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BLOOD

Blood is a connective tissue. It provides one of the means of communication between the cells of
different parts of the body and the external environment, e.g. it carries:
• Oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs for excretion
• Nutrients from the alimentary tract to the tissues and cell wastes to the excretory organs,
principally the kidneys
• Hormones secreted by endocrine glands to their target glands and tissues
• Heat produced in active tissues to other less active tissues
• Protective substances, e.g. antibodies, to areas of infection
• Clotting factors that coagulate blood, minimising its loss from ruptured blood vessels.

Blood makes up about 7% of body weight (about 5.6litres in a 70 kg man). This proportion is less
in women and considerably greater in children, gradually decreasing until the adult level is reached

Composition of blood

Plasma

Blood is composed of a straw-coloured transparent fluid, plasma, in which different types of cells
are suspended.
Plasma constitutes about 55% and cells about 45% of blood volume
The constituents of plasma are water (90 to 92%) and dissolved substances, including:
• Plasma proteins: albumins, globulins (including antibodies), fibrinogen, clotting factors
• Inorganic salts (mineral salts): sodium chloride, sodium bicarbonate, potassium, magnesium,
phosphate, iron, calcium, copper, iodine, cobalt
• Nutrients, principally from digested foods, e.g. monosaccharides (mainly glucose), amino acids,
fatty acids, glycerol and vitamins
• Organic waste materials, e.g. urea, uric acid, creatinine
• Hormones
• Enzymes, e.g. certain clotting factors
• Gases, e.g. oxygen, carbon dioxide, nitrogen.

Plasma proteins
 Plasma proteins, which make up about 7% of plasma, are normally retained within the blood,
because they are too big to escape through the capillary pores into the tissues.
 They are largely responsible for creating the osmotic pressure of blood (normally 25 mmHg or
3.3 kPa), which keeps plasma fluid within the circulation.
 If plasma protein levels fall, because of either reduced production or loss from the blood
vessels, osmotic pressure is also reduced, and fluid moves into the tissues (oedema) and body
cavities.

Albumins.
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 These are formed in the liver. They are the most abundant plasma proteins and their main
function is to maintain a normal plasma osmotic pressure.
 Albumins also act as carrier molecules for lipids and steroid hormones.

Globulins.
Most are formed in the liver and the remainder in lymphoid tissue. Their main functions are:
• as antibodies (immunoglobulins), - They bind to, and neutralise, foreign materials (antigens) such
as micro-organisms
• transportation of some hormones and mineral salts; e.g. thyroglobulin carries the hormone
thyroxine and transferrin carries the mineral iron
• inhibition of some proteolytic enzymes, e.g. 2 macroglobulin inhibits trypsin activity.

Clotting factors.
These are substances essential for coagulation of blood. They include:
I-fibrinogen
II-Prothrombin
III-Tissue factor(thromboplastin)
IV-calcium
V-labile factor(proaccelerin
VII-stable factor, proconvertin
VIII-antihaemophilic globulin(AHG), antihaemophilic factor A
IX-Christmas factor, antihaemophilic factor B, Plasma thromboplastin component (PTC)
X-stuart prower factor
XI-antihaemophilic factor C, plasma thromboplastin antecedent (PTA)
XII-hageman factor
XIII-fibrin stabilizing factor
Vitamin K-essential for synthesis of factors II, VII, IX and X.
 Serum is plasma from whichclotting factors have been removed .

Inorganic salts (mineral salts)

 These are involved in a wide variety of activities, including cell formation, contraction of
muscles, transmission of nerve impulses, formation of secretions and maintenance of the
balance between acids and alkalis.
 In health the blood is slightly alkaline. Alkalinity and acidity are
 Expressed in terms of pH, which is a measure of hydrogen ion concentration, or [H+] .
 The pH of blood is maintained between 7.35 and 7.45 by an ongoing complicated series of
chemical activities, involving buffering systems.

Nutrients
Food is digested in the alimentary tract and the resultant nutrients are absorbed, e.g.
monosaccharides, amino acids, fatty acids, glycerol and vitamins.

