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Blood Cell Formation

Terms in this set (26)

haemopoiesis starts from which type of cell? 3 fates of this cell?
PLURIPOTENT STEM CELL >
i. self-renewal
ii. myeloid stem cell
iii. lymphoid stem cell
sites of haemopoiesis:
foetus 0-2 months
foetus 2-7 months
foetus 5-9 months
infants
adults
foetus 0-2m: yolk sac

foetus 2-7m: liver, spleen

foetus 5-9m: bone marrow

infants: bone marrow (all bones)

adults: bone marrow axial & ends of long bones (sacrum, pelvis, vertebrae, ribs, skull, sternum, ends of femurs)
haemopoietic stem cells (HSC):
features (4)
locations (3)
fate? (3)
types of division?
which factors influence the types of division occurring?
self-renewal capacity
UNspecialised: able to differentiate
rare (v few)
quiescent (not in cell cycle, in G0)

i. bone marrow
ii. peripheral blood (after given G-CSF)
iii. umbilical cord blood

i. self-renewal (identical copy)
ii. apoptosis (e.g. faulty cell)
iii. differentiation (e.g. > neutrophil)

i. symmetrical division:
a) > 2 differentiated cells (-number HSCs)
b) > 2 copies (+number HSCs
ii. asymmetrical division > 1 differentiated & 1 copy (= number HSCs)

~ bone marrow micro-environment (the "niche"_
~ internal cues (signals: hedgehog, Wnt, notch)
bone marrow micro-environment:
stroma
extracellular matrix
stroma = cells supporting haematopoietic cells:
macrophages
fibroblasts
endothelial cells
fat cells
reticulum cells

ECM:
fibronectin
haemonectin
collagen
proteoglycans
laminin
2 methods to sample bone marrow
1. Aspirate: suck out cells (cytology blood film)

2. Trephine: core biopsy, preserves architecture
hereditary bone marrow conditions: 3 examples (& brief desc)
1. thalassaemias (lack globin)
2. sickle cell anaemia (abnormal globin)
3. Fanconi anaemia

& hereditary leukaemias (rare), Dyskeratosis congenita, Schwachman-Diamond syndrome, Diamond-Blackfan anaemia, thrombocytopenia w/ absent radii
acquired bone marrow conditions (12 examples & brief desc)
1. aplastic anaemia (-prod all blood cells)
2. leukaemia (abnormal wbcs)
3. myelodysplastic syndrome (MDS: immature bcs)
4. myeloproliferative disorders (MPD)
5. lymphoproliferative disorders (e.g. NHL, CLL)
6. myelofibrosis (+fibrous tissue in bm)

7. metastatic malignancy (e.g. from breast)
8. infxn (e.g. TB)
9. drugs/toxins
10. chemotherapy (depresses bm)
11. haematinic deficiency (iron, B12, folate)
leukaemogenesis: how do cells become leukaemic
HSC > mutation > leukaemic SC (neoplastic) >
grows, differentiates > clonogenic leukaemic cells >
proliferate, differentiation blocked at an early stage (maturation arrest) > non-clonogenic leukaemia blast cells (immature)
clonal HSC disorders:
definition
3 pieces of evidence that these disorders are clonal
clonal = arise from a SINGLE ancestral cell

1. almost all lymphoproliferative disorders carry a UNIQUE rearrangement of Ig/Tc rec gene (vs non-malignant lymphoid proliferations are polyclonal)

2. ACQUIRED molecular changes arising during malignancy (e.g. CML t9:22 (bcr-abl fusion) philadelphia chromosome)

3. X-chrom inactiation studies in women w/ leukaemia show that clonal proliferation carries EITHER an active maternal or paternal X chrom (ie only 1)
myeloproliferative disorders (MPDs):
definition
3 examples
2 associated mutations
can progress to?
MPD = ++numbers one or more mature blood cells

i. Polycythaemia rubra vera (+RBCs)
ii. Essential thrombocytosis (+plts)
iii. Myelofibrosis (+fibrous tissue in bone marrow)

~ JAK2V617F mut
~ calreticulin mut

can progress > AML
MPDs: Essential Thrombocytosis
blood count diagnosis
3 clinical features
can transform to? (2)
treatment for stratified risk groups: low, intermediate, high (1st vs 2nd line), pregnancy, 2 other treatments to consider, a new drug (and why it's mechanism of action works well)
plts > 600 persistently

thrombosis
haemorrhage
splenomegaly

transform > PRV, MF (other MPDs)

