Week 1: Feeling Tired

Haematopoietic system
The haematopoietic system consists of blood, bone marrow, the spleen and
lymphoid tissue (including MALT)
o In adults, the predominant site of haematopoiesis is bone marrow of the
vertebrae and pelvis, sternum and ribs (with tibial and femur
haematopoiesis in childhood)
Bone marrow function includes haematopoiesis which is the production of blood
cells (RBCs, WBCs and platelets)
Haematopoiesis consists of several major processes:
o Erythropoiesis (generation of erythrocytes)
o Thrombopoiesis (generation of platelets)
o Granulopoiesis (generation of granulocytesneutrophils, eosinophils and
basophils)
o Lymphopoiesis (generation of lymphocytesT-cells and B-cells)



Erythropoiesis
Erythropoiesis is the generation of RBCs (erythrocytes) which last on average of
120 days
Differentiates from CFU-E and heavily affected by erythropoietin
Transitions from a proerythroblast to a
Megakaryocytopoiesis/thrombopoiesis
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Granulopoiesis
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Lymphopoiesis
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Embryology of the
haematopoietic system
Precursors of the
haematopoietic system arise
from primitive
haematopoietic stem cells
which originate from the
yolk sac and the aorta-
gonadal-mesonephros
mesoderm
These primitive cells seed the liver by about 4 weeks and interact to form
definitive HSCs
Following that, HSCs seed bone marrow as well as the thymic rudiment at around
week 7
Finally, colonisation of the spleen occurs from around week 12 and there is further
T-cell population of the fetal thymus, lymph nodes, spleen and gut

Disorders of the red blood cells
Overview of anaemia
Anaemia = reduction in total circulating RBC mass below normal limits
o Basically means that there are fewer or lesser RBCs than normal
o Leads to many symptoms due to impaired oxygen carrying capacity (includes
fatigue) but also symptoms characteristic of a certain type of anaemia
Most common cause of anaemia differ based on region (nutritional iron deficiency
in poorer/less developed countries/lower SES while blood loss more common in
more developed countries)
Different classifications of anaemia exist based on physiological or clinical
distinctions
Important to consider laboratory findings of normocytic, microcytic or macrocytic
anaemia and by their mechanism: haemolysis, decreased erythropoiesis or blood
loss
Normocytic anaemia
Anaemia Pathophysiology Other Notes
Acute blood loss Normochromic, normocytic
Blood results in decreased RBC
mass, but no early changes
After bleeding there is an
increase in reticulocytes
Chronic blood loss iron
deficiency anaemia
Consider trauma/Sx, GIT
bleeding and menstruation
Anaemia of
chronic disease
Inflammatory state increases
hepcidin and iron
sequestration decreased
available iron for Hb
Usually normal/elevated
ferritin but decreased Tf/TIBC
Can be microcytic in severe
disease
Iron can be stained in blood
marrow
Chronic kidney
disease
Decreased kidney function
EPO diminished
erythropoiesis

Marrow
infiltration/fibrosis

Haemolytic
anaemias

Aplastic anaemia
Anaemia of blood loss
Can result from acute or chronic blood loss
Anaemia from acute blood loss usually results from the loss of intravascular volume
o Restoration of volume by fluid in the interstitial compartment lowers
haematocrit
o Meanwhile reduction in oxygenation results in erythropoietin to be released
from the kidneys increase in CFU-E (a colony forming unit, destined for
erythroblast)
o Results in a normocytic, normochromic anaemia
Chronic blood loss results when regenerative capacity of the marrow for RBCs is
exceeded or when there is insufficient iron for effective erythrocyte production to
occur (resulting in anaemia of iron deficiency)
Treatment involves rectifying the underlying cause of bleeding and to replenish
nutrients and use blood transfusions for haemodynamic stability
Anaemia of chronic disease
Result of chronic inflammatory state from infections or other diseases
o Consider SLE, Crohns disease, rheumatoid arthritis, other autoimmune
states, and malignancies
Theorised to be based on iron-sequestration from blood (decreased microbial
usage) resulting in increased ferritin stores and decreased transferrin
Haemolytic anaemia
Characterised by increased haemolysis (erythrocyte lifespan below normal 120
days), increased EPO levels, accumulation of Hb degradation products
Can be congenital or acquired
Chronic kidney disease
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Microcytic anaemia
Anaemia Pathophysiology Other Notes
Iron deficiency
anaemia

Thalassaemia
Sideroblastic
anaemia
Genetic or acquired defect in
mitochondrial processing of
iron


Sideroblastic anaemia
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Macrocytic anaemia
Anaemia Pathophysiology Other Notes
Megaloblastic
anaemia
Results from vitamin B12 or
folate deficiency
Deficiency results in aberrant
DNA synthesis
Clinical features include
jaundice and pallor, glossitis
and subacute spinal cord
degeneration (B12 only)
Anaemia Pathophysiology Other Notes
Normoblastic
anaemia
Alcohol and other toxic
metabolites

Sickle cell
anaemia

Macrocytic anaemia
Divided into either megaloblastic or non-megaloblastic types based on bone
marrow findings
Megaloblastic anaemias can be characterised by megaloblasts
o Typical of certain nutrient deficiency anaemias (specifically B12 and folate
deficiencies)
Non-megaloblastic
Methyl-malonic acid to determine between
Megaloblastic anaemia
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Other types of anaemia
Anaemia Pathophysiology Other Notes
Sickle cell
anaemia


Polycythaemia
Polycythaemia is a result of an abnormally high red cell count often with a
corresponding increase in Hb level
Can result from a variety of causes including dehydration (relative polycythaemia)
or from increase in red cell mass (absolute polycythaemia)
Can be primary (low EPO) or secondary (high EPO) due to other changes
o Primary polycythaemia generally results from congenital causes
Clinical aspects of anaemia
Clinical features of anaemia
Can often co-present with other signs/symptoms e.g. jaundice in haemolytic
anaemia
Patients can also be asymptomatic depending on severity
Symptoms Signs
Pallor
Tachycardia
Systolic flow murmur
Cardiac failure
Fatigue
Headaches
Syncope/pre-syncope
Angina
Intermittent claudication
Palpitations
Glossitis (vitamin B deficiency)
Jaundice (haemolytic)

Investigations of anaemia
Blood tests and microscopy required to investigate anaemia and other
haematological abnormalities
Bone marrow may be needed to investigate aplastic anaemia or other primary
causes
Blood transfusions
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Iron Metabolism
Overview
Duodenum uptake of iron
Random notes



Iron deficiency most common cause of anaemia (including microcytic anaemia)
Thalassaemia
Sideroblastic anaemia
o Genetic or acquired
o Caused by mitochondrial failure to process iron into haem
o Increase in Fe
2+
ROS