What is the function of RBC?
carry oxygen to tissues and return carbon dioxide from tissues to lungs
83
what is most of gaseous exchange in lungs + RBA acheived through?
Hb protein
84
in what stae can Hb bind to Oxygen?
Each haem group contains Fe which is reduced to Fe 2+. When it is in this state can bind to oxygen
85
what does one Hb protein mol consist of?
multi subunit protein (tetramer) made of 2 alpha, 2 bet subunits
heme:
one per unit
has Fe atom
carries 02
in RBC
86
whats anaemia?
Reduction in haemoglobin concentration, haemocrit or red blood cell count
87
What compensatory mechanisms occur during anaemia
- Increased oxygen extraction by tissues (vua 2, 3 DPG)
| - Increased stroke volume and heart rate
88
Anaemia is classified as a reduction in the number of RBCs. What are the values that determine this in men and women?
in men below 130g/l and in women below 120g/l
89
the signs and symptoms of anaemia depend on the degree of anaemia and rate of development. What two things might anaemic patients experience?
decreased oxygen delivery to tissues and hypovolemia with acute bleeding
90
How might anaemic patients present? symptoms
```
Extetional dyspnoea
Fatigue
Palpitation
Headache and drowsiness
Angina and intermittent claudication
```
non-specific!
91
why are palpitations a symptom of anaemia?
heart has to work harder to pump blood around body
92
What might be the reason for anaemic patients experiencing headaches and drowsiness?
nutrient imbalances
93
List three things that can occur in anaemic patients as a result of volume depletion due to bleeding?
fatigue, muscle cramps and postural dizziness
94
What are the three main causes for anaemia in relation to red blood cells and blood?
reduced RBC production
increased RBC destruction
blood loss
95
Causes of reduced red cell production
- Lack of haemantinics (nutrients)iron, vit B12 and folate
- Bone marrow disorders
- Bone marrow suppression due to chemo
- Reduced EPO production in renal failure
- Anaemia of chronic disease
96
Causes of increased red cell destruction
- Inherited haemolytic anaemias
| - Acquired haemolyic anaemia
97
Inherited haemolytic anaemias- 2 examples?
spherocytosis and sickle cell disease
98
Acquired haemolytic anaemias- examples?
coombs positive autoimmune
| - warm and cold AIHA
99
What type of anaemia is caused by bone marrow disorders?
aplastic anaemia
100
Outline some of the reasons for increased destruction of RBCs?
- inherited such as spherocytosis or sickle cell
- accquired such as coombs antibodies
- reticulocytosis
101
What type of anaemia is it if mcv is low due to iron defiency?
microcytic
102
What type of anaemia is it if the mcv is high due to folate or b12 deficiency?
macrocytic
103
What is the term given to anaemia where the mcv is normal such as anaemia of chronic disease?
normocytic
104
What property of a red cell can determine the type of anaemia
Red cell size and shape
105
what does MCV tell you?
if anameia = micro/macro/normocytic
classification!
106
What cause of anaemia is most likely if MCV is normal and reticulocyte count is low?
anaemia of chronic disease such as renal or bone marrow failure
107
What cause of anaemia is most likely if MCV is normal and reticulocyte count is high?
hemolysis or blood loss
108
Calcium can conserve iron by recycling it from which cells?
senescent red blood cells
109
what do you measure with...
a) microcytic (low Hb)
b) macrocytic (high Hb)
a) Ferritin (establish cause if deficient)
| b) B12 and folate
110
Loss of iron in men can be met by absorbing how much iron daily?
1-2mg
111
What is the daily requirement of iron required for erythropoesis?
20mg
112
total body iron
3000-4000mg
113
What is ferritin?
storage form of iron
114
Who is at risk of iron deficiency?
- infants who are premature or born to iron deficient mothers
- young women due to pregnancy and menstruation
- men and women with haemorrhoids due to GI blood loss
- children and adults with coeliac disease
115
treatment for iron deficiency anemia
iron supplements
116
What can anaemia of chronic disease cause
Mild microcytic or normocytic anaemia
117
in which type of anaemia may the blood ffilm show pencil cells?
iron deficiency
118
What would you expect the blood results of iron deficiency anaemia to reflect in terms of:
1. MCV
2. MCH
3. WBC
4. platelets
5. Hb?
1. low
2. low
3. normal
4. normal or raised
5. low
119
What do most hospitals use to assess iron status?
serum ferritin
120
transferrin saturation may be helpful in diagnosing iron defiency anaemia in which group of patients?
patients with cancer
Fe deficiency: total binding inc. saturation dec
121
iron deficiency anaemia can occur with normal or high Ferritin levels? T/F?
true
122
Why might ferritin levels be raised in liver dysfunction which may be the underlying reason for the anaemia?
ferritin is released by hepatocytes when damaged
123
Ferritin may be raised in patients where there is an increased haem turnover. Give 2 reasons why there may be an increased haem turnover in these patients?
haemolysis and trauma incl surgury
124
How long does a red blood cell live for
120 days
125
What is a reticulocyte?
immature RBC
126
What does the reticulocyte count show
The bone marrow's response to anaemia
127
What are the signs of autoimmune haemolysis
Reticulocyte count raised at 350, Coombs test strongly positive, spleen enlarged
128
Treatment of autoimmune haemolysis
Prednisolone 1mg/kg with folic acid
129
What questions would you ask when taking the history of a patient with expected anaemia?
