BMEN 302:

HUMAN BIOLOGY II

LECTURE 2
THE CIRCULATORY
SYSTEM
 OUTLINE FOR TODAY
1. Overview
2. Major functions
3. Sub-systems
4. Review on blood
5. RBC physiology
a. Oxygen transport
b. Regulation of RBCproduction
c. Disorders of RBCs
6. WBC physiology
a. Mechanism of action of WBCs
7. Platelets
a. Haemostasis
8. Blood Groups
 The Circulatory System
• Deals with the circulation of fluid throughout the
whole body.

• The circulated fluid (blood & lymph) carry vital

substances to cells and carry away waste and
undesirable products away from these cells.

• It is mainly concerned with homeostasis and

providing optimum environment/resources for
proper functioning of cells in the body.
Circulatory vrs Cardiovascular

• The circulatory system encompasses

• The Heart
• Blood Vessels
• Blood
• Lymph and Lymphatic vessels

• The Cardiovascular system is the part of the

circulatory system that deals with blood
transport
The Cardiovascular System

•Major functions are:

1. Transportation:
• Transport O2from lungs to the body cells
CO2from cells to lungs for exhalation
• Transports nutrients from the GI tract to
body cells
• Transports hormones from endocrine
glands to other body cells (thus can be
said to play a role in coordination)
• Transports waste products to especially
lungs & kidneys for elimination
The Cardiovascular System
Major Functions
2. Regulation:
• Circulating blood helps to maintain
homeostasis in all body fluids.
• pH regulation through buffers.
• Regulation of body temperature through
heat absorbing & coolant properties of
water in plasma, variable rate through
skin where excess heat can be loss.
• Blood osmotic pressure also influences
the water content of cells.
The Cardiovascular System
Major Functions
3. Protection:
• Blood clotting protects against excessive
loss of blood after injury.
• White blood cells protect against disease
through its phagocytotic activities.
• Blood also carries other substances like
antibodies that aid in protection against
diseases
The Cardiovascular System

• The CVsystem is a closed circulatory system

• It consists of 5 sub-systems:
1. Pump (Heart/ Cardiac System)
2. Distribution System (Arterial System)
3. Exchange System (Capillary System)
4. Collection & Return System (Venous System)
5. Transport Medium System (Blood)
BLOOD
Review
• Constitutes about 20% of ECF(8% of total bodyweight)
• Characteristics
• Volume: 5-6L (in males); 4-5L (in female)
• Temperature: 38oC
• pH: 7.35 – 7.45
• Density: >density of water
• Viscosity: about 4.5 – 5.5 times that of water

liquid connective tissue composed of formed elements:

erythrocytes, leukocytes, and platelets and a fluid
extracellular matrix called plasma; component of the
cardiovascular system
Figure 18.5 Summary
of Formed Elements
in Blood—Book-
Anatomy &
physiology 7.28
RED BLOOD CELL
PHYSIOLOGY
RBC Physiology

• Packed Cell Volume (PCV): Arrangement to show separation into

different components (volumes) when blood allowed to settle
either slowly or by centrifugation.
• Two distinct layers separated by a thin layer/ buffycoat.
• Hematocrit (Hct) is the Packed Red Blood Cell Volume
• Fraction/% of total blood volume composed of RBCs
• Optimisation of function to transportO2
• No nucleus (increased space)
• Lack of mitochondria (doesn’t use carried O2for ATP
generation)
• Biconcave shape offers greater surface area for its
volume than other shapes like sphere, cube & also
allows for cells to fold over and squeeze through
tiny vessels
• Above provides large surface area for diffusion of
gas molecules
LIFE CYCLE OF RBCs
 ERYTHROCYTE PRODUCTION

•Known as erythropoiesis

•About 2-3 million RBCs produced every second (20ml/day)

•Entire process of getting a matured RBC takes about 5 - 7days

•Usually occurs in the bone marrow in the adult (infants –

spleen & liver)
 Haematocytoblast (stem cell)

Proerythroblast (committed cell)

