Red Blood Cells, Anemia, Polycythemia

8/3/2019 Red Blood Cells, Anemia, Polycythemia

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RED BLOOD CELLS,ANEMIA, POLYCYTHEMIA

General Physiology


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RED BLOOD CELLS

FUNCTIONS:

Transport ofHemoglobin => main or major function

Transport of Carbonic anhydrase = this enzymecatalyzes, hastens, and fastens the reactionbetween CO2 & H2O =>CO2 becomestransported from the tissues to the lungs in the formof bicarbonate ion (HCO3-)

Hemoglobin is an excellent ACID BASE BUFFER (asmost protein is) => RBCs are responsible for mostof the buffering power of the whole blood


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RED BLOOD CELLS: Shape and Size

Biconcave discs in shape;

bag that can be deformed into almost any shape

Normally, the RBCs have a great excess of cellmembrane relatively compared to the quantity of

the material inside

With this, deformation does not stretch the

membrane great greatly and does cause rupture This shape can change remarkably as the RBCs

pass thru the capillaries


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QUANTITY OF HEMOGLOBIN

Maximum conc of Hgb in the RBC fluid: 34 gm/dl

Concentration never rises above this value == this is themetabolic limit of the cells hemoglobin-forming

mechanism In normal individual, the % of Hgb concentration is

almost near the maximum in each cell

Each gram of pure hemoglobin is capable of combining

with about 1.39 ml of Oxygen Normal reference range for men: 14-16 gm/dl

Normal reference range for women: 12-14 gm/dl


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Areas of the body that produce the

RBCs.

Early embryonic life: in the YOLK SAC (primitive

nucleated RBCs)

Middle trimester of gestation: in the LIVER,

majoritySPLEEN & LYMPH NODES, minority

Last month of gestation and after birth: exclusively

in the BONE MARROW


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Among the bones.

The marrow of essentially ALL BONES produces redblood cells until the person is 5 years old5 years old

The marrow of the long bones (except the proximal

portions of the humeri and tibiae) until 20 years old20 years oldthey become quite fatty

After 20years of age, red blood cell production occur

only in the marrow of MEMBRANOUS BONES

(vertebrae, sternum, ribs, and ilia)

***the marrow becomes less productive asage increases


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GENESIS OF RBCS

Proerythroblast

Basophil erythroblast (stain with basic dyes)

Polychromatophil erythroblast

Orthochromatic erythroblast

Reticulocyte

Erythrocyte


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RETICULOCYTE

The RBC is already filled with hemoglobin to aconcentration of 34% in this stage

The form of RBC wherein the nucleus is condensed to a

small size, with its remnant being extruded, while the ERis reabsorbed

It still contains a small amount of basophilic material,consisting of remnants of Golgi apparatus,mitochondria, and organelles

Its movement from the bone marrow to the capillaries:DIAPEDESISDIAPEDESIS (squeezing thru the pores of the capillary

membranes)


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REGULATION OF RBC PRODUCTION

WHY IS THERE A NEED TO REGULATE RBCWHY IS THERE A NEED TO REGULATE RBC

PRODUCTION?????PRODUCTION?????

Regulation is within narrow limits so that an

adequate number of red cells is always available

to provide sufficient tissue oxygenation

Regulation is also not above the narrow limits so

that the cells do not become so concentrated thatthey impede blood flow


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REGULATORS..

1. Tissue Oxygenation basic regulator of RBC productionAny condition that causes the quantity of oxygen

transported to the tissues to decrease increases the rate ofRBC production

Severe hemorrhage severe anemia BM begins toproduce large quantities of RBCs

Destruction of major portions of the bones ( by radiation)=> BM works hard to produce RBCs => hyperplasia of

remaining BM tissueVery high altitudes =>quantity of oxygen in the air is

decreased => insufficient O2 is transported to the tissues=> RBC production becomes increased


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Remember.

It is notthe concentration of RBCs in the bloodthatIt is notthe concentration of RBCs in the bloodthat

controlsthe rate of RBC production, BUTthecontrolsthe rate of RBC production, BUTthe

functionalability of the RBCsto transport oxygen tofunctionalability of the RBCsto transport oxygen to

the tissues in relation to the tissue demand forthe tissues in relation to the tissue demand foroxygen.oxygen.


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Diseased states can also regulate

Some diseases of the circulation that cause decreased blood flowSome diseases of the circulation that cause decreased blood flow

thru the peripheral vesselsandthose that cause failure of oxygenthru the peripheral vesselsandthose that cause failure of oxygen

absorption bythe bloodas it passesthru the lungs can alsoabsorption bythe bloodas it passesthru the lungs can also

increase the rate of RBC productionincrease the rate of RBC production.

