BLOOD PHYSIOLOGY

Lecture No.2

Main Functions of Blood1. Transport:A giant transportation system2. Milieu or homeostatic funtion: Organism tries

to keep blood composition stable and it helps to hold interstitial environment stability

3. Defense/protection: 3.1. Defense against blood loss or bleeding –

hemostasis, blood coagulation. 3.2. Defense against foreign biological material

or immunological defenseNB: To realize those functions blood has to be

permanently circulating

Body Water• Adult person contains ~60% of water, i.e.

70 kg weighting person 42 L• 2/3 (~28 l) of body water is intracellular

fluid ja 1/3 (~14 l) extracellular fluid• 4/5 of extracellular fluid (~11 l) is

interstitial fluid and 1/5 (~3 l ) the blood plasma

• Extracellular fluid also contains transcellular fluids: cerebrospinal fluid (CSF), secretions of exocrine glands, etc

Body Fluids• Glandular secretions, filtrates or

composites of several simultaneously running processes

• Body fluids usually contain many components

• Body fluids have several functions based on their component properties.

Transfer of substances between different fluid compartments

• Inside of the compartment: concentration or pressure gradient

• Between compartments:Extracellular space – cells: ordinary and osmotic diffusionBlood plasma – interstitial space: diffusion and filtration (see the Starling equation by microcirculation or ultrafiltration in kidneys)

Estimation of the fluid compartment volume

• The most popular way to estimate those volumes is the dilution method, which takes into account a decrease of indicator substantce content in a new common volume.

• D2O as an indicator is good to measure total body water

• Inulin is good to measure volume of extracellular fluid compartmet, because it can penetrate capillaries but not cell membranes.

• Evans blue or radioactive 131I are good to measure blood plasma volume, because they do well in circulation.

BloodHematolology and many other special terms Blood has a holy reputation, other body fluids

do not possess much importance but participates in homeostasis

The maintenance of a relatively constant volume and a stable composition of blood is very essential in homeostasis.

The total body fluid volume and the total amounts of solutes as well as their concentrations are relatively constant during steady state conditions, as required for homeostasis.

Blood Circulation

Blood, general features

• Fluid connective tissue, amount 7-8% of body weight, ~5 L

• ~55% of blood volume is plasma and ~45% cells

• Blood is a temporary home for its constituents, they have different ways and mechanisms to appear and leave blood.

Physical and chemical properties of blood

Blood volume: 4-5 liters(F); 5-6 liters (M)Total blood density 1050-1060 g/LPlasma density 1024-1030 g/LDensity of blood cells 1089-1097 g/LOsmotic pressure 7.4 - 7.6 atmColloid-osmotic or oncotic pressure 25-30 mmHg 0.002 atmFreezing temperature – 0.55° CTotal relative viscosity 4.0 - 5.5Plasma relative viscosity ~1.8 pH – 7.4Salinity - 0.85% - .90%

Hematocrit

The ratio of blood cells to total blood volume

Hematocrit• Hematocrit (PCV) is the percentage of the blood

that is made up of red blood cells.• It is normally 40-45 vol %)• It is determined by centrifuging blood in a

hematocrit tube (capillary tube) until the cells become tightly packed at the bottom of the tube.

• When the hematocrit and the quantity of the hemoglobin is each respective cell are normal, the blood contains an average 15 grams of Hgb in every 100 ml.

• Each gram of pure Hgb is capable of combining with approximately 1.39 ml of oxygen.

CompositionofBlood

Blood Plasma

• Blood plasma is the liquid portion of clotted blood• 90-92% water• 6-8% plasma proteins• 1-2% heterogenic group of low molecular weight

substances• Because the plasma and interstitial fluids are separated

only by highly permeable capillary membranes, their ionic compositions are similar.

• The most important difference between these 2 compartments is the higher concentration of proteins in the plasma; the capillaries have a low permeability of the plasma proteins and, therefore leak only small amounts of proteins into the interstitial spaces.

Plasma Proteins

• Albumins (60%)

• Globulins: α-, β- and γ-globulins

• Fibrinogen (40%)

• Electrophoresis is

classical method to

separate these proteins

Plasma Proteins• Albumins are homogeneous groups of proteins produced

by hepatocytes with molecular weight: ~70 000 D• Essentially all the albumin and fibrinogen of the plasma

proteins as well as 50-80% of the globulins are formed in the liver.

• Some globulins are formed in the lymphoid tissues. These are mainly the gamma globulins that constitute the antibodies.

• A person with severe renal disease loses as much as 20 g of PP in the urine/day for months.

