CARDIOVASCULAR PHYSIOLOGY

Blood as a Circulatory Fluid & the

Dynamics of Blood & Lymph Flow
 INTRODUCTION
• The circulatory system supplies inspired O2 as well
as substances absorbed from the gastrointestinal
tract to the tissues, returns CO2 to the lungs and
other products of metabolism to the kidneys,
functions in the regulation of body temperature, and
distributes hormones and other agents that regulate
cell function
• The blood, the carrier of these substances, is
pumped through a closed system of blood vessels by
the heart
• From the left ventricle, blood is pumped through the
arteries and arterioles to the capillaries, where it
equilibrates with the interstitial fluid
• The capillaries drain through venules into the veins
and back to the right atrium
• Some tissue fluids enter another system of closed
vessels, the lymphatics, which drain lymph via the
thoracic duct and the right lymphatic duct into the
venous system
• The circulation is controlled by multiple regulatory
systems that function in general to maintain
adequate capillary blood flow when possible in all
organs, but particularly in the heart and brain
• Blood flows through the circulation primarily because
of the forward motion imparted to it by the pumping
of the heart, although in the case of the systemic
circulation, diastolic recoil of the walls of the arteries,
compression of the veins by skeletal muscles during
exercise, and the negative pressure in the thorax
during inspiration also move the blood forward
• The resistance to flow depends to a minor degree on
the viscosity of the blood but mostly on the diameter
of the vessels, and principally that of the arterioles
• The blood flow to each tissue is regulated by local
chemical and general neural and humoral
mechanisms that dilate or constrict its vessels
 BLOOD AS A CIRCULATORY FLUID
• Blood consists of a protein-rich fluid known as
plasma, in which are suspended cellular elements:
white blood cells, red blood cells, and platelets
• The normal total circulating blood volume is about
8% of the body weight (5600 mL in a 70-kg man)
• About 55% of this volume is plasma
 BONE MARROW
• In the adult, red blood cells, many white blood cells,
and platelets are formed in the bone marrow
• In the fetus, blood cells are also formed in the liver
and spleen, and in adults such extramedullary
hematopoiesis may occur in diseases in which the
bone marrow becomes destroyed or fibrosed
• In children, blood cells
are actively produced in
the marrow cavities of
all the bones. By age 20,
the marrow in the
cavities of the long
bones, except for the
upper humerus and
femur, has become
inactive
• The bone marrow is one of the largest organs in the body,
approaching the size and weight of the liver. It is also one
of the most active
• Normally, 75% of the cells in the marrow belong to the
white blood cell–producing myeloid series and only 25%
are maturing red cells, even though there are over 500
times as many red cells in the circulation as there are white
cells
• This difference in the marrow reflects the fact that the
average life span of white cells is short, whereas that of
red cells is long
• Hematopoietic stem cells (HSCs) are bone marrow
cells that are capable of producing all types of blood
cells
• They differentiate into one or another type of
committed stem cells (progenitor cells)
• These in turn form the various differentiated types of
blood cells
• There are separate pools of progenitor cells for
megakaryocytes, lymphocytes, erythrocytes, eosinophils,
and basophils; neutrophils and monocytes arise from a
common precursor
• The bone marrow stem cells are also the source of
osteoclasts, Kupffer cells, mast cells, dendritic cells, and
Langerhans cells
• The HSCs are few in number but are capable of completely
replacing the bone marrow when injected into a patient
whose own bone marrow has been entirely destroyed
• The HSCs are derived from uncommitted, totipotent
stem cells that can be stimulated to form any cell in
the body
• Adults have a few of these, but they are more readily
obtained from the blastocysts of embryos
 WHITE BLOOD CELLS
• Normally, human blood contains 4,000–11,000 white
blood cells per microliter
• Of these, the granulocytes (polymorphonuclear
leukocytes, PMNs) are the most numerous
• Young granulocytes have horseshoe-shaped nuclei
that become multilobed as the cells grow older