Erythroblast
Synthesis of haemoglobin begins

Normoblast
Nucleus etc expelled

Reticulocyte
Cell released from bone marrow into blood

Erythrocyte
  Increase in number of cells
 synthesis of haemoglobin
 loss of nucleus, mitochondria
 reduction in cell size
 Regulation of RBC Production
• The total mass of RBCs in the circulatory systems is
tightly regulated (negative feedback) within a narrow
limit to ensure that:
1. (above lower limit): An adequate number of RBCs
is always available to provide sufficient transport
of O2from the lungs to tissues
2. (below upper limit): The cells do not become too
numerous to impede blood flow

• RBCnumbers (4.2 – 6.1million/μl of blood)

• Averagely: 4.8 – 5.4 million/μl of blood
Regulation of RBC Production

•The main factor is the level of O2in the body

•Any condition that causes the quantity of O2

transported to the tissues to decrease
ordinarily increases rate of RBCproduction
Regulation of RBC Production

•Factors/Conditions include:
•Anaemia (from haemorrhage, low iron, lack
of some amino acids, vitamins)
•High altitude (have low O2air)
•Destruction of major portions of bone
marrow (e.g. from radiation)
•Poor blood flow (due to disease e.g. cardiac
problems)
•Low blood volume
Regulation of RBC Production

• Erythropoietin (EPO) is the hormone that stimulates

RBC production
• Produced in kidneys (90%) & liver (10%)

• During hypoxia, erythropoietin serves as the principal

stimulus for increased RBC production

• In the absence of erythropoietin, hypoxia alone has

basically no stimulating effect on RBC production

• Normal process
Increase in
RBC
Production
 RBC Disorders

• Anaemia is the main disorder

• Refers to state in which there is reduction in red

blood cell mass in the blood or Hb content of the
blood resulting in decrease in O2carrying capacity of
the blood

• Three main causes/categories:

1. Blood loss (bleeding or haemorrhage)
2. Decreased or malfunction in RBC production
• Can be due to deficiency in molecules needed for erythropoiesis
3. Excessive destruction of RBC
 Disorders (RBC)
Sickle cell anaemia
• Genetic disorder – sufferers
carry abnormal haemoglobin

• Normal Hb is Haemoglobin A
(Hb A)
• 2 α chains and 2 β
polypeptide chains
• Abnormal Hb e.g. HbS (sickle
cell anaemia)
• In Hb S,amino acid Valine
replaces Glutamic acid at a
point in each β chain
Disorders (RBC)
Sickle cell anaemia
• When exposed to low O2, Hb S forms long crystals inside the RBCs
• Crystals cause the RBCs to elongate (up to about 15µm in length) and
assume a "sickle" shape
• These make it almost impossible for the cells to pass through many small
capillaries
• The spiked ends of the crystals are also a further hazard:
• possibility of causing a rupture in the cellmembranes
WHITE BLOOD CELL
PHYSIOLOGY
Physiology of WBCs

• WBC not as numerous as RBC

• outnumbered by RBCs (1:700)
• 5,000-10,000 cells/μl of blood

• They generally function in body’s defence

against the effects of pathogens and other
foreign substances

• Achieved through phagocytosis and other

immune responses
 WBC Review
Neutrophils

Granulocytes Eosinophils

Basophils
Leukocytes

Lymphocytes
Agranulocytes
Monocytes
 WBC - Mechanism of Action

• WBCs leave the bloodstream into the interstitial fluid (site

of invasion or injury) through the process called
emigration
• Steps:
1. WBCs roll along the endothelium
2. Stick to endothelium with the help of special adhesion
molecules
3. Squeeze between the endothelial cells into theinterstitial
fluid
 Mechanism of Action

• Neutrophils and macrophages are very active in phagocytosis

• These phagocytes are attracted to microbe invaders &
inflammed tissues through the phenomenon called
chemotaxis
• Stimuli for chemotaxis include:
• Toxins (released by microbes)
• Kinins (specialized products of damaged tissues)
Mechanism of Action

