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Transcript Hematopoiesis

HematologyThe study of Blood
Production of Blood Cells
Production of Red Blood Cells
Chapter 32 and pages 861-864
Lecture outline
I. Functions of blood
II. Properties of whole blood
III. Whole blood components
A. Plasma
i. Components of plasma
B. Formed elements
i. Site of hematopoiesis
ii. Hemocytoblast- determined but not differentiated
iii. Erythropoiesis
a. “Ingredients”
b. Process
IV. Red blood cell characteristics
A. General “need to know” information, indices
B. Components within a red blood cell
i. Hemoglobin
a. Globin chains
b. Pyrrole groups
c. iron
C. Steady-state maintenance of RBC counts
i. Erythropoietin
ii. Removal/destruction of RBC
a. jaundice
RBC pathologies
A. Polycythemia
i. Primary
ii. secondary
B. Anemia
i. Defective RBC production
a. Iron deficiency
b. Aplastic anemia
c. megaloblastic
ii. Blood loss
a. Hemorrhagic (chronic, acute)
b. Acquired (transfusion, venom, drugs)
c. Inherited (thalassemia, sickle cell, hereditary
spherocytosis, G6PD deficiency)
Anemia: a reduced carrying capacity of
 Anemia is not a reduced hematocrit (Hct), because you can have
less O2 for other reasons.You can be anemic with normal levels
of RBC’s if the hemoglobin is abnormal, and has less iron.
Functions of Blood
• Transportation
– Gases, nutrients,
hormones, wastes,
• Regulation
– Body fluid volume
– Body fluid pH
– Body T°
– Electrolyte levels
• Protection from
pathogens and bleeding
These red blood cells function
in oxygen transport
Used with permission given by A. Imholtz
 Blood transports O2, CO2, nutrients, wastes,
hormones, lipids, etc. The blood also regulates body
temperature. Hormones can adjust blood volume, urine
output, and maintain pH (which needs to be 7.40). A
person with blood pH of 7.35 or 7.45 will not feel well,
act strangely. There are buffers in the blood to keep the
pH steady, and lungs and kidneys help with this. We also
have WBCs in our blood for immune system function,
and platelets for clotting.
Blood – Physical
 Adult ♂ contains 5-6L
 Adult ♀ contains 4-5L
 T is about 100.4 F
 5 times as viscous as water
 What accounts for its viscosity?
 pH ranges from 7.35 – 7.45 (slightly
 What happens at either extreme?
Without O2
With O2
 Color ranges—oxygen poor vs.
oxygen rich
Used with permission given by A. Imholtz
 Adults have 4-6 liters of blood (Let’s call it 5 liters for this
class). The heart pumps all of it every 60 seconds. The
temperature of our core is higher than the superficial
temperature. Blood is 5x thicker than water because of the
RBC’s. Increase the numbers of RBC’s, and you will increase
viscosity, increase heart workload.
 The color of blood is bright red or dark burgundy, depending on
oxygenation. Blood is intracellular fluid (RBC’s, 45%) and extra
cellular fluid (plasma, 55%). In plasma is mostly water, plus
dissolved hormones, proteins, electrolytes. Don’t memorize the
next two slides that show everything in the blood; just understand
that there are many things in the blood. Water is the solvent. 7g%
of the plasma is protein, albumin is the most abundant. Albumin
helps keep the water in the plasma by keeping the particle count
high. Problems with water leaving the vascular compartment will
lead to ascites, so albumin in the blood acts as osmotic
Whole Blood
Formed Elements
1. Water (92%)
2. Plasma Proteins (7%)
3. Other Solutes (1%)
1. Red Blood Cells-erythrocytes
2. Platelets- thrombocytes
3. White Blood Cells- leukocytes
Used with permission given by A. Imholtz
Transports, organic and inorganic
molecules, formed elements, and heat
Water (92%)
Albumins (60%): Contribute to plasma
osmotic pressure; Transport lipids,
steroid hormones
Proteins (7g%)
Globulins (35%): Transport ions,
hormones, lipids; Immune function
Fibrinogen (4%): Essential component
of clotting system
Other Solutes (1%)
Regulatory Proteins (<1%): Enzymes, Hormones
Electrolytes: Ions necessary for vital cellular activity. Contribute to
osmotic pressure of body fluids. Major electrolytes are Na+
(140meq/L),K+ (3-5 mEq/L), Ca2+, Mg2+, Cl-, HCO3-, HPO42-, SO42Organic Nutrients: Used for ATP production, cell growth and maintenance;
Includes lipids (800mg %) , carbohydrates (80-120mg%) , cholesterol
(200mg%) and amino acids
Organic Wastes: Carried to sites of breakdown or excretion; Includes urea, uric
11acid, creatinine, bilirubin, and ammonium ions
 Besides albumin, there are other proteins in the blood,
such as fibrinogen (inactive form of fibrin). Fibrin is the
fiber that grows across a cut and makes a scab. Other
proteins include regulatory and proteolytic enzymes.
Other substances in blood include glucose, lipids,
cholesterol, bilirubin (waste product of RBC
destruction), and creatinine (waste product of kidney).
We check those levels in the blood to ascertain kidney
function. There are lots of solutes in the blood!
 You need to measure hematocrit (Hct), hemoglobin (Hgb), and do a RBC count. With
this information, you can then calculate MCV, MCH, and MCHC. By the way, RBC =
 MCV(mean corpuscular volume) calculated as MCV = Hct / RBC count. Normal is 80-
100 µm
 MCH (mean corpuscular hemoglobin) calculated as MCH = Hb / RBC count. Normal
is 32 pcicograms (10 -12 micrograms). There is not much, but hemoglobin is still the
most abundant protein in RBC’s.
 MCHC (mean corpuscular hemoglobin concentration) is the ratio of MCH to MCV. It is
calculated as MCHC = Hb/Hct. Normal is 34%
 MCD (mean corpuscular diameter) normal is 7-8 µm wide, 2 µm thick.
Red blood cellneed to know information
 Hematocrit: % volume of blood that is red
 Men ~45% (42-52%)
 Women ~40% (37-47%)
 Hemoglobin concentration -Wt of Hb in 100
ml blood
 15-16 (male) gm Hb/100 ml blood
 13-14 (female) gm Hb/100 ml blood
 Oxygen carrying capacity:
 gm Hb/100 ml blood * 1.34 ml O2/gm Hb
 ~21 ml O2/ 100 ml blood for men
 ~19 ml O2/ 100 ml blood for women
100 ml
Red Blood Cell “Indices”
 Mean Corpuscular Volume
 MCV 80-100 m3
 Mean Corpuscular Hemoglobin
 32g (10-12; picogram)
 Wt of Hb in a single RBC
 Mean Corpuscular Hemoglobin Concentration
 34%
 Concentration of Hb to volume in a single RBC (i.e., solute/solvent).
