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MBBS Lecture


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Pigment present inside RBCs Carries O 2 and CO 2 Responsible for red color of blood Deficiency is called anaemia

Disadvantages of Free Hb:

Disadvantages of Free Hb increase in blood viscosity, causing a rise in blood pressure. osmotic pressure of plasma to @ 100mm Hg which interferes with fluid exchange between capillaries & tissue spaces. Loss in urine ( Haemoglobinuria ) kidney damage by forming acid haematin . Taken up & rapidly destroyed by the tissue Macrophase system.

Normal values:

Normal values In foetus - just before birth the Hb concentration of blood from umbilical cord is = 16.5 to 18.5 gm/dl. After birth=23gm% this occurs due to –transfusion of cells from placenta to infant & haemoconcentration by reduction of plasma volume At the end of 3 months = 10.5 gm/dl At the end of 1 year = 12.5gm/dl Adult male = 14-18 gm/dl Adult female = 12-15.5 gm/dl Clinically 14.8gm% Hb is considered 100% Hb

Quantity of Haemoglobin in the Cells & amount of O2 carried. :

Quantity of Haemoglobin in the Cells & amount of O2 carried. Men: Hb : 15 grams per 100 ml of blood; and Women: Hb : 14 grams per 100 ml. one gram of haemoglobin carries 1.34 ml of oxygen when fully saturated . Therefore, in man 100 ml of blood can carry @ 20 ml of oxygen and in women@ 19 ml of oxygen.


Haemoglobin Human hemoglobin A, present in adults, consists of four subunits: two α -subunits and two ß-subunits. The α - and ß-subunits are homologous and have similar three-dimensional structures. The capacity of hemoglobin to bind oxygen depends on the presence of a bound prosthetic group ( heme ) . The heme group is responsible for the distinctive red color of blood.

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The heme group consists of a protoporphyrin , and a central i r on atom. Protoporphyrin is made up of four pyrrole rings linked by methene bridges to form a tetrapyrrole ring. Four methyl groups, two vinyl groups, and two propionate side chains are attached.

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Iron- protoporhyrin - globin forms a subunit 4 subunits join to form a molecule of Hb Iron is in ferrous ( Fe 2+ ) form Fe 2+ binds 4 pyrrole rings, polypeptide chain and a molecule of O 2 STRUCTURE OF HEMOGLOBIN

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4 pyrroles join to form a ring called porphyrins 4 polypeptide chains constitute globin α,β,γ and δ are four important polypeptide chains α chain has 141 a.a β and γ chain have 146 a.a

GLOBIN (protein part or apoprotein): :

GLOBIN (protein part or apoprotein ): It is composed of four polypeptide chains 2 α and 2 β chains. The α -chain contains 141 amino acids and β -chain contains 146 amino acids. Each β -polypeptide chain is folded into 8 right handed α -helices ( starting from NH 2 -terminal) α -subunit is folded into 7 α -helices. The ratio of haem to globin is 1:1 . So each haem moiety is linked to one peptide chain.

Attachment of haem to globin:

Attachment of haem to globin One Hb molecule contain 4 units of Haem each attached to one of the 4 polypeptide chains, constituting globin . Thus one Hb mol. Can carry 4 molecules (8 atoms) of oxygen. Oxygenation of 1 st haem mol. In Hb increases the affinity of second mol. for O 2

Attachment of haem to globin:

Attachment of haem to globin and affinity for O 2 in 3 rd haem mol. Therefore 4 th haem-gr of Hb has highest affinity for O 2 . This shifting affinity of Hb for O 2 result in sigmoid shape of O 2 -Hb curve. Oxygenation of Hb is very rapid <.01 seconds. Hb at it’s normal con. Increases the O 2 carying capacity of blood 70 folds

Hb-oxygen dissociation curve:

