General physiology - Blood

BLOOD PHYSIOLOGY

Dr.Lara Owies

• Plasma volume• Blood volume• plasma composition & function• blood composition & cell count• White blood cell types & function• Platelets count & function• Hemostasis, mechanism &

disorders

Lecture Outline

blood consists of 3 types of specialized cellular elements:

erythrocytes(RBC) Whole cells

leukocytes(WBC) whole cells

Platelets(thrombocytes) Cell fragments

suspended in a complex liquid plasma

Blood Volume & Plasma Volume

packed cell volume(PCV):

the fraction of the blood composed of red blood cellsdetermined by centrifuging

men=0.40

women=0.36

severe anemia= 0.10

Polycythemia= 0.65

Hematocrit

Measuring plasma volume:

serum albumin labeled with radioactive iodine (125I-albumin).

Evans blue dye (T-1824)

Measurements

Measuring blood volume

Total blood volume

Example:

Plasma volume=3 liters, hematocrit =0.40

= 5 liters

Measurements

Measuring blood volume

Another way: inject into the circulation red blood cells that have been labeled with radioactive chromium (51Cr).

Measurments

The average blood volume of adults is about 7% of body weight , or about 5 liters.

60 % :plasma

40% :RBC’S

these percentages differ, depending on gender, weight, and other factors.

Blood & plasma Volume

Plasma Composition & Function

3 liters.

the noncellular part of the blood

it exchanges substances continuously with the interstitial fluid through the pores of the capillary membranes.

These pores are highly permeable to all solutes except proteins

Blood plasma

Composition:

contains large amounts of sodium and chloride ions, reasonably large amounts of bicarbonate ions.

but only small quantities of potassium,calcium, magnesium, phosphate, and organic acid ions.

The composition of plasma is regulated by the kidneys.

Blood Plasma

The largest portion of the blood

90% water.

Water is a medium for materials being carried in the blood , & can absorb and distribute heat

Blood Plasma

Inorganic constituants :

1% of plasma weight

Most abundant ions in plasma Na⁺,Cl⁻

HCO₃⁻,K⁺, Ca⁺² in smaller amounts

They function in:

membrane excitability

osmotic distribution of fluid between Extracelluar fluid and cells

buffering of pH changes.

Blood Plasma

Organic constituants:

plasma protiens(6-8% of plasma weight)

Nutrients : glucose , Amino Acids, Lipids ,Vitamins.

waste products: creatinin, bilirubin , urea

Dissolved gases O2,CO2

Hormones

Blood Plasma

Plasma protiens functions

maintain plasma volume

Partially responsible for buffering pH .

Bind substances that poorly dissolve in plasma ( thyroid hormone , cholesterol , iron)

Blood clotting factors are plasma protiens

Inactive circulating precursor molcules (ex:angiotensinogenangiotensin).

Gamma globulins are immunoglobulins (antibodies)which are crucial to body defence mechanism.

Blood Plasma

Blood composition & cell count

Erythrocytes(RBC’s)

Function:

transport hemoglobin, which in turn carries oxygen

contain carbonic anhydrase, Acid-Base buffer( by hemoglobin)

Red Blood Cells

biconcave discs

diameter of about 7.8 micrometers and a thickness of 2.5 micrometers at the thickest point and 1 micrometer or less in the center.

The average volume of the red blood cell is 90 to 95 cubic micrometers.

The shapes of red blood cells can change remarkably as the cells squeeze through capillaries.

Red Blood Cells

Concentration of Red Blood Cells in the Blood.

In normal men, per cubic millimeter is 5,200,000 (±300,000)

in normal women 4,700,000 (±300,000).

Persons living at high altitudes have greater numbers of red blood cells.

Quantity of Hemoglobin in the Cells.

Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells.

Red Blood Cells

In men :15 grams of hemoglobin per 100 milliliters of cells In women: 14 grams per 100 milliliters.

each gram of pure hemoglobin can combine 1.34 milliliters of oxygen.

In normal man, 20 milliliters of oxygen can be carried in

combination with hemoglobin in each 100 milliliters of blood.

in normal woman, 19 milliliters of oxygen can be carried.