low risk (<40yo): aspirin

intermediate (40-60): aspirin +- hydroxycarbamide

high (>60yo or high risk features e.g. plt > 1500, prev thrombosis, thrombotic rfs (e.g. diabetes, +BP))
1st line = aspirin + hydroxycarbamide
2nd = aspirin + anagrelide
pregnancy = IFNα
also consider: busulphan, 32P but !leukaemogenesis
new: JAK2 inhibitors (RUXOLITINIB) - JAK2 mut > continuous activation JAK2 rec > ++proliferation
hydroxycarbamide: how does it work
= ribonucleotide reductase inhibitor > -production deoxyribonucleotides
anagrelide: how does it work?
inhibits megakaryocyte differentiation > -plts
Myelodysplastic syndromes (MDS):
what is it?
risk score based on (3)
can progress to?
caused by? 1 example mut?
which cells may be present?
types of MDS?
most common presentation (age group, symptom)
management (6)
dysplasia & ineffective haemopoiesis in at least 1 blood cell type

risk score ~ % blasts in bm, karyotype, which cytopoenias

can progress > AML

due to ACQUIRED GENETIC ABNORMALITIES (e.g. del 17p), for example from chemo/radio

may have ++myeloblasts (SCs)
many sub-types (e.g. refractory anaemia w/excess blasts)

+elderly w/fatigue due to anaemia

i. supportive: blood/plt transfusion (+-iron chelation if young)
ii. growth factors: EPO +- G-CSF
iii. immunosuppression: anti-thymocyte globulin (ATG)
iv. low dose chemo (e.g. hydroxycarbamide) - or intense chemo if young/fit
v. demethylating agents
vi. allogeneic SC transplant
Fanconi Anaemia:
inheritance pattern, genetic subtypes, 2 genetic abnormalities
+risk which cancer?
5 s/s
treatment (1), supportive care (2), monitoring (1)
auto rec (APLASTIC): 7 gene subtypes (FANC A-G)
short telomeres & chromosomal instability > +risk AML

i. microphthalmia
ii. GI & GU malform
iii. mental retardation
iv. hearing loss
v. CNS (e.g. hydrocephalus)

premature bm failure > treat: allogeneic SC transplant (NB screen related donors for FA too)
supportive: corticosteroids, androgens
lifetime 2° tumour surveillance
3 types of stem cell transplant (& their subtypes)
1) AUTOLOGOUS: use pt's own blood scs

2) ALLOGENEIC: scs from donor (can be: peripheral blood scs, bm, umbilical cord blood)
i. syngeneic (identical twins)
ii. allogeneic sibling (HLA-identical)
iii. haplotype identical (half-matched relative)
iv. volunteer unrelated/VUD (HLA-matched)
indications for autologous vs allogeneic SC transplants
autologous: NHL, relapsed HL, CLL

allogeneic: AML, aplastic anaemia
how does autologous SC transplantation work? (2 methods)
give pts G-CSF > mobilise scs from peripheral blood > harvest by apheresis
OR (if fail to mobilise) give Mozobil
3 sources of stem cells in the body (for transplantation)
bone marrow
peripheral blood
umbilical cord blood (& placenta)
allogeneic stem cell transplantation:
full vs low intensity methods
added benefit of allogeneic (compared to autologous)?
(full) Myeloablative: ++total body irradiation & high-dose chemo (wipe out host bm) > receive bm transplant from donor > HOST BLOOD SYSTEM REPLACED W/DONOR BLOOD SYSTEM

(less) 'Mini': (less) tbi & low-dose chemo > bm transplant > pt has 'mixed chimera' (some host cells and some donor cells) > donor lymphocyte infusion > eventually only donor cells
(good for pts not eligible for conventional sct)

GvL effect can help treat malignancy (but it's part of GvHD which is problematic) > -risk relapse
donor lymphocyte infusion: what is its function?
prevent/treat relapse after sct
can induce GvL but also GvHD
volunteer unrelated donor (VUD):
why is it important?
most preferable donor demographic? why?
1 issue regarding ethnicity
(most pts don't have family donor vs 70% chance of finding vud)

+risk GvHD vs family donor > prefer young males
!shortage non-caucasian donors
umbilical cord blood transplant: 2 pros vs 3 cons
pro:
i. +rapidly available vs vud
ii. cord bcs are immunonaive so need less rigorous matching

cons:
i. small quantity (may need double cord transplant)
ii. slower engraftment (integration into host)
iii. if relapse cannot go back for DLI (none available)
graft vs host disease (GvHD):
what is it?
acute vs chronic
3 s/s
treatment
GvHD: donor's immune system recognises host body as foreign > attacks it
i. acute: within 100d
ii. chronic: after 100d

rash
jaundice
diarrhoea

treat: immunosuppression
graft vs leukaemia effect (GvL):
what is it?
2 example conditions treated
what is the aim regarding GvHD and GvL
subset of GvHD: donor cells also attacks host leukaemia cells > destroy them

myeloma
lymphoma

aim: minimise GvHD and maximise GvL
stem cell transplantation issues (12)
i. -donor availability (age limit 65yo)
ii. mortality
iii. GvHD
iv. immunosuppressed (+infxn)
v. infertility
vi. cataracts
vii. hypothyroidism
viii. dry eyes/mouth
ix. 2° malignancy
x. osteoporosis
xi. avascular necrosis
xii. relapse
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