Haemoglobin (Hb) is the red oxygen-carrying pigment within red blood cells and consists of different globin chains with iron-containing heme fraction.

The globin chains combined to make different types of haemoglobin which are genetically determined.
Normal haemoglobin (haemoglobin A) consists of 2 α-globin chains and 2 β-globin chains. The actual haemoglobin model of an individual is achieved at about the 6th month of life with the normal pattern being ≥95% HbA, ≤3.5% HbA 2 , and <2.5% HbF.
Haemoglobinopathies are a group of inherited genetic disorders of haemoglobin characterised by anomalies of structure, function or

production of globin chains that lead to a low/absent production of haemoglobin. There are over 1000 structural and functional haemoglobin variants and thalassaemias with sickle cell (HbS) and HbC being the most common forms in our environment.

Sickle Cell Disease

Sickle cell disease (SCD) is the most common hereditary haematologic disorder characterised by sickle red cells leading to clinical symptoms. The inheritance of two
HbS is termed sickle cell anaemia (SCA) or homozygous sickle cell disease (HbSS).

There are four chromosomal haplotypes associated with HbS mutation named according to the region where they are most frequent: Nigeria, Benin, Bantu, Senegal, and Arab-Indian. All sickle cell haemoglobinopathies are inherited in an autosomal recessive
fashion.
The prevalence of HbAS (carrier state) among Nigerians is 20-30%. The highest incidence of SCD occurs in sub-Saharan Africa where 2-4% of the population is affected
and contributes about 5% to under-5 mortality and up to 26.5% of deaths in Nigerian children aged 5-15 years. With the improvement in life expectancy of SCD individuals as a result of better and comprehensive care, frequent observation of various chronic complications, including kidney diseases is evident.
HbS is formed from a single base change of thymine for adenine, and the consequent substitution of glutamic acid with valine at the sixth codon of the β-globin gene.

Deoxygenation of HbS triggers an event leading to distortion of shape and decreased deformability of the cells representing the primary event in the disease pathogenesis.
The extent and rate at which HbS-carrying red cell polymerise depend on three factors:

i. The intracellular haemoglobin concentration
ii. The degree of deoxygenation
iii. The presence/absence of haemoglobin F.

The clinical hallmark of SCD, particularly SCA, is vaso-occlusion and haemolysis.

Clinical Manifestations of SCD
Normal red blood cells move freely in the circulation and have a life span of 120 days.
Sickled red blood cells have a shortened life span of approximately 20 to 30 days and
can get stuck in capillaries known as vaso-occlusive or painful crisis. This results in
intense pain, severe anaemia, susceptibility to infections, tissue or organ damage, and
shortened life expectancy. A sickle cell crisis can be triggered by:

o sudden changes in body temperature
o dehydration
o hypoxia
o infection- bacterial, viral or protozoan infection e.g. malaria.

Complications of SCA
o Bacterial sepsis
o Vaso-occlusive crisis- it is the most common form of acute crisis in SCD due to tissue hypoxia leading to tissue ischaemia and infarction. it is characterised by
unremitting pain in any part of the body but commonly occurs in the extremities, chest, or abdomen. Dactylitis is usually the first sign of pain manifesting as symmetric or unilateral swelling of the hands and/or feet.
 Acute Chest Syndrome (ACS)– due to pulmonary microvascular occlusion and is a common cause of death. Although commoner in childhood, it occurs in all ages and repeated episodes predisposes to pulmonary hypertension.
o. Acute splenic sequestration occurs primarily in infants and young children whose spleen has not yet become fibrotic. it exacerbates anaemia.

o. Hepatic sequestration may occur causing right upper quadrant pain. Rapid enlargement of the liver can occur and may be accompanied by intrahepatic cholestasis and renal failure.
o. Aplastic crisis occurs when bone marrow erythropoiesis slows during acute infection due to human parvovirus.
o. Neurologic complications include headache, seizures, cerebral venous thrombosis, silent or overt stroke.
o. Priapism- most common in young boys. It is an involuntary, persistent and painful penile erection lasting more than 30 minutes. It is a true urologic
emergency as it can cause erectile dysfunction.
o. Other complications include sickle cell retinopathy, nephropathy, leg ulcers, avascular necrosis of the femoral and humeral heads, and delayed onset of
puberty.

Clinical Complications of Untreated beta Thalassaemia Major include:

1. Failure to thrive
2. Hypersplenism
3. Overactivity of bone marrow and bone deformities

4. Lethargy and fatigue from severe anaemia leading to early death.
Diagnosis of thalassaemia;
Full Blood Count (FBC) will show microcytic hypochromic anaemia.
Haemoglobin electrophoresis
Genetic testing; DNA sequencing, Probe amplification etc.

