1. Sickle Cell
syndrome

2. CONTENTS:
 Introduction
 History
 Incidence
 Pathophysiology
 Types
 Genetic inheritence
 Clinical manifestations
 Investigations
 Treatment
 Complications
 Prognosis

3. INTRODUCTION
 Haemoglobinopathy refers to a disease
state (opathy) involving the haemoglobin
(Hb) molecule.
 Sickle cell syndrome is a type of
qualitative haemoglobinopathy, occuring
due to point mutation in β-like gene,
leading to structural alteration in β-chain,
of globin part of Hb and affecting the
functional capacity of RBCs.

4.  Sickle-cell disease (SCD), or sickle-cell
anaemia or drepanocytosis, is an autosomal
co-dominant genetic blood disorder
characterized by red blood cell that assume
an abnormal, rigid, sickle shape.
 +Recurrent episodes of painful crises, and
progressive end-organ damage

5. HISTORY
• Sickle cell anaemia was
observed by a Chicago
physician, James Herrick
in 1910 in a West indian
student with severe
anaemia.
• In 1927, Hahn and
Gillespie described the
pathologic basis of the
disorder and its
relationship to the
haemoglobin molecule.

6.  In 1946, Beet reported that malarial
parasites were present less frequently in
blood smears from patients with SCD
compared with normal individuals.
 It was determined that sickle cell trait
confers resistance against infection with
plasmodium falciparum occuring early in
childhood between the time, that
passively acquired immunity passes and
active immunity develops.

7.  Pauling and Co-workers defined the
genetics of the disorder and clearly
distinguished heterozygous sickle trait
(Hb AS)from the homozygous state (Hb
SS).

8. INCIDENCE:
 The highest frequency of sickle cell trait
is in Africa where the frequency is 20-
40%,the high prevalence can be
explained by the selective survival
advantage it confers in areas where
Falciparum malaria is endemic.
 In the United states, approximately 12%
of african Americans have a
Haemoglobin variant.

9.  It has also been found in individuals from
the middle east, India, and the
mediterranian.
 Also from regions of caribbean and
central & South America.
 Sickle cell is becoming more prominent in
southern India, particularly in certain
tribes.

11. Incidence with Malaria
 The sickle gene occurs with greatest
frequency in central africa ,the near
East, the region around the
mediterranian,and parts of India.
 The frequency of gene parallels the
incidence of P. falciparum and seems
to offer some protection in young
patients with cerebral falciparum
malaria.

12. Malaria prevalence
HBS Allele

13. PATHO-PHYSIOLOGY:

14.  Basic molecular lesion:
 In HbS, basic genetic defect is Single
point mutation in one amino acid out of
146 in haemoglobin molecule.
 There is substitution of a Valine for
Glutamic acid, at 6th residue position
of β-Globin, producing Hb α₂ β₂ S
 Glutamic acid has a net charge of -1,
whereas Valine as a net charge of +0.
This amino acid substitution results in
charge of +1, resulting a structural
change in the Hb molecule.

15. Gower 1: 2 2
Gower 2: 2 2
Portland: 2 2
------------------
F: 2 2
A2: 2 2
A: 2 2
< 2%
< 3%
96%
Hemoglobins by age > 1 yr

16. Molecular pathology of SCD
The sickle mutation
GAG
Glutamic acid
GTG
Valine
The s Mutation
6th Codon of -Globin Gene

17. In Sickle Cell Disease
Gower 1: 2 2
Gower 2: 2 2
Portland: 2 2
------------------
F: 2 2
A2: 2 2
S: 2
s
2
2-20%
3%
80-95%
Hemoglobins in SS by age > 1 yr

19.  Mechanism of Sickling.
 During deoxygenation the red cells
containing Hb S change from biconcave
disc shape to an elongated Cresent
shape, this process is ‘Sickling’.
 The Molecule of Hb under
deoxygenated condition polymerize to
form Pseudocrystalloid structures
known as ‘Tactoids’.
 These aggregate to form elongated rod
like polymers
 These elongated fibres align and distord
the red cells to classic Sickle cell.