 Mean Corpuscular Diameter
 MCD 7-8 m
 Color Index
 CI 0.9 – 1.1
A “corpuscle”
 COLOR (Chromasia; indicates how much Hgb is there)
Normal is 1.0
 Normochromic is 1
 Hypochromic is less than 1. Can’t have hyperchromic RBC’s. A
disorder that appears hyperchromic is
 Hereditary Spherocytosis. It is the most common inherited
disorder that affects the RBC membrane. RBC comes out of
marrow normal, but with time, the membrane is lost, but none of
the contents are lost, RBC gets smaller and concentrated, looks
redder. Thus, it could look hyperchromatic.
 Normocytic is normal size.
 Microcytic (small)
 Macrocytic or Megaloblastic (big)
 Poikilocytosis is abnormal shapes, such as sickled or
sphaerocytes. Cells with abnormal size or shape will be
removed from circulation faster, get anemia.
 Chromasia- indication of
 Hyper/hypochromic
 normochromic
 Anisocytosis – cells of
abnormal size; indication of MCV
 Microcytic
 Macrocytic/ Megalocytic
 normocytic
 Poikilocytosis – cells of
abnormal shape
 Spherocytosis
 Sickle cell
 Echinocyte
 We have 5 liters of blood, 25 trillion RBC’s, 4.5 million in one microliter. We
need the rate of old blood cells that die to match the rate of new ones being
made. RBC’s are made by stem cells in bone marrow. Too many RBC’s is
polycythemia, too few is anemia. RBC shape should be biconcave because
that increases surface area for O2 binding and allows it to be flexible to get
through capillaries. When a RBC gets older, its membrane is less flexible, gets
stuck in liver and is detected and destroyed. Because of the shape increasing
surface area, there is rapid gas exchange across cell membranes for wastes and
O2.You know that hemoglobin binds O2, but CO2 can also bind to
hemoglobin, but only if O2 is not there.
 An embryo (< 3 months) makes blood in yolk sac
 Fetus (> 3 months) makes blood in the liver
 At birth, makes blood in the bone marrow
 Blood that is made in the bone marrow is specifically
made in the axial and appendicular skeleton until the age
of 20. Thereafter, it can only be made in the axial
skeleton, mainly in the sternum and iliac crest.
Let’s talk about formed elementsSites Of Hemopoietic Activity
Bone marrow
Yolk sac
 A stem cell that is completely undifferentiated yet is called a
pleuripotent stem cell.
 A pleuripotent stem cell can differentiate into any cell
type: nerve, muscle, blood, etc. Since we are discussing
blood cell formation, we will focus on a pleuripotent stem
cell that differentiates into a Hemocytoblast.
 The “pluripotent hemopoietic stem
cell” or “hemocytoblast” is the
precursor of all blood cells.
Found in bone marrow.
Undergoes mitotic divisions
daughter cells differentiate
This is the source of all new blood
 The “colony-forming unit, myeloid
stem cell line”
 The “colony forming unit, lymphoid
stem cell line”
Myeloid stem cell
 Hemocytoblasts can differentiate into any blood cell
type. Therefore, they are not pleuripotent anymore, but they
are still multipotent (they are “determined”, but not
completely differentiated). A hemocytoblast will
continue to differentiate into one of two cell types:
 Lymphoid line generates B and T cells
 Myeloid line generates red and all other blood cells.
Scientists doing stem cell research have found a way to turn a
multipotent cell back into a pleuripotent cell by just Inserting four
genes into a multipotent cell!
 To make a good RBC, you need to start with good
ingredients: a good hemocytoblast, proper nucleotides, folic
acid, vitamin B12, and other vitamins.You also need growth
inducers, differentiation markers (signals), amino acids
(Adenine, Thymine, cytosine, guanine), heme (a pyrrole ring
and globin proteins), and iron.
The Recipe for Normal
 Healthy stem cells
 Growth inducers (interleukins)
 Differentiation inducers
 Cell Division (Mitosis)
 DNA replication- vitamin B12 and folic
acid coenzymes
 building blocks of DNA
 (Adenine, Thymine, Cytosine, Guanine)
 Hemoglobin Synthesis
 amino acids, heme and iron
 Newly formed red blood cells have to get from the bone marrow into a blood
vessel. To do this, they squeeze through the endothelial cells of the vessel, but
their nucleus cannot fit, so it gets pinched off. The new RBC in the bloodstream
has a little bit of endoplasmic reticulum and bits of DNA deposits left over from
where the nucleus was pinched off, so a brand new (immature) RBC in the
bloodstream is called a reticulocyte. Thus, RBC’s are in an immature state
when they are released into the bloodstream. It takes about 1-2 days for these
endoplasmic bits to dissolve. Until then, you can see the difference between a
reticulocyte and a mature RBC under the microscope when looking at a blood
smear. Reticulocytes are immature red blood cells. Only about 1% of the RBC’s
should be reticulocytes. If there are more, it indicates a problem.
Pluripotent stem cell
Myeloid Stem Cell
Could become an RBC or several types of WBC
Destined to become an RBC; “more” determined but still
not differentiated
Various stages. Actively synthesize Hb
Just lost its nucleus. Enters the circulation – should be no
more than 1% among all RBCs.
Mature RBC--Differentiated. (After a reticulocyte
has been in the blood stream for 1-2 days)
is a functional advantage of the fact that the RBC lacks mitochondria?
 As long as a RBC is flexible, it can weave around the web of reticular fibers in
the liver and spleen without getting stuck. Those that get stuck are phagocytized
by macrophages. RBC’s that are old or hemoglobin abnormalities (sickle cells)
tend to be less flexible, and are caught in reticular fibers and destroyed. This can
also happen to reticulocytes.
 This process takes 7 days: hemocytoblast  myeloid stem cell 
reticulocyte  RBC
 Up until the reticulocyte is released, it retains its shredded endoplasmic
reticulum, trying to undergo protein synthesis to make hemoglobin as much as
Red Blood Cell physical
properties and components
 Most abundant blood cells – ¼ of
body cells
 4.5 - 5.5 x 10 6 cells / mm3
 Why a biconcave disc?
 Provides a large surface area for O2
 Enables them to bend and flex when
entering small capillaries
 simply membranous bags of
hemoglobin, a protein found in
extreme abundance in RBCs, which
binds and transports O2 and CO2
Rate of Production
Bone Marrow
Rate of
 Erythropoiesis is stimulated by a hormone
called EPO, which is secreted by the kidney.