Organic waste products

 Urea, creatinine and uric acid are the waste products of protein metabolism. They are
formed in the liver and conveyed in blood to the kidneys for excretion.
 Carbon dioxide,released by all cells, is conveyed to the lungs for excretion.
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Hormones
These are chemical compounds synthesised by endocrine glands. Hormones pass directly from the
cells of the glands into the blood which transports them to their target tissues and organs elsewhere
in the body, where they influence cellular activity.

Gases
Oxygen, carbon dioxide and nitrogen are transported round the body in solution in plasma. Oxygen
and carbon dioxide are also transported in combination with haemoglobin in red blood cells. Most
oxygen is carried in combination with haemoglobin and most carbon dioxide as bicarbonate ions
dissolved in plasma.

Cellular content of blood

There are three types of blood cells
• Erythrocytes or red cells
• Thrombocytes or platelets
• Leukocytes or white cells.

Red Blood Cells (erythrocytes)

The most numerous type in the blood (45%).

 Average 7 µm in diameter.
 Women average about 4.8 million of these cells per cubic millimeter (mm3; which is the
same as a microliter [µl]) of blood.
 Men average about 5.4 x 106 per µl.
 These values can vary over quite a range depending on such factors as health and altitude.
 Red blood cells are responsible for the transport of oxygen and carbon dioxide. - Filled
with hemoglobin (Hb) for gas transport
 Biconcave discs, anucleate, essentially no organelles
 Contain the plasma membrane protein spectrin and other proteins which Provide flexibility
to change shape as necessary
 RBCs are the major factor contributing to blood viscosity
 RBC precursors mature in the bone marrow closely attached to a macrophage.

 They manufacture hemoglobin until it accounts for some 90% of the dry weight of the cell.
 In mammals, the nucleus is squeezed out of the cell and is ingested by the macrophage.
 All the mitochondria as well as the endoplasmic reticulum and Golgi apparatus are
destroyed.
 No-longer-needed proteins are expelled from the cell in vesicles called exosomes.
 Thus RBCs are terminally differentiated i.e they can never divide.
 They live about 120 days and then are ingested by phagocytic cells in the liver and spleen.
 Most of the iron in their hemoglobin is reclaimed for reuse. The remainder of the heme
portion of the molecule is degraded into bile pigments and excreted by the liver.
 Some 3 million RBCs die and are scavenged by the liver each second.
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Structural characteristics of erythrocytes that contribute to gas transport

 Biconcave shape—huge surface area relative to volume

 >97% hemoglobin (not counting water)
 No mitochondria; ATP production is anaerobic; no O2 is used in generation of ATP

Development and maturation of Erythrocytes

The process of development of red blood cells from pluripotent stem cells takes about 7 days and
is called erythropoiesis . It is characterised by two main features:
• maturation of the cell
• formation of haemoglobin inside the cell

Maturation of the cell. During this process the cell decreases in size, loses its nucleus and
synthesizes ribosomes. These changes depend on a number of factors, especially the presence of
vitamin B12 and folic acid.
These are present in sufficient quantity in a normal diet containing dairy products, meat
and green vegetables. If the diet contains more than is needed, they are stored in the liver.
Deficiency of either vitamin B12 or folic acid leads to impaired red cell production.

Formation of haemoglobin. Haemoglobin is a complex protein, consisting of globin and an iron-

containing substance called haem, and is synthesised inside developing erythrocytes in red bone
marrow.
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Control of erythropoiesis
o The number of red cells remains fairly constant, which means that the bone marrow
produces erythrocytes at the rate at which they are destroyed. This is due to a homeostatic
negative feedback mechanism.
o The primary stimulus to increased erythropoiesis is hypoxia, i.e. deficient oxygen supply
to body cells. This occurs when:
o the oxygen-carrying power of blood is reduced by e.g. haemorrhage or excessive
erythrocyte breakdown (haemolysis) due to disease
o the oxygen tension in the air is reduced, as at high altitudes.
o Insufficient hemoglobin (e.g., iron deficiency

o Hypoxia increases erythrocyte formation by stimulating the production of the hormone

erythropoietin, mainly by the kidneys.
o Erythropoietin stimulates an increase in the production of proerythroblasts and the release
of increased numbers of reticulocytes into the blood.
o These changes increase the oxygen-carrying capacity of the blood and reverse tissue
hypoxia, the original stimulus.
o When the tissue hypoxia is overcome, erythropoietin production declines. When
erythropoietin
o levels are low, red cell formation does not take place even in the presence of hypoxia, and
anaemia (the inability of the blood to carry adequate oxygen for body needs) develops.

