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Red Blood Cells, Anemia
and Polycythemia
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine
Red Blood Cells (Erythrocytes)
transport of hemoglobin (O2)
in some animals it circulates as free protein
in humans within RBC – loss by filtration 3%
large quantity of carbonic anhydrase (CO2
and H2O)
an excelent acid-base buffer (proteins)
biconcave discs (φ=7,8 μm; V=90-95 μm3)
shape can change remarkably (squeeze through
capillaries, excess of membrane)
M = 5,2x1012
F = 4,7x1012
chemoglobin in RBC < 340 g/L
Ht = 40-45%
chemohlobin in blood = 160-140 g/L
yolk sac (few early weeks)
liver; spleen and lymph nodes(middle
trimester of gestation)
bone marrow
beyond the age of 20 most RBC are
produced in membranous bones (vertebrae,
sternum, ribs and ilia)
growth inducers – proteins which control
growth and reproduction of stem cells
interleukin-3 – promotes growth and
reproduction of virtually all stem cells
differentiation inducers (low oxygen,
infectious diseases)
tissue oxygenation – most essential
regulator (viscosity)
hemorrhage, x-ray therapy, high altitudes,
cardiac failure, lung diseases
erythropoietin (glycoprotein; 34000)
90% is formed in kidneys (unknown, liver)
fibroblast-like interstitial cells surrounding the
renal tissue hypoxia (and some other)  
HIF-1   erythropoietin
quick secretion (min – 24 h), RBC in 5 days
production of proerythroblasts, speeding up
erythropoietic cells are among the most
rapidly growing and reproducing cells
person’s nutritional status
vitamin B12 and folic acid (thymidine)
macrocytes – flimsy membrane and irregular,
large shape – shorten life span (1/2-1/3 normal)
B12 – pernicious anemia (atrophic gastric
mucosa; parietal cells – intrinsic factor)
folic (pteroylglutaminic) acid – widely
spread but destroyed during cooking – sprue
Formation of Hemoglobin
begins in proerythroblasts and continues
even into the reticulocyte stage
succinyl-CoA from Krebs metabolic cycle
alpha, beta, gamma and delta chains
most common – hemoglobin A (2 alpha, 2
beta chains)
each hemoglobin molecule transports 4
molecules of oxygen
sickle cell anemia –the amino acid valine is
substituted for glutamic acid at one point in
each of the two beta chains
15 μm elongated crystals in low oxygen
loosely and reversibly combining with O2
“coordination bond”, molecular oxygen
Iron Metabolism
hemoglobin, myoglobin, cytochromeoksidase, peroxidase and catalase
total iron in the body – 4-5g (65% in
hemoglobin, 4% in myoglobin, 15-30% in
reticuloendothelial system and liver
parenchymal cells)
transferrin molecule binds strongly with
receptors in the cell membrane s of
erythroblasts in bone marrow – endocytosis
inadequate quantities of transferrin – failure
to transport iron to the erythroblasts –
hypochromic anemia
Absorption of Iron
liver secretes moderate amounts of
apotransferrin into the bile – transferrin
(with the iron, pinocytosis into enterocyts,
plasma transferrin)
absorption is slow and limited; total body
iron is regulated mainly by altering the rate
of absorption
Life Span of RBC
average circulating time  120 days
cytoplasmic enzymes:
maintaining pliability of the cell membrane
maintain membrane transport of ions
keep the iron in ferrous, rather than ferric form
prevent oxidation of the RBC proteins
many RBC self-destruct in the spleen (when
squeezing through the red pulp)
hemoglobin is phagocytized by
macrophages (Kupffer cells of the liver) 
iron and bilirubin (from porphyrin portion)
Anemias (deficiency of
microcytic hypochromic anemia – blood
loss anemia (acute and chronic)
aplastic anemia – bone marrow aplasia
(high-dose radiation, chemotherapy, drugs,
toxic chemicals – insecticides or benzene)
megaloblastic anemia (lack of B12
(pernicious) or folic acid)
hemolytic anemia (abnormalities
(hereditary) of RBC)
hereditary spherocytosis (small and spherical
sickle cell anemia (hemoglobin S, crisis)
erythroblastosis fetalis
Effects of Anemia on Circulation
viscosity of blood depends largely on RBC
fall in blood viscosity  decrease in total
resistance (added tissue hypoxia –
vasodilation)  increase in CO (3-4x) 
increased pumping workload on the heart
problems during exercise – acute cardiac
secondary polycythemia – due to hypoxia
(at high altitude, cardiac failure) – 6-7 x
1012 (30%)
polycythemia vera (erythremia) – 7-8 x 1012
(Ht = 60-70%) – genetic aberration in the
hemocytoblastic cells
increased viscosity – CO almost normal
(decreased venous return, but increased
blood volume), ruddy complexion with a
bluish (cyanotic) tint to the skin)
Blood Types; Transfusion;
Tissue and Organ
first attempts were unsuccessful
transfusion reaction and death
blood posses antigenic and immune
at least 30 commonly occurring, and
hundreds of other antigens
most of antigens are week, used to establish
systems: O-A-B and Rh
OAB system is discovered by Austrian
scientist Karl Landsteiner 1900. (three
types, awarded Nobel prize 1930;
simultaneously with Czech serologist Jan
also with Alexander S Wiener identified Rh
factor 1937.
