genesis is important for anything

1. DR BIKAL LAMICHHANE
INTERNAL MEDICINE,NAMS
HEMOGLOBIN AND
ERYTHROPOIESIS

2. Hemoglobin
 Hemoglobin is the basic metalloprotein that is present in
the red blood cells which are responsible for carrying
oxygen
 Critical for normal oxygen delivery to tissues
 Can alter red cell shape, deformability, and viscosity
STRUCTURE AND TYPES:
 Different hemoglobins produced during embryonic, fetal,
and adult life.
 Consists of a tetramer of globin polypeptide chains: a
pair of α-like chains 141 amino acids long and a pair of β-
like chains 146 amino acids long.

3.  The major adult hemoglobin, HbA, has the structure
α2β2.
 HbF (α2γ2) predominates during most of gestation.
 HbA2 (α2δ2) is minor adult hemoglobin.
 Red cells, first appearing at about 6 weeks after
conception, contain the embryonic hemoglobins Hb
Portland (ζ2γ2), Hb Gower I (ζ2ε2), and Hb Gower II
(α2ε2).
 At 10–11 weeks, fetal hemoglobin (HbF; α2γ2) becomes
predominant.
 The switch to nearly exclusive synthesis of adult
hemoglobin (HbA; α2β2) occurs at about 38 weeks

4.  Each globin chain enfolds a single heme moiety,
consisting of a protoporphyrin IX ring complexed with
a single iron atom in the ferrous state (Fe2+).
 Each heme moiety can bind a single oxygen
molecule.
 A molecule of hemoglobin can transport up to four
oxygen molecules.
 Each globin chain has a highly helical secondary
structure.

5.  Their globular tertiary structures cause the exterior
surfaces to be rich in polar (hydrophilic) amino acids
that enhance solubility, and the interior to be lined with
nonpolar groups, forming a hydrophobic pocket into
which heme is inserted.
 The tetrameric quaternary structure of HbA contains two
αβ dimers.
 Numerous tight interactions (i.e., α1β1 contacts) hold
the α and β chains together. The complete tetramer is
held together by interfaces (i.e., α1β2 contacts)
between the α-like chain of one dimer and the non-α
chain of the other dimer.

6.  The hemoglobin tetramer is highly soluble, but
individual globin chains are insoluble.
 Unpaired globin precipitates, forming inclusions .
 Normal globin chain synthesis is balanced so that
each newly synthesized α or non-α globin chain will
have an available partner with which to pair.

8. FIG. STRUCTURE OF HEMOGLOBIN

9. HEMOGLOBIN SYNTHESIS

11. GLOBIN SYNTHESIS

12. 
Globin synthesis, starts at 3rd week of gestation
Embryonic
Haemoglobin Gower I ( z2e2)
Haemoglobin Portland ( z2g2)
Haemoglobin Gower II (a2e2)
Fetal : HbF (a2g2), HbA (a2b2)
Adult : HbA, HbA2 ( a2d2), HbF.

13. GLOBIN CHAIN SWITCH

14. Derivatives of hemoglobin

Oxyhemoglobin (oxyHb) = Hb with O2
Deoxyhemoglobin (deoxyHb) = Hb without O2
Methemoglobin (metHb) contains Fe3+ instead of Fe2+ in heme
groups
Carbonylhemoglobin (HbCO) – CO binds to Fe2+ in heme in case
of CO poisoning or smoking. CO has 200x higher affinity to Fe2+
than O2.

Carbaminohemoglobin (HbCO2) - CO2 is non-covalently bound
to globin chain of Hb. HbCO2 transports CO2 in blood (about 23%).

Glycohemoglobin (HbA1c) is formed spontaneously by
nonenzymatic reaction with Glc. People with DM have more HbA1c
than normal (› 7%). Measurement of blood HbA1c is useful to get
info about long-term control of glycemia.

15. FUNCTION OF HEMOGLOBIN
. To support oxygen transport, hemoglobin must bind
O2 efficiently at the partial pressure of oxygen (Po2)
of the alveolus, retain it in the circulation, and
release it to tissues at the Po2 of tissue capillary
beds.
. Oxygen acquisition and delivery depend on a
property inherent in the tetrameric arrangement of
heme and globin subunits within the hemoglobin
called cooperativity or heme-heme interaction.

16.  At low oxygen tensions, the hemoglobin tetramer is
fully deoxygenated .
 Oxygen binding begins slowly as O2 tension rises.

 As soon as some oxygen has been bound by the
tetramer, an abrupt increase occurs in the slope of
the curve.
 Thus, hemoglobin molecules that have bound some
oxygen develop a higher oxygen affinity, greatly
accelerating their ability to combine with more
oxygen.
 This explains S-shaped oxygen equilibrium curve.