Hb-oxygen dissociation curve


Haemoglobin Reaction of Hb & oxygen Oxygenation not oxidation One Hb can bind to four O 2 molecules Less than .01 sec required for oxygenation b chain move closer when oxygenated When oxygenated 2,3-DPG is pushed out b chains are pulled apart when O 2 is unloaded, permitting entry of 2,3-DPG resulting in lower affinity of O 2

Oxy & deoxyhaemoglobin:

Oxy & deoxyhaemoglobin

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Types 4 types of poly peptide chains based on amino acid composition and sequence. alpha, beta, gamma, delta Adult Hb Hb A = 2 alpha (141 AA)+ 2 beta (146 AA) chains (α 2 β 2 ) Hb A 2 = 2 alpha (141 AA)+ 2 delta (146 AA) chains (2.5%) 1 (α 2 δ 2 ) (10 AA differ) Fetal Hb Hb F = 2 alpha (141 AA)+ 2 gamma (146 AA) chains ( α 2 γ 2 ) (37 AA differ) 99% replaced with adult Hb with in a year of birth.


TYPES OF HEMOGLOBIN HbA - Adult Type- α 2 β 2 HbA 2 - 2% of adult Hb - α 2 δ 2 HbF - Fetal Type- α 2 γ 2 Hb gower 1 - ε 2 ζ 2 Hb gower 2 - ζ 2 β 2

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HbA - Adult Type - α2β2 It is the main form of normal adult Hb . It is spheroidal molecule with a molecular weight of 68000 HbA 2 - 2% of adult Hb - α 2 δ 2 In Hb A 2 10 individual Amino Acids differ from those in beta chain of HbA

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III. Fetal haemoglobin = HbF ( α 2 γ 2 ): It is present normally in newborn and early fetal life and at age of 5 months 90 % of fetal haemoglobin is replaced by adult haemoglobin ( HbA 1 ) - It consists of 2 alpha chains and 2 gamma chains. - In gamma chain there is 37 amino acid different from those in HB A. - HbF has a great affinity for O 2 because γ -chains do not bind 2,3 DPG well. DPG is responsible for lowering the O 2 affinity of Hb and allowing Hb to release O 2 at the low PO 2 of tissues.

Fetal Hb-(HB-F):

Fetal Hb -(HB-F) Due to this movement of o 2 from maternal to fetal circulation is facilitated. At PO 2 20 mmHg , Hb -F is 70% saturated while Hb -A is only 30-35% saturated. Life span of Hb -F is much less (80 days) as compared to that of Hb -A(120 days)

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Hemoglobin Genes and Gene Products

Synthesis of globin:

Synthesis of globin Various types of globin combines with haem to from different haemoglobin Eight functional globin chains, arranged in two clusters the b - cluster ( b , g , d and e globin genes) on the short arm of chromosome 11 a - cluster ( a and z globin genes) on the short arm of chromosome 16

Globin gene clusters:

Globin gene clusters

Synthesis of globin:

Globin synthesis, starts at 3 rd week of gestation Embryonic Haemoglobin Gower I ( z 2 e 2 ) Haemoglobin Portland ( z 2 g 2 ) Haemoglobin Gower II ( a 2 e2 ) Fetal : HbF ( a 2 g 2 ), HbA ( a 2 b 2 ) Adult : HbA, HbA2 ( a 2 d 2 ), HbF. Synthesis of globin

Globin chain switch:

Globin chain switch

Hemoglobin (Hb):

Hemoglobin ( Hb ) Red, oxygen carrying pigment present in RBCs. Heme (4%) Globin (96%) Quantity 700-900g in body 29-32 pico gram/RBC(MCH) RBCs (MCHC) Male= 36g/100ml Female = 34g/100ml Molecular Weight 68,000 30

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deoxyHb deoxyMb Myoglobin and Hemoglobin Structure     oxyMb (MbO 2 ) O 2


