HEMOGLOBINOPATHIES

Chris G. Mramba: DCM, BCM, MB ChB,

 Haemolytic anaemia
 Haemolysis indicates that there is a shortening of the normal red
cell lifespan of 120 days.
 There are many causes, classified as inherited or acquired
 To compensate, the bone marrow may increase its output of red
cells six-to eight-fold by increasing the proportion of red cells
produced, expanding the volume of active marrow, and releasing
reticulocytes prematurely.
 Anaemia only occurs if the rate of destruction exceeds this
increased production rate
Introduction to Haemoglobinopathies
 These diseases are caused by mutations affecting the genes encoding
the globin chains of the haemoglobin molecule.
 Normal haemoglobin is comprised of two alpha and two non-alpha
globin chains.
 Alpha globin chains are produced throughout life, including in the
fetus, so severe mutations may cause intrauterine death
Introduction to Haemoglobinopathies
 Production of non-alpha chains varies with age; fetal haemoglobin
(HbF-αα/γγ) has two gamma chains, while the predominant adult
haemoglobin (HbA-αα/ββ) has two beta chains.
 Thus, disorders affecting the beta chains do not present until after 6
months of age.
 A constant small amount of haemoglobin A2 (HbA2-αα/δδ, usually
less than 2%) is made from birth
The geographical distribution of the common
haemoglobinopathies
CLASSIFICATION OF HAEMOGLOBINOPATHIES
 Qualitative abnormalities
 sickle-cell anemia

 Quantitative abnormalities
 Thalassaemias
 Alpha-thalassaemia
 excess beta chains are present,
 Beta-thalassaemia
 excess alpha chains are present.
 SICKLE-CELL ANAEMIA

 Sickle-cell disease results from a single glutamic acid to valine substitution

at position 6 of the beta-globin polypeptide chain. It is inherited as an
autosomal recessive trait
 Homozygotes only produce abnormal beta chains that make haemoglobin
S (HbS, termed SS), and this results in the clinical syndrome of sickle-cell
disease.
 Heterozygotes produce a mixture of normal and abnormal beta chains
that make normal HbA and HbS (termed AS), and this results in the
clinically asymptomatic sickle-cell trait.
Epidemiology
 The heterozygote frequency is over 20% in tropical Africa
 In black American populations, the sickle-cell trait has a frequency of
8%.
 Individuals with sickle-cell trait are relatively resistant to the lethal
effects of falciparum malaria in early childhood.
 The high prevalence in equatorial Africa can be explained by the
survival advantage it confers in areas where falciparum malaria is
endemic.
 However, homozygous patients with sickle-cell anaemia do not have
correspondingly greater resistance to falciparum malaria.
 Pathogenesis
 When haemoglobin S is
deoxygenated, the molecules of
haemoglobin polymerise to form
pseudocrystalline structures known as
‘tactoids’.
 These distort the red cell membrane
and produce characteristic sickle-
shaped cells.
Pathogenesis
 The polymerisation is reversible when re-oxygenation occurs.
 The distortion of the red cell membrane, however, may become
permanent and the red cell ‘irreversibly sickled’.
 The greater the concentration of sickle-cell haemoglobin in the
individual cell, the more easily tactoids are formed, but this process
may be enhanced or retarded by the presence of other haemoglobins.
 Thus, the abnormal haemoglobin C variant participates in the
polymerisation more readily than haemoglobin A, whereas
haemoglobin F strongly inhibits polymerization.
Clinical features
 Sickling is precipitated by hypoxia, acidosis, dehydration and
infection.
 Irreversibly sickled cells have a shortened survival and plug vessels in
the microcirculation.
 This results in a number of acute syndromes, termed ‘crises’, and
chronic organ damage
 1) Painful vaso-occlusive crisis
 Plugging of small vessels in the bone
produces acute severe bone pain. This
affects areas of active marrow: the
hands and feet in children (so-called
dactylitis) or the femora, humeri, ribs,
pelvis and vertebrae in adults.
 Patients usually have a systemic
response with tachycardia, sweating
and a fever.
 This is the most common crisis.
2) Sickle chest syndrome
 This may follow a vasoocclusive
crisis and is the most common
cause of death in adult sickle
disease.
 Bone marrow infarction results
in fat emboli to the lungs, which
cause further sickling and
infarction, leading to
ventilatory failure if not treated
 3) Sequestration Crisis
 Thrombosis of the venous outflow
from an organ causes loss of
function and acute painful
enlargement.
 In children, the spleen is the most
common site.
 Massive splenic enlargement may
result in severe anaemia,
circulatory collapse and death.
 Recurrent sickling in the spleen in childhood results in infarction and
adults may have no functional spleen.
 In adults, the liver may undergo sequestration with severe pain due to
capsular stretching.

