RBC Structure and
Function
RBC Structure and Function
Production of RBCs:
(1) Fetal Life Liver,
Spleen, Bone
Marrow (BM)
(2) Child/Adult BM. (Child-lots of the
skeleton is involved, Adult-mostly the
axial skeleton is involved).
(3) Extreme hematologic Stress
Liver and Spleen can revert to making
RBC ("Extramedullary Hematopoiesis").
Ex: kid with severe anemia due to
thalassemia with hepatosplenomegaly.
BM Environment: cellular proliferation and
maturation. A fine reticular meshwork supports
cellular elements as vascular sinuses course
through the marrow cavity allowing for the inflow of
plasma nutrients but retaining developing cells
until they are mature.
RBCs mature around a central macrophage.
RBC Development: Stem cell multipotent stem cell
BFU-E CFU-E erythroblast RBC
RBC Lifespan: From earliest recognizable erythroblast
to a mature RBC it takes 3-4 days, reticulocyte
(nucleus has been extruded, but some RNA is left
over) for about 1 day, and mature RBC lives 120
days.
Hemoglobin synthesis: Three components of
hemoglobin: (1) globin, (2) protoporphyrin, (3) iron
(protoporphyrin and iron combine to form Heme).
Iron enters the developing RBC and ultimately
enters the mitochondria to support heme synthesis.
In the mitochondria the first step of heme
synthesis takes place as glycine and succinyl CoA
combine to form delta aminolevulinic acid.
Synthesis shifts into the cytoplasm but ultimately
returns to the mitochondria for final steps in the
formation of protoporphyrin IX and, eventually
heme, as protoporphyrin and iron combine.
"Sideroblastic anemia" = Congenital absence of
enzymes along the path of proto-porphyrin
synthesis may lead to severe impairment of heme
synthesis
Globin chain synthesis: various Hgb's:
Hgb
A = 2 alpha chains and 2 beta
chains
Hgb A2 = 2 alpha chains and 2 delta
chains
Hgb F = 2 alpha chains and 2
gamma chains
Changes of Hgb throughout life: Birth most Hgb
present is of the fetal variety
4-6 months gradual decline in synthesis of fetal
Hgb with a corresponding increase in Hgb A
6-8 months approximately 97% of Hgb is Hgb A,
2% is Hgb A-2 and 1% is Hgb F
Clinical correlate: beta chain Hgb disorders such as
sickle cell disease do not clinically manifest until 46 months of age since fetal Hgb predominates
during early infancy
Mature RBC = biconcave disk, no nucleus, cant
reproduce, cant produce energy (no mitoch), very
little cytoplasm, diameter = 8 m m, width = 2 m m,
volume = 90 femtoliters
Three
Constituents of RBCs: RBC
membrane + internal metabolic apparatus
(ie a bit of cytoplasm) + hemoglobin
RBC membrane: Has lipid bilayer
membrane with proteins in it. Underneath
it is a cytoskeleton of proteins allowing
rubbery elasticity with main protein being
Spectrin. Ankyrin anchors cytoskeleton
to membrane. Na/K ATPase channel is
abundant on membrane (ATP from
pentose phosphate shunt thats why
G6PD deficient people have problems).
Membrane antigen structure there are
over 300 RBC membrane Ags. They are
Polysaccharides. (A, B, Rh, Duffy, etc).
Embden-Meyerhof
Pathway glycolysis from glucose to
lactate, net 2 ATPs produced and
used to support membrane ion
pumps. When deficiencies of the
E-M path exist, RBC survival is
reduced, leading to hemolysis
Methemoglobin Reductase Pathway prevents iron of Hgb from being oxidized,
makes NADH which is reducing power. Hgb iron
must be in reduced state (Fe+2) in order to
transport O 2. The environment is constantly
generating oxidant stress and therefore a
tendency to oxidize iron to Fe3+. The
methemoglobin reductase pathway counteracts
this by reducing iron to the +2 state. Patients
with methemoglobin reductase deficiency have
a substantial quantity of methemoglobin (Hgb
with iron in the oxidated state) associated with
reduced O 2 carrying capacity.
Luebering-Rapaport Pathway - modifies
affinity of binding of Hgb and O2, makes 2,3-DPG
which shifts saturation curve to the right. This
pathway is an off-shute of the E-M pathway
leading to generation of 2-3 DPG. 2-3 DPG is an
important regulator of Hgb-O2 release (increased
2-3 DPG giving rise to increased O2 release). An
increased rate of glycolysis leads to an increase
in intracellular 2-3 DPG concentration. When
venous blood is increasingly deoxygenated, the
rate of glycolysis increases leading to increased
2-3 DPG production and increased O2 release to
the tissues. This is an appropriate response to
ensure adequate O2 delivery.
Hexose-Monophosphate
Shunt
(Phosphoglucoate Pathway) - This pathway
couples oxidative metabolism with NADP
and glutathione reductase to provide antioxidant substrate which ultimately
combats the effects of oxygen stresses
(environmental, medications). If the shunt
is defective (as is the case in patients with
G6PD deficiency) oxidative insults lead to
oxidation of globin chains and denaturation
of Hgb leading to precipitates (Heinz
bodies) in the RBC, membrane damage
and, ultimately, cell death.
P50
= PO2 at which Hgb is 50% saturated
Right shift (O2 released easily) of the
curve is caused by: O2 affinity, pH,
2,3-DPG, pCO2, temp
Left shift (O2 bound tightly) of the curve
is caused by: O2 affinity, pH, 2,3DPG, pCO2, temp
Kidneys are sensors (Juxtatubular cells)
for O2 delivery EPO
Reticuloendothelial cells participate in the destruction of
senescent RBC's.
Destruction of RBCs happens within reticuloendothelial
cells NOT in the circulation. Globin and heme get
recycled, porphyrin is degraded to bilirubin which is
conjugated by the liver and excreted in the gut. Rate
limiting step is conjugation. Indirect (unconjugated)
bilirubin is result if this doesnt happen.
Normally ~10% RBCs lyse while in circulation Hgb gets
released into circulation and rapidly disassociates into
alpha and beta dimers which are bound by haptoglobin.
The Hgb/haptoglobin complex is transported to the liver.
If haptoglobin is depleted, free Hgb circulates and is
filtered by the kidney. Free Hgb is either reabsorbed by
renal tubular cells or excreted as free Hgb in the urine
The role of the RBC in the transport of O 2 from the lungs to
the tissues is central. A variety of integrated physiologic
components contributes to active O 2 supply to tissues
including pulmonary function, and hemodynamic factors
(C.O., regional blood flow, blood volume, viscosity).
Regulation of the Erythron: In the basal ideal state, blood
enters the tissue at a PO2 of 95 and exits at a PO2 of 40.
Therefore, 25% of O2 transported by Hgb is release. O2
delivery may be altered by: (1) Hgb-O 2 affinity and (2)
increase in the number of RBC's.
Pulmonary function/hemodynamic factors: The lungs and
heart manifest a physiologic response in the face of
decreased O2 carrying capacity associated with anemia.
Alterations in regional blood flow as well as a marked
increase in cardiac output can compensate for 50% fall in
O2 carrying capacity in the anemic patient. As a result,
patients with significant anemia frequently have
tachycardia and an increased cardiac ejection fraction.