 In conditions where there are not enough RBC’s in the
body (e.g. Erythroblastosis Fetalis), oxygen levels will
decrease. The kidneys will sense that, and produce EPO,
which stimulates stem cells to divide faster, and hastens
the release of immature RBCs into the bloodstream, so
we will see more reticulocytes in a blood smear.
 When the RBC is fully mature, it lacks organelles. This is
good, because it can transport more O2 if it does not
contain any mitochondria, which consume oxygen.
However, there is a disadvantage, to not having a nucleus
and other organelles: a RBC can’t repair any damage or
express new proteins. That’s why they only live 120 days;
they accumulate damage, lose their flexibility, and get
destroyed. A true RBC count should be at a steady state,
new ones replace dying ones.
I want my
 A Hemoglobin molecule consists of three parts
 Globin chains (proteins from gene expression)
 Heme Group
 Pyrrole ring Iron
Heme Group
 Large protein consisting
of 4 polypeptides
 2  chains and 2 β chains
 Each chain contains a single
molecule of heme, an ironcontaining pigment
 The iron ion in heme is able to reversibly
bind an oxygen molecule thanks to the
surrounding globin chains.
 Meaning, O2 can bind to Hb at the lungs and
then be released at the tissues
Note the 2  chains and 2 β
chains. Notice how each has
an associated heme molecule
with an iron atom.
•Based on the above, how
many molecules of O2 can
each Hb protein bind?
 To make the globin chains, we need genes. If there is a defect in the gene, the
globin chains are defective, as in the case of sickle cell disease. Since it is the
iron that binds the oxygen, why do we need globin at all? Because iron binds to
oxygen so strongly, it will never let go unless hemoglobin is there to move its
structure to block the magnetism of the iron. We need for iron to bind strongly
to the oxygen in the lungs. When there is no oxygen on a hemoglobin molecule,
the globin chains move a little, exposing the iron so it can grab some oxygen
while in the lungs. Once the iron is bound to oxygen, the globin chains move a
little, decreasing the hold of iron onto the oxygen, so that the first oxygendepleted cell that it comes close to can pull the oxygen molecule off of the
hemoglobin complex. This is considered reversible binding of oxygen;
hemoglobin has an affinity for oxygen in lungs, and low affinity to oxygen in the
 There are different types of globin chains. In an adult, there are 2 alpha globin chains and
2 beta chains. Therefore, adult hemoglobin is called A2B2. Since each globin chain
is a protein, and there are four proteins bound to each other, hemoglobin has quaternary
structure. An embryo has embryonic hemoglobin, called A2E2. An embryo does
not have working blood vessels yet, since oxygen is coming in from the placenta.
Therefore, an embryo needs Hgb with a higher affinity for oxygen than mom’s A2B2, to
rip the oxygen off mom’s hemoglobin. When the embryo develops into a fetus, its blood
vessels get bigger, have closer proximity to mom’s blood vessels, needs a little less
affinity than embryonic hemoglobin, but the fetus still needs to have hemoglobin that has
a higher affinity for oxygen than A2B2, so fetal hemoglobin is A2G2. Around the
time of birth, the baby’s hemoglobin becomes A2B2. Once a baby is breathing on its
own, it needs hemoglobin with lower affinity. Therefore, the order of affinity for oxygen
of the different types of hemoglobin is HgbE (A2E2), HgbF (A2G2), then HgbA (A2B2).
Globin Chains
 Why not just use iron/heme group?
 Determine Hb’s affinity for oxygen
 Are expression products of different genes (chromosomes 11,
 Different genes are expressed throughout life and have
different affinities for oxygen
 Embryonic Hb (HbE) 22 (before 3 months gestation)
 Fetal (HbF) 22
(replaced within 6 months of birth)
 Adult (HbA) 22
= heme group (+ iron)
= alpha chain
= Beta chain
 Within each globin chain is a heme group. A heme group
consists of a pyrrole ring, with an iron atom in the middle.
Since there are four globin chains per hemoglobin molecule,
each Hgb has 4 irons.
 Hemoglobin is made in the mitochondria of the
erythrocyte while it is developing (in the proerythroblast
stage). Once iron is added to the pyrrole ring, the entire
structure is called heme. When you add the four globin
chains to heme, it is now called hemoglobin. When a
macrophage phagocytizes a RBC, the hemoglobin is
taken apart into its components. The iron and globin are
recycled, but the pyrrole group is cannot be reused, so it
needs to be eliminated from the body as a waste product.
The making of a pyrrole ring in
proerythroblast mitochondria
Alpha and Beta Globin polypeptide chains are synthesized
at the ribosome in the cytoplasm.
Completed porphyrin rings are sent to meet them in the
cytoplasm, where they all bind to form Hb.
 We get iron from our diet. It is absorbed from the intestine and released into
the plasma, where it binds to a plasma protein called apotransferrin (when
it is not bound to iron) or transferrin (when it is bound to iron).
Since we have said that the plasma protein has bound to the iron, we will now
call it transferrin. The transferrin protein takes the iron to cells in the body that
need iron, or the iron is stored intracellularly in two different forms.
 Ferritin is a protein within a cell that has bound onto the iron. This same protein, when
unbound, is called apoferritin.
 Hemosiderin is a complex in cells that binds to iron and does not release it for use very easily;
it is very insoluble. Macrophages that phagocytize RBC’s tend to accumulate hemosiderin
deposits. Too much hemosiderin in a cell or in tissues is toxic.
 Obtained in the diet
 Released into plasma
 Binds to protein called “apotransferrin”
 Travels in circulation as transferrin
 Delivered to cells needing iron or stored
intracellularly in two different forms
 Apoferritin- to form iron- bound ferritin
 Hemosiderin-extremely insoluble; toxic to cells;
iron over-load
 Ferrous (reduced; +2) form binds indirectly to
 Ferric (oxidized; +3) form cannot bind oxygen
 Hb with iron in ferric form is called
 Ferrous (reduced +2) form binds indirectly to oxygen.
We need it in this state.
 Ferric (oxidized +3) form cannot bind to oxygen. Hgb
with iron in ferric form is called methemoglobin.
 We have proteins to convert iron from its ferric to the ferrous
state. There are some household products and pesticides that
change ferrous to ferric, and our body may not enough available
energy to convert it back to the ferrous form we can use.
 EPO (erythropoietin) is a hormone; 90% of EPO is
made in the kidney, 10% is made in the liver. It
stimulates all the stem cells of blood, many of which
develop into RBCs. The RBCs are ready to exit the bone
marrow and enter the circulation in 5 days, plus another
2 days of maturation within the circulatory system. If
you lose kidney function, you can become
anemic. EPO is released by the kidney in response to
low oxygen levels in the tissues (hypoxia).