 Priapism is a complication seen in affected men

 Priapism- {mean 15 years of age}
 Commonly, possibly up to half of boys
and men with sickle cell have
experienced priapism (reporting bias).
 The majority of cases are low-flow,
ischemic priapism.
 Often provoked by
 vaso-occlusive crisis,
 sexual activity,

 fever,

 dehydration,

 drug use, or associated with normal daily

sleep-associated tumescence.
Management- Priapism
 Fluids, pain control.
 If not rapidly controlled, needle aspiration, irrigation with
phenylephrine (standard priapism aspiration/infusion technique)
 Exchange transfusion for refractory cases (although has not been
proven to decrease time to detumescence)
4) Aplastic crisis
 Infection with human parvovirus
B19 results in a severe but self-
limiting red cell aplasia.
 This produces very low
haemoglobin, which may cause
heart failure.
 Unlike in all other sickle crises,
the reticulocyte count is low.
Investigations for SCD
1. Hemoglobin Electrophoresis
2. Complete Blood Count (CBC) and Peripheral Blood Smear
3. Sickle Solubility Test (Sickling Test)
4. Genetic Testing
5. Blood Chemistry Tests
6. Imaging Studies
7. Reticulocyte Count
8. Liver Function Tests (LFTs) and Kidney Function Tests
9. Echocardiogram
10. Oxygen Saturation
 Hemoglobin Electrophoresis  Complete Blood Count (CBC) and
 Purpose: Peripheral Blood Smear
 Thisis the gold standard test for  Purpose:
diagnosing sickle cell disease. It  To assess anemia and the shape of red
separates and identifies different types blood cells.
of hemoglobin in the blood.
 Result:
 Result:
 CBC often shows anemia, typically
 InSCD, hemoglobin S (HbS) will be
predominant. Hemoglobin electrophoresis normocytic and normochromic in
can also differentiate between sickle cell sickle cell disease. Peripheral smear
disease and sickle cell trait, where a shows characteristic sickle-shaped
person has both HbS and HbA (normal red blood cells, target cells, and
hemoglobin). nucleated red blood cells.
 Sickle Solubility Test (Sickling  Genetic Testing
Test)  Purpose:
 Purpose:  To confirm sickle cell mutations in the
A quick screening test that determines HBB gene that codes for beta-
if hemoglobin S is present. globin.
 Result:  Result:

 Positive in individuals with HbS (e.g.,  Detects mutations specific to sickle

sickle cell trait or sickle cell disease). cell disease, which can help in cases
However, it does not differentiate where electrophoresis results are
between the trait and disease, so unclear or for prenatal diagnosis.
further testing is needed.
 Blood Chemistry Tests  Reticulocyte Count
 Purpose:  Purpose:
 To monitor for organ damage,  To assess the bone marrow’s
especially liver and kidney function. response to anemia.
 Tests:  Result:
 Include liver function tests (ALT, AST,  Reticulocytecount is typically
bilirubin), renal function tests (BUN, elevated due to increased
creatinine), and electrolyte levels. production of red blood cells in
 High bilirubin levels are common due response to chronic hemolysis.
to hemolysis (breakdown of red blood
cells).
 Echocardiogram  Oxygen Saturation
 Purpose:  Purpose:
 To evaluate the heart for complications  To check for hypoxia, as patients
like pulmonary hypertension, a common
with SCD are at risk of
risk in patients with SCD.
decreased oxygen levels.
 Result:
 Elevated pressures or other cardiac
 Result:
issues may be detected, indicating the  Low oxygen saturation may
need for further treatment. indicate the need for
supplemental oxygen or further
interventions.
Liver Function Tests (LFTs) and Kidney Function
Tests
 Purpose:
To monitor potential organ damage over time.

 Result:
High bilirubin (from hemolysis), abnormal liver
enzymes, or impaired kidney function may indicate
complications.
 Imaging Studies
 X-rays:
 To identify bone abnormalities or avascular necrosis, particularly in the hip joints.
 Ultrasound:
 Toscreen for gallstones, which are common due to increased bilirubin from
hemolysis.
 Transcranial Doppler Ultrasound (TCD):
 Used in children with SCD to assess the risk of stroke by measuring blood flow in
the brain's arteries.
 MRI or CT Scan:
 To assess for stroke or other complications if neurological symptoms are present.
Management of SCD
 Managing sickle cell disease (SCD) involves a combination of
preventive measures, symptom control, and treatment of complications.
 The main goals of management are
 To reduce pain episodes,
 To prevent complications,

 To improve quality of life.