Hemogobin

.each of the four iron atoms can combine reversibly with one molecule of O2

Each hemoglobin molecule can pick up 4 O2 passengers in the lungs.

98.5% of the O2 is carried in the blood is bound to hemoglobin

Due to iron, hemoglobin is a pigment

O2 binds loosely to iron atoms so that the combination is easily reversible

Hemoglobin

Each hemoglobin molecule contain 4 hemoglobin chains :Alpha , beta, gama , delta chains.

In adults: hemoglobin A ; 2 alpha and 2 beta chains

Sickle cell anemia results from abnormalities in 2 beta chains of hemoglobin

Hemoglobin

Transport and storage of iron

Iron in plasma : transferrin

Iron inside cell cytoplasm: ferritin (storage iron)

Small quantities as insolube hemosederin

Iron

Transferrin delivers iron to erythroblast cells in bone marrow to form hemoglobin

Low transferrin in blood failure to transport iron to the erythroblasts severe hypochromic anemia

Hypochromic anemia: red cells that contain much less hemoglobin than normal

Iron

When red blood cells are destroyed, the hemoglobin released from the cells is ingested by monocyte-macrophage cells.

There, iron is liberated and is stored mainly in the ferritin pool to be used as needed for the formation of new hemoglobin.

Iron

Life span and destruction of RBC’s

circulate for 120 days before being destroyed

do not have a nucleus ,mitochondria, or endoplasmic reticulum

they do have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of ATP.

Red Blood Cells

Life span and destruction of RBC’S

Red cells are destructed in the spleen

the hemoglobin is phagocytized by macrophages:

especially by the Kupffer cells (liver) macrophages of the spleen and bone marrow.

Iron and bilirubin are released into the blood

Red Blood Cels

deficiency of hemoglobin in the blood , which can be caused by too few RBC’s

1. Blood Loss Anemia.

2. Microcytic Hypochromic Anemia

3. Aplastic Anemia.

4. Megaloblastic anemia.

anemia

5. Hemolytic anemia (hereditary)

hereditary spherocytosis

sickle cell anemia

West African and American blacks, sickle cell disease “crisis”

*Anemia

erythroblastosis fetalis Rh-positive red blood cells in the fetus are attacked by antibodies from an Rh-negative mother

effects of anemia:1. greatly increased cardiac output2. increased pumping workload on the heart.

Anemia

1. Secondary polycythemia causes:

too little oxygen in the breathed air (highaltitudes)

failure of oxygen delivery to the tissues ( in cardiac failure) ex: Physiologic polycythemia

polycythemia

2. Polycythemia vera ( erythremia)

Genetic

The blast cells no longer stop producing red cells when too many cells are already present

Hematocrit & total blood volume increase

Cyanotic (bluish )skin

*Polycythemia

White Blood Cell Types & Function

The mobile units of the body’s protective system

Formed in: Bone Marrow lymph tissue

After formation, they are transported in the blood to different parts of the body where they are needed.

White Blood Cells

Types of White Blood Cells.

Polymorphonuclear granulocytes(granular appearance & multiple nuclei):

1. neutrophils2. eosinophils3. basophils

Mononuclear agranulocytes

1. monocytes 2. lymphocytes3. plasma cells

Characteristics of WBC’s

Granulocytes & monocytes protect the body by phagocytosis

The lymphocytes and plasma cells function mainly in connection with the immune system.


Concentrations of the Different White Blood Cells in the Blood. adult human being has about 7000 white

blood cells per microliter of blood The normal percentages of different WBC’s


granulocytes: normally 4 to 8 hours circulating in the

blood and another 4 to 5 days in tissues In times of serious tissue infection,this total

life span is often shortened to only a few hours because the granulocytes are destroyed.

Life Span of the White Blood Cells

The monocytes 10 to20 hours in the blood

Then ,through the capillary membranes into the tissues.

Once in the tissues , they become tissue macrophages

tissue macrophages can live for months unless destroyed while performing phagocytic functions.


Lymphocytes life spans of weeks or months

enter the circulatory system continually ,from the lymph nodes and other lymphoid tissue.