• Most of them contain neutrophilic granules
(neutrophils), but a few contain granules that stain
with acidic dyes (eosinophils), and some have
basophilic granules (basophils)
• The other two cell types found normally in peripheral
blood are lymphocytes, which have large round
nuclei and scanty cytoplasm, and monocytes, which
have abundant agranular cytoplasm and kidney-
shaped nuclei
Cell Cells/μL (average) Approximate Percentage of Total
Normal Range White Cells
Total white blood 9,000 4,000-11,000
cells
Granulocytes
Neutrophils 5,400 3,000-6,000 50-70
Eosinophils 275 150-300 1-4
Basophils 35 0-100 0.4
Lymphocytes 2,750 1,500-4,000 20-40
Monocytes 540 300-600 2-8
Erythrocytes
Females 4.8 x 106
Males 5.4 x 106
Platelets 300,00 200,000-500,000
1. Monocytes
• Tissues monocytes = macrophages (phacocytes and APCs)
– alveolar macrophages, microglia, kupfer cells, osteoclasts
• Free monocytes
2. Basophils
• Granules – Heparin, Histamine
3. Eosinophil
• Granules – cationic peptide, major basic protein (killing parasites)
• Role in type 1 hypersensitivity
4. Neutrophils
• Phagocytosis
• Formation of free radicals
5. Lymphocytes
• B cells – plasma cells – secrete antibodies
• T cells
– T helper cells – help b cells to turn into plasma cells and produce abs
– Cytotoxic cells – induce apoptosis of infected or cancer cells
 PLATELETS
• Platelets are small, granulated bodies that aggregate
at sites of vascular injury
• They lack nuclei and are 2–4 μm in diameter (Figure
31–3). There are about 300,000/μL of circulating
blood, and they normally have a half-life of about 4
days
• The megakaryocytes, giant cells in the bone marrow,
form platelets by pinching off bits of cytoplasm and
extruding them into the circulation
• Between 60% and 75% of the platelets that have
been extruded from the bone marrow are in the
circulating blood, and the remainder are mostly in
the spleen
• Role in clotting
• Splenectomy causes an increase in the platelet count
(thrombocytosis)
 RED BLOOD CELLS
• The red blood cells (erythrocytes) carry hemoglobin
in the circulation
• They are biconcave disks that are manufactured in
the bone marrow. In mammals, they lose their nuclei
before entering the circulation. In humans, they
survive in the circulation for an average of 120 days
• The average normal red blood cell count is 5.4
million/μL in men and 4.8 million/μL in women
• The number of red cells is expressed as the
hematocrit, or the percentage of the blood, by
volume, that is occupied by erythrocytes
• Each human red blood cell is about 7.5 μm in
diameter and 2 μm thick, and each contains
approximately 29 pg of hemoglobin
• There are thus about 3 × 1013 red blood cells and
about 900 g of hemoglobin in the circulating blood of
an adult man
• The feedback control of erythropoiesis is done by
erythropoietin, while IL-1, IL-3, IL-6 (interleukin), and
GM-CSF (granulocyte-macrophage colony-stimulating
factor) are key in development of the relevant
erythroid stem cells
Characteristics of human red cells
Red cell formation and destruction
 Hemoglobin
• The red, oxygen-carrying pigment in the red blood
cells
• Hemoglobin = Heme (iron [Fe 2+] and
protoporphyrin), polypeptides (globin)
• Globular molecule made up of four subunits
• There are two pairs of polypeptides in each
hemoglobin molecule
• In normal adult human hemoglobin (hemoglobin A),
the two polypeptides are called α chains and β chains
• Thus, hemoglobin A is designated α2β2 (2 alpha and
2 beta subunits)
• Not all the hemoglobin in the blood of normal adults
is hemoglobin A. About 2.5% of the hemoglobin is
hemoglobin A2, in which β chains are replaced by δ
chains (α2δ2)
• There are small amounts of hemoglobin A derivatives
closely associated with hemoglobin A that represent
glycated hemoglobins
• One of these, hemoglobin A1c (HbA1c), has a glucose
attached to the terminal valine in each β chain and is
of special interest because it increases in the blood
of patients with poorly controlled diabetes mellitus
and is measured clinically as a marker of the
progression of that disease and/or the effectiveness
of treatment
 Diagrammatic representation of a molecule
of hemoglobin
Four subunits of Hb
• There are two α and
two β polypeptide
chains, each containing
a heme moiety
• These moieties are
represented by the blue
disks
 Reactions of hemoglobin
• O2 binds to the Fe2+ in the heme moiety of
hemoglobin to form oxyhemoglobin
