Biology Molecular of

Hematopoesis
Sry Suryani Widjaja
Biochemistry Department
September 2019
• Haemopoiesis starts with a pluripotential stem cell that can self -
renew but also give rise to the separate cell lineages.
• This haemopoietic stem cell is rare, perhaps 1 in every 20 million
nucleated cells in bone marrow.
• immunological testing it is CD34 + CD38 − and negative for lineage
markers (Lin − ) and has the appearance of a small or medium - sized
lymphocyte.
• The cells reside in specialized ‘ niches ’ .
• Cell differentiation occurs from the stem cell via committed
haemopoietic progenitors which are restricted in their
developmental potential.
Erythrocyte (Red Cell)
• Function :
• carry haemoglobin into close contact with the tissues and for
successful gaseous exchange.
• the red cell, 8 μ m in diameter, must be able: to pass
repeatedly through the microcirculation whose minimum
diameter is 3.5 μ m.
• to maintain haemoglobin in a reduced (ferrous) state and to
maintain osmotic equilibrium despite the high concentration
of protein (haemoglobin) in the cell.
•
• Its total journey throughout its 120 - day lifespan
has been estimated to be 480 km (300 miles).
• To fulfil these functions
• the cell is a flexible biconcave disc with an ability to
generate energy as adenosine triphosphate (ATP)
• by the anaerobic glycolytic (Embden –Meyerhof)
pathway.
• generate reducing power as NADH by this pathway and
as reduced nicotinamide adenine dinucleotide
phosphate (NADPH) by the hexose monophosphate
shunt
Red cell metabolism
Embden – Meyerhof pathway
Hexose monophosphate shunt
Red cell membrane

• comprises a lipid bilayer, integral membrane proteins and a

membrane skeleton.
• Approximately 50% of the membrane is protein, 20% phospholipids,
20% cholesterol molecules and up to 10% is carbohydrate.
• Carbohydrates occur only on the external surface while proteins are
either peripheral or integral, penetrating the lipid bilayer.
• The membrane skeleton are important in maintaining the biconcave
shape.

• Defects of the proteins may explain some of the abnormalities of

shape of the red cell membrane (e.g. hereditary spherocytosis and
elliptocytosis).

• alterations in lipid composition because of congenital or acquired

abnormalities in plasma cholesterol or phospholipid may be
associated with other membrane abnormalities (e.g. in liver disease).
Neutrophils Kinetics
• the granulopoietic series progenitor cells, myeloblasts, promyelocytes
and myelocytes form a proliferative or mitotic pool of cells.
• the metamyelocytes, band and segmented granulocytes make up a
post - mitotic maturation compartment.
• Large numbers of band and segmented neutrophils are held in the
marrow as a ‘ reserve pool ’ or storage compartment.
• The bone marrow normally contains more myeloid cells than
erythroid cells in the ratio of 2 : 1 to 12 : 1, the largest proportion
being neutrophils and metamyelocytes.
• In the stable or normal state, the bone marrow storage compartment
contains 10 – 15 times the number of granulocytes found in the
peripheral blood.
• Following their release from the bone marrow, granulocytes spend
only 6 – 10 hours in the circulation before moving into the tissues
where they perform their phagocytic function.
•
• In the bloodstream there are two pools:
• the circulating pool (included in the blood count) and the
marginating pool (not included in the blood count).
• They spend on average 4 – 5 days in the tissues before
they are destroyed during defensive action or as the result
of senescence.
• In the bloodstream there are two pools:
• the circulating pool (included in the blood count) and the
marginating pool (not included in the blood count).
• They spend on average 4 – 5 days in the tissues before
they are destroyed during defensive action or as the result
of senescence.
Control of granulopoiesis: myeloid growth factors
 The normal function of neutrophils and
monocytes
• Divided into three phases.
• Chemotaxis (cell mobilization and migration)
• Phagocytosis
• Killing and digestion
• Defects of phagocytic cell f unction
• Chemotaxis
• These defects occur
• in rare congenital abnormalities (e.g. ‘ lazy leucocyte ’ syndrome)
• more common acquired abnormalities either of the environment
(e.g. corticosteroid therapy) or of the leucocytes themselves (e.g.
in acute or chronic myeloid leukaemia, myelodysplasia and the
myeloproliferative syndromes).
• Phagocytosis
• These defects usually arise because of a lack of
opsonization which may be caused by congenital or
acquired causes of hypogammaglobulinaemia or lack
of complement components.
• Killing
• illustrated by the rare X - linked or autosomal recessive
chronic granulomatous disease that results from abnormal
leucocyte oxidative metabolism.
• abnormality affecting different elements of the respiratory
burst oxidase or its activating mechanism.
• recurring infections, usually bacterial but sometimes
fungal, which present in infancy or early childhood in
most cases.
• Other rare congenital abnormalities may also result in
defects of bacterial killing (e.g. myeloperoxidase
deficiency and the Chédiak – Higashi syndrome).
• Acute or chronic myeloid leukaemia and
myelodysplastic syndromes may also be associated
with defective killing of ingested microorganisms.
• Benign disorders
• Pelger – Huët anomaly
• In this uncommon condition bilobed neutrophils are found in the
peripheral blood. Occasional unsegmented neutrophils are also
seen. Inheritance is autosomal dominant.
• May – Hegglina nomaly
• In this rare condition the neutrophils contain basophilic inclusions
of RNA (resembling Döhle bodies) in the cytoplasm. There is an
associated mild thrombocytopenia with giant platelets.
Inheritance is autosomal dominant.
Thrombopoesis
• The time interval from differentiation of the human stem cell
to the production of platelets averages 10 days.

• The normal platelet count is approximately 250 × 10 9 /L (range 150 –

400 × 10 9 /L) and the normal platelet lifespan is 7 – 10 days.
Platelet Structure
• Platelets are extremely small and discoid, 3.0 × 0.5 μ m in
diameter, with a mean volume of 7 – 11 fL.

• The platelet contains three types of storage granules: dense,

α and lysosomes.
• The more frequent specific α granules contain clotting
factors, VWF, platelet - derived growth factor (PDGF) and
• other proteins.
•.
• Dense granules are less common and contain adenosine diphosphate
(ADP), adenosine triphosphate (ATP), serotonin and calcium.
• Lysosomes contain hydrolytic enzymes. Platelets are also rich in
signalling and cytoskeletal proteins which support the rapid switch
from quiescent to activation that follows vessel damage.
• Platelet function falls into three: adhesion , aggregation and
release reactions and amplification.
• The main function of platelets is the formation of mechanical
plugs during the normal haemostatic response to vascular
injury.
Platelet Aggregation

• This is characterized by cross - linking of platelets

through active GPIIb/IIIa receptors with fibrinogen
bridges.
Platelet release reaction and amplification

• Primary activation by various agonists induces intracellular signalling,

leading to the release of α granule contents.
• These have an important role in platelet aggregate formation and
stabilization and, in addition, the ADP released from dense granules
has a major positive feedback role in promoting platelet activation.
The synthesis of prostacyclin and thromboxane A 2 .