Examples: prolonged cardiac failure; lung diseases tissue

hypoxia resulting from these diseased state increases the

rate of RBC production => increase in hematocrit =>

increase in total blood volume


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REGULATORS. .

2. ERYTHROPOIETIN. This circulating hormone(glycoprotein) is the principal factor that stimulates

RBC production

Hypoxia has little effect or no effect in stimulatingRBC production in the ABSENCE of ERYTHROPOIETIN

If the erythropoietin system is FUNCTIONAL, hypoxia

can cause the marked increase in erythropoietinproduction which in return enhances RBC production

until hypoxia is relieved


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ERYTHROPOIETIN

90% is formed in the KIDNEYSKIDNEYS (in the

juxtaglomerular portion or by the renal tubular

epithelial cells)

10% is secreted or formed by the LIVERLIVER

When both kidneys are removed or destroyed byWhen both kidneys are removed or destroyed by

disease, the person becomes invariably anemicdisease, the person becomes invariably anemic

the remaining 10% produced by the liver canthe remaining 10% produced by the liver cancause or effect only 1/3 to RBC formation ascause or effect only 1/3 to RBC formation as

needed by the bodyneeded by the body


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ERYTHROPOIETIN

It begins to be formed within minutes to hours and

reaches a maximum production at 24HRS when a

person is placed in a low oxygen condition

Yet no new RBCs appear circulating in the blood

until about 5days later

Reason: erythropoietins important effect is to

stimulate the production of PROERYTHROBLASTSfrom the hematopoietic stem cells in the BM


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ERYTHROPOIETIN

This hormone also hastens the genesis of RBC

Causes the proerythroblasts to pass more rapidly

thru the different erythroblastic stages than

normally => speeding up production of new cells

This rapid production continues as long as the

person remains in a low oxygen state or until

enough red cells are produced to carry adequateamount of O2 to the tissues despite the low oxygen


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ERYTHROPOIETIN

In the absence of erythropoietin, few RBCs are

produced by the BM

In the presence large quantities of erythropoietin

and in the presence of plenty of iron and other

other nutrients => rate of RBC production can rise

to 10X or more the normal

the ERYTHROPOIETIN CONTROL MECHANISM for RBCproduction is a powerful one


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MATURATION OF RED BLOOD CELLS

NUTRITION plays and greatly affects the

maturation and rate of RBC production

Two important VITAMINS: VITAMIN B12 and

FOLIC ACID

Both are essential for the synthesis of DNA; both

are required for the formation of thymidine

triphosphate, an essential building blocks of DNA


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Lack of Vit B12/Folic Acid

Failure of nuclear maturation and division

Diminished DNA

Lack of Vit B12 and Folic Acid


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Consequence

Failure to proliferate rapidly

Type of cells produced: MACROCYTES

Larger than normal, with flimsy membrane

Irregular, large and oval, instead of the usual biconcavedisc

MACROCYTES are capable of carrying oxygennormally, but are considered fragile

Fragility causes them to have short life, one-half to one-

third normal Vit B12 and Folic Acid Deficiency: causes MATURATION

FAILURE in the process of eryhtropoiesis


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What causes the abnormality in the

function and morphology?

abnormality

Inability of the cells to synthesize adequate quantities of DNA Slow production of the cells, but does not prevent excess formation of

RNA by the DNA in those cells that do not succeed in being produced

Cellenlargement

Quantity of RNA in each cell becomes greater than normal Excess production of cytoplasmic Hgb and other constituents

Abnormalshape

Abnormalities of all the cells DNA

Structural components of the cell membrane and cytoskeletonare also malformed=> abnormal cell shapes and increasedcell membrane fragility


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MATURATION FAILURES (Diseases)

PERNICIOUS ANEMIA

Causes maturation failure due to failure to absorb Vit B12

from the GIT

Basic abnormality is an atrophic gastric mucosa => fails tosecrete normal gastric secretions

One of the important secretions of the parietal cells of the

gastric glands: INTRINSIC FACTOR

Intrinsic Factor: combines with Vit B12 from the food, andmakes the B12 available for absorption by the GIT


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Upon absorption of Vit B12

Once Vit B12 has been absorbed from the GIT, it is

stored in large quantities in the liver (stores up to

1000x the normal level)

It is released slowly as needed to the bone marrow

and other tissues of the body

RDR to maintain normal RBC maturation:1-3microgram

3-4years of defective B12absorption are requiredtocause maturation failure anemia


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MATURATION FAILURES (Diseases)

FOLIC ACID DEFICIENCY

(PTEROYLGLUTAMIC ACID)

