1. Hemoglobin metabolism & diseases of hemoglobin

5. T & R form of Hb

6. Co-operative binding of oxygen

7. Binding of oxygen Mb Vs Hb

16. Transport of carbondioxide

17. Transport of carbondioxide

18. Bohr’s effect

19. Hemoglobinopathies
Hemoglobinopathies are the disorders caused by the synthesis of abnormal hemoglobin or insufficient production of normal hemoglobin or rarely both
Sickle cell hemoglobin:- abnormal hemoglobin
Thallasemias:- insufficient synthesis of hemoglobin

20. Sickle cell hemoglobin

21. DEFINITION:
When biological function is altered due to mutation in hemoglobin.
CAUSES:
(a) Mutation in structural gene  Abnormalities in the primary sequence of globin chain.
Exp. Hb-S, Hb-M, Hb-C, Hb-D, etc.
(b) Mutation in regulatory gene  Abnormalities in rate of synthesis. Exp. Thalassemias.
95% (single gene mutation/ point mutation) & others – frame shift mutation & terminator codon mutation
EFFECT OF ABNORMAL HAEMOGLOBIN:
Abnormalities in red cell morphology.
Clinical manifestation  haemolytic anaemia/ jaundice.

22. Genetic control of Hb synthesis 2 1
 like gene
chrom 16  G A  
chr-11
 like gene
Normally synth of  &  ( in fetus) is carefully balance  correct tetramer assembly

23. TYPES:
(a) Quantitative/ Structural gene defect
E.g. Sickle cell anaemia
(b) Qualitative/ Regulatory gene defect
E.g. Thalassaemias ( & )
STRUCTURAL HAEMOGLOBIN VARIANTS
Replacement/ alteration of single AA
Insertion/ deletion of AA or
Polypeptide fusion

24. SICKLE CELL ANAEMIA (HbS)
> 60 million carrier & 100,000 affected infant annually
Homozygous inheritance disorder
PATHOPHYSIOLOGY:
GENETIC DEFECT: Point/Frame shift
GAG  GUG [Glu acid  valine]
on 6th position of  chain of globin  HbS

25. BIOCHEMICAL EXPLANATION OF SICKLING
Glu (Hydrophilic/Polar)  Valine (hydrophobic/non-polar)
Less negative charge than HbA (Hb surface charge).
 localized stickiness on surface of  chain.
 deoxygenated HbS  sticky patch bind with complementary patch  polymerisation.
 intracellular fibres are formed.
 distortion of cells into sickle shaped.
PREVENTION OF SICKLING:
Hb in oxygenated form or  Deoxy Hb.
TYPES:
(a) Homozygous – % HbS & 0-20% HbA.
(b) Heterozygous – may be asymptomatic 20-40% HbS & 60-80% HbA.

27. SYMPTOMS:
Anaemia (6 – 8g/dL)
RBC more fragile (10 – 15 days)
Cells are rigid  solubility  obstruct the flow  vasoocclusion  tissue hypoxia.
Extreme pain & tissue death.
Susceptible to infection.
RELATIONSHIP WITH OTHER DISEASES
Protection from malaria.
 incidence to salmonella infection.

28. DIAGNOSIS
Sickling test
Electrophoresis

29. THALASSEMIAS
Autosomal recessive disorders
Gene function is abnormal.
TYPES:
(a)  Thalassemias -   chain
(b)  Thalassemias -   chain

30.  THALASSEMIAS
 synth/ total absence of  globulin
involve the genes HBA1& HBA2 and forms 4
 THALASSEMIA
 synth / total absence of  globin chain  (4) or toxic aggregates

31. Operator gene/ Regulator gene defect.
GENETICS:
Defect in mRNA for affected globin chain (quantitative/ qualitative)
DEFECTS:
Operator gene/ Regulator gene defect.
Lowered stability of mutant mRNA.
Loss of start signals for translation of mRNA.
Non-sense mutations lead to premature chain termination.
Abnormal post transcriptional processing
Rapid degradation of highly unstable globin chain.

32. Types of  Thalassemia – Four types
Missing gene
Symptoms
Silent carrier 1 No
 Thalassemia 2
Mild anaemia
Hemoglobin H Disease 3
Moderate anaemia
Hydrofetalis 4
Severe form

33. Types of  Thalassemia – two types
(a)  Thalassemia MINOR ( Thalassemia Trait)
Heterozygous state – defect in only one  globulin gene
Common in USA.
Usually asymptomatic.
(b)  Thalassemia MAJOR
Homozygous state (both gene)
At birth baby is healthy
After birth severe anemic & die 1-2 yrs.

34. LABORATORY DIAGNOSIS OF HAEMOGLOBINOPATHIES
Hb%, Full blood count
Peripheral blood film
Electrophoresis
Peptide analysis
DNA finger printing technique