lec 05 · 2021. 1. 20. · lec 05: function of hemoglobin and erythropoiesis assist. prof. dr....
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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
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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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