Anemias are caused by a low red blood cell (RBC) count or low hemoglobin in RBCs. There are three main types of anemia: hypoproliferative anemia caused by decreased RBC production; hemolytic anemia caused by increased RBC destruction; and aplastic anemia caused by rare damage to stem cells in the bone marrow. Hemolytic anemias specifically result from a shortened RBC lifespan, where the bone marrow cannot replace destroyed RBCs quickly enough. Membrane defects can also cause hemolytic anemia, such as hereditary spherocytosis caused by alpha or beta spectrin deficiencies, which results in spherical RBCs more vulnerable to spleen destruction.

1. Anemias

2. Definition
 Anemias are
defined as a low
RBCs count or a
low amount of the
hemoglobin in
RBCs.

3. Causes of anemias

4. Production of blood cells
Pluripotential
stem cell
GEMML (cell giving rise to Granulocyte, Erythroid,
Monocyte, Megakaryocyte, Lymphoid cells)
Site:
bone marrow
Time: 7 days
Differentiation,
proliferation
Lymphoid stem cells (L)
IL-2
T-cells
IL-15
NK-cells
Il-7
B-cells,
plasma cells
GEMM
ME
(megakaryocyte
erythroid)
GM
(granulocytes,
monocytes)

5. eosinophil
M-CSF
MEGM
(granulocyte
monocyte)
(megakaryocyte
erythroid)
IL-5
Basophil/
mast cells
IL-3
Monocyte/
macrophage
G-CSF
Neutrophils
BFU-E
EPO
Megakaryoblast
Plateletes
basophilic
normoblast
CFU-E
(colony forming unit
erythroid)
(burst-forming unit
erythroid)
EPO
can undergo
4-5 cell divisions
that give
16-32 mature RBCs
polychromic
normoblast
ortochromic
normoblast
Reticulocytes
circulation
(maturation to)
Erythrocytes

6. Maturation of reticulocytes to
RBCs in blood circulation (1-2
days)
 Reticulocytes still
contain ribosomes
and elements of
endoplasmic
reticulum.
 The RNA of the
ribosome can be
detected by cresyl
blue.

7. Reticulocyte count
 A typical normal range
is 0.5-1.5 %.
 Increase level of
reticulocytes as known
as reticulocytosis

8. Regulation of Erythropoiesis
 Growth factor:
 GM-CSF granylocyte-macrophage colony
stimulating factor
 Cytokines:
 IL-3, IL-4, IL-9, IL-11 – stimulate erythroid
stem cell proliferation.
 IL-2 inhibits erythropoiesis

9. Erythropoietin (EPO)

10. Structure of EPO
 Is a glycoprotein growth
factor (165 amino
acids) with high
carbohydrates content
which increase the
molecule’s stability in
the circulation

11. Erythropoietin (Epo)
 Site of synthesis:
Peritubular
lining cells of
the renal cortex
Liver
Ito cells
EPO production
predominates
in the adult
EPO production
predominates in the
fetal and perinatal period

12. Factors which stimulate Epo
production:
 Hypoxia of different genesis
 Increase hemolyzates level (products of
RBCs destruction)
 Anterior pituitary hormones: LH, FSH,
ACTH, TSH, GH
 Androgens

13. Factors which decrease Epo
production
 Estrogens decrease synthesis of Epo
 This is why in females RBCs count is less
then in males.

14. Factors affecting EPO
production
Stem cells BFU-E CFU-E Erythroid
precursor
Red-cell mass
EPO
production
Oxygen
sensor
EPO
Atmospheric
oxygen
Blood volume
Hb concentration
Oxygen affinity
Cardiopulmanary
functionRenal blood
flow
Renal oxygen
consumption

15. Regulation of the EPO production
by blood oxygenation (feed-back)
O2
Oxygen
sensor
protein (heme-containing)
changes the
conformation
to Deoxy-form
HIF
(hypoxia inducible factor-1)
O2
Hydroxylation
of HIF
EPO gene transcription
EPO production
Proteosomal
degradation
EPO production
Oxygen
sensor
protein (heme-containing)
changes the
conformation
to Oxy-form

16. Effect of Epo
 1. Epo induces proliferation and maturation
of erythroid progenitor cells (CFU-E and
BFU-E have receptors for EPO)
 2. Epo increases release of reticulocytes
from the bone marrow
 3. Epo stimulates absorption of hemoglobin
by suppressing hepcidin.