20.  These polymerised deoxy-Hb S activates a
membrane channel called Psickle that is
otherwise inactive in normal RBCs.
 These membrane channels open when the blood
Po2 decreases to less than 50mm Hg.
 Open Psickle channels allow the influx of Ca, raisin
the intracellular Ca levels & activating a second
membrane channel called the gardos channel.
 An activated gardos channel causes the efflux of K
that stimulates the efflux of Cl through another
membrane channel to maintain charge equilibrium
across the RBC membrane.

21.  The efflux of these ions leads to
dehydration, effectively increasing the
intracellular concentration of Hb S &
intensifying polymerisation.
OXY-STATE DEOXY-STATE

22.  Reversible-Irreversible Sickling:
 The oxygen dependent process is
usually reversible.
 However the damage to red cell
membrane leads to the formation of
irreversible sickled cell even after they
are exposed to normal oxygen tension.

23.  Factors determining the rate of
Sickling:
 Presence of non-Hb S
haemoglobins, Hb F.
 Intra cellular concentration of Hb S.
 Total haemoglobin concentrations.
 Extent of deoxygenation.
 Acidosis and Dehydration.
 Increased concentration of 2,3-BPG in
the red cells.

24. Pathophysiology explaining
↑SCD in malarial endemic regions:
Malarial parasite within RBC use the
oxygen within the cell
Reduce oxygen tension
RBC Sickling, injury to cells
Injured Cells get trapped in bleeding
vessel

25. Easily phagocytosed by
scavenger WBC’s.
Selective destruction of Infected RBC’s
containing Parasites.
↓↓ Number of Malarial organisms
and
↑↑ in time for Immunity to develop.

26. TYPES:
It occurs in 3 different forms:
1. Heterozygous state for Hb S: Sickle
Cell Trait(AS)
2. Homozygous state for Hb S : Sickle
Cell disease(SS)
3. Double heterozygous states
eg: Sickle β-thalassemia
Sickle C disease
Sickle SC disease

27. Sickle Cell Trait
Sickle haemoglobin (S) + Normal haemoglobin (A) in RBC
• Adequate amount of normal Hb (A) in red blood cells
• RBC remain flexible
• Carrier
• Do Not have the symptoms of the sickle cell disorders,
• with exceptions:
• Pain when Less Oxygen than usual (activities at high
altitude (12,000ft), under general anaesthesia)
• Minute kidney problems*

28. Haemoglobin C:
 Is the most common non sickling
varient encountered
 Here lysine is substituted for glutamic
acid in 6th position of β globin chain.
 Is inherited in same as HB S but manifest
as a milder disease.
 Similar to Hb S, Hb C polymerises under
low oxygen tension, but the structure of
the polymers differs.

29.  Hb polymers are long and thin
whereas the polymers in Hb C form a
short, thick crystal within the RBC.
 The shorter Hb C crystal does not
alter RBC shape to the extent of Hb S,
resulting in diminished splenic
sequestration and hemolysis.

30. Hemoglobin SC
 Is the most common double
heterozygous syndrome.
 At the 6th position, glutamic acid is
replaced by valine(Hb S) on one β-
globin chain & lysine(Hb C) on other β-
globin chain.
 Hb SC disease resembles a mild SCD.
 Growth & development are delayed
compared with normal children.

31.  In contrast to SCD, significant
symptoms here do not occur until
teenage years.
 May cause all the vaso-occlusive
complications of sickle cell
anemia, but the episodes are less
frequent, and damage is less
debilitating.

32. Hemoglobin S/β-Thalassemia:
 Double heterozygosity for Hb S & β-
thalassemia is the most common cause of
sickle cell syndrome in patients of
Mediterranean descent.
 It causes a clinical syndrome resembling
that of mild or moderate sickle cell
anaemia.
 The severity of this double heterozygous
condition depends on β-chain production
of the affected thalassemia β-genes.