O-A-B Blood Types
antigens A i B (also called agglutinogens –
cause blood cell agglutination) occur on the
surface of the RBC
because of the way of inheritance people
may have neither of them on their cells,
they may have one or they may have both
when neither A or B agglutinogen is present
– blood (person) is blood type O
only agglutinogen A – blood is type A
only agglutinogen B – blood is type B
when both agglutinogens are present –
blood is type AB
antigen H – essential precursor of OAB
blood antigens
located on chromosome 19, posses 3 exons
which are coding enzyme fucosyltransferase
enzyme creates H antigen on RBC
carbohydrate chain: β-D-galactose, β -D-Nacetilglucosamine, β -D-galactose i α-Lfucose (connection with protein or ceramid)
OAB locus is on chromosome 9, has 7
exon 7 is the biggest and contains the
greatest portion of coding sequence
OAB locus has 3 allele types: O, A, B
allele A codes glycosyltransferase which
bindes N-acetylgalactosamine on Dgalactose end of H antigen
allele B codes glycosyltransferase which
bindes α -D-galactose on D-galactose end of
H antigen
allele 0 has deletion in exon 6 – loss of
enzimatic activity – only H antigen is
Relative Frequencies of the Different Blood
AB 3%
there are 6 different allele types among
white population: (A1, A2, B1, O1, O1v i
O2), in Asian population B type is more
antibodies directed at agglutinogens
immediately after birth – not present
they are formed 2-8 month after the birth
maximum titer is reached 8-10 years of age
gamma-globulins (IgM i IgG)
why are they produced?
environmental antigens (bacteria, viruses,
plants, foods)
for anti-A agglutinins – influenza
for anti-B agglutinins – gram-negative
bacteria (E. coli)
“light in the dark” theory – viruses during
replication process incorporate parts of host
Agglutination Process
agglutinins have 2 (IgG) or 10 (IgM)
binding sites for agglutinogens
attaching to two or more RBC – bounding
together (clump of cells) – agglutination
plugging of small blood vessels throughout
the circulation – physical distortion of the
cells or phagocytosis – hemolysis of the
Acute Hemolysis
on rare occasion
hemolysis occurs immediately in circulating
activation of the complement system –
release of proteolytic enzymes (the lytic
complex) – rupture of the cell membranes
(existence of high titer of IgM antibodies –
Blood Typing
blood typing and blood matching
RBC are separated from the plasma and
diluted with saline; mixing with anti-A and
anti-B agglutinins
Rh Blood Types
spontaneous agglutinins almost never
occur (difference)
person must first be massively exposed
six common types of Rh antigens (C, D, E,
c, “d”, e; one of each pair in every person)
most prevalent is type D antigen (Rh +)
about 85 percent of white people are Rh +
in reality two genes: RHCE i RHD
proteins which carry Rh antigens are
transmembranic proteins (ion channel?)
RHD gene codes RhD protein with D
antigen (on chromosome 1p)
RHCE gene codes RhCE protein with C, E,
c, e antigens
there is no d antigen, “d” means lack of D
Rh Immune Response
maximum concentration of anti-Rh
agglutinins develop about 2 to 4 months
after transfusion
delayed, mild transfusion reaction
erythroblastosis fetalis (mother Rh -, father
Rh +, child inherits Rh from father; mother
develops agglutinins for Rh which diffuse
through the placenta into the fetus and
cause red blood cell agglutination)
firstborn usually doesn’t develop, second
born in 3%, third born in 10%
agglutination of the fetus's blood –
hemolysis – release of hemoglobin
newborn baby is usually anemic, liver and
spleen become greatly enlarged, early forms
of RBC are passed from the baby's bone
marrow into the circulatory system,
permanent mental impairment or damage to
motor areas of the brain because of
precipitation of bilirubin in the neuronal
cells – kernicterus
treatment – replacing the neonate's blood
with Rh-negative blood (400 ml during 1,5
RBC are replaced by infant's own at the
time anti-Rh agglutinins that had come
from the mother are destroyed
Prevention of Erythroblastosis
development of Rh immunoglobulin globin,
an anti-D antibody
administered to the expectant mother
starting at 28 to 30 weeks of gestation or
after delivery
Transfusion Reactions
usually agglutination of the RBC from the
donor, rarely agglutination of cells in
recipient (dilution of plasma)
hemolysis (immediate – hemolysins, later –
jaundice (more than 400 milliliters of blood
is hemolyzed in less than a day)
acute kidney failure
release of toxic substances – renal
loss of circulating RBC – circulatory
hemoglobin precipitates and blocks
many of the kidney tubules
patient dies within a week to 12 days
Transplantation of Tissues and
beside RBC antigens each tissue posses
additional set of antigens which are
responsible for immunological reactions
resisting invasion by foreign bacteria or red
Type of Transplant
autograft – tissue or whole organ from one
part of the same animal to another part
isograft – from one identical twin to another
allograft – from one human being to
another or from any animal to another
animal of the same species
xenograft – from a lower animal to a human
being or from an animal of one species to
one of another species
xenografts – immune reactions almost
always occur, causing death of the cells in
the graft within 1 day to 5 weeks after
skin, kidney (5 to 15 years), heart, liver,
glandular tissue, bone marrow, and lung
most important antigens for causing graft
rejection are a complex called the HLA
antigens (6 of these antigens are present on
the tissue cell membranes of each person,
but there are about 150 different HLA
antigens to choose from – more than a
trillion possible combinations; on the white
blood cells, as well as on the tissue cells –
tissue typing)
Prevention of Graft Rejection
suppressing the immune system
T cells are mainly the portion of the
immune system important for killing
grafted cells
glucocorticoid hormones and similar drugs
drugs that have a toxic effect on the lymphoid
system – azathioprine
cyclosporine – specific inhibitory effect on the
formation of helper T cells
infectious disease, incidence of cancer!