5. blood and its components (dr. r. veloso)

8/3/2019 5. Blood and Its Components (Dr. R. Veloso)

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BLOOD AND ITS

COMPONENTS

Rainelda Uy-Veloso, M.D.


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Objectives:

To discuss the major functions and components of theblood

To discuss the structure of Immunoglobulins and

enumerate their classes and major functions

To discuss the different structure of the different clottingfactors and the intrinsic and extrinsic pathway of blood

coagulation

To discuss the biochemical nature of the ABO blood

group


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Major functions of blood:1. Respiration transport of oxygen from the lungs to the tissues and of

CO2 from the tissues to the lungs

2. Nutrition - transport of absorbed food materials

3. Excretion transport of metabolic waste to the kidneys, lungs, skin,

and intestines for removal

4. Acid base balance maintenance

5.Water balance regulation thru the effects of blood on the exchangeof water between the circulating fluid and

the tissue fluid

6. Body temperature regulation by the distribution of body heat

7. Defense against infection by the white blood cells and circulating

antibodies9. Transport of hormones - and regulation of metabolism

10. Transport of metabolites

11. Coagulation


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Blood Components:

1. Red blood cells ( erythrocytes) Prokaryotic cells

40-50% of total blood volume

Produced in the bone marrow from stem cells at a rate of2-3 million cells per second

2. White blood cells ( Leukocytes) 1% of total blood volume

Produced in bone marrow from same kind of stem cells

Others produced in thymus gland


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3. Platelets ( Thrombocytes)Cell fragments without nuclei that work with blood clotting

chemicals at the site of woundsAdhere to the walls of blood vessels, plugging the rupture

in the vascular wall

About 1/3 size of red cells

Life span 9 -10 days

Produced in bone marrow from stem cells

4. PlasmaClear liquid water, sugar, fat, protein and salt solution

which carries the red cells, white cells, platelets and some

other chemicalsMake up 55% of bloods volume

95% consist of water

Also contains blood clotting factors, lipids, vitamins,

minerals, enzymes, antibodies and other proteins


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ANTIBODIES:

> immunoglobulins comprise about 20% of total serum

proteins

> characterized by their chemical, physical and

immunologic properties

> Physicochemical properties used for classifying

antibodies are:

1. solubility in salts and solvents2. electrophoretic mobility

3. molecular size

4. sedimentation in ultracentrifuge

> In terms of molecular weight, 3 main groups of

antibodies:1. molecular weight 150,000, 7S

2. 900,000, 19S

3. 170,000-400,000 7S to 11S

* S = sedimentation coefficient


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Immunoglobulins:

1. Ig G = about 75% in human sera= has 4 subclasses : IgG-1 to IgG-4

= main antibody in the secondary response

= the only immunoglobulin to cross the placenta

= opsonizes bacteria, making them easier to

phagocytose= fixes complement which enhances bacterial killing

= neutralizes bacterial toxins and viruses

= sedimentation coefficient 7S


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2. Ig M

= comprises about10%

in normal human sera= largest of all the immunoglobulins

= earliest antibodies synthesized in response to

antigenic stimulation

= fix complement well in the presence of

stimulation= synthesized by the fetus in utero but does not

cross the placenta, presence in the newborn is

considered a sign of intrauterine infection



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3.Ig A = comprises about 15% in human sera

= principal immunoglobulin in externalsecretions of the respiratory, intestinal

and GUT and in tears,saliva and milk

= produced by plasma cells within mucous

membrane at various locations

= can neutralize viruses and can inhibit

attachment of bacteria to epithelial cells

unless cleaved by microbial proteases

= does not fix complement

= sedimentation coefficient 7S or11S


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4.Ig D

= first encountered as a myeloma protein= found in trace amounts ( 3-5 mg/dl) in normal

sera

= has not been proved to have antibody activity

but with IgM has been demonstrated on

the surface of B lymphocytes in cordblood



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5.Ig E

= found in minute concentration (0.03mg/dl)

