This document provides an overview of haemoglobinopathies with an emphasis on sickle cell anaemia (SCA). It describes the complications and types of crises seen in SCA, how to identify them, and the modalities for treating various crises in the local environment. The introduction defines qualitative and quantitative haemoglobin abnormalities. It then outlines SCA pathogenesis, epidemiology, complications including vaso-occlusive crisis, management of crises through treatment of pain and infections, and prevention of sickle cell crises.

1. HAEMOGLOBINOPATHIES:
EMPHASIS ON SCA
BAFFA A GWARAM MPH FMCP
DEPT OF MEDICINE
BUK/AKTH

2. LEARNING OBJECTIVES
Describe Haemoglobinopathies
Describe the various complications and
types of crisis in SCA and how to identify
them.
Understand the modalities of treatment of
the various crises in our environment.
Understand ways of preventing the crises.

3. SESSION OUTLINE
Introduction to Haemoglobinopathies
Overview of SCD/SCA
Complications of SCA
Sickle Cell Crisis
Management of SCA crises
Prevention of sickle cell crises

4. INTRODUCTION
Haemoglobinopathies can be qualitative or
quantitative
Qualitative Hb abnormality due to
alteration in DNA coding leading to an abn
amino acid in the globin molecule
Quantitative Hb disorders result from
imbalance globin chain production
Haemoglobinopathies result in significant
morbidity and mortality on a world wide
scale

5. INTRODUCTION
The clinical syndromes produced by Hb
abnormalities:
Syndrome Abnormality
Haemolysis Crystalline Hb (S,C,D,E)
Unstable Hb
Thalassaemia α and β
Familial polycythaemia Altered O2 affinity
Methaemoglobinaemia Failure of reduction

6. INTRODUCTION
Thalassaemias
α Thal - mostly due to gene deletion
Silent α thal- (-α/αα)
α thal trait (αα/-- or -α/-α)
Hb H disease (--/-α)
Hb Bart’s hydrops fetalis (--/--)

7. INTRODUCTION
β Thal – most are due to single point
mutation
-β+ reduced β globin synthesis
-β0 absent β globin production
Hence;
β thal trait – carrier state
β thal intermedia
β thal major (Cooley’s anaemia)

8. INTRODUCTION
Crystalline Haemoglobins
Hb S ( glu → val at position 6 )
Hb C ( glu → lys at position 6 )
Hb D ( glu → gln at position 121)
Hb E ( glu → lys at position 26)
Hb O ( glu → lys at position 121)

9. James B. Africanus Horton
(1835 - 1883)
Nigerian born in Sierra Leone
Qualified from the Medical School
of King’s College London, at 24.
In 1874, first to publish the
features of SCD in his book
‘The Diseases of Tropical
Climates & Their Treatment’.
Research => MD Univ. of Edinburgh
A Colonel in the British Army.
A committed patriot, Horton was
an advocate for the establishment
of universities in West Africa.

10. James B Herrick
An interesting twist of history
A Chicago Cardiologist
In 1910, published the findings
of
‘Peculiar elongated and
sickled red blood cells in
a case of severe anaemia’.
1st account of pathology of SCD.
Gave SCD the name it bears today.

11. OVERVIEW OF SCD/ SCA
SCA is due to a point mutation in the β-globin
gene.
HbS differs from normal adult HbA by the
substitution of valine for glutamic acid in the 6th
position of the β-globin chain.
This lead to polymerisation of deoxyHb S and
instability of oxyHb S.
Other abnormalities of β-chain synthesis may be
inherited with Hb S, notably Hb C and the β thal.
severity: Hb SS and HbS/β0 thal > HbSC >
HbS/β+ thal

12. OVERVIEW OF SCD/ SCA
Hb SS is an example of mendelian
inheritance.
The disease course is significantly
modified by envtal factors and other genes
(β-globin haplotypes, HbF , α thal)
Including genes controlling bilirubin, HTN,
coagulation pathway, vascular cell
adhesion molecule polymorphism,
morphine receptor polymorphism

