RED BLOOD CELLS, ANEMIA, POLYCYTHEMIA

General Physiology

RED BLOOD CELLS

 

FUNCTIONS: Transport of Hemoglobin => main or major function Transport of Carbonic anhydrase = this enzyme catalyzes, hastens, and fastens the reaction between CO2 & H2O =>CO2 becomes transported from the tissues to the lungs in the form of bicarbonate ion (HCO3-) Hemoglobin is an excellent ACID BASE BUFFER (as most protein is) => RBCs are responsible for most of the buffering power of the whole blood

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 cell membrane 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

QUANTITY OF HEMOGLOBIN
Maximum conc of Hgb in the RBC fluid: 34 gm/dl Concentration never rises above this value == this is the metabolic 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

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

Among the bones.

The marrow of essentially ALL BONES produces red
blood cells until the person is 5 years old

The marrow of the long bones (except the proximal portions of the humeri and tibiae) until 20 years old they 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 as age increases

GENESIS OF RBCS
Proerythroblast Basophil erythroblast (stain with basic dyes) Polychromatophil erythroblast Orthochromatic erythroblast Reticulocyte Erythrocyte

RETICULOCYTE
The RBC is already filled with hemoglobin to a concentration 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 ER is 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: DIAPEDESIS (squeezing thru the pores of the capillary
membranes)

REGULATION OF RBC PRODUCTION

WHY IS THERE A NEED TO REGULATE RBC 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 that they impede blood flow

REGULATORS..
1. Tissue Oxygenation basic regulator of RBC production


Any condition that causes the quantity of oxygen transported to the tissues to decrease increases the rate of RBC production Severe hemorrhage severe anemia BM begins to produce large quantities of RBCs Destruction of major portions of the bones ( by radiation) => BM works hard to produce RBCs => hyperplasia of remaining BM tissue Very high altitudes =>quantity of oxygen in the air is decreased => insufficient O2 is transported to the tissues => RBC production becomes increased

Remember.
It is not the concentration of RBCs in the blood that controls the rate of RBC production, BUT the functional ability of the RBCs to transport oxygen to the tissues in relation to the tissue demand for oxygen.

Diseased states can also regulate

Some diseases of the circulation that cause decreased blood flow thru the peripheral vessels and those that cause failure of oxygen absorption by the blood as it passes thru the lungs can also increase the rate of RBC production 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

REGULATORS. .
2. ERYTHROPOIETIN. This circulating hormone (glycoprotein) is the principal factor that stimulates RBC production Hypoxia has little effect or no effect in stimulating RBC production in the ABSENCE of ERYTHROPOIETIN If the erythropoietin system is FUNCTIONAL, hypoxia can cause the marked increase in erythropoietin production which in return enhances RBC production until hypoxia is relieved

ERYTHROPOIETIN
90% is formed in the KIDNEYS (in the juxtaglomerular portion or by the renal tubular epithelial cells) 10% is secreted or formed by the LIVER When both kidneys are removed or destroyed by disease, the person becomes invariably anemic the remaining 10% produced by the liver can cause or effect only 1/3 to RBC formation as needed by the body

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 PROERYTHROBLASTS from the hematopoietic stem cells in the BM

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 adequate amount of O2 to the tissues despite the low oxygen

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 RBC
production is a powerful one

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

Lack of Vit B12/Folic Acid

Lack of Vit B12 and Folic Acid Diminished DNA

Failure of nuclear maturation and division

Consequence
Failure to proliferate rapidly Type of cells produced: MACROCYTES Larger than normal, with flimsy membrane Irregular, large and oval, instead of the usual biconcave disc MACROCYTES are capable of carrying oxygen normally, but are considered fragile Fragility causes them to have short life, one-half to onethird normal Vit B12 and Folic Acid Deficiency: causes MATURATION FAILURE in the process of eryhtropoiesis

What causes the abnormality in the function and morphology?

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 abnormality

Cell enlargement

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

Abnormalities of all the cells DNA Structural components of the cell membrane and cytoskeleton are also malformed=> abnormal cell shapes and increased Abnormal shape cell membrane fragility

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 to secrete 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, and makes the B12 available for absorption by the GIT

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 B12 absorption are required to cause maturation failure anemia

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

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

SYNTHESIS OF HgB
Succinyl-CoA (formed in the Krebs Cycle

Binds with glycine

Formation of Pyrrole molecule

Four Pyrrole molecules combine

Protoporphyrin IX

Combines with IRON

SYNTHESIS of HgB
Formation of HEME MOLECULE
Each heme molecule combines with a long peptide chain , GLOBIN

Formation of subunit of hemoglobin, called Hemoglobin chain

Four Hemoglobin chain bind together loosely to form

WHOLE HEMOGLOBIN MOLECULE

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 total of 8 oxygen atoms) that can be transported by each hemoglobin molecule

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

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 then release the oxygen readily in the tissue capillaries where the gaseous tension oxygen is much lower than in the lungs

Combination of HEMOGLOBIN with O2

O2 does not combine with the two positive bonds of the iron in the hemoglobin molecule Instead, it binds loosely with one of the so-called coordination bonds of the iron atom Loose bond =} combination is easily reversible Oxygen does not become ionic oxygen, but is carried as 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

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 heme compounds 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

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

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

Normally..
Even though mature RBCs do not have nucleus, mitochondria, or ER yet they have cytoplasmic enzymes that are capable of metabolizing glucose and small amounts of ATP and NADPH

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 of methemoglobin, which can not carry OXYGEN

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

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 OF ABNORMAL RED BLOOD CELLS AND OLD CELLS CIRCULATING IN THE BLOOD ALSO INCREASES CONSIDERABLY

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

DESTRUCTION OF HEMOGLOBIN
The porphyrin portion/molecule is converted by the macrophages (thru a series of stages) into the bile pigment called BILIRUBIN BILIRUBIN is released into the blood and later secreted by the liver into the bile

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 hemoglobin inside them MICROCYTIC, HYPOCHROMIC ANEMIA

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)

ANEMIASMajor classification
  

APLASTIC ANEMIA Bone marrow aplasia Lack of a functioning bone marrow May be due to: gamma ray radiation, excessive xray treatment, chemotherapeutics drugs which are suppresants

ANEMIASMajor classification


 

MEGALOBLASTIC ANEMIA Vit B12 and folic acid deficiency, and lack of secretion of 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 due to gastrectomy; intestinal sprue which leads to poor absorption of important vitamins and minerals

ANEMIASMajor classification
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 not loose, and are not baglike in consistency => ruptures easily even with slightest compression. 2. SICKLE CELL ANEMIA abnormal type of hemoglobin called HEMOGLOBIN S Leads to serious decrease of RBC mass DEATH

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 the appearance of being a sickle rather than biconcave disc The precipitated hemoglobin also damages the cell membrane making the RBC highly fragile

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 the peripheral 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

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 higher level Sequelae: greatly increased workload to the HEART

POLYCYTHEMIA

Two forms: SECONDARY POLYCYTHEMIA and POLYCYTHEMIA VERA

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 of delivery 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

POLYCYTHEMIA VERA
RBC count may reach 7-8Million, and the hematocrit is 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 increases to twice the normal BLOOD BECOMES VISCOUS

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)