= mediates allergic reactions in skin and other

tissues

= binds to mast cells and basophils

= serum levels are increased in some parasitic

infections by causing release of

enzymes from eosinophils= sedimentation coefficient 8S


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Clot : a thick, viscous, or coagulated mass or lump of blood

consist of plug of platelets

a network of insoluble fibrin molecules

Platelet aggregation and fibrin formation both require

the proteolytic enzyme thrombin

Blood Clotting:

a process that is controlled by a sequence of

regulated enzymatic reactions


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Proper clot formation: a tightly regulated process involving many activating and

inhibiting factors

all the precursors needed for the formation of a clot, except for

the initiators of clot formation are present in the bloodstream in

healthy individuals

1. Cascade mechanism of activation

The coagulation phase of the response to blood vesseldamage involves a cascade of zymogen activation leading to

blood clot

2. Clotting pathways

Involve 2 pathways: Intrinsic and extrinsic

Initiated by different activators

Converge to activate a final common pathway which leads

to final clot formation


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Common pathway and clot formation

1. Fibrinogen ( FactorI )

Precursor to fibrin ( FactorIa) which forms the clot structure Structure:

Long, large (340 kdal), water soluble molecule

Made of three pairs of polypeptides ( two alpha, two beta, two

gamma)

o Function: Converted to insoluble fibrin by the action of thrombin

cleavage causes the release of two pairs of peptides, the A

and B fibrinopeptides from the and polypeptides

Fibrinopeptides = responsible for keeping fibrinogen in

solution and keeping it from aggregating


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Fibrin-stabilizing factor ( Factor XIIIa)

a transamidase which covalently links fibrin monomers between

glutamine (Gln) and Lysine (Lys) residues

converts loose clots to tight clots

2. Prothrombin ( FactorII)

precursor to thrombin

Structure: amino end contains many carboxylated glutamate

(Gla) residues

Gla residues enable prothrombin to bind to

calcium and have affinity for activated

platelets

Gla residues are carboxylated by vitamin Kdependent enzyme ( inhibited by vit. K

antagonists)


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Conversion of fibrinogen to a tight clot:


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The extrinsic pathway:

Short lived and primarily responsible for the

initiation of clotting Clotting pathway is triggered by tissue factor or

Thromboplastin ( Factor III) which is notnormally found in blood

1.Tissue factor ( thromboplastin) Membrane-bound glycoprotein located in the tissue

adventitia

When exposed to vessel injury, it tightly bindsFactor VII

2. Factor VII

Converted to Factor VIIa by trace amounts ofcirculating, active proteases


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3. Tissue factor- Factor VIIa complex

a. common pathway = catalyzes the conversion of

Factor X to factor Xab. intrinsic pathway = converts Factor IX to Factor IXa

4. Extrinsic pathway inhibitor (EPI) or lipoprotein-

associated coagulation inhibitor (LACI)A circulating blood lipoprotein that inhibits the

conversion of Factor X to Xa by tissue factor-Factor

VIIa complex that is why people with Hemophilia

who have normal extrinsic pathways do not form

effective clots


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The intrinsic pathway: Responsible for most of the growth and maintenance of clots

1.Initiation of the intrinsic pathway

All of the factors needed for this activation are in the

bloodstream before initiation of clotting

Pathway is initiated by the interaction of the appropriate factors

in blood with abnormal surfaces

When complex of Factor XII, prekallikrein and high molecularweight kininogen makes contact with abnormal surface (

collagen in open wound) prekallikrein kallikrein

converts Factor XII to Factor XIIa

Factor XIIa initiates the activation cascade

Factor VIII is a modifier protein that accelerates 200,000-fold

the conversion of Factor X to Xa by Factor IXa


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2. Feedback activation

Enhanced by the feedback activation of Factors VIII

and XI by thrombin and Factor V of the common

pathway

3. Clinical correlation

instances when anticoagulation therapy isnecessary

Anticoagulation therapy is needed to prevent clots

from forming on prosthetic heart valves

Anticoagulant is needed to keep blood from

coagulating in test tubes that hold blood samples


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Hemophilias:

are inherited clotting disorders with deficiencies or abnormalities in

various clotting factors

Two most prevalent Hemophilias in the U.S.1. Classic hemophilia ( Hemophilia A)

X-linked recessive trait, predominant form of hemophilia in the

U.S (80%)

due to deficiency in Factor VIII

2. Hemophilia B

X-linked recessive trait, accounts for10% in U.S.