DERIVATIVES OF Hb 1) Oxyhaemoglobin (HbO 2 ) – oxygenation reaction – combination with Fe 2+ 2) Carbaminohaemoglobin ( CO 2 Hb)  carbon dioxide combines with globin part 3) Carboxyhaemoglobin ( COHb )  carbon monoxide binds with Fe 2+ { 250 times more affinity than oxygen }

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4) Methhaemoglobin ( HHb )  oxidized haemoglobin 5) Sulfhaemoglobin 6) Glycated haemoglobin (HbA 1c )  Glucose attached to terminal Valine in β chain. – integrated index of Diabetic control over 4 to 6 weeks

Methemoglobin :

Methemoglobin This is oxidized Hb , The Fe 2+ normally present in heme being replaced by Fe 3+, the ability to react as an O 2 carrier is lost. The normal erythrocyte contains small amount of met Hb , formed by spontaneous oxidation of Hb . Met Hb is normally reconverted to Hb by reducing systems in the RBC, the most important of which is NADH- methemoglobin reductase .

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Congenital methemoglobinemias A. Hemoglobin M ( Hb -M): It is a congenital condition due to mutation in globin biosynthesis in which distal or proximal histidine is replaced by tyrosine. B . Deficiency of NADH cytochrome b 5 methemoglobin reductase system Acquired (toxic) methemoglobinemea Usually arises following the ingestion of large amounts of drugs e.g. phenacetin or the sulphonamides , excess of nitrites or certain oxidizing agents present in the diet.

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II . Glycosylated haemoglobin ( Hb A 1c ): It is modified form of haemoglobin . it contains glucose linked to amino group present on the NH 2 - terminal ends. The reaction is non enzymatic and its rate depends on the concentration of glucose .It is present in normal value -5% of the total haemoglobin . This glycohaemoglobin gives an idea about the blood glucose level during the last three months and is useful in the assessment of diabetic control This percentage is increased in diabetic patients up to 8-14%.


FUNCTIONS OF HEMOGLOBIN 1. Transports O 2 from lungs to tissues in the form of oxy-hemoglobin 2. Transports CO 2 from tissues to lungs in the form of carbamino-hemoglobin:- 30% of total CO 2 transport 3. Acts as a buffer - important in acid-base balance- 6 times more than plasma proteins

Hemoglobin (Hb):

Hemoglobin (Hb) 250 million Hb molecules / RBC So carry 1 billion oxygen molecules / RBC Synthesis of Hb Starts at proerythroblastic stage Synthesis steps: Heme is made from acetic acid and glycine in mitochondria Acetic Acid  α- ketoglutaric Acid  Succinyl Co A (Krebs Cycle) Globin (polypeptide chain) is synthesized by Ribosomes 38



Synthesis of Haemoglobin:

Synthesis of Haemoglobin


FATE OF HAEMOGLOBIN RBCs are destroyed in RES ( mainly spleen and bone marrow) after 120 days of life. Macrophages phagocytose – hemolyse - degrade haemoglobin – form Bilirubin – transport to liver with albumin – conjugated and detoxified – secreted in bile.


HAEMOGLOBINOPATHIES Abnormal formation of Hb Due to disorders of Globin Synthesis Two main types Formation of abnormal polypeptide chain e.g.- Sickle cell Anaemia Supression of synthesis of polypeptide chain e.g - Thalassaemia

Sickle Cell anemia:

Sickle Cell anemia Sickle Cell Anemia is a genetic disorder that is characterized by the formation of hard, sticky, sickle-shaped red blood cells, in contrast to the biconcave-shaped red blood cells (RBCs) found in “normal” individuals. This disease is caused by a mutation in hemoglobin.