Steady state RBC count-Erythropoietin
 What is it? A hormone
 What is its source? 90% from kidney, 10%
from liver
 Conditions for its secretion? Kidney senses
hypoxemia (low oxygen; is most essential
regulatory of RBC production)
 Erythropoietin is always present in the
plasma we would be anemic without it!
 What are its actions?
Promotes release of reticulocytes
Stimulates stem cell mitosis
Increase in red cell number in 5 days
Synthetic EPO /Recombinant Human EPO—
”Ecrit” “Eprex” “Dynepo”
 Chemotherapy for cancer patients targets rapidly dividing cells, especially the hair
(causes hair loss), stomach lining (causes nausea), and the bone marrow (causing low
RBC count, and fatigue). They are given artificial EPO to offset the anemia. Athletes
might take EPO (illegally) for “blood doping”. It causes an increase in RBC production,
leads to more O2, more ATP, more energy, but it thickens blood, can cause heart attack.
Sports authorities have been using a drug test on athletes who use a form of EPO made
from bacteria; the bacterial particles are detectable on blood tests. Now, these
unscrupulous athletes are getting clever: someone has manufactured human EPO that
cannot be detected in these drug tests. This human EPO is approved for medicinal use in
Europe, and it is in America on the Black Market. So now, sports authorities do a RBC
count. If the RBCs are present in excess of set limit before the race starts, they are
disqualified. Some of these athletes get away with it by training with human EPO and
donating blood before the race.
 If you want to climb a high mountain, you can’t just
climb to the top in one day. There is less oxygen pressure
at high altitudes, so RBCs can’t bind oxygen as well.
What you do is go to a base camp, part way up the
mountain, and stay there for 2 weeks, so the kidney can
release EPO to stimulate RBC production. Then you go
up the mountain to the next base camp for 2 weeks.
Then you can go to the top, when the new cells can bind
to oxygen better.
 Lifespan approx. 120 days
 RBCs are subjected to incredible
mechanical stress.
 Narrow capillaries
 Limited ATP stores for replacement
of worn parts
 Why are they unable to synthesize replacements
for damaged parts?
 Membrane fragility
 Macrophages in liver and spleen
remove old RBCs
 Contents destroyed or recycled
Above, we have a macrophage
phagocytizing multiple RBCs
How many RBCs did it engulf?
Three different cells participate in
destruction of RBCs
 Macrophage
 Hepatocyte
When a RBC is old, it gets trapped in the reticular fibers of the spleen or liver, where a macrophage
detects it and engulfs it. Within the macrophage, the globin chains, porphyrrin ring, and iron are detached
from each other and liberated. What happens to each of these segments?
The Iron is released into plasma, apoferrin binds to it (so now the apoferrin is called transferring), it is
taken into cells that can use or store it. The iron is stored as ferritin or Hemosiderin.
The globin chains (proteins) are hydrolyzed into amino acids (the building blocks of proteins), which
are used for synthesis of any other proteins wherever they are needed.
The porphyrin ring is converted in the macrophage to pre-bilirubin (uncongugated). It is released into
blood, and since it is hydrophobic, it needs albumin as a protein carrier. It is taken to the liver, and enters
a hepatocyte (liver cell). Within the hepatocyte, it is conjugated it with glucuronic acid, which makes it
hydrophilic. It is then released into the bile duct, enters the intestines. The bilirubin undergoes further
conversion before it becomes part of the feces, and is responsible for the brown color. If there is a
blockage of the bile duct, it can only exit the body by the urine; it undergoes a different type of
conversion, and the urine will be a deep orange-yellow color. Without the brown color in the feces, they
will look white. White stools indicate obstruction in the bile duct.
Know what parts of a RBC can be recycled: Not all of the heme, but the globin chains, and the iron.
Heme Group Modification and Excretion
Amino acids
glucuronic acid
red cell
Free bilirubin
Stored as ferritin or
Converted to
ens and
and excreted
in feces
1. Uptake
2. Conjugation
3. Excretion (rate limiting)
 There are several different problems that occur
when bilirubin is not excreted: all types lead to
 A newborn baby has to make new RBC’s in the liver, and
is not able to deal with hemolysis. Hepatocytes are not
mature enough to add the glucouronic acid to the
porphyrin ring to conjugate it. Adults who have a gall
bladder obstruction, causes conjugated bilirubin to be
reabsorbed; they need the kidney to deal with it, and the
urine becomes orange.
Hemolytic jaundice: Free bilirubin levels
rise- RBCs are hemolyzed more quickly
than hepatocytes can conjugate
Obstructive Jaundice due to clogged bile
ducts (portal hypertension): rate of
bilirubin formation is normal, but can not
pass from blood to intestines. Most of
the bilirubin is the conjugated type.
Feces can be clay colored
Consider a bruise. The initial color is due
to blood in the interstitial spaces.
As a bruise turns green and yellow,
what must be occurring?
What must be occurring as the yellow
color fades away?
 How conjugated bilirubin is broken down and excreted
 When conjugated bilirubin leaves the bile duct and enters the
intestines, bacteria in the colon convert it to another type of
bilirubin: urobilinogen, which is further metabolized to
stercobilinogen, and finally oxidized to stercobilin. This
stercobilin gives feces its brown color. If there is unconjugated
bilirubin that arrives in the intestine (from an obstruction in the
bile duct), it will be absorbed back into the bloodstream (causing
jaundice), and the rest is filtered by kidney, converted to another
type of bilirubin (urobilin), which causes the urine to turn orange.
 What happens when a bruise goes from purple to green to yellow?
 When a blood vessel breaks, RBC’s leak out, and macrophages
phagocytize them. The macrophage breaks down the hemoglobin in
the blood cells into the heme portion, and the globin portion. The
globin portion (made of proteins) is broken down into amino acids,
which are transported to wherever in the body they are needed to
make new proteins. The heme portion is broken down into iron
(which is sent to storage or transported to where it is needed) and the
pyrrole ring is released into the tissues. There, it is converted to
biliverdin, a green type of bilirubin. The biliverdin is then reduced to
unconjugated bilirubin (yellow).
 The unconjugated bilirubin then travels to the liver through the bloodstream. Because
this bilirubin is not soluble, however, it is transported through the blood bound to serum
albumin. Once it arrives at the liver, it is conjugated with glucuronic acid (to form
conjugated bilirubin) to become more water soluble.
 This conjugated bilirubin is excreted from the liver into the gallbladder and becomes
part of bile. Intestinal bacteria convert the bilirubin into urobilinogen. From here the
urobilinogen can take two pathways. It can either be further converted into
stercobilinogen, which is then oxidized to stercobilin and passed out in the feces, or it
can be reabsorbed by the intestinal cells, transported in the blood to the kidneys, and
passed out in the urine as the oxidized product urobilin. Stercobilin and urobilin are the
products responsible for the color of feces and urine, respectively.