• The affinity of hemoglobin for O2 is affected by pH,
temperature, and the concentration in the red cells
of 2,3-bisphosphoglycerate (2,3-BPG)
• 2,3-BPG and H+ compete with O2 for binding to
deoxygenated hemoglobin, decreasing the affinity of
hemoglobin for O2 by shifting the positions of the
four peptide chains (quaternary structure)
• When blood is exposed to various drugs and other
oxidizing agents in vitro or in vivo, the ferrous iron
(Fe2+) that is normally present in hemoglobin is
converted to ferric iron (Fe3+), forming
methemoglobin
• Methemoglobin is dark-colored, and when it is
present in large quantities in the circulation, it causes
a dusky discoloration of the skin resembling cyanosis
• Some oxidation of hemoglobin to methemoglobin
occurs normally, but an enzyme system in the red
cells, the dihydronicotinamide adenine dinucleotide
(NADH)-methemoglobin reductase system, converts
methemoglobin back to hemoglobin
• Congenital absence of this system is one cause of
hereditary methemoglobinemia
• Carbon monoxide reacts with hemoglobin to form
carbon monoxyhemoglobin (carboxyhemoglobin)
• The affinity of hemoglobin for O2 is much lower than
its affinity for carbon monoxide, which consequently
displaces O2 on hemoglobin, reducing the oxygen-
carrying capacity of blood
 Hemoglobin in the fetus
• The blood of the human fetus normally contains fetal
hemoglobin (hemoglobin F)
• Its structure is similar to that of hemoglobin A except
that the β chains are replaced by γ chains; that is,
hemoglobin F is α2γ2
• Fetal hemoglobin is normally replaced by adult
hemoglobin soon after birth
• In certain individuals, it fails to disappear and persists
throughout life
• In the body, its O2 content at a given PO2 is greater
than that of adult hemoglobin because it binds 2,3-
BPG less avidly
• Hemoglobin F is therefore critical to facilitate
movement of O2 from the maternal to the fetal
circulation, particularly at later stages of gestation
where oxygen demand increases
• In young embryos there are, in addition, ζ and ε
chains, forming Gower 1 hemoglobin (ζ2ε2) and
Gower 2 hemoglobin (α2ε2)
• Switching from one form of hemoglobin to another
during development seems to be regulated largely by
oxygen availability, with relative hypoxia favoring the
production of hemoglobin F both via direct effects on
globin gene expression, as well as upregulated
production of erythropoietin
 Synthesis of hemoglobin
• The average normal hemoglobin content of blood is
16 g/dL in men and 14 g/dL in women, all of it in red
cells
• In the body of a 70-kg man, there are about 900 g of
hemoglobin, and 0.3 g of hemoglobin is destroyed
and 0.3 g synthesized every hour
• The heme portion of the hemoglobin molecule is
synthesized from glycine and succinyl-CoA
 Abnormalities of Hemoglobin production

• There are two major types of inherited disorders of

hemoglobin in humans:
• hemoglobinopathies, in which abnormal globin
polypeptide chains are produced
• thalassemias and related disorders, in which the
chains are normal in structure but produced in
decreased amounts or absent because of defects in
the regulatory portion of the globin genes
 Catabolism of hemoglobin
• When old red blood cells are destroyed by tissue
macrophages, the globin portion of the hemoglobin
molecule is split off, and the heme is converted to
biliverdin
• In humans, most of the biliverdin is converted to
bilirubin and excreted in the bile
• The iron from the heme is reused for hemoglobin
synthesis
• Exposure of the skin to white light converts bilirubin
to lumirubin, which has a shorter half-life than
bilirubin
• Phototherapy (exposure to light) is of value in
treating infants with jaundice due to hemolysis
• Iron is essential for hemoglobin synthesis; if blood is
lost from the body and the iron deficiency is not
corrected, iron deficiency anemia results
 PLASMA
• The fluid portion of the blood, the plasma, is a
remarkable solution containing an immense number
of ions, inorganic molecules, and organic molecules
that are in transit to various parts of the body or aid
in the transport of other substances
• Normal plasma volume is about 5% of body weight,
or roughly 3500 mL in a 70-kg man. Plasma clots on
standing, remaining fluid only if an anticoagulant is
added. If whole blood is allowed to clot and the clot
is removed, the remaining fluid is called serum
• Serum has essentially the same composition as