Dietary Requirements for Erythropoiesis

 Nutrients—amino acids, lipids, and carbohydrates

 Iron Stored in Hb (65%), the liver, spleen, and bone marrow
 Iron Stored in cells as ferritin and hemosiderin
 Iron Transported loosely bound to the protein transferrin
 Vitamin B12 and folic acid—necessary for DNA synthesis for cell division

Blood groups

o Individuals have different types of antigen on the surfaces of their red blood cells. These
antigens, which are inherited, determine the individual's blood group. In addition, individuals
make antibodies to these antigens, but not to their own type of antigen, since if they did the
antigens and antibodies would react causing a transfusion reaction.
o These antibodies circulate in the bloodstream and the ability to make them, like the antigens,
is genetically determined and not associated with acquired immunity.
o If individuals are transfused with blood of the same group, i.e. possessing the same antigens
on the surface of the cells, their immune system will not recognise them as foreign and will
not reject them. However, if they are given blood from an individual of a different blood type,
o i.e. with a different type of antigen on the red cells, their immune system will mount an attack
upon them and destroy the transfused cells.
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o There are many different collections of red cell surface antigens, but the most important are
the ABO and the Rhesus systems.

The ABO system

o About 55% of the population has either A-type antigens (blood group A), B-type antigens
(blood group B) or both (blood group AB) on their red cell surface. The remaining 45% have
neither A nor B type antigens (blood group O).
o The corresponding antibodies are called anti-A and anti- B.
o Blood group A individuals cannot make anti-A (and therefore do not have these antibodies in
their plasma), since otherwise a reaction to their own cells would occur; they do, however,
make anti-B.
o Blood group B individuals, for the same reasons, make only anti-A.
o Blood group AB make neither, and blood group O make both anti-A and
o anti-B.

o Because blood group AB people make neither anti-A nor anti-B antibodies, they are known as
universal recipients: transfusion of either type A or type B blood into these individuals is safe,
since there are no antibodies to react with them.
o Conversely, group O people have neither A nor B antigens on their red cell membranes, and
their blood may be safely transfused into A, B, AB or O types; group O is known as the
universal donor.

The Rhesus system

The red blood cell membrane antigen important here is the Rhesus (Rh) antigen, or Rhesus factor.
About 85% of people have this antigen; they are Rhesus positive (Rh+) and do not therefore make
anti-Rhesus antibodies.
The remaining 15% have no Rhesus antigen (they are Rhesus negative, or Rh~). Rh~ individuals
are capable of making anti-Rhesus antibodies, but are stimulated to do so only in certain
circumstances, e.g. in pregnancy, or as the result of an incompatible blood transfusion.

Fate and Destruction of Erythrocytes

• Life span: 100–120 days

• Old RBCs become fragile, and Hb begins to degenerate
• Macrophages engulf dying RBCs in the spleen
• Heme and globin are separated
• Iron is salvaged for reuse
• Heme is degraded to yellow the pigment bilirubin
• Liver secretes bilirubin (in bile)) into the intestines
• Degraded pigment leaves the body in feces as stercobilin
• Globin is metabolized into amino acids

Erythrocyte Disorders

 Anemia: blood has abnormally low O2-carrying capacity

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 A sign rather than a disease itself. It is a situation where blood O2 levels cannot support
normal metabolism
 Accompanied by fatigue, paleness, shortness of breath, and chills

Causes of Anemia

1 Insufficient erythrocytes

This may be caused by:

 Hemorrhagic anemia: acute or chronic loss of blood

 Hemolytic anemia: RBCs rupture prematurely
 Aplastic anemia: destruction or inhibition of red bone marrow

2 Low hemoglobin content

This may be caused by:

 Iron-deficiency anemia
 Secondary result of hemorrhagic anemia or
 Inadequate intake of iron-containing foods or
 Impaired iron absorption

3 Pernicious anemia

 This refers to deficiency of vitamin B12 or Lack of intrinsic factor needed for absorption
of B12

 Treated by intramuscular injection of B12 or application of Nascobal

4 Abnormal hemoglobin

Thalassemias

 Absent or faulty globin chain

 RBCs are thin, delicate, and deficient in hemoglobin

1. Sickle-cell anemia

 Defective gene codes for abnormal hemoglobin (HbS)

 Causes RBCs to become sickle shaped in low-oxygen situations

Erythrocyte Disorders
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Polycythemia: excess of RBCs that increase blood viscosity

• Results from:

 Polycythemia vera—bone marrow cancer

 Secondary polycythemia—when less O2 is available (high altitude) or when EPO
production increases
 Blood doping

 These cells have an important function in defending the body against microbes and other
foreign materials.
 Leukocytes are the largest blood cells and they account for about 1% of the blood volume.
They contain nuclei and some have granules in their cytoplasm.
 Can leave capillaries via diapedesis- Move through tissue spaces by ameboid motion and
positive chemotaxis
o Diapedesis: cells become thin, elongate and move either between or through
endothelial cells of capillaries
o Chemotaxis: attraction to and movement toward foreign materials or damaged
cells. Accumulation of dead white cells and bacteria is pus.

There are two main types:

• Granulocytes (polymorphonuclear leukocytes)
— neutrophils, eosinophils and basophils
• Agranulocytes
— monocytes and lymphocytes.

Granulocytes (polymorphonuclear leukocytes)

 Larger and shorter-lived than RBCs, Lobed nuclei and Phagocytic

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 During their formation, granulopoiesis, they follow a common line of development through
myeloblast to myelocyte before differentiating into the three types

Neutrophils

 Fine granules take up both acidic and basic dyes

 Give the cytoplasm a lilac color

 Granules contain hydrolytic enzymes or defensins
 The most abundant of the WBCs. -Constitute 59% of the total leucocyte population

 However, heavy doses of radiation, chemotherapy and many other forms of stress can
reduce the numbers of neutrophils so that formerly harmless bacteria begin to proliferate.
 Very phagocytic—Their main function is to protect against any foreign material that gains
entry to the body mainly microbes, and to remove waste materials, e.g. cell debris.
 They are attracted in large numbers to any area of infection by chemical substances,
released by damaged cells, called chemotaxins.
 Neutrophils pass through the capillary walls in the into infected tissues by amoeboid .
Thereafter they engulf and kill the microbes by phagocytosis.

 Their granules are lysosomes that contain enzymes that digest the engulfed material. The
pus that may form in the affected area consists of dead tissue cells, dead and live microbes,
and phagocytes killed by microbes.

 There is a physiological increase in circulating neutrophils following strenuous exercise

and in the later stages of normal pregnancy. Numbers are also
 increased in: microbial infection, tissue damage, e.g. inflammation, myocardial
 infarction, burns, crush injuries, metabolic disorders, e.g. diabetic ketoacidosis, acute gout,
leukaemia, heavy smoking, use of oral contraceptives.

Eosinophils

 Are Red-staining with bilobed nuclei

 Red to crimson (acidophilic) coarse, lysosome-like granules

 Digest parasitic worms that are too large to be phagocytized
 Modulators of the immune response

 Eosinophils, although capable of phagocytosis, are less active in this than neutrophils; their
specialised role appears to be in the elimination of parasites, such as worms, which are too big
to be phagocytosed.
 They are equipped with certain toxic chemicals, stored in their granules, which they release
when the eosinophil binds an infecting organism.
 Eosinophils are often found at sites of allergic inflammation, such as the asthmatic airway and
skin allergies. There, they promote tissue inflammation by releasing their array of toxic
chemicals.
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 The number of eosinophils in the blood is normally quite low (0–450/µl)..

Basophils

 • Rarest WBCs -Ordinarily representing less than 1% of the WBCs, their numbers also
increase during infection.

