Red Blood Cells (Erythrocytes)
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Red Blood Cells (Erythrocytes). Er ythrocytes (RBC). Structure Biconcave disc shape Includes Hemoglobin Lipid s , ATP, carbonic anhydrase Function O 2 and CO 2 transport. Er ythrocytes (RBC). Most abundant type of blood cells 4- 6 million /mm 3 anemi a ; number of RBC below normal

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Er ythrocytes rbc
Erythrocytes (RBC)

  • Structure

    • Biconcave disc shape

  • Includes

    • Hemoglobin

    • Lipids, ATP, carbonic anhydrase

  • Function

    • O2 and CO2 transport


Erythrocytes (RBC)

  • Most abundant type of blood cells

    • 4-6million/mm3

    • anemia; number of RBC below normal

    • polycythemia (erythrocytosis); number of RBC above normal range

  • No nucleus, mitochondria and ribosom

    • No protein synthesis

    • Energy is obtained through glycolisis, but there is no glycogen storage

  • Normal diameter 7-8 , volume 78-94 3

    • normocyte - microcyte - macrocyte


Energy use and source in RBC

  • Energy is used mainly for two functions:

    • Continuation of membrane shape - active transport

    • Homeostasis of intracellular oxidation-reduction

  • Only source of energy is glycolysis


RBC Membrane

  • The same as other biological membranes

    • Cannot synthesize its own cell membrane

  • Actin and spectrin provide strength

    • Contractility in the presence of Ca+2 ions

    • Changes in viscosity

  • Na+-K+ATPaseand Ca+2ATPase activity

  • Carbohydrates on the membrane are to do with blood types (antigens)


Hemoglobin (Hb)

  • Red color protein that carries oxygen

    • 1 g Hb binds 1,3 mlO2; 14,8 g Hb binds 20 ml O2

  • Normal range of hemoglobin: 14-16 g/dl

    • In adults, about 25-30 trillion RBC, and 900 g Hb

    • Hb constitutes 1/3 of erythrocyte weight


Hemoglobin
Hemoglobin

  • 4 globin molecules:carries CO2 (role of carbonic anhydrase)

  • 4 heme molecules:carries O2

    • Iron is required for oxygen transportation


Hematopoiesis hemopoiesis
Hematopoiesis (Hemopoiesis)

  • Production of blood cells

  • Stem cells: All formed elements of blood stem from a colony of cells

    • Proerythroblast: forms erythrocytes

    • Myeloblast: forms neutrophils, eosinophils and basophils

    • Lenfoblast: forms lymphocytes

    • Monoblast: forms monocytes

    • Megakaryoblast: forms thrombocytes



What are stem cells
What are stem cells?

  • They are of many types: epidermal, intestinal, hematopoietic, etc.

  • The defining properties of a stem cell are:

    • It is not terminally differentiated.

    • It can divide without limit.

    • When it divides, the daughter cell has a “choice”:

      • Remain a stem cell, or

      • Terminally differentiate.



Potentiality of stem cells1
Potentiality of Stem Cells

“Stem cells” have varying potentials:

  • Totipotent cells.Fertilized oocyte (zygote) & progeny of the first two cell divisions. Cells able to form the embryo and the trophoblast of the placenta.

  • Pluripotent cells. After about 4 days, the blastocyst forms; embryonic stem cells obtained from the inner cell mass, which becomes the embryo, are pluripotent, able to differentiate into almost all cells of the three germ layers – but not into an embryo.

  • Multipotential cells. Found in most tissues, these cells can produce a limited range of differentiated cell lineages appropriate to their location. (Hematopoietic stem cells from the bone marrow exemplify multipotential cells.)

  • Unipotential cells. Cells capable of generating only one cell type (epidermal stem cells, adult liver stem cells).


