Anemia and hemoglobinopathy

1. Tropical Medicine
Lecture 5
ANAEMIA
AND
HAEMOGLOBINOPATHIES
© 2021. Dr. Joseph K. Choge, PhD

2. Tropical Medicine
Lecture 5a
Anaemia
© 2021. Dr. Joseph K. Choge, PhD

3. ANAEMIA
Introduction
• Anaemia is very common;
dangerous
• Children: Haemolytic
conditions - e.g. malaria;
leukaemia); Infestations
(Hookworms);
Haemorrhages; Others
• Adults: Haemolytic diseases;
Malignancies;
Haemorrhages; Pregnancy;
Others
Activity 7.1:
• Emphasized Knowledge:
• Causes
• Clinical Presentations
• Management
approaches: Specific;
Supportive; Preventive

4. ANAEMIA - 1
Definitions
1. A state in which the haemoglobin (Hb) level is below that
which is expected, taking into account the age, sex and
community.(Davidson’s Principles and Practice of Medicine; Textbook)
2. A reduction of RBC volume or haemoglobin concentration
below the range of values occurring in healthy persons.
(Nelson’s Text book of Pediatrics)*
3. Anaemia is when Hb level is < 11g/dl.
(WHO, 1968)

5. ANAEMIA - 2
Classification/Categories
• (1) Mild Anaemia: Hb of 8-10.9g/dl
• (2) Moderate Anaemia: Hb of 5.1-7.9g/dl
• (3) Severe Anaemia: Hb <5 g/dl
• Blood transfusion is recommended for severe
anaemia (Hb <5g/dl). (Lackritz et al., 1992)

6. ANAEMIA -3
Physiology of Haemopoiesis
• Haemoglobin formed by pairing of globin
chains; each molecule contains two globin
chain pairs.
• During fetal life, different globin chains are
produced.
• The resulting haemoglobin in children differs
from that in adults.

7. ANAEMIA - 4
Physiology of Haemopiesis (cont’d)
•Normal haemopoiesis starts in yolk sac, at about 4
weeks of gestation (0-3 months of pregnancy).
•The liver and spleen take over haemopoiesis at
about 6 weeks gestation (1-9 months of gestation).
• Bone marrow takes over nearer term (birth)
onwards.

8. ANAEMIA - 5
Types of Haemoglobin
(1) Embryonal haemoglobins
- Consist of β4 and α2β2 chains
- Later replaced by fetal haemoglobin
(2) Foetal haemoglobin (Hb F)
-Contain α2γ2 chains (main chains in foetus)
- Hb F production stops at birth;
- Hb F larger than Hb A; hence higher O2 affinity
-Hb F production stops at birth
(3) Haemoglobin A (Adults)
- Its production begins at birth (c 3-6 months after birth)
- Smaller in size than Hb F

9. ANAEMIA – 6
Reasons for Hb fall after Birth
• (1) Decreased erythropoietic activity
(due to decreased production)
• (2) Increased Hb F removal from circulation
• (3) Rapid body growth
- causing decreased HbF concentration
- Exaggerated in preterms
• (4) Haemodilution

10. ANAEMIA – 7
Causes of Anaemia (Newborn Period)
(1) Haemolytic causes:
-Incompatibilities (ABO, Rhesus, Kelly, others)
- Infections (Neonatal sepsis, ‘TORCHES’)
-Haemoglobinopathies (Thalassaemia)
-Autoimmune /Antibodies (SLE, Lymphomas,
Penicillins)
- Enzymopathies (G6PD & Pyruvate kinase
deficiencies)
- Membrane (RBC) defects (Hereditary spherocytosis )

11. ANAEMIA – 8
Causes of Anaemia-Newborn-cont’d)
(2) Haemorrhagic causes (Obstetrics-related):
-Prenatal period: - Feto-maternal transfusion (trauma)
- Chronic maternal anaemia (pregnancy)
-Perinatal period:
–Twin-to-Twin Transfusion (TTS)
- Traumatic –Ruptured U/Cord, Placenta,
Liver, Spleen, Amniocentesis,
Delivery (APH, Abruptio,
delayed cord clumping,
Holding placenta below baby before
clumping,accidental placental
incision)
-Post-natal period–Iatrogenic (XS blood sampling; Vit. K-dependent HDN)
-Others (rare) – Congenital hypoplastic anaemia