After a few hours, they pass out of the blood back into the tissues by diapedesis.

Later, they re-enter the lymph and return to the blood again and again


It is mainly the neutrophils and tissue macrophages that attack and destroy invading microorganisms

The neutrophils

mature cells

attack and destroy bacteria even in the circulating blood.

Neutrophils and Macrophages

Monocyte-tissue macrophages

Monocytes immature cells while still in the blood and have little ability to fight

infectious agents at that time.

tissue macrophages

begin life as blood monocytes

They enter the tissues

They swell to a size that can barely be seen with the naked eye.

extremely capable of combating intratissue disease agents


Neutrophils and monocytes can squeeze through the pores of the blood capillaries by diapedesis

Both neutrophils and macrophages can move through the tissues by ameboid motion,

Chemotaxis:chemical substances in the tissues cause both neutrophils and macrophages to move toward the source of the chemical .


neutrophils and macrophages main function is phagocytosis

1. Antibodies adhere to bacterial membrane to make it susceptible to phagocytosis

2. the antibody combine with C3 . C3 molecules, in turn, attach to receptors on the phagocyte membrane.

This selection and phagocytosis processis called opsonization.


single neutrophil can usually phagocytize 3 to 20 bacteria

neutrophils are not capable of phagocytizing particles much larger than bacteria


Macrophages

more powerful phagocytes than neutrophils

phagocytizing as many as 100 bacteria.

They also have the ability to engulf much larger particles (red blood cells ,malarial parasites)


The phagocytic vesicle fuse with lysosomes and other granules and create digestive vesicle

Neutrophils and macrophages:

1. proteolytic enzymes

2. lipases

3. oxidizing agents


Composed of :

Monocytes

mobile macrophages

fixed macrophages

Monocyte-macrophage system

Tissue Macrophages:

the Skin and Subcutaneous Tissues (Histiocytes)

Macrophages in the Lymph Nodes

Alveolar macrophages in the lungs

Kupffer cells in the liver

Macrophages of the Spleen and Bone Marrow

Microglia in the brain

Monocyte-Macrophage System

Defense lines

a First Line of Defense : Tissue Macrophage.Within minutes begin their phagocytic actions

Second Line of Defense : Neutrophil Invasion of the Inflamed Area Is a within a few hours

Neutrophilia: acute increase in the number of neutrophisthe number of neutrophils in the blood sometimes increases from a normal of (4000 to 5000) 15,000 to 25,000 )neutrophils per microliter


Defense lines

Third Line of Defense : Second Macrophage Invasion into the Inflamed Tissue.

Fourth Line of Defense : Increased Production of Granulocytes and Monocytes by the Bone Marrow Is

It takes 3-4 days for the new granulocytes & monocytes to leave the bone marrow


Pus: cavity is often excavated in the inflamed tissues that contains varying portions of necrotic tissue, dead neutrophils, dead macrophages, and tissue fluid


2% of all the blood leukocytes

weak phagocytes,

parasitic infections.

eosinophils

release substances as: 1. hydrolytic enzymes

2. highly reactive forms of oxygen

3. major basic protein

eosinophils

In allergic reactions:

1. detoxify some of the inflammation-inducing substances released by the mast cells and basophils and probably

2. phagocytize and destroy allergen-antibody complexes

thus preventing excess spread of the local inflammatory process.

eosinophils

Basophils In the blood

basophils are similar to tissue mast cells

mast cells and basophils release:

1. heparin

2. Histamine

3. bradykinin

Basophils & mast cells

They play an important role allergic reactions

Basophils & mast cells

Release of

1. histamine, 2. bradykinin, 3. serotonin, 4. heparin,5. slow-reacting substance of anaphylaxis6. lysosomal enzymes

Low WBC’s production

Without treatment, death often ensues in less than a week after acute total leukopenia begins.