- Heavy menstrual loss, patterns, frequency and severity?
- taking aspirin?
- potential for Gi blood loss through haemorrhoids
- family history
- underlying genetic condition such as sickle cell
- any chronic disease such as rheumatoid?
- are there angular fissures or cheilosis around the mouth
- koilonychia?
- thin and underweight may suggest coeliac as an underlying cause
- ethnic origin
- evidence of chronic disease
130
Unless there is a clear indication otherwise what should be considered the cause of anaemia in young premenopausal women?
blood loss to due to menstruation
131
in a male with anaemia the patient should be referred to the GI unit for what two procedures?
endoscopy and colonscopy
132
Is there any clinical difference between ferrous fumarate, sulphate and gluconate which makes one of them a better pharmacological agent to treat iron deficiency anaemia?
no there is generally nothing to choose between them and they are equally efficacious
133
What side effects are very common with medication for iron deficiency anaemia such as ferrous sulphate, that you would want to make patients aware of?
GI intolerance, constipation, diarrhoea and nausea is very common with oral iron
134
Is it better to take iron on an empty stomach of after a meal?
better for absorption on an empty stomach but can be less tolerable so may be taken after a meal
135
What is the sufficient strength and dose of iron such as ferrous sulphate for most patients?
200mg 1-2 times daily
136
Why are slow release iron preparations illogical?
less iron be being absorbed from the preparation
137
What effect does alcohol and vitamin C have on the absorption of oral iron?
increases
138
What can be given to people to require iron who have a genuine oral intolerance?
IV such as cosmofer or ferrinject
139
Is anaemia of chronic disease macrocytic, microcytic or normocytic?
mild microytic and normocytic
140
anaemia of chronic disease caused/worsened by? (3)
malignancy, rheumatological diseases and chronic infection
141
What role do inflammatory cytokines play in anaemia of chronic disease?
cause reduced iron utilisation and impaired rbc production
142
Severity of anaemia of chronic disease reflects the disease activity and only improves upon one condition. What is this?
underlying disease is treated or controlled
143
What is the name given to the condition where red blood cells are destroyed faster than they are made?
haemolytic anaemia
144
whys it hard to distinguish between anaemua of chronic disease and early iron deficiency?
ferritin levels can be normal in both
| or raised in A of CD or low in early ID
145
blood film in
a) anaemia of CD
b) early iron deficiency
a) normocytic, normochromatic
| b) hypochromic, mild anisocytosis (diff shape + size
146
Which body structure can compensate for mild haemolytic anaemia but in severe cases survival is limited to only a few days?
bone marrow
147
The reticulocyte count reflects the bone marrows response to anaemia. What does a low reticulocyte count indicate and what does a high reticuloycte count indicate?
low means bone marrow hypoplasia and high means bone marrow is still responding
148
mild haemolysis is seen in...
thalassemia
| and sickle cell disease
149
how may patients present with haemolytic anameia (autoimmune)?
pale and jaundices (bone marrow can tey and compensate for few days but may be severe case)
150
Autoimmune haemolytic anaemia is a serious potentially fatal condition unless treated quickly. What is the first line treatment for AIHA?
raised reticulocytes..
| 1mg/kg prednisolone and folic acid
151
What is second line treatment for AIHA?
azothioprine, myophencolate, ciclosporin or rituximab
152
Difficult cases of AIHA may require organ removal. Which surgury would these patients undergo?
splenectomy
153
List some things that can cause macrocytic anaemia?
- haematinic deficiency
- myleodysplasia
- liver disease
- haemolytic anaemia (reticulocytosis)
- hypothyroidism (macrocytosis not anaemia)
154
Macrocytic anaemia is commonly assoicated with b12 and folate deficiency, List some causes of these deficiencies?