13. OVERVIEW OF SCD/ SCA
Epidemiology- Prevalence - 2% of SCA and
20-30% of the gene in Nigeria
High frequency of HbS gene in area where P.
falciparum is/was endemic, and in there
emigrant population.
HbS protects against P. Falciparum by atleast
2 mechanisms
1. Parasites consume O2 within the red cells,
induce sickling and are removed by the RES in
the early stages of erythrocytic cycle.
2. The last 12hrs of the parasite cycle are spent in
deep tissue at low O2 tension

15. ‘‘WE ARE SPECIAL PEOPLE
WITH TOO MUCH OF A
GOOD THING’’
- Hb SS patient

16. OVERVIEW OF SCD/ SCA
Pathogenesis
When HbS is deoxygenated, the
molecules of Hb polymerise to form
tactoids. This distort the red cell
membrane into sickle shaped cells.
Sickling is initially reversible with
reoxygenation.
The distortion may become permanent
and the red cell ’’irreversibly sickled’’

18. COMPLICATIONS OF SCA
In the homozygous state (HbSS) causes :-
INFARCTION
HAEMOLYTIC ANAEMIA
That lead to
♦ Increase susceptibility to infections
♦ Disturbance of growth and dev
♦ Chronic organ damage

19. COMPLICATIONS OF SCA
Chronic anaemia leads to erythroid hyperplasia
and expansion of the bone marrow which
causes sickle cell facie ( bossing, depressed
nasal bridge, gnathopathy).
CVS – Tachycardia, mummurs. Heart is
enlarged invariably after 6yrs
GIT – Mod jaundice and raised serum bil,
deranged LFT and fatty degeneration leading to
liver failure. Pigment gallstones are found in
about 10% of adult Nigerians. Hyposplenism

20. Eye – Proliferative retinopathy, blindness, retinal
artery occlusion, retinal detachment
Genitourinary – Renal papillary necrosis
leading to hematuria and renal tubular defect.
Inability to concentrate urine, freq UTI in females
and CKD in adults
Locomotor – Avascular necrosis of the head of
the femur or humerus, arthritis, osteomyelitis
and chronic leg ulceration
Pulmonary – chest pain due to pulm infarction,
pneumonia. Chronic lung dx with cor pulmonale
secondary to multiple arteriolar thrombi

21. COMPLICATIONS OF SCA
Infection – Impaired resistance to bacterial
infection esp Strep. pneumoniae and salmonella
spp because of :-
♦Inadequate opsonization
♦ Hyposplenism
♦ Lesions in skin, mucous memb and tissue
necrosis following infarction
♦ Diminished CMI
Acute viral infection are particularly severe
HIV and Hep B&C infections

22. COMPLICATIONS OF SCA
CNS – Convulsions, TIAs or strokes,
sensory hearing loss
Psychosocial – Depression ,social
withdrawal, drug addiction

23. SICKLE CELL CRISIS
Type of sickle cell crisis
Anaemic
Haemolytic
Sequestration
Aplastic
Magaloblastic
Infarctive

24. SICKLE CELL CRISIS
There are 4 types of anaemic crisis, during
which the Hb concentration falls catastrophically:
♦ Haemolytic crisis cause severe anaemia and
jaundice; they may follow infection e.g malaria,
but often no trigger is identified.
♦ Sequestration crisis occur mainly in children.
There is pooling of large volume of blood in the
spleen or liver. Spleen enlarges dramatically and
the Hb falls precipitously.
♦ Aplastic crisis is as a result of bone marrow
depression by infection- particularly Parvovirus
B19. Severe anaemia develops quickly.

25. SICKLE CELL CRISIS
♦ Megaloblastic crisis. Almost all
untreated African children with SCA are
folate deficient and more than 10% of
Africans with SCA have megaloblastic
erythropoiesis due to folate deficiency.

26. SICKLE CELL CRISIS
Infarctive (Vaso-occlusive/Painful) crisis–
Sickle cells do not flow well through small
vessels and are more adherent than
normal to vascular endothelium.
They block the capillaries and cause
infarction, with further endothelial damage
and thrombosis.
Necrosis of infarcted tissue leads to
sudden swelling, severe pain and fever.

27. SICKLE CELL CRISIS
Infarctive crises are precipitated by factors that
promote the deoxygenation of Hb in the
capillaries, but in many instances no trigger is
identified.
Triggers – Infections, dehydration, exposure to
cold , fatigue and stasis (menstruation).
Dactilitis – In children between 6mths and 2yrs
infarcts occur typically in the small bones of the
hands and feet (in older children or adults the
long bones are affected).