Leukopenia

Causes of aplasia of the bone marrow Irradiation of the body by x-rays or gamma

rays

drugs and chemicals that contain benzene

chloramphenicol (an antibiotic), thiouracil (used to treat thyrotoxicosis), and even various barbiturate hypnotics, on very rare occasions cause leukopenia

Leukopenia

Uncontrolled production of white blood cells

can be caused by cancerous mutation of

1. myelogenous cells

2. lymphogenous cells.

leukemia

Blood cells that are concerned with acquired immunity

Present in lymph nodes and other lymphoid tissues

Acquired immunity: the formation of antibody and/or activation of lymphocytes that attack and destroy the specific invading organism or toxin.

LYMPHOCYTES

Types of Acquired Immunity:

1. Humoral (B-cell ) immunity: B lymphocytes produce antibodies.

2. Cell mediated (T-cell) immunity: formation of activated T-lymphocyte that are specifically crafted in L.N to destroy the foreign agent

Lymphocytes

Both types are initiated by antigen

Antigen: is a large molecule with a special epitope ( protein /polysaccharide ) on its surface to be recognized

It starts When the invading antigen reaches the lymphoid tissue (lymph nodes, spleen, thymus …)

lymphocytes

derived originally in the embryo from pluripotent hematopoietic stem cells

Lymphocytes that migrate and differentiate in the thymus form T-lymphocyte

Lymphocytes that differentiate in the fetal liver and bone marrow form B-lymhocytes

After differentiation , B,T lymphocytes migrate to lymphoid tissues throughout the body

Lymphocytes

B-lymphocytes remain dormant in lymphoid tissue

Macrophages phagocytize the antigen and present it to T& B-lymphocytes

T-helper cells activate B-lymphocytes

B-lymphocytes enlarge and differentiate to form plasma cells

Mature plasma cells produce gamma gobulin antibodies

Antibodies are secreted into the blood

Lymhocytes

IgM, IgG, IgA, IgD, and IgE.

Ig stands for immunoglobulin

75% of Ig’s of a normal person are IgG

IgE involved in allergy

Classes of antibodies

T-lymphocytes types and function:

T-helper cells:

most numerous T-cells,

major regulator of all immune functions by forming lymphokines (interleukins, interferon …)

in the abscense of T-helper cells the immune system is paralyzed

Lymphocytes

T-helper cells functions:

1. Stimulation of Growth and Proliferation of Cytotoxic T Cells and Suppressor T Cells

2. Stimulation of B-Cell Growth and Differentiation to Form Plasma Cells and Antibodies.

3. Activation of the Macrophage System.

4. Feedback Stimulatory Effect on the Helper Cells Themselves.

Lymphocytes

T-lymphocytes types and functions: Cytotoxic T Cells(killer cells): has a protien receptor that bind to a specific

antegin and secret perforins that punchholes in the attacked antigen and release cytotoxic substances

after that they pull away and kill more cells

Lymphocytes

Cytotoxic T-cells

They are lethal to cells invaded by viruses , cancer cells , and any other foreign cells

Lymphocytes

T-lymphocytes types and functions:

Supressor T-cells :

Capable of suppressing the functions of both cytotoxic and helper T cells

plays an important role in limiting the ability of the immune system to attack a person’s own body tissues, called immune tolerance

Failure of the Tolerance Mechanism Causes Autoimmune Diseases.

Lymphocytes

Old people

after destruction of the body’s own tissues , releasing considerable quantities of “self-antigens” that cause acquired immunity

• Rheumatoid fever• Glomerulonephritis• myasthenia gravis• lupus erythematosus,

Autoimmune disease

Other functions: Delayed-reaction allergy is caused by

activated T cells and not by antibodies on repeated exposure, it does cause the

formation of activated helper and cytotoxic T cells

the eventual result of some delayed-reaction allergies can be serious tissue damage in the tissue area where the instigating antigen is present.

Lymhocytes

“Allergic” Person, Excess IgE Antibodies Genetically passed IgE has strong propensity to attach to mast

cells and basophils. ,results in immediate change of the membrane and rupture of these cells and releasing substances that causes an allergic reaction (anaphylaxis, hay fever,asthma…)

Lymphocytes

Platelet count and function

Thrombocytes

(1-4 micrometer in diameter)

fragments of another type of cell found in the bone marrow, the megakaryocyte.