• Neutrophils are the WBCs to respond quickest to bacteria

invasion/damage
• In the process of phagocytosis:
• Neutrophils first engulf invading pathogens
• Release several chemicals to destroy engulfed pathogens
• Chemical include
• Lysozyme – enzyme that can destroy certain bacteria
• Strong oxidants (e.g. O2-, H2O2, OCl-)
Mechanism of Action

• In addition, neutrophils also contain special proteins (called

defensins) which have broad antibiotic effects
• Vesicle containing defensins merge with phagosomes
containing pathogens
• Defensins are thus brought into contact with pathogens
• Defensins act by creating holes in the membranes of the
microbes
• Death of microbe occur as a result of loss of cellular
content
Mechanism of Action

• After neutrophils reach site of infection, monocytes arrive

(in larger numbers and destroy morepathogens)
• Upon arrival they enlarge and differentiate into
macrophages which clean up cellular debris and microbes
through phagocytosis
WBC in disease diagnosis

• White Blood Cell Count and Differential

• A WBC count determines the concentration of white blood cells in
the patient's blood.

• A differential determines the percentage of each of the five types

of mature white blood cells
 WBC in disease diagnosis
• An increase in the number of circulating WBCs usually
indicates inflammation or infection.
• Each type of WBCplays a different role, determining the
percentage of each type in the blood assists indiagnosing
a condition
• E.g. Neutrophils increase in response to bacterial infection
thus a high count may indicate presence of a bacterial
infection
• Eosinophils – parasitic infection &allergic reactions
• Basophils – inflammation
• Lymphocytes – viral infection
• Monocytes – inflammation, viral infection

• Decreased WBC levels usually indicative of anaemia, viral

infection, radiation therapy, medication, etc
PLATELETS
PHYSIOLOGY
 PLATELETS
REVIEW
• Platelets (thrombocytes) are cell fragments that function
primarily to stop blood loss from damaged blood vessels

• Some characteristics:
• Number about 150,000 – 400, 000/ μl of blood
• Have no nucleus
• Disc shaped
• About 2-4μm in diameter
• Short life span (about 5-9 days)
PLATELETS PHYSIOLOGY
Haemostasis
 Haemostasis
• Refers to the process of stopping blood loss.
• Aims to prevent haemorrhage.
• Platelets are key players in hemostasis, the
process by which the body seals a ruptured
blood vessel and prevents further loss of blood.

• Consequences/ Signs of excessive blood loss:

• Tachycardia
• Decreased Blood Pressure
• Decreased Perfusion
• Tachypnea
• Shock
• Loss of consciousness
TERMS DEFINITIONS
• Shock (Circulatory)–
• State of low cardiac output that is insufficient to meet
body’s physiological needs (fainting → death)

• Perfusion –
• Amount of blood supplied to a given tissue in a given time
period

• Exsanguination –
• high risk process of blood loss to a degree sufficient to
cause death
Tolerance of Blood Loss

• Healthy person can tolerate 10–15% loss of the

total blood volume without serious medical
difficulties

• Blood loss 30 – 40% requires fluid resuscitation

• Blood loss >40% - can be very fatal and requires

aggressive resuscitation to prevent death
 Haemostasis

• Haemostasis involves these mechanisms:

1. Vascular constriction/spasm
2. Formation of platelet plug
3. Formation of blood clot (coagulation)
4. Growth of fibrous tissue into blood clot to
permanently close the hole in blood vessel
 Haemostasis
• Platelets play key role
• Contain many substances which aid process:
• Clotting factors
• ADP, ATP
• Ca2+
• Serotonin – vasoconstriction
• Thromboxane A2– stimulates activation of new
platelets, increases platelet aggregation
• When a blood vessel gets damaged:
• Smooth muscles in their walls contract immediately
⇒Reduces blood loss
⇒Other haemostatic mechanisms begin

• The contraction results from various factorsincluding:

• Nervous reflexes (initiated by pain receptors)
• Substances released by activated platelets
• More complex than vascular spasm
• ⇒ Formation of a “plug” in site of leakage