• In cirrhosis of the liver, large fibrous tissue develop among hepatic cells, causing reduction of PP formation which leads decreased osmotic pressure which cause generalized edema.

The synthesis of plasma proteinsThe Rate of PP formation by the liver: extremely high at

30 g/day;17 g albumins and 5 g globulins per day.• The half life time of albumins is 10-15 days

& globulins - 5 days• Major Functions:• Albumin – provide colloid osmotic pressure in the plasma,

which prevents plasma loss from the capillaries.• Globulins – perform enzymatic functions in the plasma;

transport (e.g. metals, lipids etc), clotting factors,

antibodies against antigens• Fibrinogens – polymerizes into long fibrin threads during

blood coagulation, thereby forming blood clots, that help repair leaks in the circulatory system

Genesis of Blood Cells

Pluripotential Hematopoietic Stem Cell

• The blood cells begin their lives in the bone marrow from a single type of cell called the PHSC, from which all the circulating blood cells are derived.

• As these cells reproduce, a small portion of them remains exactly like the original PHSC and is retained in the bone marrow to maintain a supply of these, although their numbers diminish with age.

Hematopoiesis: Growth Inducers and Differentiation Inducers

Genesis of Blood Cells

• From the bone marow cells – it is the PHSCs (pluripotential hemopoietic stem cells) – from which all cells of the circulating blood are derived

• Growth and reproduction of the different stem cells are controlled by multiple proteins

• Interleukin-3, differentiation inducers, other growth inducers

Main Principles of Hemopoiesis• All cells are originated from the pluripotent

hemopoietic stem cells in the red bone marrow.• Only mature blood cells can reach circulation• When level of cell diffrentiation is higher, then

their ability for mitosis is less. • Mature blood cells are not able to divide• Hemopoiesis needs very careful regulation to

keep numbers of cells on stable level. It means that production and death of cells must be balanced.

Growth & Differentiation inducers

Growth and reproduction of the different stem cells are controlled by multiple proteins called growth inducers

• Four major growth inducers:

1. Interleukin-3 – promotes growth and reproduction

of virtually all the different types of committed

stem cells

2. Interleukin 5 & 6 – induce growth of only specific

types of cells

4. Differentiation inducers – promotes differentiation

of committed stem cells into final adult blood

cell

Hematopoiesis and Diapedesis

ERYTHROCYTES

The Role of Erythropoietin• Erythropoietin is a circulating hormone and is

the principal factor that stimulates rbc production• It is a glycoprotein, with a molecular weight of

34,000• 90% is produced by the kidney and 10% by the

liver• When both kidneys are removed from a person

or are destroyed by renal failure, the person becomes very anemic because the 10% of normal ETO formed in other tissues (mainly in the liver) is sufficient to cause only 1/3 to ½ the red cell formation needed by the body.

Maturation of RBC• Especially important for final maturation of rbc’s

are 2 vitamins: Vitamin B12 and folic acid• Both are essential for the synthesis of DNA;

each in a different way is required for the formation of TTP

• Therefore, lack of either B12 or folic acid causes diminished DNA and consequently failure of nuclear maturation and division

• Furthermore, this will also cause the bone marrow to produce macrocytes; cells with flimsy membranes, often irregular, large, oval instead of the usual biconcave shape

Apoptosis or programmed cell death is a normal physiological form of cell death that plays a key role both in the maintenance of adult tissues and in embryonic development.

In adults, programmed cell death is responsible for balancing cell proliferation and maintaining constant cell numbers in tissues undergoing cell turnover.

For example, about 5 × 1011 blood cells are eliminated by programmed cell death daily in humans, balancing their continual production in the bone marrow.

Red blood cells or erythrocytes

• Number is 4-5X1012 per liter

• Without nuclei, ~1/3 of mass is hemoglobin

• Main function is to carry oxygen

• Clinically important are blood groups – ABO and Rh systems

Erythrocytes

Hemoglobin• Content in men 130-160 g/l, in women 120-160 g/l• The Hb molecule contains 4 subunits, everyone with

heme and globin• Each chain has 4 iron atoms that bind loosely w/ 1

molecule of O2

• Synthesis of hemoglobin begins in the proerythroblasts and continues until a few days after the cells leave the bone marrow and pass into the blood stream

Hemoglobin

Formation of Hemoglobin

• First start with the formation of heme which contains 1 atom of Fe

• Next, each heme molecule combines with a long polypeptide chain, called the globin, forming a subunit of hemoglobin

• Each of these chains has a molecular weight of 16,000; 4 of them in turn bind together loosely to form the whole hemoglobin

Heme

Anemia & PolycythemiaAnemia – deficiency of Hgb or few RBCs in the blood.