12. ANAEMIA-9
Causes at Birth
Causes of Anaemia at Birth:
• (1) Haemolytic disease (HDN)- Commonest
• (2) Tearing/bad cutting of umbilical cord (delivery)
• (3) Faulty/Abnormal umbilical cord insertions/clamping
• (4) Communicating placental vessels
• (5) Placenta praevia or
• (6) Abruptio placenta
• (7) Haemorrhage from foetal side of placenta, (due to accidental incision
of placenta during Caeserian section or by transplacental haemorrhage)
• (8) Twin-Transfusion Syndrome (TTS): Blood moves from one to the other
• (9) Excess scalp blood sampling: especially in manageming foetal distress

13. ANAEMIA – 10
Causes of Delayed Anaemia (Neonatal period)
Causes of Anaemia later in Neonatal Period (Delayed Anaemia)
• (1) Haemolytic disease of the Newborn, (with or without exchange transfusion or
phototherapy)
• (2) Vitamin K overdosage: (Synkavite) given in large doses may cause anaemia in
prematures: characterized by Heinz bodies in the erythrocytes
• (3) Congenital haemolytic anaemia (hereditary spherocytosis)
• (4) Hereditary non-spherocytic haemolytic anaemia: due to enzymopathies
• (5) Bleeding from: Haemangiomas of upper G.I.T, Gastric Ulcers (from Meckel’s
diverticulum)
• (6) Repeated blood sampling: for various investigations
• (7) Mineral deficiencies: e.g. copper, may cause anaemia in infants on total parenteral
nutrition
• (8) ‘Physiological Anaemia’: fall in Hb content noticed at 8-12 weeks in term infants to
about 11gm/dl; at 6 weeks it falls to about 7-10 g/dl
Treatment:
• Transfusion with packed red cells: for anaemia of < 8g/dl
• (N.B: 2 mls/Kg of packed cells raises Hb by about 1g/dl)

14. ANAEMIA-11
Causes during 1st few days of life
Causes of Anaemia during first few days of life:
• (1) Haemolytic Disease of the Newborn – Commonest
• (2) Haemorrhagic Disease of the Newborn
• (3) Improperly clumped cord
• (4) Large cephalohaematoma
• (5) Subscapular bleeding: from ruptured liver, spleen,
adrenals, kidneys
• (6) Intracranial haemorrhage

15. ANAEMIA – 12
Causes of Anaemia (Older children/Adults)
(1) Haemolytic causes:
-Infections – (Malaria, Clostridium & Gram
negative septicaemias)
-Drugs-(Thiacetazone, Sulphurs, Chloram’col,
Cytotoxics, Vit. K analogues, Primaquine)
- Hypersplenism
-Haemoglobinopathies- SCD, Thalassaemias
-Enzymopathies -G6PD deficiency
- Pyruvate kinase deficiency
- Abnormal Autoimmune Antibodies
-ABO incompatibility

16. ANAEMIA – 13
Causes of Anaemia (Older children/Adults)-Cont’d
(2) Haemorrhagic causes:
-Acute blood loss –Trauma-(RTAs, Epistaxis,
Burns, Surgery, G.I.T bleeding)
-Chronic blood loss
- Parasites-(Hook worm, Trichuriasis, D. latum,
Kala-azar, Amoebiasis)
- Others – Bleeding disorders (Haemophilias,
Scurvy, Purpuras)

17. ANAEMIA – 14
Causes of Anaemia (Older children/Adults)- Cont’d)
(3) Diminished/Defective RBC Production:
(a) Lack of haemopoietic factors:
-Nutritional deficiency – (Iron, Folic acid, Protein
(PEM), Copper, Vitamins)
(b) Lack of haemopoietic tissue (Bone marrow failure)
- B/marrow replacement: (Leukaemias,
Neuroblastoma, Lymphomas)
- Reduced erythropoietin production: (Renal d’se,
Hypothyroidism, Hypopituitarism)
(c) Aplastic Anaemias: (Drugs-Chloramphenicol,Cytotoxics,
Benzenes, Insecticides; Hepatitis, Epstein-Barr Virus,
Autoimmunity, Radiation- induced, Poisons)

18. ANAEMIA – 15
Clinical Features of Anaemia
• (a) Symptoms resulting from tissue hypoxia:
- (Fatigue, Dyspnoea on exertion)
• (b) Manifestations also due to compensatory
attempts to ameliorate hypoxia:
- (Hyperventilation, Tachycardia, Increased
cardiac output, Oedema)- are signs of massive
haemorrhage
• (c) Suggestive clinical picture: History, Physical and
Laboratory examination: (Oedema; vital signs-BP,
Pulse, Respiration); Low Hb)

