BMB 311

Structure, Properties of
Haemoglobin including
Haemoglobinopathies
 Introduction
Overview of Haemoglobin

• Definition: Haemoglobin is a complex protein found in red blood cells (RBCs) that is
essential for transporting oxygen from the lungs to the tissues and organs of the body
and returning carbon dioxide from the tissues back to the lungs.

• Importance: It plays a crucial role in maintaining the physiological function of the body
by ensuring that tissues receive adequate oxygen to perform metabolic activities.

• Without haemoglobin, the body would not be able to sustain life.

• Outline: This lecture will cover the structure of haemoglobin, its properties, and the
various disorders known as haemoglobinopathies that affect its function.
 Structure of Haemoglobin
 Molecular Structure:

o Quaternary Structure: Haemoglobin is a tetramer composed of four

polypeptide chains: two alpha (α) chains and two beta (β) chains. Each chain
is associated with a haem group.

o Subunits: The alpha and beta chains are encoded by different genes located
on different chromosomes. The alpha chains are encoded by genes on
chromosome 16, while the beta chains are encoded by genes on chromosome
11.
o Diagram below shows the quaternary structure of haemoglobin, alpha/beta chains and the haem groups.
Haemoglobin structure
 Haem Group
o Iron-containing Component: Each haem group contains an iron atom that can
bind one molecule of oxygen (O2).

o The iron atom is in the ferrous (Fe2+) state, which is essential for oxygen
binding.

o Oxygen Binding: The binding of oxygen to the iron atom in the haem group is
a reversible process, allowing haemoglobin to pick up oxygen in the lungs and
release it in the tissues.

o Visual Representation: Diagram below shows the haem group with an iron
atom.
The heme group with an iron atom
 Functions of Haemoglobin
 Oxygen Transport:

o Mechanism: In the lungs, haemoglobin binds to oxygen to form

oxyhaemoglobin. This process is facilitated by the high partial pressure of
oxygen in the alveoli. In the tissues, where the partial pressure of oxygen is
lower, haemoglobin releases oxygen, which diffuses into the cells.

o Role: Haemoglobin ensures that oxygen is efficiently transported from the

lungs to the tissues, where it is needed for cellular respiration and energy
production.

o Visual: Diagram showing oxygen-bound and oxygen-free haem

Oxygen-bound and oxygen-free haem
T state (the tense state) and the R state (the relaxed state).

• There are two states in the hemoglobin, the T state (the tense state) and the R
state (the relaxed state). The T state has less of an affinity for oxygen than the
R state. In the concerted mode of cooperativity, the hemoglobin must either be
in its T state or R state.
T state (the tense state) and the R state (the relaxed state).
 Functions of Haemoglobin
 Carbon Dioxide Transport:
o Mechanism: Haemoglobin also plays a role in transporting carbon dioxide
(CO2) from the tissues back to the lungs. CO2 is produced as a by-product of
cellular respiration and must be removed from the body.
o Role: About 20-25% of CO2 is transported bound to haemoglobin as
carbaminohaemoglobin. The rest is transported dissolved in plasma or as
bicarbonate ions.
o Visual: Diagram showing CO2 transport, highlighting the different forms in
which CO2 is carried in the blood.
CO2Transport in Blood
CO2 Conversion to Bicarbonate
Binding of CO2 to Haemoglobin
 Properties of Haemoglobin
 Oxygen Affinity:

o Factors: The affinity of haemoglobin for oxygen is influenced by several

factors, including pH (Bohr effect), partial pressure of CO2, temperature, and
the presence of 2,3-bisphosphoglycerate (2,3-BPG).

o Oxygen Dissociation Curve: The oxygen dissociation curve is a graphical

representation of the relationship between the partial pressure of oxygen
(pO2) and the percentage saturation of haemoglobin. It is sigmoidal in shape,
reflecting the cooperative binding of oxygen.
Oxygen Dissociation Curve
 Properties of Haemoglobin
 Allosteric Properties:

o Cooperative Binding: The binding of one oxygen molecule to haemoglobin

increases its affinity for the next oxygen molecule. This is known as
cooperative binding and is a key feature of haemoglobin’s function.

o Bohr Effect: The Bohr effect describes how a decrease in pH (increase in H+

concentration) or an increase in CO2 concentration reduces haemoglobin’s
affinity for oxygen, facilitating oxygen release in the tissues.

o Visual: Diagram illustrating the Bohr effect, showing how changes in pH and
CO2 levels affect oxygen binding. Bohr Effect
Bohr effect
 Haemoglobinopathies
 Definition:

o Genetic Disorders: Haemoglobinopathies are a group of genetic disorders that affect the
structure or production of haemoglobin. These disorders can lead to a variety of clinical
symptoms, ranging from mild to severe.