- strict vegan diets
- autoimmine addisons pernicious anaemia
- GI (absorption) problems with terminal ileal problems such as chrohns or TB
155
How does Addisons pernicious anaemia lead to b12 deficiency?
antibodies are produced agaiinst intrinsic factor which is involved in b12 absorption
156
Where is the absorption site of
- vitamin b12
- folate
- terminal ileum
| - duodenum and jejunum
157
Where is the mechanism of
- vitamin b12
- folate
- IF
| - conversion to tetrahydrofolate
158
What are the therapeutic forms of
- vitamin b12
- folate
- hydroxycobalamin
| - folic acid
159
Which type of anaemia may show neutrophil hypersegmentation in the blood film?
b12 or folate defiency
160
average daily intake of
- vitamin B12
- folate
- 5-30mcg
| - 200-250mcg
161
dietary source of
- vitamin B12
- folate
- animal produce only
| - greens, liver
162
minimum adult requirement intake of
- vitamin B12
- folate
- 1-2 mcg
| - 150 mcg
163
body stores of
- vitamin B12
- folate
- 2-3mg (enough for few yrs)
| - 10-12mcg (enough for few months)
164
What changes what you expect to see in the levels of MCV, WBC and platelets in macrocytic b12 or folate deficiency anaemia?
high mcv, normal or low wbc and normal or low platelets
165
to investigate macrocytic anaemia the levels of which two things should be checked as well as the function of one organ in the body?
measure b12 and folate levels and investigate thyroid function
166
what may blood film also show along w inc MCV, in B12/ folate deficiency?
neutrophil hypersegmentation
167
The blood film of a macrocytic anaemic patient may shown signs of mylodysplasia. These can be caused by certain drugs. Name the drugs that can cause this?
methotrexate, phenytoin, valproate and co triamaxozole
168
Explain how B12 is absorbed and uptaken in the body?
(not in slides) COBALAMIN
- present in meat and animal derived products
- b12 rapidly degraded by stomach acid and stabilised by complexing with haptocorrin (to prevent degradation)
- IF forms a complex with b12 in the duodenum which is alkaline and transported to the terminal ileum
- IF interacts with cubulin receptor and is taken into endosomes and degraded
- cobalamin attaches to lyosomal transporter which goes to vesicle forming complex with trans cobalamin 2
- transported in blood around the body
169
Which cells release IF and secrete HCl?
parietal cells
170
Which gland produces and secretes haptocorrin?
salivary glands
171
Where is the cubulin receptor located in the terminal ileum?
luminal surface of epithelial cells of terminal ileum
172
investigating macrocytic anaemia... steps?
1. check B12 and folate levels
(most gPs measure thyroid function, but rare cause
wont usually think of haemolytic anaemias
blood films may show signs of myelodysplasia (or other marrow problem)
some drugs can cause macrocytosis
173
whats myelodysplasia?
| treatment?
variety of clonal marrow abnormlaities, usually w macrocytic anaemia
many treated by reg transfusions but some respond to EPO
174
why must underlying cause be established with anaemia?
as its not a diagnosis, anaemia
175
B12 balance requires...
1-2 micrograms daily absorption
176
ssevere form of B12/ folate def?
pancytopenia
177
what can Fe deficiency without anaemia cause?
significant fatigue
178
serum ferritin + transferrin saturation (total Fe binding capacity) are affected by?
inflammation/ malignancy
179
Sources of Vitamin B12 (cobalamin)
* Meat
* Fish
* Dairy products
* Eggs
* Cheese
180
whats Haptocorrin?
| produced by and role?
AKA: R-protein/ transcobalamin 1
• Produced by salivary glands
• B12 rapidly degraded by stomach acid
• Stabilised by complexing with haptocorrin
181
whats Intrinsic factor?
| produced by and link with haptocorrin?
* Very similar structure
* Produced by gastric parietal cells
* Forms a complex with B12 in duodenum
182
1. Vitamin B12 in stomach
* In acidic environment, B12 which is complexed to normal dietary proteins is released.
* To prevent degradation, forms complex with haptocorrin (purple C) for protection.
* Gastric parietal cells also then release intrinsic factor, a protein produced in the stomach (blue C)
* Complex moves to duodenum (alkaline environment) if pancreas normal functioning.
* Intrinsic factor and complex arrive
* New complex forms (swap)
• B12-IF complex remains stable until transported to terminal ileum. Last part of small bowel
183
2, Vitamin B12 absorption in terminal ileum:
* Cubilin receptor on luminal surface interacts with IF-Cbl complex and taken up into endosomes
* IF and Cbl separated
* IF degraded, Cbl attached to lysosomal transporter and sent to secretory vesicle. Forms complex with third protein: TC II. Transported uopt and distributed around body
184
summary of cobalamin lec
* B12 (cobalamin) from food
* Released from protein bay stomach acid binds to R-protein
* Released form R-protein by alkaline duodenum binds to Intrinsic factor
* Taken up by cubulin on cells in Terminal Ileum
185
summary of cobalamin lec
* B12 (cobalamin) from food
* Released from protein bay stomach acid binds to R-protein
* Released form R-protein by alkaline duodenum binds to Intrinsic factor
* B12 Taken up by cubulin on cells in Terminal Ileum