19. ANAEMIA -16
Clinical Features of Iron Deficiency Anaemia
Essentials of Diagnosis:
• Suggestive history : (e.g. Poverty); *Worm infestation; Failure to thrive ,
Irritability, Fatigue, Good weight gain but flaby, Poor intellectual performance and
muscle tone, Anorexia; *Poor dietary intake of iron; Age usually 6months-2yrs;
rare after 3 yrs; ; Pica common in all age groups
• Physical examination: Pallor, Delayed motor development, Koilonychia, Tongue
atrophy, Stomatitis, Gastric achlorhydria and altered small bowel mucosa causing
protein and occult blood losses
• Laboratory picture:
Microcytic hypochromic anaemia picture
• Low -(MCV, MCH for age, serum iron, serum feriritin, haematocrit)/PCV;
• Elevated -(Total iron-binding capacity, Free Erythrocyte Protoporphyrin-FEP;
Normal reticulocyte count but elevated in severe cases)
• If iron trial therapy results in rise in Hb, then iron deficiency is confirmed.

20. ANAEMIA - 17
Complications of Iron Deficiency Anaemia
• (1) Increased susceptibility to infections
• (2) Heart Failure – In severe cases
• (3) Delayed motor development
• (4) Protein-Energy Malnutrition –May be
precipitated due to anorexia and irritability

21. ANAEMIA -18
Clinical Features of Megabloblastic & Folic Acid Deficiency
Anaemia
• Essentials of Diagnosis:
(Pallor, Fatigue, Macrocytic anaemia; Megaloblastic bone marrow)
• Common Causes:
(1) Folic acid deficiency
(2) Vitamin B12 deficiency
(3) Ascorbic acid deficiency
(4) D. latum (fish tape worm)
(5) Drugs (anticonvulsants-Phenytoin, Primidone,
Phenobarbital, Phenylbutazone); INH & cycloserine,
Nitrofurantoin; Methotrexate);
(6) Sickle cell disease

22. ANAEMIA – 19
Clinical Features of Folic Acid Deficiency
• Dietary deficiency occurs most frequently in infancy.
• Suggestive history: (Anorexia, Weakness in infancy; occurs acutely within first few months of life; rarely
associated with neurological features).
• Physical examination: Pallor; Occasional glossitis and beefy red tongue.
• Laboratory picture:
-Low (Hb, RBC count, Reticulocyte count, leucocytes,
neutrophils, platelets-moderately low)
-Peripheral Bld smear: Macrocytic; significant
anisocytosis and poikilocytosis
- RBCs: Normochromic but may be hypochromic if iron deficiency is
coexistent.
-Bone Marrow: Megaloblastic, nucleated RBCs ; with delayed maturation
- Urine: Formiminoglutamic acid (FIGLU) –Present in urine after histidine
loading.
- Schilling Test: Shows failure of vitamin B12 absorption due to lack of gastric intrinsic factor.
-Will differentiate folic acid from B12 deficiency

23. ANAEMIA – 20
Investigations
Investigations depend on suspected cause(s):
• (a) Hb Level/PCV level – Low in case of anaemia
• (b) Investigate for various infections:
-(Stool o/c, BS, Cultures, e.t.c)
• (c) Investigate for haemoglobinopathies/Enzymopathies:
- (Peripheral blood films-SCD, Spherocytosis, BS for MPs)
- Indirect Coomb’s test-(+ve in incompatibilities; -ve in membrane
defects)
- Kleihauer Test- (Checking mother’s bld for feto-maternal
haemorrhage)
• (d) Others: Bleeding /clotting time, Blood pH, APT test, e.t.c
• Treat anaemia as per cause (s)

24. ANAEMIA – 21
Treatment of Iron Deficiency Anaemia
• (1) Haematinics (oral iron): FeSO4 1.5-2mg/kg TDS X 2-
3months (Mild cases) or
• (2) Parenteral Iron (Imferon): Intramuscular.
 Total Dose Iron = (Desired Hb – Initial Hb) X 80X 3.4X Kg
100
 Additional 30% given to replace deficient iron stores
• (3) Ascorbic Acid (Vitamin C): Large doses given to increase iron
absorption from food; but probably doesn’t affect the efficacy of
iron medication.
• (4) Blood Transfusion PRN:
(a) Whole blood (mls) = 6X Hb deficit X weight (kg);
(b) Packed RB cells (mls) = ≤ 10 mls/kg
• (5) Encourage iron-rich diet

25. ANAEMIA – 22
Treatment of Folic Acid Deficiency Anaemia
(1) Oral folic acid: Given as tablets (5mg OD X 2-3
weeks) usually sufficient; a significant rise in
reticulocyte count will occur within a few days
after start of recovery.
(2) Ascorbic Acid (Vitamin C): A dose of 200mg/Day is
given orally concurrently with folic acid.
(3) Vitamin B12: This may be given in case of coexistent
generalized malnutrition.
N.B: For preterm infants, folic acid should be given at a dose
of 25-50micrograms/Day X 3 months of life, because their
absorption of folate is poor.