1. Platelets become activated by chemicals secreted from injury

site
2. Platelets begin to adhere to parts of damaged vessel
3. Develop projections which enable them stick to other platelets
4. Release their contents which activate more platelets and
makes them sticky too and cause them to adhere to previous
ones
5. This gathering of platelets is called platelet aggregation.
6. When the collection is large enough it creates a mass called
platelet plug .
• Plug effective in stopping blood loss in small vessels.
• Initially loose but reinforced and become tight by fibrin
threads formed during clotting.
• Blood clot / Thrombus –
• thickened gelatinous mass of blood which results at end of
coagulation

• Clotting involves several substances called clotting factors

• Complex interaction between clotting factors ultimately
results in clot formation

• Positive feedback mechanism

 COAGULATION FACTORS
FACTOR NAME SOURCE

I Fibrinogen Liver

II Prothrombin Liver

III Tissue Factor or Thromboplastin Damaged tissues, activated platelets

IV Calcium Diet, bones, platelets

V Proaccelerin (Labile Factor) Liver, platelets

VII Proconvertin (Stable factor) Liver

VIII Antihaemophilic factor A Platelets, endothelial cells

IX Antihaemophilic factor B, Christmas factor Liver

X Stuart-Prower factor Liver

XI Plasma thromboplastin antecedent Liver

XII Hageman factor Liver

XIII Fibrin stabilising factor Liver, platelets

• Clotting can be divided into three stages
• Stage 1:
• Several reactions that results in the formationof
prothrombinase (prothrombin activator).
• Two distinct pathways (intrinsic & extrinsic) leadto
prothrombinase formation
• Once prothrombinase is formed, the steps in the next
2 stages are same for both pathways. These 2 stages
are termed the common pathway
• Stage 2:
• Prothrombinase converts prothrombin (plasma protein
formed by the liver) into the enzyme thrombin in the
presence of Ca2+.

• Stage 3:
• Thrombin converts soluble fibrinogen (another plasma
protein formed by the liver) into insoluble fibrin. Fibrin forms
the threads of the clot.
• Thrombin also activates factor XIII (fibrin stabilizing factor)
which strengthens and stabilizes the fibrin threads into a
sturdy clot
Blood Clots
SUMMARY OF HAEMOSTASIS
Blood Clotting Disorders
Excessive or Abnormal Clotting
• Vitamin K deficiency
• Cofactor – required for the proper functioning of processof
coagulation
• Haemophilia
• Thrombocytopenia
• Thrombosis

• Embolus – drifting blood clot

• Can cause embolism, i.e. blockage of a vessel
• Tissue whose blood supply is blocked is starved off O2and vital
nutrients and gets damaged
• This affected damaged tissue area is called aninfarct
• Infarcts in brain – stroke
• Infarcts in heart – myocardial infarction or heartattack
BLOOD GROUPS

• A blood group is a classification of blood based on the

presence or absence of a variety of antigens on the
surface of RBCs

• Antigens (also known as agglutinogens or

isoantigens) are genetically determined

• Antigens usually glycoproteins/ glycolipids

BLOOD GROUPS

• Within a particular blood group, you can have two

or more different blood types
• There are about 30 different human blood groups

• The two major ones are the

1. ABO blood group
2. Rh blood group
 ABO BLOOD GROUP
• Most important blood group especially with regards to blood
transfusion
• Classification based on 2 glycolipid agglutinogens on the surface
of RBCs
• Agglutinogens A and B
• Based on the antigens, there are 4 blood types
• A (has only antigenA)
• B (has only antigen B)
• AB (has both A andB)
• O(has neither)
 ABO BLOOD GROUPS

BLOOD TYPE GENOTYPE

A AA or AO

B BB or BO

AB AB

O OO
 ABO BLOOD GROUPS
• In addition to the agglutinogens on RBCs, blood plasma
usually contains antibodies or agglutinins that react with
the A or B antigens if the two aremixed.