 Know what happens during hemoglobin breakdown: what happens to all its parts, where
does bilirubin go?
 When a person has jaundice, is it high levels of conjugated or unconjugated bilirubin? It
depends on what is causing the jaundice.
 Pre-hepatic jaundice is caused by anything which causes an increased rate of hemolysis
(breakdown of red blood cells). This can be caused by such things as malaria, sickle cell
anemia, Hereditary Spherocytosis, Hemolytic Disease of the Newborn (HDN), glucose
6-phosphate dehydrogenase deficiency (G6DH). Pre-hepatic jaundice will have
increased unconjugated bilirubin in the serum.
 Post-hepatic jaundice, also called obstructive jaundice, is caused by a blockage in
the bile duct (portal hypertension), usually by gallstones. Post-hepatic jaundice will
have increased conjugated bilirubin in the serum.
 Hepatic jaundice is from the inability of hepatocytes to conjugate and excrete bilirubin.
This includes acute hepatitis, hepatotoxicity and alcoholic liver disease. Hepatic jaundice
will have increased unconjugated bilirubin in the serum. In alcoholics, their
conjugated bilirubin can also be high.
 In alcoholics, their unconjugated bilirubin levels are high in the
serum because their hepatocytes are damaged. Their conjugated
bilirubin levels are high because they also lack albumin, ascites
occurs, and the abdominal fluid puts pressure on bile duct, so the
conjugated bilirubin is not removed from body. It gets reabsorbed
by intestines, and the serum levels of conjugated bilirubin are also
increased. Treatment for ascites is to drain it out and take a
diuretic. Gotta get the melon tapped!
 Polycythemia (too many RBC’s)
 Anemia (too few RBC’s)
 Defective
 Iron Deficiency Anemia
 Aplastic Anemia (cells are not generated)
 Megaloblastic Anemia
 Thalassemia
 Hereditary Spherocytosis
 Sickle Cell Anemia
 G6PD Deficiency (Glucose 6 Phosphate Deficiency)
 Blood Loss (Hemorrhagic Anemia)
 Traumatic hemorrhage
 Hemolytic anemia (crosses over into the defective category)
Extrinsic (Acquired)
 Intrinsic (Inherited)
 This condition is too many RBC’s, affects viscosity and
blood flow, and causes an increased work load for the
heart. The heart needs a more forceful
contraction, becomes enlarged over time. It is
something to be concerned about, since there is an
underlying problem that keeps the RBC’s developing too
quickly. The heart can only enlarge safely to a certain
limit; after that, it cannot pump properly, and the person
can get heart failure. Types of polycythemia:
Types of Polycythemia
 Relative Polycythemia
 Absolute Polycythemia
 Primary
 Secondary
Relative Polycythemia
 This is a decrease in the plasma volume (dehydration), but
the RBC count is normal. The hematocrit will be high,
and EPO is normal, since it is the ratio of RBC’s/plasma.
Before thinking it is primary polycythemia, check the heart
rate, urine output, and ask about dehydration. A dehydrated
person will have high hematocrit, low blood pressure, high
heart rate, and low urine output.
Absolute Polycythemia
 This is the overproduction of red blood cells, and may be due
to a primary process in the bone marrow (a
myeloproliferative syndrome), or it may be a reaction to
chronically low oxygen levels.
Primary Polycythemia
(Polycythemia Vera, or idiopathic polycythemia)
 Problem with myeloproliferation: There is a problem with stem cells replicating too
much (can also affect WBCs). If the problem is in the hemocytoblasts, all cells
increased. If just the myelogenous stem cell is a problem , the lymphocytes are not
elevated. The hematocrit is high and EPO levels will be low because the
kidneys are satisfied with enough oxygen, but the stem cells don’t obey the negative
feedback. Kidneys are normal. Treatment is to donate blood frequently, and replace
with IV of isosmotic solution.
Secondary polycythemia
 Problem is a reaction to chronically low oxygen levels, such as during pregnancy,
or living in high altitudes. In this case, hematocrit is high and EPO level
is high. The kidneys are normal. Treatment is just to monitor the situation for
secondary problems: these people need the extra oxygen.
 Problem in the kidneys, causing inappropriate increase in EPO. May be caused by
kidney disorder, tissue hypoxia (from heart or lung disease, including smoking),
hepatic problems, or athletes’ blood doping. Hematocrit is high and EPO is
high. Treatment is low flow oxygen.
RBC pathology--Polycythemia- An elevated
hematocrit --an increase in the number of erythrocytes in the blood.
How does polycythemia affect blood viscosity and
thus affect blood flow?
Three Pathophysiological Categories of Polycythemia
1.Relative Polycythemia (Red Blood Cell Mass Normal,
Plasma Volume Decreased) – re-hydrate patient
2. Polycythemia Vera
3. Secondary Polycythemia
Stem Cell Disorder- genetic
problem or cancer
Tissue hypoxia increasing EPO production
or due to renal or hepatic disease causing
inappropriate increase in EPO production,
respiratory, or cardiac failure, high altitudes,
pregnancy, etc.
Hct and often WBC and platelets
are increased (total blood
Only Hct is increased
EPO level
Decreased or low normal
Normal or increased
Blood let and add istonic saline
Low flow oxygen if necessary
 Anemia is any condition that causes a reduced oxygen
carrying capacity.
 It is not defined as a low Hct, since that is only one type of
Two categories of anemia:
 Defective RBC Production
 Dietary
 Genetic
 Blood Loss (Hemorrhagic Anemia)
 Traumatic
 Hemorrhagic
Defective RBC Production
 Dietary (will get better when diet improves)
 Iron Deficiency Anemia (abnormal Hgb)
 Megaloblastic Anemia (abnormal cell size)
 Genetic
 Aplastic Anemia (cells are not generated)
 Thalassemia (abnormal Hgb)
 Hereditary Spherocytosis (abnormal membrane)
 Sickle Cell Anemia (abnormal Hgb)
 G6PD (Glucose 6 Phosphate) Deficiency (cannot repair own
Blood Loss
(Hemorrhagic Anemia)
 Blood Loss (Hemorrhagic Anemia)
 Traumatic Hemorrhage
 Hemolytic Anemia (genetic defect in Hgb, but considered in this
 Extrinsic (Acquired)
 Intrinsic (Inherited)
A Condition where the blood has an abnormally low oxygencarrying capacity from low Hb concentration
•Why are anemic individuals often short of breath, fatigued, and chilly?