Rbc formation erythropoiesis
RBC Formation (Erythropoiesis)

  • In the adult, all blood cell formation (including erythropoiesis) occurs in the red bone marrow

  • All blood cells develop from stem cells called hemocytoblasts

Red Blood Cells

Monocytes

Platelets

Granulocytes

Myeloid Stem Cell

Hemocytoblast

Lymphoid Stem Cell

Lymphocytes



Erythropoiesis production of rbc
Erythropoiesis (production of RBC) hematopoietic stem cell (P-HSC)

Weeks 16-20

Week 2

Week 6

Birth

Week 8

Myeloid phase

Spleen

Hepatic phase

Mesoblastic phase

Myeloid phase

Prenatal Life

Postnatal Life


P hematopoietic stem cell (P-HSC)renatal period-1

  • Mesoblastic phase

  • It starts in the vitellus sac at the second week

    • These are erythrocytes with nuclei

  • Embriyonic hemoglobins:

    • Hb Gower I, Gower II and Portland 1


P hematopoietic stem cell (P-HSC)renatal period-2

  • Hepatic phase

  • Liver takes part starting from the week 6

  • Spleen is involved starting from the week 8

  • Fetal hemoglobin:

    • HbF (2 and 2 )


P hematopoietic stem cell (P-HSC)renatal period-3

  • myeloid phase

  • Starts between the weeks 16 and 20 in the bone marrow

    • All bones

    • Hemopoiesis

  • HbA (2 and 2 ): mature hemoglobin


P hematopoietic stem cell (P-HSC)ostnatal Period

  • Only in the bone marrow(myeloid)

    • All bones contribute up to the age of 5

    • Later, erythropoiesis regresses from the distal to the proxymale

    • vertebra, sternum, costa, cranium and femur

    • Red bone marrow turns into yellow marrow (reversible)

      • Lipid infiltration


Sites of hemopoiesis in postnatal life hematopoietic stem cell (P-HSC)


E hematopoietic stem cell (P-HSC)rythropoiesis

  • BFU-E and CFU-E cells

    • Response to different levels of EPO

  • proerythroblast

  • basophil erythroblast

  • Polychromatophil erythroblast

  • Orthochromatophil erythroblast

  • Reticulocyte

  • Erythrocytes


Genesis of Red Blood Cells hematopoietic stem cell (P-HSC)


Regulation of Erythropoiesis hematopoietic stem cell (P-HSC)

  • Primary stimulus is hypoxia

  • Tissue oxygenation

    • Blood flow

    • Blood hemoglobin levels

    • Oxygen saturation of hemoglobin

    • Affinity of hemoglobin to oxygen


E hematopoietic stem cell (P-HSC)rythropoietin (EPO)

  • Fetus and newborn

    • 85% Liver

      • hepatocyte, Kupffer cells, endothelial cells

    • 15% kidney

      • Endothelial cells, glomerulus, JGH, proxymal tubule

  • Adult

    • 85% kidney

    • 15% liver and other tissues

      • glomus caroticum, macrophages


Regulation of Erythropoiesis hematopoietic stem cell (P-HSC)


E rythropoiesis
E hematopoietic stem cell (P-HSC)rythropoiesis

  • Erythropoietin: a hormone that stimulates erythropoiesis

    • It stimulates both differentiation and maturation


Maturation of red blood cells – Vit B hematopoietic stem cell (P-HSC)12 and Folic acid

  • Both vitamins are necessary for DNA synthesis

  • Deficiency of either of these vitamins causes maturation failure in the process of erythropoiesis

  • Pernicious anemia – Megaloblastic anemia

  • Vit B12 absorption and storage

  • Intrinsic factor: released from parietal cells in the stomach

  • Complex of Vit B12 + intrinsic factor cannot be digested by the enzymes in the stomach

  • Lack of intrinsic factor causes serious absorption abnormalities of Vit B12


Deformability of Erythrocytes hematopoietic stem cell (P-HSC)


H hematopoietic stem cell (P-HSC)emoglobin (Hb)

  • Normal range of hemoglobin: 14-16 g/dl

    • Men: 16 g/dl = 21 ml O2 /dl blood

    • Women: 14 g/dl = 19 ml O2 /dl blood


Formation of hemoglobin
Formation of Hemoglobin hematopoietic stem cell (P-HSC)

  • 2 succinyl-CoA + 2 glycine = pyrrole

  • 4 pyrrole protoporphyrin IX

  • protoporphyrin IX + Fe++ Heme

  • Heme + globin hemoglobin chain (alpha or beta)

  • 2 alpha + 2 beta chains Hemoglobin A


Hemoglobi n
Hemoglobi hematopoietic stem cell (P-HSC)n

  • Hemoglobin synthesis begins in the proerythroblasts and continues until reticulocytes

  • It consists of iron containing heme and globin

  • Hemoglobin A contains 2a ve 2b chain

  • There are different types of these chains (a, b, d ve g)

  • Hb molecule binds to oxygen loosely and reversibly


Hemoglobin a
Hemoglobin hematopoietic stem cell (P-HSC) A

  • 4 globin molecules:carries CO2 (role of carbonic anhydrase)

  • 4 hem molecules:carries O2

    • Iron is required for oxygen transportation


Lifecycle of an rbc
Lifecycle of an RBC hematopoietic stem cell (P-HSC)

  • RBCs are subjected to incredible mechanical stress.