CAUSED BY GIT absorption abnormalities, like sprue (small

intestinal disease)

Difficulty in absorbing both the Vit B12 and Folic Acid


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SYNTHESIS/FORMATION OF

Hemoglobin

Begins in the proerythroblasts

Continues slightly even into the reticulocyte stage

When the retic leaves the BM and passes into the

blood stream => continue to form minute quantities

of HgB for another day or so


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SYNTHESIS OF HgB

Protoporphyrin IX

Combines with IRON

Formation of Pyrrole molecule

Four Pyrrole molecules combine

Succinyl-CoA (formed in the Krebs Cycle

Binds with glycine


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SYNTHESIS of HgB

Four Hemoglobin chain bind together loosely toform

WHOLE HEMOGLOBIN MOLECULE

Formation of subunit of hemoglobin, calledHemoglobin chain

Formation of HEME MOLECULE

Each heme molecule combines with a long peptide chain , GLOBIN


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Hemoglobin structure

Because each chain has a heme prosthetic group

=> (4) four iron atoms in each hemoglobin molecule

Each one can bind with 1 molecule of oxygen =>

making a total of 4 molecules of oxygen (or a totalof 8 oxygen atoms) that can be transported by

each hemoglobin molecule


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Hemoglobin variants

Variations in the different subunit hemoglobin chains

Depending on the amino acid composition of the

polypeptide portion

Types of chains: alpha chain, beta chain, gamma

chain, delta chain

Most common form of hemoglobin in the adult

human being: HEMOGLOBIN A Hemoglobin A is a combination of two alpha

chains and two beta chains


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Combination of HEMOGLOBIN with O2

Hemoglobin combines loosely and reversibly with

oxygen

Primary function of hemoglobin in the Body: ability

to combine with oxygen in the lungs, and thenrelease the oxygen readily in the tissue capillaries

where the gaseous tension oxygen is much lower

than in the lungs


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Combination of HEMOGLOBIN with O2

O2 does not combine with the two positive bonds of theiron in the hemoglobin molecule

Instead, it binds loosely with one of the so-calledcoordination bonds of the iron atom

Loose bond =} combination is easily reversible

Oxygen does not become ionic oxygen, but is carriedas molecular oxygen, composed of two oxygen atoms,to the tissues, where, because of the loose, readily

reversible combination O2 is released into the tissue fluids in the form of

dissolved molecular oxygen, rather than ionic oxygen


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Iron Storage

Total quantity of iron in the body: averages 4-5

grams

65% is in the form of hemoglobin, 4% in the form

of myoglobin, 1% in the form of various hemecompounds that promote intracellular oxidation,

0.1% is combined with the protein transferrin in the

blood plasma, 15-30% is stored mainly in the RES

and liver parenchyma in the form of FERRITIN


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Daily Loss of Iron

Human excretes about 1mg of iron each day =>

feces

Additional quantities of iron are lost whenever

bleeding occurs

Menstrual loss brings about iron loss of average:

2mg/day


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DESTRUCTION OF RED BLOOD CELLS

Normally, RBCs circulate an average of 120 days

before they are destroyed == due to wearing out

of life processes

As they age, RBCS BECOME FRAGILE!!!

They rupture during passage through some tight

spot of the circulation as they squeeze through

the red pulp of the SPLEEN


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Normally..

Even though mature RBCs do not have

nucleus, mitochondria, orER yetthey

have cytoplasmic enzymes thatarecapable of metabolizing glucose and

smallamounts ofATPandNADPH


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Roles of NADPH

Maintain the pliability of the cell membrane

Maintain membrane transport of ions

Keep the iron of the hemoglobin in the ferrous form

(rather than the ferric form)

Prevent oxidation of the proteins in the RBC

* ferric form of iron causes formation ofmethemoglobin, which can not carry OXYGEN


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As the RBCs become old

These metabolic systems become

also progressively less active with

time The RBCs become more and more

fragile>>> presumably because

their life processes wear out


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ROLE OF THE SPLEEN?