Blood loss
Defective RBC production
(leads to iron def.)
ThalassemiaMHC and MCV
Sickle Celldrugs
Hereditary spherocytosis-loss of
spectrin normal MHC and
increased MCHC
Iron deficiency
and MCV
G6PD deficiency
 MCV is the blood volume of the blood cell (small =microcytic, large =megaloblastic)
 MCH is the amount of Hgb in a RBC (low =hypochromic)
 MCHC is the concentration of Hgb compared to the entire volume of the cell.
If you got 50/100 on an exam, your score is 50%. Let’s say this is normal:
 MCH = 40
 MCV = 80
 Then MCHC is 40/80 = 50%
 If cells are megaloblastic (elevated MCV) and normotonic (MCHC is normal), the cell got
bigger, but the amount of Hgb must have increased as the cell enlarged. This is the case with
megaloblastic anemia. The MCV might be 80 (elevated), the MCV might be 160 (elevated) but
the MCHC is 80/160 = 50% (normal).
 What happens to the MCHC if cells are microcytic (low MCH) and hypochromic (low MCV)?
 Ratio may be 20/60, so MCHC is low (33%). This is seen in thalassemia and iron deficiency
 In some diseases, the person starts out with normochromic and normocytic cells, but with
time, the cell shrinks, but hemoglobin stays the same. This will be a low MCH, normal MCV,
low MCHC.
 Example: 20/80 = 25% MCHC.
 Be mindful of the size, amount of hemoglobin, and how the MCHC will change.
 Either the person does not eat enough iron, or cannot absorb iron
from the intestine, or not enough iron is in storage. This causes the
hemoglobin to not be made correctly. Cells become
microcytic, hypochromic, and low MCH, MCV, MCHC.
Children and pregnant women often get this form of anemia.
NOTE: Iron pills are bright red, look like candy; be careful!
Children can get them and overdose. Iron deficiency anemia often
causes weird cravings for things like dirt and charcoal. They often
like to chew ice all the time. Anemia is there because there is not
enough iron, can’t carry the oxygen. When the cells are too small,
their membranes are not properly flexible, get hung up on
reticulocytes, and destroyed.
Defective- Iron Deficiency
 almost always blood loss (chronic)
 exceptions (children, pregnancy)
 Understand iron metabolism- transport
and storage of iron (apotransferrin to
transferrin; apoferritin to ferritin;
 Cells can be hypochromic and microcytic
and poikilocytotic (too little Hemoglobin)
due to insufficiency
 Decreased, MCH, MCHC and MCV
 Pica
 Caused by lack of dietary vitamin B12 and folic acid
 A coenzyme is a non-protein chemical compound that binds to a protein and
is required for the protein's biological activity. Coenzymes are called "helper
molecules" since they assist in biochemical transformations. They help an
enzyme to be more efficient. Coenzymes are not proteins, they don’t have
amino acids to provide a binding site, unlike an enzyme (which is a catalyst).
Many coenzymes are vitamins, or made from vitamins. The coenzyme binds
to a different area on the enzyme and causes the enzyme to shift so
that its substrate binding site opens up to allow the substrate to
bind. The enzyme’s amino acids have to be in correct order to allow the proper
binding site for its substrate. The coenzyme does not change.
 deficiency in dietary Folic acid or Vitamin B12
 Coenzymes in synthesis of thymidine; DNA synthesis is halted and therefore
mitosis rates are low
 RNA production is elevated, Elevated rates of protein synthesis
 Cells become megaloblastic, irregularly shaped (poikilocytotic) and have
fragile membranes so they are removed sooner (hemolytic)
 Increased MCV, increased MCH and normal MCHC (increased Hb synthesis)
Vitamin B12 and folic acid
are coenzymes
 They are important for synthesis of thymine (a DNA nucleotide).
Lack of thymine still allows DNA replication, but the cell cannot
divide, so it gets bigger. Since the cell can use its RNA, the focus is
on protein synthesis. Megaloblastic cells get larger, can’t divide,
but protein synthesis continues, so there is an increase in Hgb in
the cell. MCH and MCV go up, but proportionally to each
other. Can get 50/100 and 100/200. Stem cells stay locked in the
growth phase.
This is the missing
fragment of the enzyme.
When this is vacant, the
apoenzyme doesn’t have
the proper conformation
to function.
This is the coenzyme.
Our vitamins are
coenzymes, linking to
particular apoenzymes.
This is the
enzyme’s active
site, the working
end of any
Product C
Folic acid
 Folic acid is actually another B vitamin (B9). It is found in
vegetables (especially green leafy ones), fortified grains, and
fruits. The liver has several months’ storage for folic
acid. People who are often deficient in folic acid are children
and pregnant women, people with poor nutrition,
alcoholism, or sprue (iliac disease, loss of microvilli in small
intestine, don’t absorb as much).
Vitamin B12
 Vitamin B12 can only be synthesized by bacteria and is found primarily in meat, eggs and
dairy products. Because strict vegetarians (vegans) don’t eat these products, they are
often deficient in vitamin B12, unless they take it in pill form. Vitamin B12 cannot be
absorbed from the intestines to the bloodstream without intrinsic factor, which is
secreted by the parietal cells in the stomach. People who have had a gastrectomy also
lose their parietal and chief cells. Remember, parietal cells release intrinsic factor and
HCL (P  I + HCL … don’t get into a “pickle” on a test). Chief cells in the stomach
make pepsinogin, and HCl converts that to pepsin (digestive enzyme). Intrinsic factor
is needed to allow the small intestine can absorb vitamin B12. People who lack
of intrinsic factor from gastric surgery will need weekly vitamin B12 shots for life. They
can’t take it orally because it cannot be absorbed without the intrinsic factor. A person
who has megaloblastic anemia from a lack of intrinsic factor is said to have a particular
type of megaloblastic anemia, called pernicious anemia. The liver has several
years’ storage of vitamin B12 (3-5 years).
Megaloblastic Anemias
• Folic acid
–Leafy green veggies
–Greater demand during pregnancy for neural tube
–Stored supply (liver-6-9 months)
–Poor nutrition, alcoholism, sprue, and anti-cancer
drugs interfere
 Vitamin B12
 Meat, dairy, eggs
 Stomach mucosa; parietal cells produce intrinsic factor, a glycoprotein
which is necessary for Vitamin B12 absorption. Join in stomach, then Vit
B12 released and absorbed in the ileum.
 Seen with poor nutrition and strict vegetarians/ gastritis or gastrectomy,
gastric atrophy, when lack IF
 Stored supply (liver 3-5 years)
Primary aplastic anemia is idiopathic (unknown cause). Stem cells are not replicating
enough. Need stem cell transplant.