plasma, except that its fibrinogen and clotting factors
II, V, and VIII have been removed and it has a higher
serotonin content because of the breakdown of
platelets during clotting
 Plasma proteins
• The plasma proteins consist of albumin, globulin,
and fibrinogen fractions
• Most capillary walls are relatively impermeable to
the proteins in plasma, and the proteins therefore
exert an osmotic force of about 25 mm Hg across the
capillary wall that pulls water into the blood
• The plasma proteins are also responsible for 15% of
the buffering capacity of proteins in the blood because
of the weak ionization of their substituent COOH and
NH2 groups
• At the normal plasma pH of 7.40, the proteins are
mostly in the anionic form
• Plasma proteins may have specific functions (eg,
antibodies and the proteins concerned with blood
clotting), whereas others function as nonspecific
carriers for various hormones, other solutes, and drugs
 Origin of plasma proteins
• Circulating antibodies are manufactured by
lymphocytes. Most of the other plasma proteins are
synthesized in the liver
• Data on the turnover of albumin show that synthesis
plays an important role in the maintenance of normal
levels
• In normal adult humans, the plasma albumin level is
3.5–5.0 g/dL, 38–45% of this albumin is intravascular,
and much of the rest of it is in the skin
• Degraded albumin is replaced by hepatic synthesis of
200–400 mg/kg/day
• Albumin synthesis is carefully regulated
• It is decreased during fasting and increased in
conditions such as nephrosis in which there is
excessive albumin loss
 Hypoproteinemia
• Plasma protein levels are maintained during
starvation until body protein stores are markedly
depleted
• However, in prolonged starvation and in
malabsorption syndromes due to intestinal diseases,
plasma protein levels are low (hypoproteinemia)
• They are also low in liver disease, because hepatic
protein synthesis is depressed, and in nephrosis,
because large amounts of albumin are lost in the
urine
• Because of the decrease in the plasma oncotic
pressure, edema tends to develop
• Rarely, there is congenital absence of one or another
plasma protein, e.g. afibrinogenemia, characterized
by defective blood clotting
 LYMPH
• Lymph is tissue fluid that enters the lymphatic vessels
• It drains into the venous blood via the thoracic and
right lymphatic ducts
• In most locations, it contains proteins that have
traversed capillary walls and can then return to the
blood via the lymph e.g. clotting factors
• Nevertheless, its protein content is generally lower
than that of plasma, which contains about 7 g/dL, but
lymph protein content varies with the region from
which the lymph drains
• Water-insoluble fats are absorbed from the intestine
into the lymphatics, and the lymph in the thoracic
duct after a meal is milky because of its high fat
content
• Lymphocytes also enter the circulation principally
through the lymphatics, and there are appreciable
numbers of lymphocytes in thoracic duct lymph
Approximate protein content of lymph in humans
 BLOOD TYPES
• The membranes of human red cells contain a variety
of blood group antigens, which are also called
agglutinogens
• The most important and best known of these are the
A and B antigens, but there are many more
 The ABO system
• The A and B antigens are inherited as mendelian
dominants, and individuals are divided into four
major blood types on this basis
– Type A individuals have the A antigen
– Type B have the B
– Type AB have both
– Type O have neither
• The A and B antigens are complex oligosaccharides
that differ in their terminal sugar
• Antibodies against red cell agglutinogens are called
agglutinins
• Antigens very similar to A and B are common in
intestinal bacteria and possibly in foods to which
newborn individuals are exposed
• Therefore, infants rapidly develop antibodies against
the antigens not present in their own cells
• Thus, type A individuals develop anti-B antibodies, type B
individuals develop anti-A antibodies, type O individuals
develop both, and type AB individuals develop neither
• When the plasma of a type A individual is mixed with
type B red cells, the anti-B antibodies cause the type B
red cells to clump (agglutinate)
• ABO blood typing is performed by mixing an individual’s
red blood cells with antisera containing the various
agglutinins on a slide and seeing whether agglutination
occurs.