• Large, purplish-black (basophilic) granules contain histamine- Histamine: an inflammatory

chemical that acts as a vasodilator and attracts other WBCs to inflamed sites

• Are functionally similar to mast cells

 Basophils, which are closely associated with allergic reactions, contain cytoplasmic granules
packed with heparin (an anticoagulant), histamine (an inflammatory agent) and other
substances that promote inflammation.
 Usually the stimulus that causes basophils to release the contents of their granules is an
allergen of some type. This binds to antibody-type receptors on the basophil membrane.
 A cell type very similar to basophils, except that it is found in the tissues, not in the circulation,
is the mast cell. Mast cells release their granule contents within seconds of binding an allergen,
which accounts for the rapid onset of allergic symptoms followingexposure to, for example,
pollen in hay fever.

Agranulocytes
The types of leukocyte with a large nucleus and no granules in their cytoplasm are monocytes and
lymphocytes and they make up 25% to 50% of all leukocytes.

Monocytes

• Constitute 4 % of the total leucocyte population

 -Monocytes are mononuclear leukocytes that typically have a horseshoe or kidney-shaped

nucleus, and are the largest type of white blood cell.
 Abundant pale-blue cytoplasm and are Dark purple-staining, U- or kidney-shaped nuclei
 -Monocytes help devour microorganisms that don't belong in the body by surrounding them
and digesting them.
 These are large mononuclear cells that originate in red bone marrow. Some circulate in the
blood and are actively motile and phagocytic while others migrate into the tissues where they
develop into macrophages. Macrophages are large, motile, phagocytic cells that engulf
foreign material, that enters the body, dead and dying cells of the body and cellular and
extracellular debris (e.g., the extruded nuclei of developing red blood cells
 Both types of cell produce interleukin 1 which:
o acts on the hypothalamus, causing the rise in body temperature associated with
microbial infections
o stimulates the production of some globulins by the liver
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o enhances the production of activated T-lymphocytes.

The monocyte-macrophage system. This system, which is sometimes called the

reticuloendothelial system, consists of the body's complement of monocytes and macrophages.
Some macrophages are mobile whereas others are fixed. These include:

o Histiocytes in connective tissues

o Microglia in the brain
o Kupffer cells in the liver
o Alveolar macrophages in the lungs
o Sinus-lining macrophages (reticular cells) in the spleen, lymph nodes and thymus gland
o mesangial cells in the glomerulus of nephrons in the kidney
o osteoclasts in bone.

Lymphocytes
Constitute 34% of the total leucocyte population

• Large, dark-purple, circular nuclei with a thin rim of blue cytoplasm

Lymphocytes are smaller than monocytes and have large nuclei. They circulate in the blood and
are present in great numbers in lymphatic tissue such as lymph nodes and the spleen.
Although all lymphocytes originate from one type of stem cell, when they are activated in
lymphatic tissue, two distinct types of lymphocyte are produced —
T-lymphocytes and B-lymphocytes.

Types of specialised T-lymphocyte

 Memory T-cells These provide cell-mediated immunity by responding rapidly to another
encounter with the same antigen.
 Cytotoxic T-cells These directly inactivate any cells carrying antigens.
 They attach themselves to the target cell and release powerful toxins. The main role of
cytotoxic T-lymphocytes is in destruction of abnormal body cells, e.g. infected cells and
cancer cells.
 inflammatory T cells that recruit macrophages and neutrophils to the site of infection or
other tissue damage
 Helper T-cells These are essential for correct functioning of not only cell-mediated
immunity, but also antibody-mediated immunity.

T-helpers are the commonest of the T-lymphocytes; their main functions include:
• production of special chemicals called cytokines, e.g. interleukins and interferons, which support
and promote cytotoxic T-lymphocytes and macrophages
• cooperating with B-lymphocytes to produce antibodies; although B-lymphocytes are responsible
for antibody manufacture, they require to be stimulated by a helper T-lymphocyte first.
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B-lymphocytes. These are processed in the bone marrow. Their role is in production of antibodies
(immunoglobulins), which are proteins designed to bind to, and cause the destruction of, an
antigen.