26. HAEMOGLOBINOPATHIES
© 2021. DR. JOSEPH K. CHOGE, PHD
Tropical Medicine
Lecture 5b

27. Haemoglobinopathies - 1
Introduction
• Haemoglobin is a tetramer consisting of 2 pairs of
globin chains (subunits/proteins). Hemoglobin is
produced by genes that control the expression of the
hemoglobin protein.
• Abnormalities in these proteins/genes are referred to
as haemoglobinopathies. *
• Defects in these genes can produce abnormal
hemoglobins and anemia, which are conditions
termed "haemoglobinopathies".*

28. Haemoglobinopathies – 2 (Cont’d)
Classification of H’pathies
• (1) Membrane (RBC) Defects:
 Hereditary spherocytosis,
 Hereditary elliptocytosis
 Hereditary persistence of fetal hemoglobin (HPFH)*
• (2) Structural Haemoglobin Defects:
 Sickle Cell Disease (SCD),
 Thalassaemias (α and β)
• (3) Enzyme Defects:
 Glucose-6-Phosphate Dehydrogenase (G6PD)
deficiency;
 Pyruvate kinase (PK) deficiency

29. Sickle Cell Disease - 3
Introductory Definitions
• Sickle-cell disease (SCD), or sickle-cell anaemia (SCA) or drepanocytosis, is a
hereditary (autosomal recessive) blood disorder, characterized by red blood cells
that assume an abnormal, rigid, sickle shape. *
• Sickle cell disorder refers to states in which the red blood cell undergoes sickling
when it is deoxygenated. In the process, it is likely to haemolyze.
• Sickle cell diseases are disorders in which sickling produces prominent clinical
manifestations.
• Sickle cell haemoglobin is identical to haemoglobin A, except that a single amino
acid, valine is substituted for glutamic acid, in the β chain.
• The heterozygous state (sickle cell trait; Hb AS) is usually asymptomatic; Hb AS
carriage rate in parts of West Africa is about 40% and about 5-10% amongst
African Americans.
• Included among sickle cell disorders are: Sickle cell anaemia (Hb AS), Sickle cell
haemoglobin C disease (Hb SC), Sickle cell haemoglobin D disease (Hb SD) and
Sickle cell β-thalassaemia disorders.

30. Sickle Cell Disease – 4
Pathophysiology
• Although Haemoglobin S (Hb S) functions normally in the
oxygenated state, Hb S forms molecular polymers that elongate and
distort the RBCs into the characteristic sickle shape during de-
oxygenated state
• Sickling is triggered by hypoxia, acidosis, increased or decreased
temperature and dehydration
• Sickle cells are destroyed prematurely; whereby they cause
increased blood viscosity and may obstruct blood flow in small
vessels (especially capillaries)
• Sickle cells occlude microcirculation, resulting in infarction, pain
and dysfunction in various organs

31. Sickle Cell Disease – 5
Blood vessel picture

32. Sickle Cell Disease - 6
Clinical Manifestations
• Homozygotes of SCD develop recurrent episodes of haemolysis (crises)
from infancy
• Clinical features are due to infection, anaemia or vaso-occlusion
• Thromboses in mesenteric, intracranial or bone blood vessels produce
severe pain (painful crisis), simulating acute abdominal emergencies,
meningitis or arthritis. (cf. types of crises)
• Poor prognosis, especially in early childhood, is associated with poverty,
overcrowding and inadequate health care.
• However, prognosis is better (survival to adulthood) if good general health
and nutrition are maintained.
• Death may occur in late childhood or early adulthood, from infections,
cardiac failure or thrombotic episodes.