 Types:

o Sickle Cell Disease: Caused by a mutation in the beta-globin gene, leading to the
production of abnormal haemoglobin known as haemoglobin S (HbS).

o Thalassemias: A group of disorders caused by reduced or absent production of one of the

globin chains, leading to imbalanced haemoglobin production.

o
 Sickle Cell Disease
 Cause:

o Mutation: Sickle cell disease is caused by a single nucleotide mutation in the

beta-globin gene, resulting in the substitution of glutamic acid by valine at the
sixth position of the beta-globin chain.

 Pathophysiology:

o Effect: The mutation causes haemoglobin to polymerize under low oxygen

conditions, leading to the formation of rigid, sickle-shaped cells. These cells
can obstruct blood flow, causing pain and tissue damage.
Comparison of normal vs. sickle-shaped cells
 Sickle Cell Disease
 Symptoms:

o Pain: Episodes of severe pain, known as sickle cell crises, due to blocked blood
flow.

o Anaemia: Chronic haemolytic anaemia due to the destruction of sickle cells.

o Infections: Increased susceptibility to infections due to spleen damage.

 Treatment:

o Management: Pain relief, blood transfusions, hydroxyurea to reduce the

frequency of crises, and gene therapy as a potential cure.
 Thalassemias

 Types:

o Alpha Thalassemia: Caused by deletions or mutations in the alpha-globin

genes, leading to reduced production of alpha chains.

o Beta Thalassemia: Caused by mutations in the beta-globin gene, leading to

reduced or absent production of beta chains.

 Pathophysiology:

o Effect: The imbalance in globin chain production leads to ineffective

erythropoiesis and haemolysis, resulting in anaemia and other complications.
Normal vs. thalassaemic cells
 Thalassaemia
 Symptoms:

o Anaemia: Varying degrees of anaemia, depending on the severity of the thalassemia.

o Fatigue: Due to reduced oxygen-carrying capacity of the blood.

o Bone Deformities: Due to bone marrow expansion in an attempt to produce more red

blood cells.

 Treatment:

o Management: Regular blood transfusions, iron chelation therapy to prevent iron overload,

and bone marrow transplant as a potential cure.

 Other Haemoglobinopathies
 Less Common Disorders:

o Haemoglobin C: Caused by a mutation in the beta-globin gene, leading to the production

of haemoglobin C (HbC). HbC can cause mild haemolytic anaemia and splenomegaly.

o Haemoglobin D and E: Other variants caused by different mutations in the globin genes,
leading to varying clinical symptoms.

 Symptoms and Treatments:

o Overview: Symptoms vary by disorder, ranging from mild anaemia to more severe
complications. Treatments include supportive care, blood transfusions, and specific
interventions based on the type of haemoglobinopathy.
 Pathophysiology of Haemoglobinopathies
 Mechanisms of Disease:

o Sickle Cell Disease: The mutation in the beta-globin gene leads to the
production of abnormal haemoglobin S (HbS).

o Under low oxygen conditions, HbS polymerizes, causing red blood cells to
become rigid and sickle-shaped. These sickle cells can obstruct blood flow,
leading to ischemia and pain.
 Pathophysiology of Haemoglobinopathies
 Mechanisms of Disease:

o Thalassemias: The reduced or absent production of one of the globin chains

(alpha or beta) leads to an imbalance in the globin chain production.

o This results in ineffective erythropoiesis, haemolysis, and anaemia.

o The excess unpaired globin chains precipitate within red blood cells, causing
damage and premature destruction.
 Clinical Manifestations of Haemoglobinopathies
 Sickle Cell Disease:

o Vaso-occlusive Crises: Episodes of severe pain due to blocked blood flow in

the microcirculation.

o Acute Chest Syndrome: A life-threatening condition characterized by chest

pain, fever, and respiratory distress.

o Splenic Sequestration: Sudden pooling of blood in the spleen, leading to

hypovolemic shock.

o Chronic Complications: Organ damage, stroke, and increased risk of

infections.
 Clinical Manifestations of Haemoglobinopathies
 Thalassaemias:

o Anaemia: Varying degrees of anaemia, depending on the severity of the

thalassemia.

o Growth Retardation: Delayed growth and development in children.

o Bone Deformities: Expansion of bone marrow spaces leading to skeletal

abnormalities.

o Iron Overload: Due to frequent blood transfusions, leading to damage to

organs such as the heart and liver.

 Management of Haemoglobinopathies
 Sickle Cell Disease:

o Pain Management: Use of analgesics, hydration, and oxygen therapy during vaso-

occlusive crises.

o Hydroxyurea: A medication that increases the production of fetal haemoglobin

(HbF), which reduces the frequency of sickle cell crises.

o Blood Transfusions: Regular transfusions to maintain adequate haemoglobin levels

and prevent complications.

o Bone Marrow Transplant: A potential cure for sickle cell disease, especially in

children with severe disease.