18.  The Bohr effect : ability of hemoglobin to deliver more
oxygen to tissues at low pH. Thus, hemoglobin has a
lower oxygen affinity at low pH.
 The major small molecule that alters oxygen affinity in
humans is 2,3-bisphosphoglycerate (2,3-BPG/ 2,3-DPG),
which lowers oxygen affinity when bound to hemoglobin.
 HbA has a reasonably high affinity for 2,3-BPG. HbF
does not bind 2,3-BPG, so it tends to have a higher
oxygen affinity in vivo.
 Normal oxygen transport thus depends on the tetrameric
structure of the proteins, the proper arrangement of
hydrophilic and hydrophobic amino acids, and interaction
with protons or 2,3-BPG.

19. ERYTHROPOIESIS
 Hematopoiesis : process by which the formed elements of
blood are produced.
 Hematopoietic stem cells are capable of producing red cells,
all classes of granulocytes, monocytes, platelets, and the cells
of the immune system.
 Regulatory influence of growth factors and hormones eg.for
red cell production, erythropoietin (EPO) is the primary
regulatory hormone.
 EPO is required for the maintenance of committed erythroid
progenitor cells that, in the absence of the hormone, undergo
programmed cell death (apoptosis).
 This regulated process of red cell production is erythropoiesis.

21. GROWTH FACTORS AND
CYTOKINES

23.  During development, haematopoiesis occurs in the
yolk sac, liver and spleen, and subsequently in red
bone marrow in the medullary cavity of all bones.
 In childhood,red marrow is progressively replaced by
fat (yellow marrow).
 In adults, normal haematopoiesis is restricted to the
vertebrae, pelvis, sternum, ribs, clavicles, skull,
upper humerus and proximal femor.
 However, red marrow can expand in response to
increased demands for blood cells.

24. SITE

25.  In the bone marrow, the first morphologically
recognizable erythroid precursor is the
pronormoblast.
 This cell can undergo four to five cell divisions, which
result in the production of 16–32 mature red cells.
 With increased EPO production, or administration of
EPO , early progenitor cell numbers are amplified
and, give rise to increased numbers of erythrocytes.
 The regulation of EPO production is linked to tissue
oxygenation.

26.  The mature red cell is 8 μm in diameter, anucleate,
discoid in shape, and extremely pliable.
 Membrane integrity is maintained by the intracellular
generation of ATP.
 Normal red cell production results in the daily
replacement of 0.8–1% of all circulating red cells in the
body and average red cell lives 100–120 days.

27.  The organ responsible for red cell production is
called the erythron : a dynamic organ made up of a
rapidly proliferating pool of marrow erythroid
precursor cells and a large mass of mature
circulating red blood cells.
 The size of the red cell mass reflects the balance of
red cell production and destruction.
 The glycoprotein hormone EPO, is produced and
released by peritubular capillary lining cells within
the kidney.
 Highly specialized epithelial-like cells.

28.  A small amount of EPO is produced by hepatocytes.
 The fundamental stimulus for EPO production is the
availability of O2 for tissue metabolic needs.
 Key to EPO gene regulation is hypoxia-inducible factor
(HIF)-1α.
 In the presence of O2, HIF-1α is hydroxylated at a key
proline, allowing HIF-1α to be ubiquitinated and degraded
via the proteasome pathway.
 If O2 becomes limiting, this critical hydroxylation step
does not occur, allowing HIF-1α to partner with other
proteins, translocate to the nucleus, and upregulate the
expression of the EPO gene.

29. The physiologic regulation of red cell
production by tissue oxygen tension.

30. Erythropoietin (EPO) levels in response to anemia.
When the hemoglobin level falls to 120 g/L (12
g/dL), plasma EPO levels increase logarithmically

31. Impaired O2 delivery to the kidney can result from :
 Decreased red cell mass (anemia)
 Hypoxemia
 Impaired blood flow to the kidney (renal artery
stenosis).
o EPO normal level 10–25 U/L.
o When the hemoglobin concentration falls below 10–
12 g/dL plasma EPO levels increase in proportion to
the severity of the anemia.

32.  Half-clearance time 6–9 h.
 With EPO stimulation, red cell production can
increase four- to fivefold within a 1- to 2-week period,
but only in the presence of adequate nutrients,
especially iron.
 The functional capacity of the erythron, therefore,
requires normal renal production of EPO, a
functioning erythroid marrow, and an adequate
supply of substrates for hemoglobin synthesis.

35. FIG. Hierarchy of hematopoietic
differentiation

36. REFERENCES
 HARRISON’S PRINCIPLES OF INTERNAL
MEDICINE -20TH EDITION
 DAVIDSON’S PRINCIPLE AND PRACTICE OF
MEDICINE -23RD EDITION

37. THANK YOU