33. Sickle Cell Disease - 7
Clinical Manifestations (cont’d)
• Sickle cell anaemia is not present at birth but develops by 4 months of age, as
haemoglobin F (Hb F) is replaced by haemoglobin S (Hb S).
• The sickle cell anaemia is superimposed by effects of intermittent crises, namely: *
• (i) Splenic Sequestration crisis
• (ii) Aplastic crisis
• (iii) Vaso-occlusive crisis (thrombotic crisis)
• (iv) Abdominal crisis
• (v) Central Nervous System (CNS) crisis
• (vi) Pulmonary crisis
• (v) Haemolytic crisis
• (vi) Megaloblastic crisis
• Other manifestations include:
• Infection,
• Dactylitis (hand-and-foot syndrome - Bone pain) and
• Priapism

34. Sickle Cell Disease - 8
Types of Sickle Cell Crises
• “Sickle cell crisis" or “Sickling crisis" describes
several independent acute conditions occurring in
patients with sickle cell disease.
• Sickle cell disease results in anemia and crises
that could be of many types including the vaso-
occlusive crisis, aplastic crisis, sequestration
crisis, haemolytic crisis and others.
• Most episodes of sickle cell crises last between
five and seven days.

35. Sickle Cell Disease - 9
Types of Sickle Cell Crises (cont’d)
(1) Splenic Sequestration Crisis: *
• Refers to acute pooling of blood in the spleen (causing massive splenomegaly);
• It may occur in roughly 50% of children before third year of life.
• It causes acute abdominal pain and hypovolaemia.
• It may, in severe cases, cause shock and death.
• Episodes of splenic infarction ultimately lead to asplenia in most children over 5
years of age.(Asplenia refers to the absence of normal spleen function and is associated
with some serious infection risks.)
• Spleen is usually infarcted before the end of childhood in individuals suffering
from sickle-cell anemia.
• Autosplenectomy increases the risk of infection from encapsulated organisms (e.g.
pneumococcus, Salmonella osteomyelitis) *
Treatment:
• Patient may require blood transfusion
• Preventive antibiotics and vaccinations are recommended for those with asplenia.

36. Sickle Cell Disease - 10
Types of Sickle Cell Crises (Cont’d)
(2) Aplastic Crisis:
• Acute marrow aplasia may be triggered by many
viral infections, particularly parvovirus
• The combination of marrow failure with haemolysis
may lead rapidly to life-threatening anaemia
• Its associated with reticulocytopenia and low
haematocrit
Treatment:
• Patients may require blood transfusion

37. Sickle Cell Disease - 11
Types of Sickle Cell Crises (Cont’d)
(3) Vaso-Occlusive Crisis:
• These represent the most frequent and prominent features of SCD;
• Decreased deformability of red cells results in occlusion of small blood vessels,
causing local infarction.
• Most patients experience some pain on a daily basis.
Management:
• (i) Analgesics: Painful crises are treated symptomatically with analgesics;
• (ii) Anti-inflammatory drugs: For milder crises, a subgroup of patients
manage on NSAIDs (such as diclofenac or naproxen).
• (iii) Opioids: pain management requires opioid administration at regular
intervals until the crisis has settled. For more severe crises, most patients
require in-patient management for intravenous opioids; patient-controlled
analgesia (PCA) devices are commonly used in this setting.
• (iv) Anti-pruritics: Diphenhydramine is also an effective agent that controls
any itching associated with the use of opioids.

38. Sickle Cell Disease - 12
Types of Sickle Cell Crises (Cont’d)
(4) Haemolytic crisis:
• Haemolytic crises are acute accelerated drops in
haemoglobin level.
• The red blood cells break down at a faster rate.
This is particularly common in patients with co-
existent G6PD deficiency.
Management:
• Supportive
• Blood transfusions, prn

39. Sickle Cell Disease - 13
Types of Sickle Cell Crises (Cont’d)
(5) Abdominal Crisis:
• Due to vaso-occlusion and infarction of the liver,
spleen, mesentery or abdominal lymph nodes.
• Recurrent episodes of splenic infarction eventually
cause autosplenectomy.
Treatment:
• (i) Analgesics
• (ii) Plenty of fluids
• (iii) Partial exchange transfusion-to reduce HbS to
40% and raise Hb above 10-12g/dl

40. Sickle Cell Disease - 14
Types of Sickle Cell Crises (Cont’d)
(6) Pulmonary Crisis (Acute Chest Syndrome):
• Due to pulmonary infarction with local pneumonitis
• Lungs dysfunction: Characterized by fever, chest pain, pleurisy,
difficulty breathing, and pulmonary infiltrate (from fibrosis and
increased pulmonary shunting) on a chest X-ray; Reduced Pao2,
• CVS dysfunction: Myocardial dysfunction (myocardial infarction) may
occur due to fibrosis and haemosiderosis; ECG changes due to left
ventricular failure
• It can be triggered by painful crisis, respiratory infection, bone-marrow
embolization, or possibly by atelectasis, opiate administration, or surgery
Treatment:
• (i) Antibiotics: for possible pneumonia
• (ii) Anti-pyretics/Analgesics: for fever/pain
• (iii) Partial exchange transfusion--to reduce HbS to 40% and raise Hb
above 10-12g/dl