17. Role of hepcidin
 Is peptide hormone
produced by the liver.
 Increase iron storage
in cells
 Prevents enterocytes
from secreting iron
into the hepatic portal
system
 Antifungal and
antibacterial activities

18. Classification of anemias
Aplastic
(rare)
Hypoproliferative Hemolytic
Inherited Acquired
due to
decrease
production
of all cells
by the bone
marrow
due to deficient Epo
or deminished
response to it
due to shortned life-span
of RBCs

20. Causes:
 Causes of aplastic anemia usually bind
with damage of the stem cells in the bone
marrow:
 Exposure to toxic substances
 Cancer therapy
 Autoimmune disease
 Viral infection

21. Clinical signs
Due to
RBCs count platelets
count
WBCs
count
lack of energy
feeling of
tiredness, fatigue
prolonged
bleeding
frequent
nosebleeds
increased number
and severity
of infections

22. Hypoproliferative anemia (marrow
production defect)
Iron
deficiency
Epo
Anemia of chronic diseases:
(INF-gamma, TNF-beta-inflamatory
cytokines suppress the response of
the erythroid cells to EPO)
Anemia in renal disease
production of EPO)(
Endocrine deficiency states
(eg. Hypothyroidism -
hypometabolic state)
Protein starvation
Hypoproliferative anemia

23. Treatment of hypoproliferative
anemia
 1. Transfusions
 2. Epo therapy

24. Hemolytic anemia

25.  Definition. Hemolytic anemias are defined as
decreased red cell mass resulting from an
increase rate of erythrocytes destruction.
 Normal red cells have a lifespan 100-120
days.
 At the end of this lifespan, both normal and
damaged cells are ‘recognized’ by
macrophages in the spleen and removed
from the circulation

26.  In hemolytic anemia,
red cell lifespan is
shortened.
 The bone marrow is
not able to produce
new RBCs quickly
to replace destroyed
RBCs

27. Causes
Inherited
Abnormal Hb
Abnormal RBCs
Acquired
Autoimmune diseases
Blood group incompatibility
Drug-induced
Chronic disorders

28. Extravascular and intravascular
hemolysis
Mechanisms of RBCs destruction
Extravascular
(RBCs are digested by
macrophage in the spleen)
Intravascular
(RBCs lysis in the
circulation)

29. Laboratory testing
Bilirubin
Plasma
Extravascular Intravascular
Unconjugated Unconjugated
Haptoglobin Absent
Plasma hemoglobin N
LDH
Bilirubin
Extravascular Intravascular
Hemosiderin
Hemoglobin
0 0
0 +
0 ++
Urine

30. Hemolytic anemia due
to membranopathy

31. Composition of RBCs
membrane
50% of lipids
(help determine
membrane fluidity)
Phospholipids
cholesterol
50% of proteins
Integral Peripheral
(help determine
membrane integrity)
Band 3,
glycophorins
A and C)
Stomatin
(help determine
biconcave shape and
flexibility)
Ankyrin
Tropomyosin
Alpha and beta-
spectrin(form an
anion channel)

32. Diagram of the RBCs
membrane
3
A
A
stomatin C
4.1
ankyrin
actin
spectrin
(alpha)
spectrin
(beta)
outer
inner
lipid
bilayer
lipid
bilayer
lipid
bilayer
Polysaccharides
Tropomyosin
Adductin

33. Disease Defect of
proteins
Degree of
anemia
Shape of RBCs
Hereditary
spherocytosis
(HS)
α-spectrin Severe Spherocytes
Are not flexible
β-spectrin Mild
Ankyrin Mild
Hereditary
stomatocytosis
Stomatin
deficiency
Mild Cup-shaped
have one
surface
concave and
other side as
convex
Hereditary
elliptocytosis
Protein 4.1
deficiency
Mild Ovalocytosis

34. Clinical presentation:
 Extravascular Hemolysis in the spleen.
Plasma hemoglobin is slightly raised.
 Splenomegaly
 UCB-emia and risk for jaundice and pigment
stones
 Reticulocytosis (5-20%).

35. Osmotic fragility test is positive
 When RBCs are exposed to a hypotonic
saline solution (<0.9%) only few normal
RBCs are hemolyzed.
 But 50% of spherocytes lyses under this
conditions.
 ↓ ability of RBCs to extrude sodium →
retention of water → osmotic injury