1. DNA testing (for prenatal diagnosis) by polymerase chain reaction (PCR) on samples obtained by chorionic villous sampling at 10-12 weeks gestation.
2. Peripheral smear shows sickle-shaped and nucleated RBCs.
3. FBC: normocytic anaemia (microcytosis suggests a concomitant alpha or beta thalassemia) and reticulocytosis ≥10%.
4. Haemoglobin electrophoresis using cellulose acetate or acid citrate agar.
5. thin-layer isoelectric focusing (IEF)
6. haemoglobin fractionation by high performance liquid chromatography (HPLC)

Diagnosis of Thalassaemia;
Full Blood Count (FBC) will show microcytic hypochromic anaemia.
Haemoglobin electrophoresis
Genetic testing; DNA sequencing, Probe amplification etc.

Treatment includes regular health maintenance measures as well as specific treatment of the complications as they arise. Complications are treated supportively.
i. Broad-spectrum antibiotics (for infection)
ii. Analgesics and IV hydration (for vaso-occlusive pain crisis)
iii. Oxygen (for hypoxia).
iv.  Blood transfusions- simple transfusion is done when the goal is to correct anaemia but exchange transfusion is required during severe acute events such as stroke or acute chest syndrome to decrease HbS percentage and prevent ischaemia. If the initial Hb is < 7 g/dL, give simple red cell transfusion prior to the exchange transfusion. cells. Chronic transfusion therapy is indicated for the prevention of recurrent cerebral thrombosis in an effort to maintain the HbS percentage at less than 30%.
v. Stem cell transplantation, gene therapy.

Indications for hospitalization in a child with SCD include:
i. Suspected serious (including systemic) infection
ii. Aplastic crisis
iii. Acute chest syndrome or stroke
iv. Intractable pain.

Management of Painful Crisis on the Ward
Management is supportive unless there are complications or indications for exchange transfusion. General management includes:

i.  Reassurance that the patient’s pain will be relieved as soon as possible.
ii.  Establish a position of maximum comfort
iii. Establish IV assess as soon as possible
iv.  Hyperhydration (see Table 1)
v.  Analgesia: use analgesic ladder according to pain severity. Give paracetamol (15mg/kg up to 1g QDS) or ibuprofen (5-10mg/kg up to 400mgTDS) as a single agent or in combination depending on the severity.
If pain persist, continue paracetamol and ibuprofen and add oral codeine phosphate (0.5-1mg/kg up to 30mg TDS) or subcutaneous morphine (begin with 0.1-0.2mg/kg up to 2.5mg and titrate until pain is controlled). If the patient requires regular ongoing opiate pain relief, morphine slow-release tablet
(MST)may be used in place of codeine phosphate. To find the equivalent dose, divide total daily dose of codeine by 8-10 and give half this amount as MST BD.
NB: offer all patients who are taking an opioid: laxative on regular basis, anti-emetics as needed, and anti-pruritic as needed.
vi. Antibiotics: children with SCD are immunocompromised and are susceptible to
encapsulated organisms such as Pneumococcus, Neisseria, Haemophilus influenzae and Salmonella all of which are capable of causing life-threatening sepsis.
In uncomplicated painful crisis without specific evidence of infection, increase prophylactic penicillin V to 4 times per day after cultures have been taken.
vii. Oxygen supplementation when necessary
viii. Identification and treatment of infection
ix.  Regular observation and reassessment

Management of Beta Thalassaemia Major
The aim is to correct severe anaemia.

This includes:
1. Blood transfusions every 3-5 weeks, usually starting from 9 to 12 months of age
2. Iron chelation therapy
3. Splenectomy for hypersplenism
4. Regular follow up visits.
5. Daily vitamin C supplementation
6. Bone marrow or stem cell transplantation
7. Psycho-social support
8. Gene therapy

Prevention;
– Premarital screening.
– Genetic counselling for parent with beta thalassaemia trait.
– Neonatal screening for early diagnosis.

Long Term Interventions that Reduce Mortality include:
i.  Immunizations against pneumococcal, H. influenzae and meningococcal illnesses.
ii.  Prophylactic antibiotics with oral penicillin in all children 5 years at a dose of 7.5mg/kg up to 500mg twice daily. Those who have previously been admitted to hospital with a serious infection or who have had splenectomy should remain on this after age 5 years.
iii. The usual practice is to give folic acid at a dose of 5mg orally once daily. It can however be given at 2.5mg once per week to children less than 3years of age and
5mg once per week to those above 3 years of age.
iv.  Anti-malarial prophylaxis especially during the transmission season. this should usually be started as soon as the first rain has occurred and should continue
until the end of the calendar year. Give mefloquine 5-10mg/kg up to 250mg once weekly.
v.  Use of hydroxyurea is shown to reduce sickling and thus, decrease painful episodes, acute chest syndrome and requirement for blood transfusion.
vi.  Annual transcranial doppler flow ultrasound in children age 2 to 16 years can help predict risk of stroke. Children at high risk should be commenced on
chronic blood transfusion programme to keep HbS at <30% of total haemoglobin. Iron overload is common and must be screened for and treated.