41. Sickle Cell Disease - 15
Types of Sickle Cell Crises (Cont’d)
(7) Central Nervous System (CNS) Crisis:
• Due to vaso-occlusion in the brain, resulting in meningeal signs,
seizures, stroke, blindness, radiculopathy and/or vertigo
• Stroke/Cerebro-vascular accident (CVA) nowadays found to be
due to lesions of major vessels (especially, internal carotid, anterior
and middle cerebral arteries)
• CNS organ dysfunctions manifest with: motor disabilities, mental
retardation, cortical atrophy and ventricular dilatation
Management of painful crisis:
• (i) Analgesics
• (ii) Plenty of fluids
• (iii) Partial exchange transfusion: to limit acute sickling in poorly
perfused areas of the brain.

42. Sickle Cell Disease – 16
Types of Crises (Cont’d)
(8) Megaloblastic Crisis:
• Bone marrow output failure may also occur (as in aplastic
anaemia), from a deficiency of folic acid
• Occurs especially in late pregnancy
Treatment:
• Folic acid supplements: especially during late pregnancy

43. Sickle Cell Disease - 17
Types of Sickle Cell Crises (Cont’d)
(9) Dactylitis (Hand-and-foot syndrome):
• Due to ischaemic necrosis/infarction of small bones, resulting in painful
symmetric swelling of hands and/or feet
• Often seen in toddlers as early as 6 months of age;
• Older children experience pain in long bones and back
• Severe episodes cause aseptic necrosis of bone and can last up to a month
• May occur in children with sickle trait.
• Radiological features: Necrosis of femural and humeral heads; widening
of medullary cavity; cortical thinning; ‘hair-on-end’ appearance; ‘fish
mouth’ vertebrae sign
Management of painful crisis:
• (i) Analgesics
• (ii) Plenty of fluids
• (iii) Partial exchange transfusion

44. Sickle Cell Disease - 18
Types of Sickle Cell Crises (Cont’d)
(10) SCD and Infections:
• Increased susceptibility of SCD children to bacterial infections (especially
pneumonia, babesiosis) probably mainly due to impaired splenic function
(hence reason for hospitalizations)
• Predisposition to Salmonella or Staphylococcus osteomyelitis may be due
to predisposing bone necrosis
• However, SCD tends to protect against haemolysis from Plasmodium
falciparum, because parasitized cells are destroyed by the ‘sickling’
process, along with their parasites *
• Pregnant SCD women: Increased incidence of pyelonephritis, pulmonary
infarction, pneumonia, acute chest syndrome, APH, prematurity, LBW
babies, foetal death, maternal megaloblastic anaemia responsive to folic
acid especially in late pregnancy; SCD maternal mortality remains high in
many parts of the world

45. Sickle Cell Disease - 19
Other Organ Dysfunction features
• Kidneys: Nephrotic syndrome, Chronic renal failure, Proteinuria, Increased
renal blood flow, Renal tubular acidification defect; Increased glomerular
filtration rate; Renal papillary necrosis *, Painless haematuria;
• Liver and Biliary system: Abnormal L.F.Ts; Sudden painful/chronic
hepatomegaly; cholelithiasis; Intra-hepatic vaso-occlusion crisis
• Eyes: Retinopathy
• Ears: Sensori-neural hearing loss
• Adenoids/Tonsils: Adenotonsillar adenopathy
• Chronic leg ulcers: due to poor blood supply
• Skin: Cutaneous ulcers due to thrombotic blockage of blood vessels
• Growth and Development: Delayed growth and sexual maturation,
functional hyposplenia, autosplenectomy can occur
• Priapism:. Painful and sustained penile erection, due to vaso-occlusion in
the corpora cavenosus; Repeated episodes may result in impotence *

46. Sickle Cell Disease - 20
Diagnosis of SCD/Anaemia
(i) In utero diagnosis: By restriction endonuclease analysis of
DNA from foetal fibroblasts obtained by amniocentesis
(i) Newborn period: SCD identified by:
(a) Hb electrophoresis,
(b) PCR amplification of DNA
(i) Older Children:
(a) Sickling Test-induced by adding sodium
metabusulfite to the smear
(b) Hb Electrophoresis