28. SICKLE CELL CRISIS
Stroke – Infarctive strokes are common in
children while haemorrhagic stroke occur more
in adults.
Acute chest syndrome (ACS) – common cause
of death. Chest wall pain, pleurisy, fever, cough
and SOB. Has infitrates in the lungs. Resemble
infection, infarction or embolism.
Acute Bone Marrow Necrosis - Acute bone
marrow necrosis is now recognized more often
as a complication of sickle cell disease with the
introduction of magnetic resonance imaging
(MRI) techniques.

29. SICKLE CELL CRISIS
Any tissue of the body can be the site of an infarction:-
♦ Bony infarct (skull, ribs, long bones, spine
and girdle)
♦ Splenic and hepatic infarcts
♦ Pulmonary micro infarcts
♦ Mesenteric infarcts
♦ Cortical or papillary infarcts
Priapism is a potentially serious problem for young men
with sickle cell disease. Priapism lasting more than three
or four hours is a medical emergency since it can
produce impotence.

30. MANAGEMENT OF SCA CRISES
Ideally patients should carry a sickle cell identity
card.
Take history
Investigate – Hb (?steady state Hb), WCC and
retics, thick and thin smear for MP. Examine
urine and do other tests as indicated.
Give a course of curative anti-malarial and
continue with anti-malarial prophylaxis and folic
acid

31. MANAGEMENT OF SCA CRISES
Anaemic crisis - Many patients whose Hb has
fallen below their usual steady state level
recover with no more than anti-malarial therapy,
folic acid and antibiotics if indicated.
Blood transfusion is indicated only if:
♦ The patient has respiratory distress
♦ The patient has incipient or actual cardiac failure
♦ There is a sequestration crisis the Hb is <6g/dl
♦ Obstetric delivery is imminent and Hb is < 8g/dl
♦ Major surgery is indicated and the Hb is < 8g/dl
(Donor blood should be Hb AA)

32. MANAGEMENT OF SCA CRISES
Infarctive crisis –
There is no specific treatment.
♦ Treat the cause if known; give appropriate
antibiotics if infected
♦ Manage pain
♦ Maintain hydration and acid base balance;
replace fluid liberally, either orally or IV
♦ Give O2 to patients with severe chest pain
or pnuemonia

33. MANAGEMENT OF SCA CRISES
Management of pain
-Severe pain- morphine in full therapeutic dose ±
NSAID or promethazine
-Less severe pain- Dihydrocodeine
-Mild pain- Paracetamol
♦ Assess the severity of pain regularly :adjust
doses accordingly
♦ Never prescribe analgesics ‘as required’
♦ Give supply of PCM for self treatment
♦ Fentanyl patches are excellent for prolonged
moderate to severe pain if available

34. MANAGEMENT OF SCA CRISES
Patients with SCA and unexplained fever should
be cultured thoroughly. If the clinical condition
suggests septicemia, the best action is to start
broad spectrum antibiotics after complete
culturing.
Signs of systemic infection include fever,
shaking chills, lethargy, malaise, and
hypotension.
Patients with septicemia can expire in only a
few hours. Therefore, observation is not a good
option when sepsis is suspected.

35. MANAGEMENT OF SCA CRISES
Stroke management includes rehydration and
red cell transfusion, preferably exchange
transfusion with the target of reducing HbS to
30% of total Hb.
ACS requires prompt and vigorous treatment.
Give O2 if pO2 can not be kept above 70mmHg
on air. Treat infection, usually due to S.
pneumoniae, H influenza, Mycoplasma,
Legionella
Exchange transfusion is the treatment of choice
for ACS. The procedure involves exchange of
the total blood volume and is done most
efficiently using an apheresis machine.

36. MANAGEMENT OF SCA CRISES
The treatment of splenic sequestration crisis
includes intravenous fluids and transfusion as
necessary to maintain the intravascular volume.
A child who suffers one episode of splenic
sequestration crisis is at greater risk of a second
attack .
In hepatic sequestration, Fluids, oxygen and
analgesia are the usual management
interventions taken. The benefit of more
aggressive measures such as exchange
transfusion is unknown.