• The two antibodies are

• Anti-A antibody (reacts with antigen A)
• Anti-B antibody (reacts with antigen B)

• An individual does not develop antibodies that reactwith

their own antigens
• Individual have antibodies against antigens lacked by their
RBCs
ANTIGENS & ANTIBODIES OF
ABO BLOOOD TYPES
BLOOD ANTIGEN ON RBC ANTIBODY IN PLASMA
TYPE SURFACE
A A Anti-B

B B Anti-A

AB BOTH A & B Neither

O NONE Both anti-A and anti-B

 Process of Agglutination

• When an antibody in plasma gets mixed up with its

corresponding antigen (e.g. Anti-A mixed with antigenA),
the RBCs agglutinate
• Agglutination occurs as the agglutinins attach themselves to
the RBCs
• Causes the RBCs to clump together
• Clumps can plug small blood vessels
• Subsequently (hrs – days), haemolysis of theRBCs occur,
destroyed by phagocytic WBCs
Agglutination
 Rh Blood Group

• Group so-called because antigen was discovered in the blood

of the Rhesus monkey

• Six common types of Rh antigens – each called an Rh factor

• Antigen D – most prevalent and significant

• People with antigen D – Rh+(Rh/ RhD positive)
• People without antigen D – Rh-(Rh/ RhDnegative)
 Rh Blood Group
• In most populations Rh+individuals greatly dominate
(sometimes almost entirely)

• Anti-Rh antibodies not spontaneously produced in plasma(as

occurs in ABO system)

• An Rh-person must have had contact with Rh+blood before

developing anti-Rh antibodies
• Most common problem with Rh incompatibility
• Also known as erythroblastosis fetalis
• Disease of the foetus and newborn child characterised by
agglutination and phagocytosis of foetus’ RBCs (sometimes
newborn’s as well)
• HDFN occurs when an Rh-mother is pregnant with an Rh+
child
 Mechanism of HDFN
• Normally there is no direct contact between maternal and
foetal blood while a woman is pregnant

• However, if even a small amount of Rh+foetal blood leaks

through the placenta into the bloodstream of the mother,the
mother will start to make anti-Rh antibodies

• Usually, the greatest possibility of foetal blood leakageinto

the maternal circulation occurs during delivery when
trauma is so high
Mechanism of HDFN

• Usually the first Rh+born baby is not affected

• Subsequently if the mother gets pregnant again with
another Rh+baby, her anti-Rh antibodies can cross the
placenta and enter the bloodstream of the foetus

• Haemolysis of the foetal RBCs occurs as a result

 Effect of HDFN on the baby

• Haemolysis leads to jaundice in the baby

• Haemoglobin released after destruction of RBCs which is
converted to bilirubin
• The jaundiced newborn baby is also usually anaemic at birth
• If anaemia is severe, death can occur.
• Also the high bilirubin level can sometimes cause brain damage
when it gets into the brain
 Prevention of HDFN
• An injection of anti-Rh antibodies called anti-Rh gamma globulin
(RhoGAM) can be given to the mother to prevent HDFN

• Rh-mothers receive RhoGAM soon after every delivery, miscarriage or

abortion

• The RhoGAM antibodies bind to and inactivate the foetal Rh antigens, if

present

• The mother’s immune system then does not respond to the antigen by
producing antibodies

• It is given as part of modern routine antenatal care at about 28 – 32

weeks of pregnancy, and within 72 hours after delivery
 Blood Transfusion
• A transfusion simply refers to the transfer of whole blood or
blood components (RBCs only or platelets only) into the
bloodstream

• Due to the possible severe consequences that result when

blood mismatches occur, careful precautions are taken to
ensure that a recipient receives compatible blood

• Certain blood types can not be given to people with

incompatible blood types
 Blood Compatibility Table
Recipient Donor
• AB contain no antibodies so can
receive from all types (Universal
A B AB O
Recipient)
A
(anti-B)
YES YES • O contains no antigens and thus
B can be given to all types
YES YES
(anti-A) (Universal Donor)
AB
YES YES YES YES
(neither)
O
YES
(both)

 Rh- individuals can receive only from Rh- people

 Rh+ people can receive from both Rh- and Rh+
 Rh- people can donate to both Rh- and Rh+
Rh+ people can donate to only Rh+
Image courtesy: Wikipedia