47. Sickle Cell Disease – 21
Management of SCD
(1) EXCHANGE TRANSFUSION: Limits acute sickling in poorly perfused areas of the brain;
Maintenance exchange transfusion may be needed for about 4 years, to keep Hb S <20% so as to lower
recurrence of stroke to <10% *
(2) ANTI-SICKLING TREATMENT:
(a) Foetal haemoglobin - stimulating agents (to increase foetal haemoglobin) : e.g. Hydroxyl urea that may
prevent further stroke; More recent agents include: 5-Azaxytidine, Recombinant human erythropoietin,
Butyric acid analogues
(b) Red cell HbS-reducing agents: Decreased salt intake, DDAVP, Antibiotics (Monencin, Gramicin, others),
Calcium channel blockers: (Nitrendipine, Nifedipine, Verapamil); Membrane active agents: (Cetiedil,
Tellurite, Zinc)
(c) Hb solubility - increasing agents: Covalent Agents: (Cyanate, Carbamyl phosphate, Cytamine, Pyridoxal,
Methyl acetimidate, Dimethyl acetimidate, Glyceraldehyde, Dibromoacetyl salicylic acid, Bis-(3,5-
dibromosalicyl) fumerate, Bis-(3,5-’Dibromosalicyl) succinate, Nirtogen mustard; Non-covalent agents:
Urea, Butylurea, I-phenylalanine
(3) BONE MARROW TRANSPLANTATION: Contemplated in severe cases; i.e. in case of repeated chest
syndrome and CNS complications
(4) GENERAL CARE: Good nutrition; Folate supplements; Regular immunization; Daily penicillin
prophylaxis until at least five years of age (prevent infections); For crises: Hydration prn; Narcotic analgesics
prn. Ideally, the child should be managed in a multi-disciplinary specialization services for parents and affected
children
(5) PREVENTION: Genetic Counseling, to those affected (children and parents); Family Planning (to
already married couples, who have had normal children, to stop having more children- risk of SCD child

48. Sickle Cell Trait (Heterozygous form)
Clinical Manifestations - 22
Clinical picture:
• Clinical features are similar to SCD but are less severe;
• However, severe infarctions can occur and may be fatal;
• Hb S concentration in red cells is low in sickle cell trait; hence sickling doesn’t
occur under normal circumstances;
• Usually asymptomatic;
• Haematuria may occur
Haematology picture:
• Anaemia is mild;
• Blood smear may show target cells ± sickle cells;
• Sickle cell preparations are positive;
• Hb electrophoresis shows SC pattern
Significance of Sickle Cell Trait:
• Genetic implications may mandate counseling those with haemoglobin SC trait;
• Consists of Hb-S and Hb-C.

49. Thalassaemia – 23
Epidemiology:
• Common in Mediterranean countries, India, Far East and parts of North Africa;
• Haemoglobin S and B thalassaemia traits are combined.
Pathophysiology:
• Typical facial features occur due to bone marrow hperplasia
Clinical/Haematological features: *
• May vary depending upon the amount of synthesis of adult haemoglobin;
• B thalassaemia presents with: progressive, severe haemolytic anaemia; clinically
apparent after 6 months of age; failure to thrive; growth retardation; delayed
puberty; hepato-splenomegaly; hyposplenism
• Frontal bossing, osteoporosis and pathological fractures; jaundice and gallstones
also found
• If the adult haemoglobin is 0%, the patient will have severe features of the diseases.
• Iron toxicity following exchange transfusion: Diabetes mellitus, cirrhosis, CCF,
adrenal insufficiency, failure to undergo puberty; possible death
Management:
• Transfusion therapy with packed cells every 4 weeks;
• Chelation therapy: to treat likely iron overload following transfusion
• Splenectomy: This reduces transfusion requirements and should be considered for
patients with hypersplenism
• Bone marrow Transplantation: Weighed against risk of life-long transfusion;
commonly used in the developed world