Secondary aplastic anemia can be caused by several things.
 Drugs like antibiotics (chloramphenicol) might cause loss of stem cell production
 Chemicals (pesticides with benzenes)
 Radiation
 A virus
 Malignancy
 Immune suppression
 Decreased EPO from any of the following: Problem with kidney. Rena disease, AIDS,
chronic infections, hypometabolic state with protein deprivation, or hypopituitarism.
Defective- Aplastic
• Primary
 idiopathic
• Secondary
 Drugs - chemotherapy, antibiotics,
 Chemicals - benzene
 Radiation
 Immune suppression of stem cell
 Malignancy
 Hypoproliferative from reduced
Renal Disease, AIDS, chronic infections,
Hypometabolic state--protein deprivation,
hypothyroidism, hypopituitarism
Compare the 2 slides of red bone marrow.
Blue dots indicates developing blood cells.
Left-hand slide is during aplastic anemia;
right-hand slide is almost back to normal
 Alpha Thalassemia
 Beta Thalassemia
 Major Beta Thalassemia
 Minor Beta Thalassemia
Alpha Thalassemia
 Alpha Thalassemia is a mutation in one or more of the gene that makes the alpha
globin chains of hemoglobin.You need two alpha globin chains in each hemoglobin
molecule. If there are not enough, the Hgb molecule substitutes another beta globin
chain, so the hemoglobin is now A1B3 or just A0B4, both of which will precipitate out of
solution, interfering with DNA replication, gene expression, and development. Cells
from alpha thalassemia are microcytic, hypochromic. Low MCV low MCH, but not
proportionally. There are three genes that code for alpha globin, so alpha thalassemia
is not common. You get two of these genes from one parent, and two from the other
parent. If you have a mutation in one gene, there are three other genes that
can make the alpha globin, so there are no problems. But if there are
mutations in two of the genes, might have mild episodes of anemia, never
diagnosed as thalassemia. If you have 3 genes damaged, will have chronic
problem. All 4 genes damaged, will die in utero.
Beta Thalassemia
 Beta Thalassemia has only two genes that code for beta globin.You get one gene from
one parent, one from the other parent. A mutation in just one gene can be a problem, so
beta thalassemia is more common than alpha thalassemia. Beta thalassemia interferes
with cell function. Cells are microcytic, hypochromic, and MCV, MCH, and
MCHC are all low. Because these defective cells are phagocytized in the liver and
spleen, person gets hepatosplenomegaly. Because these cells are removed from
circulation, EPO levels are high, more RBC’s are made, and this causes expansion of
intermedulary cavity (where Erythropoiesis is going on), and this causes skeletal
abnormalities; also get iron overload and cellular toxicity. In severe cases,
there will be reversal to fetal hemoglobin: the gene for gamma globulin chains is
turned on again, and the fetal hemoglobin will take the place of the missing alpha chains.
Fetal hemoglobin has less affinity for oxygen, but it’s better than nothing.
 Thalassemia Major (Cooley’s anemia): both genes are mutated (homozygous)
 Thalassemia Minor: one gene is mutated (heterozygous).
What are the Thalassemias?
 A group of diseases characterized by
defects in synthesis of one or more
globin chains (-, -thalassemia)
Some severe, others mild
Unaffected chain is in excess and
accumulates in erythropoietic cell
and causes impaired DNA synthesis
Hypochromic, microcytic
Organ failure
Thalassemia- 2
 Thalassa (Greek) = Sea
 -Thal or Thal. major
(Cooley’s anemia)
 Shortened RBC lifespan, early
removal (hemolysis)
Expansion of intramedullary spaces
Skeletal abnormalities
Increased iron absorption, iron
overload and its consequences
HbF can persist
 HS is the most common inherited blood membrane disorder.
Initially, all three values of MCV, MCH, and MCHC are normal.
People with HS lack a certain protein, so the membrane
becomes smaller, all inside becomes smaller, and since
membrane is also an abnormal shape, the cells are phagocytized.
MCV decreases, MCH stays the same, MCHC decreases. If
the room collapses with the same 100 people in it, everything
inside is more concentrated. Know just the end result.
Hereditary spherocytosis
• Spherocytosis (membrane)-microcytic
(MCV ), normochromic, and spherical
(poikilocytic). Easily ruptured. MCHC is
• Most common inherited blood membrane
• Autosomal dominant
• Gradual loss of membrane, so MCHC increases Photo credit:
• Treat with splenectomy
 Sickle Cell Anemia is from a gene mutation that causes a defect in the beta
globin chain, not the same mutation as thalassemia. Glutamic acid (polar,
hydrophilic amino acid) is replaced by Valine (nonpolar amino
acid) in position 6. At first, all three values are normal for MCV, MCH,
MCHC. There are no problems as long as the RBC does not sickle. It sickles
from being near hypoxic tissue; causes the beta globin chains line up
in long rods (change in shape). When the cells are in this sickle shape, it
blocks blood vessels, impedes blood flow, generates even more hypoxia, and
more sickling. Things that cause tissue hypoxia include being at high altitudes
(airplane or mountain climbing), scuba diving, sleeping (breathing is more
shallow while sleeping), respiratory or other illness, overexertion. These
conditions lead to a sickle crisis, which is very painful. The cells are caught in
reticular fibers and removed, resulting in a reduced RBC count, and anemia.
Sickle cell trait (heterozygous) vs. Disease (homozygous)
The defective gene is on chromosome 11; you get one chromosome 11 from mom and one from dad.
If both parents are heterozygous and you inherit two normal chromosomes (25% chance), both beta
globin chains are normal, you do not have sickle cell disease or sickle cell trait, and you can make A2B2.
However, if you live in Africa, you might die from malaria. That’s why there are not a lot of people in
Africa that have both normal chromosomes.
Sickle Cell Disease (HgbSS) is when you inherit both abnormal chromosomes (25% chance of this
happening from two heterozygous parents). This form is deadly; they tend to die from anemia.
Sickle Cell Trait (HgbSA) is when you inherit one normal chromosome and one abnormal (50%
chance), you can make a mixture of hemoglobin: some will be A2B2 (normal) and some will have normal
alpha chains but the beta chain is affected. This is Sickle Cell Trait, and is not as severe as Sickle Cell
Disease. The heterozygous form is often seen in Africans, those from a country that has a lot of malaria.
Those who have one bad copy can survive malaria. Those who have two good copies die of malaria. Those
with two bad copies die of anemia.
Sickle Cell
 Gene defect; defect in code for  chain leads to HbS
 Nucleotide mutation leads to amino acid substitution
 Valine (nonpolar) is substituted in place of glutamic
acid (polar) in position #6
 When peptide chain folds, it doesn’t take on the proper
shape (conformation)!