 Management of Haemoglobinopathies
 Thalassaemias:

o Regular Blood Transfusions: To maintain adequate haemoglobin levels and prevent

complications.

o Iron Chelation Therapy: To remove excess iron from the body and prevent organ

damage.

o Bone Marrow Transplant: A potential cure for severe thalassemia, especially in

children.

o Gene Therapy: Emerging as a potential treatment option for both sickle cell disease
 Diagnosis of Haemoglobinopathies
 Diagnostic and Ancillary Tests:

o Blood Tests:

 Full Blood Count (FBC) – ancillary test: Measures the levels of different blood cells,
including red blood cells (RBCs), white blood cells (WBCs), and platelets. It also provides
information on haemoglobin concentration and haematocrit.

 Haemoglobin Electrophoresis – Diagnostic: A laboratory technique used to separate

and identify different types of haemoglobin based on their movement in an electric
field. This test can detect abnormal haemoglobin variants such as HbS, HbC, and others.

 High-Performance Liquid Chromatography (HPLC) - Diagnostic: Another method used

to identify and quantify different haemoglobin variants.
 Diagnosis of Haemoglobinopathies
 Diagnostic and Ancillary Tests contd.:

o Genetic Testing - Diagnostic:

 DNA Analysis: Identifies specific mutations in the globin genes that cause
haemoglobinopathies. This can be done through techniques such as
polymerase chain reaction (PCR) and sequencing.

 Prenatal Testing: Genetic testing can be performed on a fetus to detect

haemoglobinopathies before birth. This is done using techniques such as
amniocentesis or chorionic villus sampling (CVS).
 Diagnosis of Haemoglobinopathies
 Importance of Early Detection:

o Benefits: Early diagnosis allows for timely intervention and management,

which can improve outcomes and quality of life for individuals with
haemoglobinopathies.

o It also enables genetic counselling for affected families.

 Psychological and Social Impact
 Psychological Impact:

o Chronic Pain: The constant pain experienced by individuals with sickle cell

disease can lead to depression, anxiety, and reduced quality of life.

o Fatigue and Anaemia: The chronic fatigue associated with thalassaemias can

affect mental health and daily functioning.

 Psychological and Social Impact
 Social Impact:

o Stigma: Individuals with haemoglobinopathies may face social stigma and

discrimination due to their condition.

o Education and Employment: Frequent hospital visits and health complications

can disrupt education and employment opportunities.

o Support Systems: The importance of family, community, and healthcare

support in managing the psychological and social challenges.
 Public Health and Awareness
 Screening Programs:

o New-born Screening: Early detection of haemoglobinopathies through new-

born screening programs can improve outcomes.

o Carrier Screening: Identifying carriers of haemoglobinopathies through

genetic testing and counselling.

 Public Health and Awareness
 Education and Awareness:

o Public Awareness Campaigns: Raising awareness about haemoglobinopathies

and their impact on individuals and families.

o Educational Programs: Providing education to healthcare professionals,

patients, and the public about the diagnosis, management, and prevention of
haemoglobinopathies.
 Future Directions in Research

 Gene Editing Technologies:

o CRISPR-Cas9: Advances in gene editing technologies hold promise for curing

haemoglobinopathies by correcting the underlying genetic mutations.

o Ongoing Research: Current studies and clinical trials exploring the use of gene

editing for haemoglobinopathies.

 Future Directions in Research
 Stem Cell Research:

o Induced Pluripotent Stem Cells (iPSCs): Research into using iPSCs to generate
healthy red blood cells for transplantation.

o Hematopoietic Stem Cell Transplantation: Advances in stem cell

transplantation techniques to improve outcomes for patients with
haemoglobinopathies.
 Future Directions in Research
 Pharmacological Advances:

o New Drugs: Development of new drugs to manage symptoms and

complications of haemoglobinopathies.

o Clinical Trials: Ongoing trials testing the efficacy and safety of new
treatments.
 Global Perspective
 Prevalence of Haemoglobinopathies:

o Global Distribution: The prevalence of haemoglobinopathies varies by region,

with higher rates in certain parts of Africa, the Mediterranean, the Middle
East, and Southeast Asia.

o Epidemiology: Understanding the epidemiology of haemoglobinopathies to

inform public health strategies.
 Global Perspective
o Visual: Maps and infographics showing the global distribution and prevalence
of haemoglobinopathies.
 Global Perspective
 International Efforts:

o Collaborative Research: International collaborations to advance research and

improve outcomes for individuals with haemoglobinopathies.

o Global Health Initiatives: Efforts by organizations such as the World Health

Organization (WHO) to address haemoglobinopathies as a global health
priority.
 Conclusion
 Summary of Key Points:

o Recap: Haemoglobin is a vital protein responsible for oxygen transport in the

body.

o Its structure and properties enable it to perform this function efficiently.

o Haemoglobinopathies are genetic disorders that affect haemoglobin’s structure

or production, leading to various clinical symptoms.

o Key Takeaways: Understanding the structure and function of haemoglobin, the

impact of haemoglobinopathies, and the importance of early diagnosis and
THANK YOU