Spectroscopic view of RBC in Sickle cell anemia:

Spectroscopic view of RBC in Sickle cell anemia 46

Sickle cell anaemia: :

Sickle cell anaemia : Valine replaces glutamate in the 6 th position of β chain. Is common in African blacks Hb crystallizes & takes sickle shape under hypoxic conditions. Increased tendancy towards haemolysis

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Heterozygous  H alf the circulating hemoglobin is abnormal and half is normal. Have sickle cell trait Homozygous  all of the hemoglobin is abnormal . Develop the full blown disease

Sickle Cell Disease:

Sickle Cell Disease Hemoglobin S ( HbS ) ≥ 50% Hb present. Homozygotic HbSS (sickle cell anemia) - HbS = 100% Hb present, Giving Sickle cell disease HbSA disease - heterozygote for HbS and HbA , with intermediate clinical severity. It is called Sickle cell trait

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Basic abnormality - glutamic acid is replaced by valine at the sixth position of the  - globin chain. 2 normal  - globin and 2 abnormal  - globin chains forms HbS . HbS carries O 2 normally but begins to form semisolid aggregate structures once O 2 is unloaded to the tissues. These HbS aggregates distort RBCs and cause them to lose their normal elasticity. Molecular and cellular changes of hemoglobin S

Anemia - reduced O2 carrying capacity of the blood:

Anemia - reduced O 2 carrying capacity of the blood Abnormal hemoglobin in RBCs : Sickle Cell - one amino acid in the beta chains is wrong. In low O 2 conditions the beta chains form stiff rods which cause RBCs to sickle blocking small vessels.

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Hb-S polymerizes at low O 2 tensions, and this causes the red cells to become sickle-shaped, hemolyze , and form aggregates that block blood vessels. The result is the severe hemolytic anemia known as sickle cell anemia.

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The sickle cell gene is an example of a gene that has persisted and spread in the population. It originated in the black population in Africa, and it confers resistance to one type of malaria. Africa = 40% of the black population have the sickle cell trait. In United States 10 % Treatment: Bone marrow Transplatation Hb-F production by hydroxyurea .


Thalassemia Thalassemia is a group of inherited disorders of hemoglobin synthesis characterized by a reduced or absent output of one or more of the globin chains of adult hemoglobin . The name is derived from the Greek words Thalasso = Sea" and "Hemia = Blood" in reference to anemia of the sea . Thalassemia result from over 150 mutations of the globin genes that result in the absence or a reduction of the globin chains( α or β ) 55

Thalassaemias: :

Thalassaemias : The name is derived from the Greek word thalassa,which means sea.Greek identified this disease present around Mediterranean sea. They are hereditary hemolytic diseases in which the synthesis of either α - or β - globin chain is reduced/absent. This decreased rate of synthesis of the globin chains is due to mutation affecting the regulatory gene rather than the structural gene.


Chromosomes 57

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Alpha (  ) thalassemia It appears when a person does not produce enough alpha chains for hemoglobin. It is mainly prevalent in the Africa, the Middle East , India, and occasionally in Mediterranean region countries. There are four types categorized according to the severity of their effects on persons with thalassemia :- Silent Carrier State (1 affected gene) Alpha Thalassemia Trait (2 affected genes) Hemoglobin H Disease (3 affected genes) Alpha Thalassemia Major (also called hydrops fetalis, 4 affected genes) 58

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α - thalassaemias : there are decreased or absent synthesis of α -chains of haemoglobin with compensatory increase in the synthesis of other chains. a.Homozygous α -chain thalassaemia ( thalassaemia α major): Incompatible with life, and present as hydrops foetalis usually die in utero , due to complete absence of α -chains which are required for synthesis of HbF . b.Heterozygous α -chain thalassaemia thalassaemia α minor,(trait):

Alpha Thalassemia:

Alpha Thalassemia Alpha thalassemia is caused by mutations in the alpha chain of the hemoglobin molecule Major :all four alpha chain genes are deleted , which is so severe that death can occur in utero (prior to birth). Minor : two alpha chain genes are deleted Silent Carrier State ,Mild .