due to deficiency in Factor IX of the intrinsic pathway


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Regulation of Clotting: Necessary so that clots do not expand beyond the site of injury or exist

longer than necessary

Is controlled by inhibiting clot formation and degrading clots at theproper time

Natural inhibition of clot formation:

The large volume and flow of blood assures that thrombin which are

released from platelets upon activation are quickly removed from theclotting site and carried to the liver where they are degraded

1. Extrinsic Pathway Inhibitor(EPI)= shifts clot formation from theextrinsic to the intrinsic pathway but not a general inhibitor

2. Antithrombin III = a slow inhibitor of the following factors:

a. Thrombin

b. Factor IXa

c. Factor Xa

d. Factor XIa


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3. Activated protein C = a vitamin K dependent

= Gla-containing protease that

inactivates the modifying proteins

(Factors Va and VIIIa)

= stimulated by another vitamin K

dependent protein, Protein S

4. Thrombomodulin = converts thrombin from an enzyme

that is crucial to clot formation toone that inhibits clot formation

= is bound to the plasma membrane

endothelial cells and prevents clot

formation from extending to normal


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Clot degradation ( Fibrinolysis)

A clot is a transient component of wound healing thatbegins to be degraded soon after formation

Plasmin = the protease that specifically degrades clots

Tissue plasminogen activator (t-PA) = the protease that

converts plasminogen to plasmin


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DRUGSTHAT AFFECT CLOTTING:

A. Procoagulants = promote the formation of clots

1.Thrombin = used therapeutically to promote clot formation if

added topically to wounds

2.Blood plasma or Purified clotting factors = inhibit a bleedingevent

3.Desmopressin = analog of antidiuretic hormone

= used to elevate levels of Factor VIII in mild cases

of Hemophilia A= promotes release of clotting factors including

Factor VIII from blood vessel endothelium


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B. Anticoagulants1. Heparin = binds to and increases the inhibitory activity of

antithrombin III

= commonly used postsurgically to prevent clots fromforming on prosthetic implants

= used in test tubes to keep blood drawn for clinicallaboratory analysis from clotting

2. Hirudin = synthesized from the European medicinal leech

= most potent natural inhibitor of thrombin

3. Coumarins = act by inhibiting the vitamin K-dependent carboxylation of Gla residues in several of the clottingfactors

= taken orally, prophylactically used in patients with

prosthetic implants that are in direct contact with blood= reduce the chance of clot formation on the abnormal

surfaces of the prosthesis


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C. Fibrinolyticsare agents that employ enzymatic reactions to dissolve clots

Two types commonly used to dissolve clots that cause heartattacks:

1. Streptokinase = enzyme from streptococci that facilitatesthe breakdown of clots by binding to andactivating plasminogen

= causes conformational change inplasminogen which make plasminogenactive without cleavage activeplasminogen can convert inactiveplasminogen to plasmin which isproteolytically active

2. Tissue Plasminogen Activator ( t-PA) = binds to fibrinclots and becomes a potent activator ofplasminogen

= is now produced by recombinant DNA

technology


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ABO SYSTEM, Blood Typing

1. ABO System and Blood typing

ABO alloantigen system is the basis for blood

typing and transfusion

A and B antigens are carbohydrate molecules

on the surface of red blood cells and other cells possible combination of these antigens on

erythrocytes are A, B, AB and O (no A or B

antigen)


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Type A = expresses two genes of A ( i.e. AA)

= has circulating anti-B antibodies in the plasma

Type B = expresses two genes of B (i.e. BB)

= has circulating anti-A antibodies in the plasma

Type AB = expresses both A and B antigens ( co-

dominant)= have neither anti-A and anti-B circulating

antibodies

Type O = do not express either A or B on their red blood

cells= have both anti-A and anti-B antibodies

circulating in the plasma


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* The plasma contains the antibody against the absent

antigens. This forms the basis for both blood typing as

well as transfusion compatibility or incompatibility.

* If a persons blood is mixed with a specific antiserum against

antigen A and this results in agglutination, and no

agglutination with antiserum against B, the person is

Type A

*Agglutination with anti-B antiserum indicates blood type B

*Agglutination with both anti-A and anti-B antiserum indicates

blood type AB

* No agglutination with both anti-A and anti-B antiserum

indicate blood group O

*Type O = universal donor

*Type AB = universal recipient

5. blood and its components (dr. r. veloso)

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