50. Thalassaemia – 24
Genetics of Thalassaemia

51. Thalassaemia -25
Biochemistry & Pathophysiology of Thalassaemia

52. Enzyme Defects – 26
Glucose-6-Phosphate Dehydrogenase Deficiency
Epidemiology: Most severe forms of G6PD deficiency affect those of Mediterranean and
Chinese ancestry; Others are Middle East and Oriental populations; Commonest enzyme
defect; affects > 400 million world wide
Pathogenesis/Pathophysiology: G6PD is the first enzyme of the pentose phosphate path
way of glucose metabolism; G6PD deficiency, an X-linked recessive disorder, reduces the
cell’s ability to inactivate or reduce oxidizing compounds;
Clinical features: Neonatal jaundice; acute haemolytic anaemia; splenomegaly; haemolytic
episodes occur 2-3 days after oxidant ingestion
Precipitating drugs: Antimalarials: (Primaquine, Pamaquin, chloroquine); Antibiotics:
(Sulphonamides, Nitrofurantoin, Nalidixic acid, Ciproxin); Analgesics: (Aspirin, Phenacetin);
Others: (Dapsone, Naphthalene (mothballs); Anti-helminthics: (Napthol; Stibophen,
Niridazole); Infections: (Hepatitis A and B; Cytomegalovirus, Pneumonia, Typhoid fever);
Miscellaneous: (Vit.K; Probenecid)
Management: Exchange transfusion (neonates); Blood transfusion during haemolysis;
Avoid drugs/foods precipitating attacks/symptoms

53. Enzyme Defects – 27
Pyruvate Kinase (PK) Deficiency
Epidemiology:
• Autosomal recessive disorder; affects Northern Europe descendants; Less common
than G6PD deficiency
Pathophysiology:
• PK deficiency affects the ability of the cells to generate energy
• Consequently, potassium leakage from the cells results in haemolysis
Haematology picture:
• Usually presents with moderate anaemia; high reticulocyte count produces
macrocytosis and hyperchromasia; spiculated pyknocytes; Red cell PK level
decreased to 5% of normal; PK level in reticulocytes is high; measured level may
need to be adjusted for the reticulocyte count
Intermittent Treatment:
• Transfusion: for severely affected patients
• Exchange Transfusion: for severely affected neonates
• Splenectomy: decreases transfusion requirements; should be avoided till > 5yrs of
age, if possible

54. Membrane (RBC) Defects – 28
Hereditary Spherocytosis (HS)
Genetics: Autosomal dominant in 80% of affected; affects all races
Pathophysiology:
• HS is due to abnormality of an RBC membrane protein (usually spectrin), resulting in membrane instability
• Characteristic spherical shape due to a combination of membrane weakness and high permeability to
sodium and water
• Weakened cells are sequestrated and destroyed in the spleen
Clinical Picture:
• Variable degrees of anaemia, jaundice and splenomegaly, mostly in early childhood
• Important: HS is common in infants with Haemolytic Disease of the Newborn (HDN)
• After diagnosis is made, ultrasound to exclude gallstones should be made
Haematological picture:
• Anaemia is: mild, normocytic but frequently hyperchromic
• Peripheral smear: shows microspherocytosis and polychromasia; reticulocyte count and bilirubin are high
• Osmotic fragility test: Increased (if available)
Treatment:
• Folic acid supplementation; 1 mg/day
• Leucocyte-depleted packed cell transfusion: for severe erthroblastopenic crisis
• Splenectomy: Treatment of choice for cure; most require it if spectrin content is <30%; best for >5ys
• Prophylaxis: Splenectomized children should be given either Haemophilus influenzae type B and
pneumococcal vaccines or prophylactic penicillin 250mg BID for life

55. Membrane (RBC) Defects – 28
Hereditary Elliptocytosis
Genetics/Epidemiology:
• Most elliptocyte-related disorders (seen in peripheral smears) are autosomal
dominant.
• More common among West Africans than Western populations
Pathophysiology:
• Abnormality in the protein of the RBC membrane
Clinical/Haematological picture:
• Mild cases have no symptoms
• More severe varieties have neonatal poikilocytosis and haemolysis, mild,
chronic haemolytic anaemia or hereditary pyropoikilocytosis (a severe
disorder with microspherocytosis and poikilocytosis)
Treatment:
• Supportive care: for children with severe haemolytic anaemia, until age of
5 yrs, when they can have
• Splenectomy

56. References
• Anjaiah, B. (2009). Clinical Paediatrics. 4th edition. Paras
Publishing.
• Kliegman, R.M, et al., (editors). (2011). Nelson Textbook of
Pediatrics. 19th edition. Elsevier Saunders Publishers.
• Lichtman, M.A., et al (editors). (2006). Williams Hematology. 7th
edition. McGraw-Hill Medical Publishers.
• Newell, S.J. and Darling, J.C. (2008). Lecture notes: Paediatrics.
8th edition. Blackwell Publishing.
• Seear, M. (2000). A Manual of Tropical Pediatrics. Cambridge
Low-price editions. Cambridge University Press.
• www. wikipedia website: the free encyclopedia