Types of Anemia are:

1. Blood loss anemia - after rapid hemorrhage

2. Aplastic anemia - lack of functioning bone marrow

3. Hemolytic anemia - due to fragile cells that rupture easily

4. Megaloblastic anemia-due to loss of any of Vitamin B12, folic acid and intrinsic factor from the stomach mucosa

Polycythemia – large quantities of extra RBCs

Types: Secondary or Physiologic polycythemia – seen in those who lives in higher altitudes

Polycythemia vera - excess production of blood cells(rbc, wbc and platelets, hematocrit & blood volume)

Which of the 3 factors cause the type of anemia?

What happens in Sickle cell Anemia?

• Abnormalities of the chains can alter the physical characteristics of the Hgb. In sickle cell anemia, the AA VAL is substituted for GLU at one point in each of the 2 beta chains.

• When this type of Hgb is exposed to low O2 it forms elongated crystals inside the RBCs about 15 um in length.

• These make it almost impossible for the cells to pass through many small capillaries, and the spiked ends of the crystals are likely to rupture the cell membranes leading to sickle cell anemia

The ABO Blood Groups

Rhesus (Rh) System

• A person is Rh+ (~85%) when he or she has on erythocytes D antigen, otherwise they are Rh-.

• Initially plasma doesn’t have antibodies.• Anti D antibodies are produced during

sensibilization when D antigens reach Rh-

organism• The Rh system is important by

haemotransfusion and mother-fetus Rh conflict or erythroblastosis fetalis

White blood cells or Leukocytes

• Normal amount is 4-10 x 105 WBCs in 1 L blood.• Main function immunological defense by:

1. actually destroying invading bacteria or viruses

2. forming antibodies and sensitized lymphocytes• Heterogenous group of cells and exceptionally big

number of WBCs are outside of circulation where they are needed

• The real value of WBC is that most of them are specifically transported to areas of serious infection and inflammation, thereby providing a rapid or potent defense against infectious agents.

Types of Leukocytes

• Blood provides a medium for the maintenance of homeostasis in

the cell’s environment. • Blood functions as transport

system for nutrients and gases to the cells and removing waste products and CO2 the interstitial fluid around the cells.

• Blood serves to link the various organs of the body, integrating them through the action of hormones

Leukocyte Formula (Schilling’s Hemogram)

Concentrations of the Different WBCs in the Blood:A. Granulocytes

Neutrophilic granulocytes 50-70%Eosinophilic granulocytes 2-4%Basophilic granulocytes 0.5-1%

B. AgranulocytesLymphocytes 25-40% (T- and B-lymphocytes)Monocytes 4-8%

Leukocytes

Classification of immunological defense mechanisms

• Unspecific mechanisms:- humoral mechanisms: the complement

system- cellular mechanisms: phagocytosis, very

potent phagocytotic potential have neutrophils and monocytes• Specific mechanisms:

- humoral mechanisms: antibodies from plasma cells, antigene-antibody reaction

- cellular mechanisms: cytotoxic effect of T- lymphocytes

Neutrophils and MacrophagesNeutrophils and macrophages – mainly attack and

destroy invading bacteria, viruses and other injurious agents.

How do they do these?

1.They enter the tissue spaces by diapedesis

2.They move through tissue spaces by ameboid motion

3.They are attracted to inflamed tissue areas by chemotaxis

Inflammation: Role of Neutrophils and Macrophages

• When tissue injury occurs, whether caused by bacteria, trauma, chemical, heat, or any other phenomenon, multiple substances are released by the injured tissues and cause dramatic changes in the surrounding uninjured tissues. This entire complex of tissue changes is called inflammation.

• Inflammation is characterized by:

(1) Vasodilation of the local blood vessels with increased blood flow; (2)increased permeability of the capillaries allowing leakage of large quantities of liquid; (3) clotting of the fluid in the interstitial spaces; (4) migration of large numbers of granulocytes and monocytes; and (5) swelling of the tissue cells

What is the “walling-off” effect of inflammation?

One of the first results of inflammation is to “wall-off’ the area of injury from the remaining tissues. The tissue spaces and the lymphatics in the inflamed area are blocked by fibrinogen clots so that after a while, fluid barely flows through the spaces.

This walling-off process delays the spread of bacteria or toxic products.

Next Meeting

• Quiz on Blood Physiology (Guyton & Hall)

(pp. 419-428 – Red Blood cells, Anemia & polycythemia

pp. 429-437 – Leukocytes, Resistance to Infection, & Inflammation

pp. 451-455-Blood Groups/Transfusion

• Assignment: Immunity