Summary of ABO system
 Transfusion reactions
• Dangerous hemolytic transfusion reactions occur
when blood is transfused into an individual with an
incompatible blood type; that is, an individual who
has agglutinins against the red cells in the transfusion
• The plasma in the transfusion is usually so diluted in
the recipient that it rarely causes agglutination even
when the titer of agglutinins against the recipient’s
cells is high
• However, when the recipient’s plasma has agglutinins
against the donor’s red cells, the cells agglutinate
and hemolyze
• Free hemoglobin is liberated into the plasma. The
severity of the resulting transfusion reaction may
vary from an asymptomatic minor rise in the plasma
bilirubin level to severe jaundice and renal tubular
damage leading to anuria and death
• Persons with type AB blood are “universal recipients”
because they have no circulating agglutinins and can
be given blood of any type without developing a
transfusion reaction due to ABO incompatibility
• Type O individuals are “universal donors” because
they lack A and B antigens, and type O blood can be
given to anyone without producing a transfusion
reaction due to ABO incompatibility
• This does not mean, however, that blood should ever
be transfused without being cross-matched except in
the most extreme emergencies, since the possibility
of reactions or sensitization due to incompatibilities
in systems other than ABO systems always exists. In
cross-matching, donor red cells are mixed with
recipient plasma on a slide and checked for
agglutination
• A procedure that has recently become popular is to
withdraw the patient’s own blood in advance of elective
surgery and then infuse this blood back (autologous
transfusion) if a transfusion is needed during the surgery
• With iron treatment, 1000–1500 mL can be withdrawn
over a 3-week period
• Advantages of banking one’s own blood: less risk of
transmission of infectious diseases by heterologous
transfusions, and elimination of the risk of transfusion
reactions
 Other agglutinogens
• In addition to the ABO system of antigens in human
red cells, there are systems such as the Rh, MNSs,
Lutheran, Kell, Kidd, and many others. There are over
500 billion possible known blood group phenotypes,
and because undiscovered antigens undoubtedly
exist, it has been calculated that the number of
phenotypes is actually in the trillions
 The RH group
• Aside from the antigens of the ABO system, those of
the Rh system are of the greatest clinical importance
• The Rh factor, named for the rhesus monkey, is a
system composed primarily of the C, D, and E
antigens, although it actually contains many more
• Unlike the ABO antigens, the system has not been
detected in tissues other than red cells
• D is by far the most antigenic component, and the
term Rh-positive as it is generally used means that
the individual has agglutinogen D
• The Rh-negative individual has no D antigen and
forms the anti-D agglutinin when injected with D-
positive cells
• The Rh typing serum used in routine blood typing is
anti-D serum
• Unlike the antibodies of the ABO system, anti-D
antibodies do not develop without exposure of a D-
negative individual to D-positive red cells by
transfusion or entrance of fetal blood into the
maternal circulation
• However, D-negative individuals who have received a
transfusion of D-positive blood (even years
previously) can have appreciable anti-D titers and
thus may develop transfusion reactions when
transfused again with D-positive blood
 Hemolytic disease of the newborn
• Another complication due to Rh incompatibility
arises when an Rh-negative mother carries an Rh-
positive fetus
• Small amounts of fetal blood leak into the maternal
circulation at the time of delivery, and some mothers
develop significant titers of anti-Rh agglutinins during
the postpartum period
• During the next pregnancy, the mother’s agglutinins
cross the placenta to the fetus (erythroblastosis
fetalis)
• When anti-Rh agglutinins cross the placenta to an
Rh-positive fetus, they can cause hemolysis and
various forms of hemolytic disease of the newborn
• If hemolysis in the fetus is severe, the infant may die
in utero or may develop anemia, severe jaundice,
and edema (hydrops fetalis)
• Kernicterus, a neurologic syndrome in which
unconjugated bilirubin is deposited in the basal
ganglia, may also develop, especially if birth is
complicated by a period of hypoxia
• Bilirubin rarely penetrates the brain in adults, but it
does in infants with erythroblastosis, possibly in part
because the blood-brain barrier is more permeable in
infancy
• However, the main reasons that the concentration of
unconjugated bilirubin is very high in this condition
are that production is increased and the bilirubin-
conjugating system is not yet mature
• About 50% of Rh-negative individuals are sensitized
(develop an anti-Rh titer) by transfusion of Rh-
positive blood
• Because sensitization of Rh-negative mothers by
carrying an Rh-positive fetus generally occurs at
birth, the first child is usually normal
• However, hemolytic disease occurs in about 17% of
the Rh-positive fetuses born to Rh-negative mothers
who have previously been pregnant one or more
times with Rh-positive fetuses
• Fortunately, it is usually possible to prevent
sensitization from occurring the first time by
administering a single dose of anti-Rh antibodies in
the form of Rh immune globulin during the
postpartum period
• Such passive immunization does not harm the
mother and has been demonstrated to prevent
active antibody formation by the mother
• In obstetric clinics, the institution of such treatment
on a routine basis to unsensitized Rh-negative
women who have delivered an Rh-positive baby has
reduced the overall incidence of hemolytic disease
by more than 90%
• In addition, fetal Rh typing with material obtained by
amniocentesis or chorionic villus sampling is now
possible, and treatment with a small dose of Rh
immune serum will prevent sensitization during
pregnancy