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All 4 genes deleted 3 genes defective & 1 normal 2 genes normal 2 genes defective

Types of α thalassemia:

Types of α thalassemia Silent Carrier State (1 affected gene) The silent carrier will have normal hemoglobin levels and red cell indices but can pass on the affected gene to their offspring. Often, these individuals are identified only after having a child with Hb H disease or alpha thalassemia trait. Alpha Thalassemia Trait (2 affected genes) Patients who have alpha thalassemia trait have red blood cells that are microcytic, hypochromic, have decreased MCV, and have a mild chronic anemia, but they do not generally experience any other symptoms. This is an anemia that does not respond to iron supplements. 62

Types of α thalassemia:

Types of α thalassemia Hemoglobin H Disease (3 affected genes) With this condition, the decrease in the amount of alpha globin chains produced causes an excess of beta chains, which then aggregate into beta tetramers (groups of 4 beta chains), known as Hemoglobin H. Hb H disease can cause moderate to severe anemia and splenomegaly (enlarged spleen). Some individuals are asymptomatic while others have severe anemia. Hemoglobin H disease is found most often in individuals of Southeast Asian or Mediterranean descent. 63

Types of α thalassemia:

Types of α thalassemia Alpha Thalassemia Major (also called hydrops fetalis, 4 affected genes) This is the most severe form of alpha thalassemia. In this condition, no alpha globin is produced, therefore, no Hb A or Hb F are produced. 64

Hydrops Fetalis:

Hydrops Fetalis Foetuses affected by alpha thalassemia major become anaemic early in pregnancy. They become hydropic and frequently have enlarged hearts and livers (swollen abdomen). This diagnosis is frequently made in the last months of pregnancy when a fetal ultrasound indicates a hydropic foetus. About 80% of the time, the mother will have toxaemia and can develop severe postpartum bleeding (haemorrhage). Foetuses with alpha thalassemia major are usually miscarried, stillborn, or die shortly after birth. 65

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It appears when a person does not produce enough beta chains for hemoglobin. It is mainly prevalent in the Mediterranean region countries, such as Greece, Cyprus, Italy, Palestine and Lebanon. There are 3 types categorized according to severity: Thalassemia minor Thalassemia intermedia Thalassemia major Beta ( ß ) thalassemia 66

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B ) β - thalassaemias : Synthesis of of β -chains is decreased or absent whereas synthesis of α -chains is normal and will combine with δ -chains giving excess of HbA 2 ( α 2 δ 2 ) or it may combine with γ -chains producing excess of HbF ( α 2 γ 2 ). The abnormal haemoglobin do not function as normal haemoglobin - Homozygous ( Thalassaemia β - major = Cooley's anaemia = Mediterranian sea anaemia ): There is complete absence of β - globin chain and there is marked increase of HbF . - Heterozygous thalassaemia ( Thalassaemia β - minor): There is slow rate of synthesis of β - globin chain.


THALASSEMIA DIAGNOSIS complete blood count (CBC) - a measurement of size, number, and maturity of different blood cells in a specific volume of blood. hemoglobin electrophoresis with A2 and F quantitation - a lab procedure that differentiates the types of hemoglobin present. FEP (free-erythrocyte protoporphyrin ) and ferritin - to exclude iron deficiency anemia

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Management and treatment Thalassemia minor (trait) : No need for any treatment, since the carriers are usually symptomless . Thalassemia major: The severe life-threatening anemia, requires regular life long blood transfusion, to compensate for damaged red blood cells . The continuous blood transfusion will eventually lead to iron overload, which must be treated with chelation therapy to avoid organ failure. 71

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Management and treatment Other novel treatments like bone-marrow transplantation are very costly. New treatments includes the use of oral chelators, to replace the chelation treatment using Desferal delivered by infusion under the skin through a battery-operated pump. Gene therapy is also an option still researched 72

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Other molecules containing Haem :- i ) Myoglobin – present in muscles - combination with single polypeptide chain. ii) Neuroglobin – present in CNS iii) Cytochrome enzymes – present in mitochondria iv ) Peroxidases

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