33.  If there is no globin chain production
from the β-thalessaemia globin gene (S-β0-
thal), the clinical course is similar to that of
homozygous sickle cell anaemia
 If there is production 0f β globin (S-β+-thal),
patients tend to have a milder condition than
patients with Hb SC.
 These patients can be distinguished from
individuals with Sickle cell trait
-greater amount of Hb S than Hb A
-↑↑ levels of Hb A2 and Hb F.
-microcytosis from thalassaemia
-hemolytic anaemia.
-abnormal blood morphology.
-splenomegaly.

34. GENETICS
 Sickle cell anemia is an autosomal co
dominent genetic disorder. For the
disease to be expressed, a person
must inherit either two copies of Hb S
variant(Sickle Cell Disease) or one
copy of Hb S and one copy of another
variant(Sickle Cell Trait)

35. Inheritance of Sickle Cell Anemia
 If both parents have sickle
cell trait (HbAS) there is a one
in four (25%) chance that any
given child could be born with
sickle cell anemia.
 There is also a one in four
chance that any given child
could be completely
unaffected.
 There is a one in two (50%)
chance that any given child
will get the sickle cell trait

36.  If one parent has sickle cell
anaemia (HbSS) and the
other is completely unaffected
(HbAA) then all the children
will have sickle cell trait.
 None will have sickle cell
anemia.
 The parent who has sickle cell
anemia (HbSS) can only pass
the sickle hemoglobin gene to
each of their children.

37. • If one parent has sickle
cell trait (HbAS) and the
other has sickle cell
anaemia (HbSS) there is a
one in two (50%) chance
that any given child will get
sickle cell trait and a one in
two (50%) chance that any
given child will get sickle cell
anemia.
• No children will be completely
unaffected

38. • If one parent has sickle cell
trait (HbAS) and the other
does not carry the sickle
hemoglobin at all (HbAA)
then none of the children will
have sickle cell anemia.
• There is a one in two (50%)
chance that any given child will
get one copy of the HbAS gene
and therefore have the sickle
cell trait.
• It is equally likely that any given
child will get two HbAA genes
and be completely unaffected.

40. CLINICAL MANIFESTATIONS:

41.  The clinical manifestations of the sickle
cell syndrome can vary from
asymptomatic to a potentially lethal
state as characterized by Sickle cell
disease.
 Individuals affected with Sickle cell
disease are characteristically
asymptomatic until the the second half
of the first year of life owing to the
protective effect of Hb F.

42.  During the first 6 months of life, mutated
β chains are produced to gradually
replace normal ᴕchains, causing Hb S
levels to increase as Hb F levels
decrease.
 Erythrocytes containing Hb S become
susceptible to hemolysis, and a
progressive hemolytic anaemia and
slenomegaly may become evident.

43. Acute manifestations. Chronic manifestations.
 Vaso-occlusive crisis.
-painful crisis.
-acute chest
syndrome.
-Priapism.
 Cerebro-vascular events.
-Thrombotic stroke.
-Haemorrhagic stroke.
 Aplastic crisis.
 Splenic sequestration.
 Osteomyelitis.
 Chronic renal disease.
-Isosthenuria.
-CRF.
 Chronic pulmonary
disease.
 Sickle hepatopathy.
 Proliferative Retinopathy.
 Avascular Necrosis.
 Skin ulcers.

44. Crisis:
 Typical course of sickle cell patient is, the
period of relatively normal functioning,
despite chronic anaemia, punctuated by
periods of either pain in various anatomical
sites, or other manifestations termed as
“crisis”
 It is acute in onset
 These have been classified as
-vaso occlusive painful crisis
-aplastic crisis
-sequestration crisis
-hemolytic crisis

45. I. VASO-OCCLUSION
 Is the hallmark feature of SCD, accounting for
most hospital & emergency dept visits.
 It results from complex interplay between
sickled red cells, neutrophils, endothelium, &
plasma factors.
 End result is that of tissue hypoxia leading to
tissue death & accompanying pain.
 Fever is often present even in the absense of
infection.