Pain Management
 Hydration:
 Ensuring
patients are well-hydrated helps prevent sickling episodes, as
dehydration can trigger vaso-occlusive crises.
 Pain Relief:
 Painful
crises are managed with NSAIDs for mild pain and opioids for
moderate to severe pain.
 Acetaminophen and ibuprofen are commonly used, while opioids (like
morphine or hydromorphone) are reserved for more severe pain.
 Non-Pharmacologic Methods:
 Heat application, massage, physical therapy, and relaxation techniques can
be helpful adjuncts to pain medication.
Hydroxyurea Therapy
 Purpose:
 Hydroxyurea is the mainstay of treatment in SCD to reduce the frequency of
painful crises and acute chest syndrome.
 Mechanism:
 It increases fetal hemoglobin (HbF) production, which reduces the
concentration of sickle hemoglobin (HbS) in red blood cells, making them less
likely to sickle.
 Monitoring:
 Bloodcounts are monitored regularly to watch for side effects like
decreased white blood cells or platelets.
L-Glutamine
 Purpose:
 FDA-approved for reducing acute complications in SCD.
 Mechanism:
 Helpsreduce oxidative stress in red blood cells, reducing the risk of sickling
and vaso-occlusion.
 Administration:
 Given orally, often alongside hydroxyurea for added benefit.
Blood Transfusions
 Types:
 Regular (chronic) transfusions may be used to prevent complications in high-
risk patients, such as those with a history of stroke.
 Purpose:
 Increasesthe number of normal red blood cells, reducing HbS concentration
and thereby decreasing sickling.
 Risks:
 Long-term transfusions may lead to iron overload, so iron chelation therapy
(e.g., deferoxamine or deferasirox) may be required.
 Bone Marrow (Stem Cell)  Gene Therapy (Emerging
Transplantation Treatment)
 Purpose:  Description:
 The only curative treatment for SCD,  Gene therapy is being developed
used primarily in children with severe as a potential cure, either by
complications. correcting the defective gene or
 Challenges: by reactivating fetal hemoglobin.
 Finding a compatible donor can be  Current Status:
difficult, and there are significant risks  Clinicaltrials are ongoing, and it
associated with transplantation, may become a viable option in the
including graft-versus-host disease. future for more patients.
Preventive Care
 Vaccination:
 Patientswith SCD are at increased risk of infections, particularly from
encapsulated bacteria (e.g., pneumococcus and Haemophilus influenzae).
Vaccinations include pneumococcal, meningococcal, and Haemophilus influenzae
type b (Hib) vaccines.
 Prophylactic Antibiotics:
 Daily penicillin is often given to children with SCD until age five to prevent
serious bacterial infections.
 Regular Health Screening:
 Regular eye exams, echocardiograms, and transcranial Doppler ultrasounds (in
children) are recommended to monitor for complications like retinopathy,
pulmonary hypertension, and stroke risk.
 Management of Complications
 Acute Chest Syndrome (ACS):
 This serious complication is managed with oxygen, antibiotics, pain control, hydration, and sometimes
blood transfusions.
 Stroke Prevention:
 Children at high risk for stroke may receive regular blood transfusions, and adults may be managed with
antiplatelet or anticoagulant therapy.
 Infection Management:
 Fever in SCD patients is treated as a medical emergency, with prompt antibiotics and hospital admission
as needed.
 Leg Ulcers:
 Treated with wound care, pain management, and sometimes topical or systemic antibiotics if infected.

 Gallstones:
 Common due to chronic hemolysis, and cholecystectomy (gallbladder removal) may be considered if
symptomatic.
Lifestyle and Supportive Measures
 Avoidance of Triggers:
 Patients
are advised to avoid extreme temperatures, high altitudes, and
dehydration, as these can trigger sickling crises.
 Regular Exercise:
 Moderate exercise is encouraged, though extreme exertion should be
avoided.
 Psychosocial Support:
 SCD is a chronic condition with significant physical and emotional impact.
Counseling, support groups, and mental health services are important to
help patients cope with the challenges of the disease.
Monitoring and Follow-up

 Regular Appointments:
 Patients with SCD need regular follow-ups with hematologists and specialists
to monitor for complications, adjust medications, and address any new
symptoms.

