ERYTHROCYTE FUNCTION, METABOLISM, PRODUCTION, BREAKDOWN

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 moiety contains an iron atom in 2+ valence state (Fe2+).
• A globin chain of specific a a sequence attached to each heme group.
• Hb. a tetramer, containing 4 heme units & 4 globin chains.
• globin chains identical pairs (dimers), designated as α- or δ-chains.
HEME SYNTHESIS

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

enzyme δ-aminolevulinic acid synthase, whose synthesis is controlled
by negative feedback from heme conc. within erythrocyte.
• Lead inhibits most of steps in heme synthesis to some degree.
• Lead also inhibits delivery of iron to site of ferrochelatase activity.
• Chloramphenicol may inhibit heme synthesis.
• Porphyrins & their precursors: intermediates of heme biosynthesis.
• Certain enzyme deficiencies in synthetic pathway can lead to excessive
accumulation of porphyrins & precursors.
• Excesses of porphyrins: porphyrias.
• Excess porphyrins escape RBCs & deposited in tissues or excreted in urine
& other body fluids.
• After formation of protoporphyrin, iron is inserted into the molecule by
ferrochelatase, & heme is formed.
• Heme & globin synthesis balanced (inc. in one results in an inc. in other).
Hematopoiesis
Hematopoiesis
• A. Stem cells, progenitor cells, & precursor cells
• Pluripotential & multipotential stem cells (CFU-GEMM or CD34+ cells)
• Have capacity for self-renewal & differentiate into progenitor cells.
• Controlled by growth-promoting stimuli produced by marrow stromal
cells.
• A variety of growth factors & cytokines involved (SCF, IL-3, IL-9, IL-11,
& erythropoietin).
• When a stem cell differentiates, it loses some of its ability to self-
replicate & also loses some of its potentiality.
Progenitor cells
• Some early progenitor cells have capability of differentiating into more
than one cell line
• (e.g., CFU-GEMM has the potential to differentiate into granulocytes,
erythrocytes, monocytes, or megakaryocytes).
• Other progenitor cells unipotential (e.g., CFU-E can only differentiate into
erythroid cells).
• Progenitor cells have limited capacity for self renewal & differentiate into
precursor cells of various cell lines.
• not recognizable morphologically with Romanowsky stains, resemble
• small lymphocytes.
Precursor cells

• Precursor cells 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.
Hematopoiesis
Erythropoiesis
• In mammals, erythropoiesis occurs extravascularly in bone marrow parenchyma.
• In avian species, erythropoiesis occurs within vascular sinuses of bone marrow
(intravascular or intrasinusoidal development).
• Characteristic morphologic changes during maturation from rubriblast to mature
RBCs a.
• Cells become smaller.
• Nuclei become smaller & chromatin aggregated:
• Cell division stops in late rubricyte stage when a critical intracellular conc. of Hb
reached.
• Nucleus extruded at metarubricyte state, a reticulocyte formed in mammals.
• In contrast, avian reticulocytes & mature erythrocytes retain their nuclei.
• Cytoplasmic color changes from blue to orange as hemoglobin is formed & RNA
lost.
• In mammals, 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 erythropoietic progenitor cell until 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 can be increased up to seven times the normal rate
in humans,
• providing the necessary stimulation & nutrients are present.
• Capacity to increase production varies with animal species, greatest in
birds & dogs, least in cattle & horses.
• Increase in no. of RBCs primarily via increased stem cell input
. Regulation of erythropoiesis
• Erythropoietin (Epo)
• Majority of Epo is produced by peritubular interstitial cells of kidney
in response to hypoxia,
• Liver may account for 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.
• Interleukin-3 (IL-3) & colony-stimulating factors (GM-CSF and G-CSF).
• IL-3 produced by activated T-lymphocytes;
• GM-CSF by activated T-lymphocytes, macrophages, endothelial cells, &
fibroblasts;
• G-CSF by macrophages, monocytes, neutrophils, endothelial cells, and
fibroblasts.
• Action: these factors stimulate the 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.

• 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 cow, 160 days; sheep, 150 days; horse, 145 days;
dog, 110 days; pig, 86 days; cat, 70 days; bird, approximately 35 days.
• Thus, ruminant blood smears infrequent reticulocytosis in health,
while avian blood smears may have 4% to 5% reticulocytes in health.
In certain disease states, anemia may develop more quickly in birds &
cats than in large animals because of normally short erythrocyte
lifespan.
• 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.
• Birds lack biliverdin reductase; therefore, end product biliverdin not bilirubin.
Biliverdin is green, gives characteristic color to bruises in avian tissue.
• Intravascular lysis with release of Hb into plasma, minor route of senescent RBCs removal
• Free Hb in plasma binds to α2-globulin, haptoglobin.
• Hemoglobinhaptoglobin complex is cleared from plasma by liver, preventing loss of hemoglobin
in the 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 the β-globulin, hemopexin