Thalassaemias
Thalassaemia is a genetic condition which affects the quantity of haemoglobin produced. The four clinically significant thalassaemias are:
i. Alfa (α) thalassaemia major, which is clinically significant to the foetus and mother
ii. Haemoglobin H disease (α-thalassaemia 3 gene deletion), which is clinically significant after birth.
iii. Beta (β) thalassaemia major, which is clinically significant after birth

iv. Beta (β) thalassaemia intermedia, which has variable clinical significance after birth.

Alfa thalassaemia
Normal adult haemoglobin has 2 α-globin chains the production of which is controlled by 4 α-globin genes (2 from each parent). In α-thalassaemia, there is either a reduced or absent production of α-globin chains due to mutation in one or more α-globin genes.
Types:
1. Alpha plus (α+) thalassaemia- inherited either one or 2 faulty alpha globin genes (-α/αα) or (-α/-α). It is characterised by minimal change in Hb level and can be
confused with iron-deficiency anaemia in the antenatal period.
2. Alpha zero (α o ) thalassaemia- individuals have not inherited any alpha globin chain genes from one parent (- -/αα). The individual is generally healthy but has
mild anaemia with MCH usually <25pg.
3. Haemoglobin H disease- individual with haemoglobin H disease (- -/-α) has only functioning alpha globin gene. it is a mild to moderate condition with MCH of
15pg to 25pg.
4. Alpha (α o ) thalassaemia major (Bart’s Hydrops Fetalis)- there are no functioning alpha globin genes (- -/- -) and as such no alpha globin chains are produced
resulting in severe life-threatening anaemia in the foetus. The hydropic foetus can usually be diagnosed by ultrasound scan during the second trimester of
pregnancy.

Beta (β) thalassaemia
Types:
1. Beta thalassaemia carrier- inherited one faulty haemoglobin A gene. MCH is <27pg and HbF 0f between 1-10%. Could be further classified as:
a. Beta+ thalassaemia– where a reduced amount of Hb A is produced.
b. Beta 0 thalassaemia– where no Hb A is produced by that gene.

2. Beta thalassaemia intermedia- beta globin chain production is significantly reduced but not completely absent. The individual usually has a degree of
anaemia, splenomegaly and requires occasional blood transfusion during ill-health.
3. Beta thalassaemia major (Cooley’s anaemia)- commonly found in the Mediterranean region. The production of beta globin chain is severely reduced
or absent and is due to defective beta globin genes which are inherited from both parents. It results in severe, life-threatening anaemia which usually requires
regular blood transfusions to sustain life.

Smith-Whitley K, Kwiatkowski JL. Hemoglobinopathies. In: Kliegman RM, St. Geme JW,
Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed.
Philadelphia, PA: Elsevier; 2020:chap 489.
Galadanci N, Wudil BJ, Balogun TM, et al. Current sickle cell disease management
practices in Nigeria. Int Health. 2014;6(1):23–28. doi: 10.1093/inthealth/iht022 [PMC free
article] [PubMed] [ CrossRef ] [Google Scholar]

Sickle cell disease in sub-Saharan Africa: transferable strategies for prevention and care.
Kevin Esoh, MSc, Edmond Wonkman-Tingang, Ambroise Wonkman.
DOI:https://doi.org/10.1016/S2352-3026(21)00191-5. September 02, 2021
Howard J. Sickle cell disease and other hemoglobinopathies. In: Goldman L, Schafer AI,
eds. Goldman-Cecil Medicine. 26th ed. Philadelphia, PA: Elsevier; 2020:chap 154.
Weatherall DJ, Clegg JB (2001) Inherited haemoglobin disorders: an increasing global
health problem. Bulletin of the World Health Organisation, 2001, 79 (8)
Understanding haemoglobinopathies. 2018.
https://www.gov.uk/government/publications/handbook-for-sickle-cell-and-
thalassaemia-screening/understanding-haemoglobinopathies
Gerber GF. Hemoglobinopathies and sickle cell disease. In: Albert RK, Birnbaumer D,
Braunstein GD, Calligaro IL, Garg SJ, Goje O, eds. MSD manual (professional version)
2024.
Edward J Benz, Jr, MD, Emmanuele Angelucci, MD Diagnosis of thalassemia (adults and
children) 2024. https://www.uptodate.com/contents/diagnosis-of-thalassemia-adults-and-