Hematopoiesis and Erytherokinitics

THE ERYTHRON

• widely dispersed mass of erythroid cells includes circulating

erythrocytes & bone marrow precursor, progenitor, stem cells.
• Function: oxygen transport mediated by hemoglobin.
• Hb consists of heme & globin (tetramer)
• Each heme have Fe2+.
• Globin chain of specific sequence amino acid attached to each heme
group.
• Hb. a tetramer, containing 4 heme units & 4 globin chains.
HEME SYNTHESIS

• Heme synthesis unidirectional & irreversible, controlled at first step by

enzyme δ-aminolevulinic acid synthase, synthesis is controlled by
negative feedback from heme conc. within erythrocyte.

• Lead inhibits delivery of iron to site of ferrochelatase activity.

• Chloramphenicol may inhibit heme synthesis.

Hematopoiesis
Hematopoiesis
• Stem cells, progenitor cells, & precursor cells
• Stem cells
• Pluripotential & multipotential stem cells (CFU-GEMM or CD34+ cells)
• Capacity for self-renewal & differentiate into progenitor cells.
• Controlled by growth-promoting stimuli produced by marrow stromal
cells.
• Growth factors & cytokines involved (SCF, IL-3, IL-9, IL-11, & Epo)
• When a stem cell differentiates, loses some of its ability to self-
replicate & some of its potentiality.
Progenitor cells
• Multi potential progenitor cells have capability of differentiating into
more than one cell line
• (e.g., CFU-GEMM differentiate into granulocytes, erythrocytes,
monocytes, or megakaryocytes).
• Uni-potential progenitor CFU-E differentiate into erythroid cells
• Limited capacity for self renewal & differentiate into precursor cells of
various cell lines.
• not recognizable morphologically, resemble small lymphocytes.
Precursor cells

• Have no capacity for self-renewal but proliferate while differentiating

into mature, functional cells.
• First cells that can be recognized as members of a particular cell line.

• Erythropoiesis occurs extra-vascularly in bone marrow parenchyma.

Hematopoiesis
Morphologic changes during maturation from rubriblast to mature RBCs

• Cells become smaller.

• Nuclei become smaller & chromatin aggregated:
• Cell division stops in late rubricyte stage when conc. of Hb deposited
• Nucleus extruded at metarubricyte state, a reticulocyte formed in
mammals.
• Avian reticulocytes & mature erythrocytes retain their nuclei.
• Cytoplasmic color changes from blue to orange as Hb is formed &
RNA lost.
• Reticulocytes & RBCs migrate into venous sinus of bone marrow
• through transient apertures in endothelial cell cytoplasm.

• Reticulocytes remain in bone marrow for 2-3days before release &

ultimately mature in peripheral blood or spleen.
• Time from stimulation of progenitor cell to reticulocytes released
approx. five days.
• Starting with the rubriblast, three to five divisions produce eight to 32
differentiated cells.
• Bone marrow has capacity to increase erythropoiesis.
• RBCs production increased up to 7 times normal rate in humans,
• providing necessary stimulation & nutrients available
. Regulation of erythropoiesis
• 1. Erythropoietin (Epo)
• produced by peritubular interstitial cells of kidney in response to
hypoxia,
• 10% to 15% of Epo production by specific hepatocytes
• Actions of Epo
• Inhibition of apoptosis of newly formed progenitor cells &
prorubricytes, allowing them to differentiate into mature RBCs

• Stimulation of Hb. synthesis in already dividing erythroid cells.

2.Interleukin-3 (IL-3) & colony-stimulating factors (GM-CSF and G-CSF).

• IL-3: by activated T-lymphocytes;

• CSF: by activated T-lymphocytes, macrophages, endothelial cells, &
fibroblasts; monocytes, neutrophils,
• Action:
• Stimulate multiplication of a primitive erythroid
• Progenitor cell, BFU-E, & its differentiation into CFU-E progenitor cell.
• BFU-E progenitor cell insensitive to Epo stimulation alone.
• 3. Androgens
• Increase Epo release.
• Estrogens and corticosteroids decrease Epo release, not clinically
significant.
• Thyroid and pituitary hormones
• alter tissue demands for oxygen, thereby changing requirement for
erythropoiesis.
ERYTHROCYTE DESTRUCTION

• Aver. RBCs lifespan 120 days

• Aging of RBCs due to changes in enzyme content & cell membrane
structure that make cells less capable of survival & subject to removal
by spleen.
• In health, senescent RBCs removed from circulation by two routes.
• Phagocytosis: macrophages major route of senescent erythrocyte
removal
• Within phagosome, RBC releases its Hb, split into heme & globin.
• Globin: break into amino acids & reutilized.
• Iron released from heme by heme oxygenase, forming CO & biliverdin
• Biliverdin reduced by biliverdin reductase to bilirubin, excreted into
blood,
• Bilirubin binds with albumin for transport to liver.
Intravascular phagocytosis
• Release of Hb into plasma, minor route of senescent RBCs removal
• Free Hb in plasma binds to α2-globulin, haptoglobin.
• Hemoglobinhaptoglobin complex cleared from plasma by liver,
preventing loss of Hb in urine.
• Enough haptoglobin bind 150 mg/dL of Hb
• Plasma appears pink to red when 50 to 100 mg/dL of Hb present;
discoloration of plasma precedes hemoglobinuria.
• In health, plasma discoloration not observed.
• If intravascular lysis is excessive, serum haptoglobin may become
saturated.
• Free Hb then dissociates into dimers, which can pass glomerular
filter, which does not occur in health.
• With time, free Hb in plasma is oxidized to methemoglobin, which
dissociates to free ferriheme, which complexes with β-globulin,
hemopexin