 Lab Tests:
 Routine CBC, liver and kidney function tests, and iron studies (for those
receiving transfusions) are conducted to assess overall health.
THE THALASSAEMIAS
 Thalassaemia is an inherited impairment of haemoglobin production, in
which there is partial or complete failure to synthesise a specific type
of globin chain.
 In alpha thalassaemia, disruption of one or both alleles on
chromosome 16 may occur, with production of some or no alpha globin
chains.
 In beta-thalassaemia, defective production usually results from
disabling point mutations causing no (β0 ) or reduced (β– ) beta chain
production.
Beta-thalassaemia
 Failure to synthesise beta chains (beta-thalassaemia) is the most
common type of thalassaemia, most prevalent in the Mediterranean
area.
 Heterozygotes have thalassaemia minor, a condition in which there is
usually mild anaemia and little or no clinical disability, which may be
detected only when iron therapy for a mild microcytic anaemia fails.
 Homozygotes (thalassaemia major) either are unable to synthesise
haemoglobin A or, at best, produce very little; after the first 4–6
months of life, they develop profound hypochromic anaemia
Management of B-Thalassaemia
 Regular Blood Transfusions  Iron Chelation Therapy
 Purpose:  Purpose:
 Maintain hemoglobin levels to  Preventiron overload due to frequent
prevent anemia and associated blood transfusions.
symptoms.  Medications:
 Schedule:  Common agents include deferoxamine
 Typically,
every 2–4 weeks, (subcutaneous), deferasirox (oral), and
depending on the severity and deferiprone (oral).
type of beta-thalassemia (e.g.,  Monitoring:
thalassemia major).
 Regular checks on serum ferritin levels,
liver, and cardiac MRI to assess iron
accumulation.
 Folic Acid Supplementation  Bone Marrow or Stem Cell
 Purpose:
Transplantation
 Supportred blood cell  Purpose:

production.  The only potential cure for beta-thalassemia,

mostly suitable for severe cases in young
patients.
 Dosage:
 Donor Match:
 Regular folic acid supplements
 Requires a compatible donor, ideally a
are often recommended as
sibling.
part of routine care.
 Risks:
 Associated with significant risks, such as
graft-versus-host disease (GVHD) and other
transplant-related complications.
 Gene Therapy (Emerging
Treatment)
 Purpose:
 Targets the defective gene to
correct beta-globin production.

 Current Status:
 Still
in clinical trials but has shown
promise as a potential curative
approach.
Alpha-thalassaemia
 Reduced or absent alpha chain synthesis is common in Southeast Asia.
 There are two alpha gene loci on chromosome 16 and therefore each
individual carries four alpha gene alleles.
 If one is deleted, there is no clinical effect.
 If two are deleted, there may be a mild hypochromic anaemia.

 If three are deleted, the patient has haemoglobin H disease.

 If all four are deleted, the baby is stillborn (hydrops fetalis).

 Haemoglobin H is a beta-chain tetramer, formed from the excess of
beta chains, which is functionally useless, so that patients rely on their
low levels of HbA for oxygen transport.
 Treatment of haemoglobin H disease is similar to that of beta-
thalassaemia of intermediate severity, involving
 folicacid supplementation,
 transfusion if required and

 avoidance of iron therapy

 How is Thalassemia treated?
 Blood transfusions
 Severe cases of thalassemia require blood transfusions for normal oxygen
delivery.
 Iron chelation therapy
 Low levels of normal hemoglobin causes iron to accumulate in blood. Iron chelation
therapy removes iron from the blood. Removing excess iron is crucial to prevent
damage to important organs, such as the heart and liver.
 Bone marrow (stem cell) transplant
 Bone marrow transplants can be effective for young patients with severe
thalassemia. Stem cells from the bone marrow transplant produce normal blood
cells, which eliminates the need for lifelong blood transfusions and therapy.
Living with Thalassemia
 Avoid Iron-rich Foods
 Thalassemia patients with high levels of iron should keep away foods with high
iron content to avoid organ damage.
 Eat Healthy
 Individuals with thalassemia should include sufficient amounts of vitamin D and
calcium in their diet to maintain bone health. Taking supplements that contain
B-vitamins can help protect and produce healthy red blood cells.
 Avoid Risk of Infection and Get Vaccinated Regularly
 People with thalassemia are at high risk of infections. Patients should wash
their hands regularly and should be vaccinated as recommended.
 Next Lecture: enzymopathies
 REVISION QUESTIONS
1. State why disorders affecting the beta chains do not present until after 6
months of age ( 2 mks)
2. Outline the classifications of Haemoglobinopathies, stating their traits (5mks)
3. Individuals with sickle-cell trait are relatively resistant to the lethal effects of
falciparum malaria in early childhood. Justify ( 5mks)
4. Discuss ‘tactoids’ in relation to sickle-shaped cells (2mks)
5. State the basis of Acute Chest Syndrome (ACS) in SCD (5MKS)
6. Discuss priapism and its relevance is SCD (5MKS)
7. Outline the differences between alpha and beta Thalassemia (4mks)
8. Discuss treatment options and how one can live with thalassemia (10mks)