46.  This acute painful aspect of SCD can be
triggered by
-acidosis
-hypoxia
-dehydration
-infection
-fever
-extreme cold
 They manifest most often in the bones,
lungs, liver, spleen, eyes, penis, CNS &
urinary tract.

47. 1.BONES
 Pain
 The frequency of pain varies from none to
six per year
 On average each episode persists for 4 to
5 days, although protracted episodes may
last for weeks.
 Young children: mostly extremities
 Older patients: abdomen, back, chest
 Associated with intercurrent illness and
other Vaso-occlusive event

48.  Hand foot
dactylitis.
 It’s a term used to
describe painful
swelling of digits of
hands and feet(Hand-
foot
syndrome).
 Occurs early in infancy
as Haematopoietic
marrow is present in
these bones at this

49.  Most episodes resolve within 2 weeks.
 Epiphyseal infarction can result in joint
pain and swelling mimicking septic
arthritis.

50.  Infection(osteomyelitis)
.
 Impaired cellular and
humoral immunity
together with infarction of
bone contribute to this
condition.
 Non-typical serotypes of
Salmonella,
Staphylococcus, and
Gram-Negative baccili
are principle infection
offenders.

51. 2. LUNGS
 Acute chest syndrome
 Is due to pulmonary infarction from
sickling in microvasculature, infection or
both.
 Also bone marrow infarction results in
fat emboli to the lungs, being other
cause.
 Is characterized by fever, acute chest
pain & presence of pulmonary infiltrates
on the Chest X ray.
 other manifestations:

52.  In Children, acute chest syndrome
generally is precipitated by infection
characterized by Fever, cough, and
tachypnea.
 In adults, this organ failure is the most
common cause of Death.

53. 3.SPLEEN
 Sequestration splenomegaly
 Is usually seen under the age of 2 years,
in infants and young children.
 The spleen rapidly enlarges (within hours)
& most of the circulating red cell mass
becomes sequestered.
 Is characterized by a sudden trapping of
Blood in the spleen, resulting in rapid
decline in Hb, often to less than 6g/dl,
result in hypovolemic shock &
cardiovascular collapse.

54.  Characterised by rapid enlarging
spleen, pain, hypoxemia and
hypovolemic shock.
 These may be associated with fever,
pain and respiratory symtoms.
 Circulatory collapse and death can
occur in 30 min.

55.  Auto splenectomy
Multiple episodes of splenic sequestration
leading to gradual loss of function(by the
age of 6-8 yrs) termed as Auto-
splenectomy .
It confers a Non-functioning spleen, which
is reduced to a shrunken, fibrosed
structure.
Hence patients are prone to microbial
infections, especially encapsulated, such
as -S. pneumoniae.
-H. influenza

56. 4.LIVER
 Hepatomegaly.
 Chronic liver abnormality in SCD are
frequent and are reflective of different
etiologies of liver dysfunction that include
Vaso-occlusion,
Transfusion,
Iron overload,
Pigment gall stones, with bile duct
obstruction,
Acute or chronic cholecystitis,
Viral Hepatitis and
Cholestatsis.

57.  Gallstones:
 Too much bilirubin from break
down of Hb leads to gallstone
formation.
 Manifest as
Nausea, vomitting, fever, sweating
, chills, clay coloured
stools(Jaundice)

58. 5. Penis
 Priapism
 Is the painful erection of penis
caused by sicklin red cells.
 This complication usually occurs in
children and adolescents with SS or
SC with an onset at age 5 to 35.
 It occurs as a severe episode
requiring hospitalization following
multiple episodes of short duration
, termed stuttering.
 Onset in early morning, waking the
patient is common.
 Impotence with severe disease or
recurrent episodes
Uret
hra
Corpus cavernosu

59. 6.EYES
 Retinal haemorrhage:
 Microvascular obstruction occurs
followed by neovascularization and
arterio venous aneurysm.
 Haemorrhage, scarring and retinal
detachment leading to blindness are
the sequel.