Many of the RBCs fragment in the spleen (red

pulp), most specifically in the structural

trabeculae

WHEN THE SPLEEN IS REMOVED, THE NUMBER OFABNORMAL RED BLOOD CELLS AND OLD CELLS

CIRCULATING IN THE BLOOD ALSO INCREASES

CONSIDERABLY


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DESTRUCTION OF HEMOGLOBIN

Once the RBC bursts, the HEMOGLOBIN is

phagocytosed almost immediately by macrophages

Liver (Kupffer cells), spleen, bone marrow

After few hours to days, the macrophages release

the iron from the hemoglobin back into the blood to

be carried by the TRANSFERRIN either to:

BONE MARROW for production of new RBC, or LIVER and other tissues for storage in the form of

FERRITIN


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DESTRUCTION OF HEMOGLOBIN

The porphyrin portion/molecule is

converted by the macrophages (thru a

series of stages) into the bile pigmentcalled BILIRUBIN

BILIRUBIN is released into the blood

and later secreted by the liver into thebile


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ANEMIASMajor classification

BLOOD LOSS ANEMIA

usually after hemorrhage which is NOT corrected

after appropriate time

If this becomes chronic blood loss, a person

frequently can not absorb enough iron from the

intestines to form Hemoglobin as rapidly as it lost

RBCs are then produced with too little hemoglobininside them

MICROCYTIC, HYPOCHROMIC ANEMIA


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Normal replacement

After rapid hemorrhage, the body replaces the

plasma within 1-3 days (plasma replacement)

But this leaves a low concentration of rbcs

If no second hemorrhage occurs, the rbc

concentration returns to normal within 3-6 weeks

(RBC concentration replacement)


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APLASTIC ANEMIA

Bone marrow aplasia

Lack of a functioning bone marrow

May be due to: gamma ray radiation, excessive x-

ray treatment, chemotherapeutics drugs which are

suppresants


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MEGALOBLASTIC ANEMIA

Vit B12 and folic acid deficiency, and lack of secretionof INTRINSIC FACTOR (due to pernicious anemia) =>slow reproduction of the erythroblasts in the bone

marrow The RBCs formed are grow too large (oversized) with

odd shapes (bizzarre) megaloblasts

The RBCs formed are also fragile rupture easily

Causes: intestinal atrophy or absence of stomach dueto gastrectomy; intestinal sprue which leads to poorabsorption of important vitamins and minerals


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HEMOLYTIC ANEMIA- short RBC lifespan

1. HEREDITARY SPHEROCYTOSIS the RBCs are

small and spherical rather than being biconcave

discs=> cant be compressed because they are notloose, and are not baglike in consistency =>

ruptures easily even with slightest compression.

2. SICKLE CELL ANEMIA abnormal type ofhemoglobin called HEMOGLOBIN S

Leads to serious decrease of RBC mass DEATH


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HEMOGLOBIN S

When this hemoglobin is exposed to low

concentrations of oxygen, it precipitates into long

crystals inside the RBC

The crystals elongate the RBC give theappearance of being a sickle rather than biconcave

disc

The precipitated hemoglobin also damages the cellmembrane making the RBC highly fragile


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EFFECTS OF ANEMIA ON THE

CIRCULATORY SYSTEM

In severe anemia, blood viscosity may fall to as low

as 1.5X that of water, rather than the normal value

of about 3

This decreases the resistance to blood flow in theperipheral vessels => far greater than normal

quantities of blood flow through the tissues and then

return to the heart

Sequelae: TISSUE and SPACE CONGESTION

accumulation of fluid


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EFFECTS OF ANEMIA ON THE

CIRCULATORY SYSTEM

Hypoxia resulting from diminished transport of O2

by the blood cause peripheral tissue vessel

DILATATION further increase in return of blood to

the heart increasing cardiac output to a higherlevel

Sequelae: greatly increased workload to the

HEART


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POLYCYTHEMIA

Two forms:

SECONDARYPOLYCYTHEMIA and

POLYCYTHEMIA VERA


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SECONDARY POLYCYTHEMIA

Occurs when blood forming organs automatically

produce large quantities of RBCs

Like when tissues become hypoxic because of little

oxygen in the atmosphere; or when there is failure ofdelivery of oxygen to the tissues during cardiac failure

RBC count commonly rises to 6-7million/mm3

Can be PHYSIOLOGIC POLYCTHEMIA among natives

who live in places of high altitudes (14,000-17,000 ft)=> ability of these people to perform high levels of

continuous work in a rarefied atmosphere


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POLYCYTHEMIA VERA

RBC count may reach 7-8Million, and the hematocritis 60-70%

Caused by a gene aberration that occurs in the

hematoblastic cell line producing the blood cells The blast cells no longer stop producing red cells

when too many cells are already present

Also produces excess production of WBC and

platelets as well total blood volume also increasesto twice the normal BLOOD BECOMES VISCOUS


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EFFECTS OF POLYCYTHEMIA ON THE

CIRCULATORY SYSTEM

Blood flow becomes sluggish because of increased

VISCOSITY

Arterial pressure becomes elevated in 1/3 of

patients with Polycythemia

A person with PV has ruddy complexion with a

bluish cyanotic tint to the skin (due to increased

quantity of deoxygenated blood in the skin plexus)


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Red Blood Cells, Anemia, Polycythemia