    • Why are they unable to synthesize replacements for damaged parts?

  • After ≈120d, the RBC cell membrane ruptures, or the damage is detected by phagocytic cells and the RBC is engulfed.

  • If the RBC hemolyzes, its contained Hb will be excreted by the kidneys

A macrophage phagocytizing multiple RBCs


Life span and destruction of rbcs
Life span and destruction of RBCs hematopoietic stem cell (P-HSC)

  • Because of lack of nuclei, they cannot divide and grow

  • They have a life span of 120 days

  • Old erythrocytes are destructed in the spleen, liver and bone marrow

  • Hemoglobin is broken down to heme and globin

  • Iron part of heme is stored for re-use

  • Porphyrin part of hemoglobin is converted to bilirubin and secreted into bile


Iron – Fe hematopoietic stem cell (P-HSC)+2,+3

  • 50 in men and 35 mg/kg in women (total 4-5 gr)

    • 60-65% in hemoglobin

    • 4% myoglobin

    • 1% bound to plasma transferrin

    • The rest is in ferritin or hemosiderin

  • Amount of iron bound to transferrin 110-130 g

  • Daily need of iron lost through urine, feces and bleeding should be compensated


Transferrin - siderofilin hematopoietic stem cell (P-HSC)

  • It is a 1-globulin

  • It has two sides to bind iron (ferri)

    • One side leaves iron to the liver and the other to bone marrow for hemoglobin synthesis

  • Saturation of transferrin with iron (normally 35%)


Absorption of iron hematopoietic stem cell (P-HSC)

  • Iron is absorbed in ferro (+2) form

    • Absorption in all parts of the small intestine

  • It binds to apoferritin in the intestinal cells and stored as ferritin

  • Iron in ferritin is in the form of ferri (+3)

    • Liver is the largest storage site

    • Homeostasis is maintaned through the intestinal depot


Iron Transport and Metabolism hematopoietic stem cell (P-HSC)


Iron Overload Disease hematopoietic stem cell (P-HSC)

  • hemosiderin

  • hemochromatosis

    • Bronze diabetes

    • Cirrhosis

    • Cancer

    • Gonadal atrophy


Iron Deficiency hematopoietic stem cell (P-HSC)

  • Hepatic diseases

  • Deficiency of reducing substances in the digestive tract

    • Ca+2, ascorbic acid, lactic acid, pyruvate, glucose and sorbitol

    • Excessive Ca+2

  • Oxalate, phytate, phosphate

  • Important symptom: geophagy


Other factors hematopoietic stem cell (P-HSC)

  • Time of iron supplementation

  • Injections in cases of absorption problems

  • Overload of iron facilitates production of microorganisms

    • transferrin and lactoferrin are anti-microbial


Anemia hematopoietic stem cell (P-HSC)

  • Decrease in RBC count and/or amount of Hb

  • Reduced capacity of blood to carry O2

    • Tachycardia, tachypnea

    • Tiredness, feeling cold

  • General causes

    • Blood loss

    • Reduced erythropoiesis

    • Increased destruction of RBC

    • Inadequate of production of EPO


Classification of Anemias hematopoietic stem cell (P-HSC)

  • Hemorrhagic anemias; blood loss

  • Hemolytic anemias; hemolysis

  • Vitamin deficiency anemias (megaloblastic anemia)

  • Iron deficiency anemia

  • EPO deficiency caused anemia

  • Aplastic anemia (Fanconi anemia)


Hemolytic Anemias hematopoietic stem cell (P-HSC)

  • Intracorpuscular causes

    • hereditary spherocytosis

    • sickle cell anemia; HbS

    • thalassemia (Mediterranian anemia, cooley anemia)