Function : activate the blood clotting mechanism

Normally: 150,000 -300,000 cells per microliter of blood.

Platelets

Lack nuclei , cannot reproduce They have contractile proteins in their cytoplasm:

1. actin2. Myocin3. Thrombosthenin

Residual E.R & G.A that synthesize enzymes and store Ca⁺²

Able to form ATP ,ADP , Fibrin stabilizing factor

Glycoprotiens on its cell membrane

platelets

replaced once every 10 days

Half life 8-12 days

Removed mainly by spleen macrophages

in other words, about 30,000 platelets are formed each day for each microliter of blood.

platelets

Hemostasis , mechanism & disorders

Means prevention of blood loss

After a vessel is ruptured, achieved by:

1. Vascular constriction2. Platelet plug3. Blood clot formation4. Growth of fibrous tissue into the clot to

close the hole permanently

hemostasis

Vascular constriction

Trauma to the blood vessel will cause its smooth muscles to contract ,to reduce blood flow from it

for the smaller vessels, platelets release a vasoconstrictor substance, thromboxane A2

The more severe a trauma is , the greater the degree of vascular spasm

Last from minutes to hours

hemostasis

Platelet plug.

When platelets comes to contact with exposed collagen

1. change in shape and contract2. They become sticky and adhere to

collagen and von willbrand factor3. They secrete ADP & thromboxane A2 that

activate other platelets and attract them

hemostasis

Blood coagulation

form in: 15-20 minutes in sever trauma 1-2 minutes in minor trauma

Activator substances & blood proteins adhere and initiate clotting process

Within 3 minute a clot it formed

after 20 minute the clot retracts to close the vessel even further

hemostasis

Fibrous organisation or dissolution of the blood clot

The clot is either invaded by fibroblasts which forms C.T through the clot. or it can dissolve

Mechanism of blood coagulation.

a complex cascade of chemical reactions occurs in the blood involving Coagulation factors. the net result is the formation of prothrombin activator.

The prothrombin activator catalyzes conversion of prothrombin into thrombin.

the thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot.

hemostasis

Prothrombin is a plasma protein formed in the liver

Vitamin K is required in the liver for the formation of prothrombin and other clotting factors

Lack of vitamin K or presence of liver diseases lead to bleeding tendency

Hemostasis

Conversion of prothrombin to thrombin

Prothrombin activator , In the presence of Ca⁺² causes the conversion of prothrombin to thrombin.

Platelets also help in prothrombin conversion

Thrombin polymerizes fibrinogen into fibrin

within 10-15 seconds

Hemostasis

Conversion of fibrinogen to fibrin-clot formation

Fibrin stabilizing factor produced by platelets add strength to this fibrin meshwork

Blood clot meshwork of fibrin fibers running in all directions & entrapping blood cells ,platelets & plasma

Clot retraction-serum

few minutes after clot is formed , it contracts, expressing the fluid from it( serum )

serum lacks fibrinogen and clotting factors

Serum differs from plasma that it lacks these clotting factors and so it cannot clot

Hemostasis

platelet thrombosthenin , actin, and myosin molecules causes clot contraction

The contraction is activated and accelerated by thrombin & calcium ions

the clot retracts

Hemostasis

Initiation of Coagulation: Formation of Prothrombin Activator

1. extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues.

2. intrinsic pathway that begins in the blood itself.

Blood clotting factors play major roles

Hemostasis

Extrinsic pathway Traumatized vascular wall that comes in contact with

blood results in release of tissue factor(tissue thromboplastin) that function as a proteolytic enzyme

Activation of factor X Xa combine with tissue factor and factor V in the

presence of Ca⁺² to form prothrombin activator Prothrombin is then convertedto thrombin & clotting

proceeds Factor V in the activator complex is inactive until

thrombin is formed,the proteolytic action of thrombin activate factor V

Hemostasis

Activated Factor X is the actual protease that causes splitting of prothrombin to form thrombin

Factor V is an accelerator

Hemostasis

Intrinsic pathway

begins with trauma to the blood itself or exposure of the blood to collagen from a traumatized blood vessel wall.

