Lec 05:Function of Hemoglobin and

Erythropoiesis

Assist. Prof. Dr. Mudhir S. Shekha

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Heme has a variety of functions. As a cofactor

• Oxygen transport

in hemoglobin

• Storage in

myoglobin

• A prosthetic group

for cytochrome

p450 enzymes

• A reservoir of iron

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Heme has a variety of functions. As a cofactor

• Electron shuttle of enzymes in the electron transport chain

• Cellular respiration

• Signal transduction-heme regulates the antioxidant response to circadian rhythms, microRNA processing

• Cellular differentiationand proliferation

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Difference between oxygenation

and oxidation of Hemoglobin

OXYGENATION

• Iron(fe +2) IN

FERROUS STATE

• Carrier of oxygen

OXIDATION

• Iron(fe +3) IN FERRIC

STATE

• Oxygen carrying capacity is lost

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Functions of Hemoglobin

• Oxygen delivery to the tissues

• Reaction of Hb & oxygen

• Oxygenation not oxidation

• One Hb can bind to four O2 molecules

• Less than 0.01 sec required for oxygenation

• When oxygenated 2,3-DPG is pushed out

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Normal Hemoglobin Function

• When fully saturated, each gram of hemoglobin binds 1.34 ml of oxygen.

• The relation between oxygen tension and hemoglobin oxygen saturation is described by the oxygen-dissociation curve of hemoglobin.

• The characteristics of this curve are related to pH, temperature, ionic strength, and concentration of phosphorylatedcompounds, especially 2,3-diphosphoglycerate (2,3-DPG).

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O2• HBO2→ 97 %• O2 Dissolved in

Plasma→ 3%

CO2• CO2 in HB→ 20% • bicarbonate buffer

system→ 70%• CO2 Dissolved in

Plasma→ 10%

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Hb-oxygen dissociation curve

is a curve that plots the proportion of hemoglobin in its saturated (oxygen-laden) form on the vertical axis against the prevailing oxygen tension on the horizontal axis

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Hb-oxygen dissociation curve

• Right shift (easy oxygen delivery)

• High 2,3-DPG

• High H+

• High CO2• HbS

• Left shift (give up oxygen less readily)• Low 2,3-DPG

• HbF

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NORMAL VALUES OF HEMOGLOBIN

• 1 year – 10-12 gm/dl

• Males - 14 – 17 gm/100ml

• Females- 12 – 15 gm/100ml

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• Replaced at a rate of approximately 3 million new blood cells entering the circulation per second.

• Replaced before they hemolyze• Components of hemoglobin individually recycled

– Heme stripped of iron and converted to biliverdin, then bilirubin

• Iron is recycled by being stored in phagocytes, or transported throughout the blood stream bound to transferrin

• RBC life span 120 days only, short because of the lack of nuclei

• RBC is soft colloid to change shape in various sized vessels

RBC life span and circulation

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Red Blood Cell Turnover

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Erythropoiesis

• A hemocytoblast is transformed into a committed cell called the proerythroblast

• Proerythroblasts develop into early erythroblasts

• The developmental pathway consists of three phases

– Phase 1 – ribosome synthesis in early erythroblasts

– Phase 2 – hemoglobin accumulation in late erythroblasts and normoblasts

– Phase 3 – ejection of the nucleus from normoblasts and formation of reticulocytes

• Reticulocytes then become mature erythrocytes

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Erythropoiesis

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Circulating erythrocytes – the number remains constant and reflects a balance between RBC production and destruction

– Too few RBC leads to tissue hypoxia

– Too many RBC causes undesirable blood viscosity

• Erythropoiesis is hormonally controlled and depends on adequate supplies of iron, amino acids, and B vitamins

Regulation and Requirements for Erythropoiesis

Hormonal Control of ErythropoiesisErythropoietin (EPO) release by the kidneys is triggered by:

– Hypoxia due to decreased RBCs– Decreased oxygen availability– Increased tissue demand for oxygen

Enhanced erythropoiesis increases the: – RBC count in circulating blood– Oxygen carrying ability of the blood 15

Erythropoietin Mechanism

Stimulus:

• Hypoxia due to

decreased RBC

count,

• decreased

availability of O2 to

blood,

• increased tissue

demands for O2

Start

burst forming unit-erythroid

Colony Forming Unit-erythroid

Erythropoietin receptor

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Erythropoiesis requires:

– Proteins, lipids, and carbohydrates

– Iron, vitamin B12, and folic acid

– The body stores iron in Hb (65%), the liver, spleen, and bone marrow

– Intracellular iron is stored in protein-iron complexes such as ferritin and hemosiderin

– Circulating iron is loosely bound to the transport protein transferrin

Dietary Requirements of Erythropoiesis

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Destruction of erythrocytes• Cell decrease deformability in microcirculation is

associated with;

• increase in red cell rigidity

• increase in blood viscosity,

• obstructed blood flow and cell fragmentation

The changes in deformability depends on

• Maintenance of cell geometry or biconcave shape

• Normal internal or hemoglobin fluidity

• Intrinsic membrane deformability or viscoelasticproperties fragmentation

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Modes of erythrocyte destruction1. Change in membrane permeability

2. Phagocytosis where (Na+, K+) levels are altered leading to increased osmotic fragility and hemolysis

3. Macrophage phagocytosis is extra-vascular hemolysis with increased un-conjugated bilirubin

4. Fragmentation, within circulation is intravascularhemolysis, followed by hemoglobinemia and hemoglobunuria hemolysis

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1. Ferritin is the primary iron storage form . It is water-soluble protein-ironcomplex and contains a spherical shell of apoprotein enclosing a core of hydrated ferric phosphate. A single ferritin molecule can hold upto 4500 iron atoms.

2. Hemosiderin is a brown pigment that is present in reticuloendothelial cells of bone marrow, spleen and liver. And higher iron protein/iron ration than ferretin

3. Transferrin: A plasma protein that transports iron through the blood to the liver, spleen and bone marrow. 20

Iron-binding proteins

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