Thrombocytes (platelets)
 These are very small non-nucleated discs, 2 to 4 um in diameter, derived from the cytoplasm
of megakaryocytes in red bone marrow.
 They contain a variety of substances that promote blood clotting, which causes haemostasis.
 Blood normally contains 150,000–400,000 per microliter (µl) or cubic millimeter (mm3).
This number is normally maintained by a homeostatic (negative-feedback) mechanism
 If this value should drop much below 20,000/µl, there is a danger of uncontrolled bleeding
 The control ofplatelet production is not yet entirely clear but it is believed that one stimulus is
a fall in platelet count and that thrombopoietin is involved.
 The life span of platelets is between 8 and 11 days and those not used in haemostasis are
destroyed by macrophages, mainly in the spleen.
 Platelets also promote inflammation.

• Leukopoiesis

• This is the Production of WBCs. It is stimulated by chemical messengers from bone marrow
and mature WBCs-Interleukins (e.g., IL-1, IL-2) and Colony-stimulating factors (CSFs) named
for the WBC type they stimulate (e.g., granulocyte-CSF stimulates granulocytes)

Leukocyte Disorders

Leukopenia

• Abnormally low WBC count—drug induced

Leukemias

 Cancerous conditions involving WBCs named according to the abnormal WBC clone
involved

 Myelocytic leukemia involves myeloblasts

 Lymphocytic leukemia involves lymphocytes

 Acute leukemia involves blast-type cells and primarily affects children
 Chronic leukemia is more prevalent in older people

Leukemia

Characterized by:
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• Bone marrow totally occupied with cancerous leukocytes

• Immature nonfunctional WBCs in the bloodstream
• Death caused by internal hemorrhage and overwhelming infections
• Treatments include irradiation, antileukemic drugs, and stem cell transplants

Haemostasis
When a blood vessel is damaged, loss of blood is stopped and healing occurs in a series of
overlapping processes, in which platelets play a vital part.

1. Vasoconstriction. When platelets come in contact with a damaged blood vessel, their surface
becomes sticky and they adhere to the damaged wall. They then release serotonin (5-
hydroxytryptamine), which constricts (narrows) the vessel, reducing blood flow through it.
Other chemicals that cause vasoconstriction, e.g. thromboxanes, are released by the damaged
vessel itself.

2. Platelet plug formation. The adherent platelets clump to each other and release other
substances, including adenosine diphosphate (ADP), which attract more platelets to the site.
Passing platelets stick to those already at the damaged vessel and they too release their chemicals.
This is a positive feedback system by which many platelets rapidly arrive at the site of vascular
damage and quickly form a temporary seal — the platelet plug.

3. Coagulation (blood clotting). This is a complex process that also involves a positive feedback
system and only a few stages are included here.

The factors involved are numbered and this represents the order in which they were discovered
and not the order of participation in the clotting process.
Blood clotting results in formation of an insoluble thread-like mesh of fibrin which traps blood
cells and is much stronger than the rapidly formed platelet plug.
In the final stages of this process prothrombin activator acts on the plasma protein prothrombin
converting it to thrombin.
Thrombin then acts on another plasma protein fibrinogen and converts it to fibrin. Prothrombin
activator can be formed by two processes which often occur together: the extrinsic and intrinsic

The extrinsic pathway occurs rapidly (within seconds) when there is tissue damage outside the
circulation. Damaged tissue releases a complex of chemicals called thromboplastin or tissue factor,
which initiates coagulation.
The intrinsic pathway is slower (3-6 minutes) and is confined to the circulation. It is triggered by
damage to a blood vessel lining (endothelium) and the effects of platelets adhering to it. After a
time the clot shrinks, squeezing out serum, a clear sticky fluid that consists of plasma from which
clotting factors have been removed.
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4. Fibrinolysis. After the clot has formed the process of removing it and healing the damaged
blood vessel begins. The breakdown of the clot, or fibrinolysis, is the first stage. An inactive
substance called plasminogen is present in the clot and is converted to the enzyme plasmin by
activators released from the damaged endothelial cells.
Plasmin initiates the breakdown of fibrin to soluble products that are treated as waste material and
removed by phagocytosis. As the clot is removed, the healing process restores the integrity of the
blood vessel wall.