SMC, JSMU, MBBS, Blood module

1. Variants of hemoglobin
&
Haemoglobinopathies

2. Objectives
By the end of this lecture the student should be able to:
1. Describe the types of Hb
2. Review the normal structure-function relationships
of hemoglobin and expression of globin genes
3. Examine the hemoglobinopathies as disorders of
hemoglobin structure, or α- or β-globin gene
expression

3. Hemoglobin
• Heme synthesized by mitochondria, fixed with
iron
• Heme then surrounded by “globin” proteins that
surround and “protect” the heme
• Each single Hemoglobin molecule has two
globin chains, each with its own heme protein
attached
– One globin chain is alpha
– One is “non-alpha”
– Two hemoglobin molecules combine to produce
functional hgb tetramer

4. Hb-A Molecule. Hb-A is the major
adult hemoglobin.

5. Hemoglobin (cont’d)
• Alpha globin genes coded on Chrom 16
– Each Chrom 16 has 2 alpha gene loci
– four total per cell
• Non alpha globin genes on Chrom 11
– Arranged from embryonic expression to adult
expression (epsilon, gamma, delta, beta)
– Adult chromosome has one copy of beta gene
– Two per cell

6. Globin genes and hemoglobin
molecules • The various
forms of
hemoglobin
molecules and the
genes from which
they are coded

9. Types of Hb:
Hb A or HbA1: is the normal Hb in adults represents about
97% of total Hb. it is composed of 2 α and 2 β chains.
HbA2: minor adult Hb, comprised 3% of normal adult Hb.
Composed of 2 α and 2 δ chains
HbF(fetal Hb): is the main Hb during fetal life and about
60% of normal Hb at birth then disappear gradually. It is
composed of 2α and 2 γ chains.
Hb F has greater affinity for O2 than HbA so ensure O2
transfer from maternal circulation to fetus RBCs through

10. Hemoglobinopathy
An inherited mutation of the
globin genes leading to a
qualitative or quantitative
abnormality of globin synthesis

11. Broad Classification System for
Hemoglobin Disorders
• Qualitative:
– Hemoglobins differ in sequence of amino acids
composing globin chain
– Disorders called hemoglobinopathies
• Quantitative:
– Characterized by decreased production of hemoglobin
resulting from decreased synthesis of one particular
globin chain
– Called thalassemia

12. Hemoglobinopathies

13. Thalassemias

14. Sickle Cell Anemia
and
Sickle Cell Trait

15. How and Why Cells Sickle
• Hb S forms from a point mutation for the
sixth amino acid in the Beta chain.
• Valine substituted for glutamic acid.
• One benefit for AS persons is increased
resistance to malaria

16. Pathophysiology
of Sickle Cell Anemia
• SS cells may look normal when fully oxygenated; Sickling
occurs when O2 decreased.
• Cells become rigid, impeding blood flow to tissues. Tissue
death, organ infarction, and pain result.
• Have both extravascular hemolysis and intravascular hemolysis.

18. Sickle Cell Trait
Heterozygous AS with more HbA than HbS, so condition
is compensated for
Patient often has normal life span
Usually asymptomatic with occasional episodes of
hematuria
◦ Sickling can occur with drastic reduction of oxygen
tension such as severe respiratory infection, air travel in
unpressurized aircraft, anesthesia or congestive heart
failure
◦ Exercise that causes a buildup of lactic acid can cause
sickling due to lowered pH

19. Hemoglobin H Disease
• Second most severe form alpha thalassemia.
• Usually caused by presence of only one intact α
gene producing alpha chains (--/-α).
• Results in accumulation of excess unpaired gamma
or beta chains. Born with 10-40% Bart's
hemoglobin (γ4). Gradually replaced with
Hemoglobin H (β4). In adult, have about 5-40%
HbH.
γγ44 ββ44

21. Bart’s Hydrops Fetalis Syndrome
• Most severe form. Incompatible with life. Have no
functioning α chain genes (- -/- -).
• Baby born with hydrops fetalis, which is edema
and ascites caused by accumulation serous fluid in
fetal tissues as result of severe anemia. Also we will
see hepatosplenomegaly and cardiomegaly.
• Predominant Hb is Hb Bart, along with Hb
Portland and traces of HbH.
• Hb Bart's has high oxygen affinity so cannot carry
oxygen to tissues. Fetus dies in utero or shortly
after birth. At birth, you will see severe
hypochromic, microcytic anemia with numerous

23. Hereditary persistence of fetal
hemoglobin (HPFH(
• Expressing γ-globin genes at the same level in
adult life as in fetal life.
• HPFH homozygotes have only HbF (α2γ2) and
no anemia!
• HPFH heterozygous have 20-30% HbF. In
acid elution test: all RBCs contain Hb-F.
Pancellular distribution of HbF. This means
that all cells are F cells.

24. Hemoglobin E
• Commonly found in Thais
• Result of point mutation at
codon 26 of β-globin gene.
• Glutamic acid-->Lysine
• Phenotype similar to β+
-thalassemia

25. Thalassemia: An imbalance of
globin-chain synthesis
• Hemoglobin synthesis characterized by
the absence or reduced amount of one
or more of the globin chains of
hemoglobin.
• α-thalassemia
• β-thalassemia

26. Derivatives of hemoglobin
 Oxyhemoglobin (oxyHb) = Hb with O2
 Deoxyhemoglobin (deoxyHb) = Hb without O2
 Methemoglobin (metHb) contains Fe3+
instead of Fe2+
in heme groups
 Carbonylhemoglobin (HbCO) – CO binds to Fe2+
in heme in case of CO
poisoning or smoking. CO has 200x higher affinity to Fe2+
than O2.
 Carbaminohemoglobin (HbCO2) - CO2 is non-covalently bound to globin
chain of Hb. HbCO2 transports CO2 in blood (about 23%).
 Glycohemoglobin (HbA1c) is formed spontaneously by nonenzymatic
reaction with Glc. People with DM have more HbA1c than normal (› 7%).
Measurement of blood HbA1c is useful to get info about long-term
control of glycemia.

27. Thank You!