β chains link together and become stiff rods under lowO2 conditions.
RBCs to become sickle-shaped
clog small blood vessels.
Sickle cell (hemoglobin) HbS; normochromic,
normocytic poikilocytic, during episode
Easily ruptured- hemolysis
Review of Mendelian Genetics
 For any gene, carry two copies (alleles), one from each of our parents.
2 copies of
Chromosomes #11
Gene for beta chain
 We express each of these genes in a codominant fashion, that is, all the Hb in each
erythrocyte is a mix of the products (beta chains) of our two alleles.
 “HbB” is the allele for the normal “adult” beta chain; “HbS” is the allele for the “sickle”
beta chain.
 If our genotype is HbB/HbB, our maturing erythrocytes will fill with?
HbA (adult hemoglobin- with alpha and beta chains)
 If our genotype is HbB/HbS, our maturing erythrocytes will fill with?
HbA AND HbS (a mixture of normal adult hemoglobin and the “sickle
 If our genotype is HbS/HbS, our maturing erythrocytes will fill with?
HbS (alpha and “sickle” beta chain)
How do you tell if a person has the trait
or the disease?
 Run their hemoglobin on electrophoresis gel (Western Blot technique). Normal
hemoglobin will travel all the way to the end of the plate. Hemoglobin with one
mutation will travel half way down the plate. Hemoglobin with two mutations
will travel only part way down the plate. Therefore, heterozygous plates will
show two bands, (one that traveled a little, and one that traveled halfway).
 There is no advantage to having Sickle Cell Disease, but there is one advantage
for having Sickle Cell Trait: malaria resistance. Those with Sickle Cell Disease
can take a drug (hydroxyuria) to switch expression of genes to make HbF.
“SC Trait” vs. “SC Disease”
 Heterozygous individuals make some
normal Hb
 Milder disease only presenting with
 Not life threatening; 9% of African
 Evolutionary advantage: malaria
 Homozygous individuals only make
defective Hb
 Leads to “crisis”—low oxygen during
sleep, cold, infection, acidosis, etc.
 Life threatening
 Hydroxyurea to convert over to HbF
Malaria Resistance
 The good thing about having Sickle Cell Trait (the heterozygous form of Sickle Cell
Anemia)is having malaria resistance. The bad thing is dealing with frequent hypoxic
 Malaria (“bad air”) is a disease caused by plasmodium, a protozoan that is transmitted by
mosquitoes. Mosquitoes only live on nectar, except females when they are pregnant.
When a mosquito bites one infected person, it takes up the plasmodium, and spreads it to
the next person it bites. The organism travels to liver and invades RBCs, where it is
hidden from the immune system. It can replicate in there and the immune system cannot
detect it. However, its metabolism within the RBC creates hypoxia there, and cell with
the Sickle Trait will sickle, get hung up on reticular fibers, and be phagocytized, killing
the parasite. Therefore, a person with Sickle Cell Trait has a higher rate of surviving
 Malaria (Latin) = bad air, myth, false explanation for disease
 Disease caused by infection with parasite Plasmodium
 Parasite multiplies and undergoes several different stages in its lifecycle.
Moves to liver, then human RBC. Ruptures cells, multiplying and reinfecting
new RBCs. High fevers.
 Evades our immune system defenses
 The vector for transmission: the female anopheles mosquito
What does this have to do with
erythrocytes sickling?
 Parasite’s disadvantage when
erythrocytes are rapidly
removed from circulation
 Erythrocyte destruction means
fewer parasite numbers!
 Easier for individual to fight the
 Advantage to humans with SS
“trait”, not with SS “disease”
 This is the most inherited enzyme defect, x-linked. RBC’s
don’t have organelles, so they are more vulnerable to damage from
oxidants, which cause methemoglobin and denaturation of Hgb.
Oxidative damage can also cause proteins to cross link with each
other, making the RBC membrane less fluid and flexible; they
precipitates out of solution and get phagocytized. These cells also
can’t carry oxygen because iron has to be in the ferrous 2+ form.
Oxidative damage causes ferrous iron to lose an
electron, becoming ferric +3, which cannot transport
 Glutathione is an enzyme that helps remove the oxidative damage. Glutathione
will donate an electron to reduce ferric iron (+3) to ferrous (+2). The enzyme
is present in other cells as well, serving as an antioxidant. It is the oxidative
damage repair man. To keep it working (it gives electrons), it needs a supply of
electrons.You have to keep it in a reduced state. To do that, it needs glucose 6
phosphate. If you lack that, RBC does not have the enzyme to repair oxidative
damage, gets misshaped. People who have g6DP have to watch what they eat.
Oxidative drugs (like antimalarials) and foods high in oxidants (such as fava
beans) can cause serious health problems. G6PD deficiency is prevalent in the
Middle East, where fava beans are commonly part of the diet; those with the
enzyme deficiency have to be careful not to partake of that food.
G6PD Deficiency
 Blood loss, hemolytic, inherited
 Most common inherited enzyme
Many mutations (genetic variants)
RBCs more vulnerable to oxidants and
causes methemoglobin and
denaturation of Hb
Antimalarial drugs can cause hemolysis
in African populations (10%)
SEVERE deficiency in people of
Mediterranean descent.
Fava beans
 Acute hemorrhage can lead to hypovolemia and shock.
Normocytic, normochromic, normal MCV, MCH, MCHC
are normal
 Chronic hemorrhage (bleeding ulcer from oversecretion of HCL
by parietal cells) can lead to microcytic, hypochromic; low
MCV, MCH, and possibly low MCHC. RBC’s eventually have
to be made smaller and with less hemoglobin because the stomach
ulcer diminishes iron absorption. If iron is not absorbed fast
enough, they get iron deficiency anemia. Considered
hemorrhagic anemia, but can becomes iron deficiency
anemia over time.
RBC’s rupture inside vessels.
 Extrinsic (Acquired): not a problem with RBC,
something like snake venom is causing the problem, or
immune reaction, blood transfusion not matching, or drug
reaction. Normal in all three values, MCH, MCH,
 Intrinsic (inherited): problem is how the RBC is made.
Blood loss-hemorrhagic
 Blood Loss- normocytic,
normochromic (normal MCV,
 Acute, leads to hypovolemia, shock
 Chronic hemorrhage can lead to
microcytic, hypochromic RBC due
to lack of iron absorption (can’t
absorb fast enough—iron
deficiency anemia)
 Plastic blood? Water soluble
paste; no refrigeration
Blood LossHemolytic, acquired
 Acquired/ extrinsic-
normochromic (normal
• Immune responses,
mismatch typing, HDN,
venom, drugs
Image credit: