Red blood cells transport O2 to other cells and don’t use any O2 themselves for
cellular metabolism, pick up O2 is to deliver to tissues, RBC do pick up a little bit
of CO2
65% of Hb that is made while there is still a nucleus in place
35% of Hb is being made in the RBC without a nucleus (younger newer cells don’t
have as much Hb as the mature RBC)
Hb concentration per unit volume of whole blood12-16g per deciliter is normal at
sea level
2x10^11 new and 2x10^11 are exciting due to old age this is to maintain steady
state (majority of RBC are being reutilized/recycled)
RBC are bag of Hb
Few enzymes for glycolysis
Using glucose for energy only through glycolysis in the production of lactate acid,
this is why RBC are not using O2 for energy
Has ability to go through space a min diameter of 3.5um (half the RBC size)
Has to be able to deform if the fluidity of RBC is correct
FE in Hb in reduce state ferrous form +2 so O2 can attach
Ferric +3 cannot pick up O2
Has little repair mechanism but yet can last 120 days
RBC Membrane LIPIDS
Lipids are important
Phospholipids = phosphor side (water loving) lipid side (long change of carbon no
reason to interact with water)
Cholesterol to adjust the spacing
RBC very critical in being able to last 120 days
Protein on outer surface that act as receptors, when the ligand hooks up to the
receptor it will change the cell membrane that allows a change in the cytoplasm.
Peripheral proteins-cytoskeletal support: Spectrin, Actin, Ankyrin, Band 4.2, Band
4.1 (inner part of membrane) allows for the deformability, the structural to be
altered without being damaged.
If a patient doesn’t have the ability to deform their RBC then it can’t make it
through small spaces and get stuck, so beyond where the RBC is stuck is not going
to get delivered O2 and cause CELL DEATH
If there is a problem of the outer part of the membrane
(ends up being bigger) spikes outside the membrane
Wont last 120 days
If problem with inner membrane than you get
a stomatocyte (lost biconcave disk) won’t last 120 days
Structural Integrity (must have proteins to allow for deformity to occur)
Stay fluid/ability to deform RBC become elongated so the fluidity of Hb can
squeeze through as the RBC is deforming (this is why RBC cannot be completely
filled with Hb)
RBC has more surface area
1. Critical thing is the RBC membrane
2. Cell surface area to volume (less material inside compared to surface
volume
3. Cytoplasmic viscosity (has to be fluid) Hb is the major protein in RBC that
Hb has to be fluid, so if anything changes in the protein component of Hb,
so if certain amino acids change Hb may not be stable
Hb could precipitate in the cell (and eventually make it to the cell membrane
and when it goes through the spleen, the spleen will get rid of it creating less
membrane aka shorten the life span of RBC), it could change the viscosity
inside the cell (meaning it doesn’t matter how pliable that membrane is, it’s
not going to make it through)
Energy mechanism
Once the nucleus comes out of RBC and finished with ribosomes, it goes away, no
mitochondria (where does RBC get energy from? Glucose in plasma being able to
go into the cell and strictly the breakdown of glucose for energy)
If there is excess glucose in plasma it will get into the RBC and attach to Hb and
stay attach as long as that RBC is alive, a person who is diabetic A1c will still show
high levels of glucose in blood
ATP is going to be used mostly in the formation in keeping that RBC membrane in
proper form other energy need doesn’t have to keep that Hb (FE) in the reduce
state and subject to oxidated stress all over and yet the FE remains in +2 state
Thinking about Anemia
Is there something wrong with the membrane?
Is there something wrong with Hb in the RBC, is it not made right?
Did we lose surface area of the RBC, did we lose some of it in the spleen (but that
doesn’t mean we haven’t lost any Hb)?
Needed for Erythropoiesis (Problem with these will cause an ANEMIA)
• Metals = Fe, Mn, Cobalt
• Vitamins =B12, Folate (important), C, E, B6
• Amino Acids = for Hb formation
• Hormones
Erythropoietin/EPO comes from kidneys goes to bone marrow and tells it
we need RBC to be made.
 Is not an lineage cytokine it is a hormone (doesn’t work at stem cell
level does not drive stem cell to become RBC) it will speed up
maturation once the cell has been committed and can help put Hb
faster to get them out of bone marrow early.
 Stimulated proliferation
 Stimulated RNA synthesis
 Release RBC earlier
If a patient is having a problem with the kidneys, they will have a
problem with EPO production and will be anemic
Androgens can stimulate EPO being release
Males have higher Hb than females
Thyroxine is involved in overall cellular metabolism
If patient is hypothyroid (not having as much cellular metabolism,
there’s not demand for O2 there won’t be a need for making RBC)
• Growth Factors/Cytokines (Bone marrow stroma that help with maturation
of stem cells to erythroid side to make RBC)
Hb molecule is made up of 4 protein chains it has 4 Fes attach and has to be
exposed to O2 to be able to attach to O2 1,3 BPG help with 3D of Hb allows for
rearrangement of itself and either allow O2 to attach or prevent O2 from coming
off until its need. You want Hb in form that can have the attachment of O2 in the
lung and you want that Hb to take it to the tissues and deliver O2
If there is a problem with the membrane it will change the osmotic gradient in
those cells, (if there is DECREASED ATP production those cells are going to
become fragile) you don’t have membrane to maintain its shape and deform. NOT
MADE BY MITOCHONDRIA! It is done by Glycolytic pathway
Cations
RBC vs PLASMA
Na (Sodium) plasma, Ca (Calcium) higher concentration in plasma
K (potassium) RBC, Ca little in RBC, Mg (Magnesium) much more in RBC
If there is any changes in ATP formation, if the patient is having problems with a
particular enzyme in the pathway of glycolysis they will end up having an anemia
amongst other things.
Hexose Monophosphate Shunt (HMP)
A shunt off of glycolysis (glycolytic pathway), your reducing glutathione which is
going to help keep the FE IN A REDUCE STATE to transport oxygen, it’s a way to
pick anything that will oxidize that FE and take care of it so that the Fe can be in
the reduced state, If there is a problem with HMP in particular G6PD it will cause
an anemia
Fetus (ONTOGENY of hemoglobin)
The Hb in RBC is different than MOM Hb because in order to get O2 its going to
have a stronger affinity for O2 than moms Hbs, the fetus will want to take it from
mom blood to be able to utilize it for energy once it gets a certain size
Embryonic Hb is not the same structure as Adult Hb
The protein chains are different the FE isn’t different
The structure allows for the Hb to have a higher O2 affinity
Adult Hb do include fetal Hb, there is a switching (proteins on the DNA RNA to
algin amino acids there has to be switching at DNA of chain to make it more of O2
affinity than adult Hb
NO KNOWN REASON WHAT CAUSES THE SWTICHING, we know its by gestational
age, if the baby is a premature (born early) they will have much more fetal Hb
than adult and they will have it longer because they came out early. It’s a time
frame situation. THE SWITCH ISNT COMPLETE
In adult Hb if one of the chains can’t be made right because there has been an
amino acid substitution, if there a way to switch back to fetal Hb?
As an adult do we have both fetal and adult Hb?
HEMOGLOBIN
Non protein component = Heme
Protein = Globin
Protein chains
Alpha chain is going to be very critical because that is making up all of the adult
Hb
Zeta after embryonic stops as alpha chain takes over
Genes are located on CHROMOSOME 11 and 16
Chromosome 16 zeta chain =embryonic equivalent of alpha chain
Alpha chain has 2 different locations (loci) for making alpha chain, tightly
conserved
(ALPHA CHAIN LESS EXPRESSED)
Chromosome 11 (alpha will hook up to one of these to form Hb)
Epsilon = embryonic
Gamma 2 different species of gamma chain
Delta and Beta
(MORE EXPRESSED)
4 polypeptide chains that make up Hb
4 subunits each part, has protein chain (involves DNA RNA, lining of amino acids
and non-protein = heme (formed all amongst the mitochondria of the developing
RBC, 1st step of heme synthesis that regulates the whole process)
Alpha gene is duplicated
Hb have to have EQUAL AMOUNT of alpha and beta to form Hb molecule
If there is anything wrong at the DNA level it will potentially affect transcription,
or it could be transcribed but the cleaning up of it will be a problem which will
affect translation.
Globin synthesis (protein chains are being made at the ribosome) at the same
time heme is being made in and out of the mitochondria it has to be able to hook
up heme gets inserted into poly peptide chains and with FE in them ready to
accessible of oxygen
4 o2 per heme molecule
3 types that can transport oxygen
98-99% of adult Hb is 2 alpha and 2 beta
HbA 2 alpha 2 beta and each chain have Heme component non protein
component
Alpha 1 Beta 1 together and Alpha 2 and Beta 2 together
HbF 2 alpha chains 2 gamma chains <1% of the adult Hb but there is still some
there
Hb 2 2 alpha chains and 2 delta chains 2%
Last step of heme formation is the addition of Fe into that molecule
The rate limiting step for Hb synthesis is the 1st step in heme formation is the
regulatory step in Hb formation that is what is going to be telling DNA what amino
acids have to be lined up
The Hb part is DNA RNA RIBOSOMES lining up amino acid
Heme synthesis is a series of steps
1. Condensation of glycine and CoA ( rate limiting step) BOTH THE PROTEIN
AND THE HEME IS CONTROLED BY THIS STEP if this isn’t happening DNA
will not code for the protein if the synthesis continues in the cytoplasm the
final step is the corporation of iron in non-protein component, heme leaves
mitochondria and combines with globin chains
LAST STAGE IS INCORPORTAION OF IRON
If there is a problem along this way of making heme, there will be a backup of
intermediaries or in the case of not enough iron it will SLOW IT DOWN if there is
no Iron to incorporate, IRON DEFICIENCY ANEMIA
THERES NO EXCESS CHAINS IN RBC BECAUSE 1ST STEP HAS BEEN SLOWED DOWN
AND THE PROTEIN PART IS ALSO SLOWED DOWN BECAUSE OF THAT BEING THE
RATE LIMITING STEP, there’s nothing extra if there is no Iron
PROFORREA?
Central cavity allows for the dispersment