37. MANAGEMENT OF SCA CRISES
Patients with bone marrow necrosis often suffer
excruciatingly severe pain. Some patients
require epidural anesthesia for control of
wrenchingly intense pain.
Often, but not always, aplastic crisis coincide
with a painful crisis. The reticulocyte count
should be checked on admission to the hospital
in patients with SCA.
The treatment of aplastic crisis is purely
supportive, with transfusions to maintain an
acceptable hematocrit until marrow activity is
restored.

38. MANAGEMENT OF SCA CRISES
Priapism- The most commonly used intervention
in the past was irrigation of the ventral vein of
the penis by a urologist in an attempt to remove
the blockage to blood flow.
Surgery often fail to resolve the priapism and
has the risk of inducing impotence.
More recently, exchange transfusion has been
used in some of these patients with mixed
results.
Non-acute cases of priapism are sometimes
treated with conjugated estrogens or
vasodilators.

39. PREVENTION OF CRISES
Counseling
Early diagnosis
Education- General public, parents,
guardians, patient, health professionals
Sickle cell clinics
♦ Prevention of infection- anti-malarial
prophylaxis, ITNs, prophylactic oral
penicillin, Pneumococcal vaccine, H
influenza vaccine, all routine vaccines.

40. PREVENTION OF CRISIS
Sickle cell clinics (cont)
♦ Nutrition- Folic acid and oral zinc
supplements, Gen nutritional advice
♦ Self treatment – PCM
♦ Advice- Avoid triggers of crises, attend clinic
regularly, report when ill and when pregnant

41. PREVENTION OF CRISIS
Obstetric care –
Prenatal diagnosis
ANC booking early
Anti-malarial
Folic acid
Monitor- Hb, BP, Urine protein
Deliver in hospital
Supervision of puerperium- monitor for
infection
♦ Family limitation- advice not more than two
viable children

42. PREVENTION OF CRISIS
Recent therapeutic advances
Hydroxyurea
Erythropoietin
Short chain fatty acids-Isobutyramide
Clotrimazole
5-azacytidine
Transcranial doppler
Bone marrow transplantation
Gene therapy
Extended matching for red cell antigens for blood
transfusion

43. HYDROXYUREA THERAPY
Studies have shown that both sickled
and unsickled RBCs attach to vascular
endothelium using adhesion molecules
So, RBCs also contribute to vaso-occlusion
in SCD through an active process distinct
from passive mechanical obstruction.

44. Molecules That Mediate RBC Adherence to
Vascular Endothelium.

45. HYDROXYUREA THERAPY
α5ß3 integrin on vascular endothelium is the ligand
for several RBC adhesion molecules; e.g,
phosphatidylserine, sulfated glycans, CD47 & CD36.
Administration of a monoclonal antibody to α5ß3
integrin abolished vaso-occlusion in a mouse model
with SCD.
Therefore, α5ß3 integrin is a candidate cell adhesion
molecule for targeted reduction or blockage in the
treatment of SCD.

46. Evidence That WBCs Have A Role In SCD
The Severity of SCD Increases With Neutrophil Count
High WBC Count: A Risk Factor For Early Death
Clinical Improvement During Hydroxyurea Therapy
Coincides with Fall in WBC Count, even without a rise in HbF.
Sickle Cell Crisis & Acute Chest Syndrome Following
Severe Neutrophilia Induced By G-CSF; Resolved As
Hydroxyurea Therapy Brought Down WBC Count.
High Neutrophil Count: A Powerful Predictor of Good
Response to Hydroxyurea

47. References
Fleming AF,Menedez C: Blood in ;Principleof
medicine in Africa; Parry E et al (editors), 3rd
edition.p 924-70 Cambridge publishing.
Provan D et al (editors):Oxford hand book of
clinical haematology,2nd edition. P72-84 Oxford
publishing
Young NS, Stanton LG, High KA (editors):
Clinical haematology, 2nd edition. Mosby
Elsevier publishing
Halett C et al(editors): Davidson’s principle and
practice of medicine 19th edition. P737-800
Churchill Livingstone publishing

48. THANK YOU