    • glucose-6-phosphate dehydrogenase deficiency

    • Pyruvate kinase deficiency

    • Paroxysmal nocturnal hemoglobinuria

  • Extracorpuscular causes

    • Blood transfusion – autoantibodies


Sickle cell anemia
Sickle hematopoietic stem cell (P-HSC) Cell Anemia

  • Seen in black population

  • A mutation in the βchain of globin results in HbS

  • This hemoglobin precipitates as long crystals in RBC when it exposes to O2

  • As a result, RBC become sickle shaped and may cause blockage in small blood vessels


Sickle cell anemia sca
Sickle cell anemia hematopoietic stem cell (P-HSC) (SCA)

  • In SCA, aa valine takes the place of glutamic acid at the Hemoglobin beta polypeptide chain


Thalassaemia (Mediterranean Anemia) hematopoietic stem cell (P-HSC)

  • It is usually seen in populations in Mediterranean countries

  • One of the genes coding globin is faulty or missing


Glucose 6 phosphate dehydrogenase
Glucose 6-Phosphate Dehydrogenase hematopoietic stem cell (P-HSC)

  • Regenerates NADPH, allowing regeneration of glutathione

  • Protects against oxidative stress

  • Lack of G6PD leads to hemolysis during oxidative stress

    • Infection

    • Medications

    • Fava beans (that contain high level of oxidants)

  • Oxidative stress leads to Heinz body formation,extravascular hemolysis


G6pd deficiency function of g6pd
G6PD DEFICIENCY hematopoietic stem cell (P-HSC)Function of G6PD


Glucose 6 phosphate dehydrogenase g6pd anemia
Glucose -6-Phosphate Dehydrogenase (G6PD) Anemia hematopoietic stem cell (P-HSC)

Hereditary defect in RBC metabolism

  • Direct oxidation of hemoglobin damages RBC

  • occurs when person exposed to stressors: aspirin, sulfonamides, Vitamin K derivatives

    Manifestations: pallor, jaundice, hemoglobinuria, elevated reticulocyte count

    Diagnostics: quantitative assay of G6PD


Er yth roblastosis f e talis
Er hematopoietic stem cell (P-HSC)ythroblastosis Fetalis

  • It is a hemolytic type of anemia

  • Rh- mother, Rh+ father

  • First baby will be Rh+

  • Mixture of baby’s blood with that of mothers during labor

  • Sensitization develops in the mother against Rh+ and antibodies are formed against to Rh antigen

  • First baby is healthy

  • During the second pregnancy, the antibodies formed against Rh are transported to the baby through placenta and attack fetus’ RBC

  • This condition is known as erythroblastosis fetalis (hemolytic disease of new born)

  • Baby is anemic and hypoxic.

  • Exchange transfusion of compatible blood to the baby

  • If not treated, it may cause brain damage and death

  • http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1871554&pageindex=1


Vitamin Deficiency Caused Anemia hematopoietic stem cell (P-HSC)

  • folic acid

  • vitamin B12

  • vitamin B6

  • vitamin C

  • vitamin E


Iron Deficiency Anemia hematopoietic stem cell (P-HSC)

  • How does iron deficiency affect O2 transport?

  • It could develop secondary to hemorrahegia

  • Iron deficiency may also present as a result of low iron intake or absorption problems in the GI tract


Red Bone Marrow in Aplastic Anemia hematopoietic stem cell (P-HSC)

Normal Red Bone Marrow


Polycythemia hematopoietic stem cell (P-HSC)

  • Total number of erythrocytes is more than the normal range

  • Polycythemia vera (erythremia):

    • Cancer of red bone marrow

    • RBC count 7-8 million/mm3

    • Hematocrit value 60-70 %

  • Secondary polycythemia: long term hypoxia

    • Cardiac failure

    • Pulmonary diseases

    • High altitude (physiological)

    • Sportive activity (physiological)


Polycythemia hematopoietic stem cell (P-HSC)

  • Causes an increase in blood pressure

  • Less blood supply to the tissues

  • Decreased blood flow as a result of increased viscosity

  • Color of the skin with polycythemia vera looks bluish (cyanotic) – subpapillary plexus

  • For treatment, blood whould be diluted with an isotonic solution (serum physiologic)

► Some athletes try to induce physiological polycythemia?

Why and How?


Secondary Polycythemia: hematopoietic stem cell (P-HSC)Long term hypoxia


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