Hemostasis

Intrinsic pathway Blood trauma activate factor XII XIIa activate factor XI XIa activate factor IX XIa along with VIII and platelet phospholipds

activate factor XMissing factor VIIIhemophiliaLack of plateletsthrombocytopenia

Xa with factor V prothrombin activator

Hemostasis

Ca⁺² is an accelerator

in their absence blood clotting in either pathways does not occur

Both pathways occur simultaneously:

Clotting needs 15seconds in extrinsic pathway

Clotting needs 1-6 minutes in intrinsic pathway

Hemostasis

Prevention of Blood Clotting in the Normal Vascular System

Endothelial surface factors:

Smoothness of endothelial surface Glycocalyx layer on endothelium/repels

clotting factors Thrombomodulin: bind thrombin Anticoagulants in blood :antithrombin III,

heparin

Hemostasis

Lysis of clot

Plasmin

It destroys many of the clotting factors

Plasminogen entrapped inside the clot

t-PA (tissue plasminogen activator) is slowly released from injured tissue few days after the bleeding stops

Entrapped plasminogen is activated into plasmin

Hemostasis

1. Vitamin K deficiency

2. Hemophilia

3. thrombocytopenia

Bleeding disorders

Vitamin K deficiency

Vitamin K is necessary for liver formation of five of the important clotting factors:

1. prothrombin2. Factor VII3. Factor IX4. Factor X5. protein C

In the absence of vitamin K, subsequent insufficiency of these coagulation Factors in the blood can lead to serious bleeding tendencies.

Bleeding disorders

Hemophilia

In males

85% factor VIII deficiency :hemophilia A (classic hemophilia)

15% factor IX deficiency

Both factors are transmitted genetically

Bleeding disorders

Hemophilia

Bleeding occur following trauma

Even mild trauma can cause bleeding for days (e.x: tooth extraction)

Treatment of classic hemophilia is factor VIII injection

Hemophilia bleeding from large vessels

Bleeding disorders

Von Willbrand disease (vWD)

The most common hereditary coagulation abnormality

Defeciency of Von Willbrand factor (vWF)

vWF: protien required for platelet adhesion

Bleeding disorders

Thrombocytopenia

Low number of platelets circulating in the blood

Bleeding from small capillaries

Multiple small purplish blotches thrombocytopenic purura

Bleeding disorders

Thrombocytopenia

Bleeding occur when platelet number falls below 50,000/microliter

Levels below 10,000/microliter are lethal

Idiopathic thrombocytopenia:

specific antibodies destroy platelets

Treatment of thrombocytopenia: A. fresh whole blood transfusionB. splenectomy

Bleeding disorders

Thromboembolisms

Thrombus: abnormal clot that develop in a bood vessel

Emboli: free flowing clot

Causes:

Roughened endothelial surface

Slowly flowing blood

Treatment : genetically treated t-PA delivered through a catheter

Bleeding disorders

Femoral venous thrombosis & massive pulmonary embolism

Treatment: t-PA

Disseminated intravascular coagulation.

the clotting mechanism becomes activated in widespread areas of the circulation

Occurs in widespread septicemia in which endotoxins activate clotting mechanisms

Clots are small but numerous

Plug small peripheral blood vessels

Diminishes oxygen and nutrients delivery

leads to circulatory shock an death in 85% of patients

May cause bleeding

Anticoagulants

1. Heparins

increases clotting time to 30 minutes (normal=6 minutes)

the change in clotting time occurs immediately

action remains 1.5-4 hours

heparin is destroyed by the enzyme heparinase

Anticoagulants2. Coumarins

Ex:warfarin

blocking the action of vitamin K

Coagulation is not blocked immediately

Normal coagulation returns after 1-3 days of discontinuing coumarin therapy

INR international normalised ratio

1. Bleeding time

2. Clotting time

3. Prothrombin time

Blood coagulation tests

Bleeding time:

Normally 1-6 minutes

Lack of platelets causes prolonging the B.T

Blood Coagulation Tests

Clotting time

6-10 minutes

Not used anymore


Prothrombin time

Indicate the concentration of prothrombin in the blood

Normal P.T is 12 seconds


General physiology - Blood

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