60. 7.CENTRAL NERVOUS SYSTEM:
 25% of patients are affected with CNS
manifestations.
 These include Transcient Ischaemic Attack,
Strokes and Cerebral haemorrhage.
Stroke:
-in SCD is a macrovascular phenomenon, that
affects approx. 11% of patients younger than 20
yrs.
 Is highest in first decade of life.
 Ischaemic stroke is most common in children &
older adults, whereas haemorrhagic stroke in
third decade of life.

61.  Cerebral blood flow is significantly
increased in SCD because of chronic
anaemia & hypoxaemia.
 Cerebral vasculature is unable to
vasodilate further in response to
increased hypoxic stress thereby
causing ischaemia.
 Risk factors:
-Ischaemic stroke: TIA, recent or
recurrent acute chest syndrome and
Hypertention.
-Haemorrrhagic stroke: Anaemia &
Neutrophilia

62. 8.URINARY TRACT
 Renal failure:
 Incidence varies between 4-20%
 The acidic, hypoxic and hypertonic environment
of the renal medulla promotes sickling of Hb SS
RBCs leading to ischaemia of the renal
microcirculation, loss of medullary function &
renal papillary necrosis.
 Hematuria:
 Usually painless, can result from papillary
necrosis, rupture of collateral vessels, & rarely
from neoplasm.

63.  Proteinuria/Nephrotic
syndrome:
 40% of SCD patients with nephrotic
syndrome develop end-stage renal
disease
 Occurs in ~ 20% of all patients
 Occurs in 4.5% of all pediatric patients
- increased in Hemoglobin SS to 6.5%
- Increased incidence with age.
- Increased with anaemia, increased MCV,
and increased leukocyte count.

64. 9.SKIN
 Leg ulcers
 It occurs in 2-40% cases of Sickle cell
disease.
 Most common in patients older than 10
years of age.
 Typically ocurrs in lower extremities,
especially on malleoli and cause
chronic pain and disability.
 Venous stasis is the predisposing factor.

65. II. BACTERIAL INFECTIONS
 Sepsis.
 These patients have increased
susceptibility to life threatening infections
from
S. aureus,
St. pneumonia and
H. influenza.
 Acute infections are common causes of
hospitalizations and have been the most
frequent cause of death, especially in the
first 3 years of life.

66.  These are exacerbated by auto-
splenectomy effect as its ability to
function as a secondary lymphoid tissue
to clear organisms effectively from the
blood is diminished, or lost.
 Pnemonia and Osteomyelitis.

67. III. HEMATOLOGICAL DEFECTS:
 Anaemia:
 Essentially a hemolytic process, can be
correlated with intra-cellular polymer
content.
 Characterised by generalised weakness,
fatigue, shortness of breath on exertion,
poor concentration.

68. Hemolytic crisis:
 Describes the occurnence of episodesof
accelerated haemolysis characterised by
decreased blood Hb, increased
reticulocytes and other markers of
haemolysis.
 Episodes of haemolysis occur in
conditions like-
-resolutive phase of Vaso-occlusive
crisis.
-delayed haemolytic transfusion
reactions.

69.  Megaloblastic episodes.
 This results from sudden arrest of
erythropoiesis due to folate deficiency.
 FA requirement is higher in haemolytic
anaemia and this factor is responsible
for severe anaemia in patients who are
nutritionally weak.

70.  Aplastic crisis.
 Aplastic episodes (bone marrow failure)
are the most common life threatening
haemotological complications, and
usually are associated with infection,
particularly with Parvo viruses 19
resulting in a severe but self limiting red
cell aplasia.
 SCD patients usual can compensate for
the decrease in RBC survival by
increasing bone marrow output.

71.  But when bone marrow is suppressed
temporarily by bacterial or viral infections
however the haematocrit decreases
substantially with no reticulocyte
compensation.
 This produces a very low Hb which may
cause heart failure.

72. IV. CARDIAC DEFECTS:
 Enlarged heart: the hemodynamic
burden of anaemia results in elevated
cardiac output and hence ventricular
hypertrophy.
 Heart murmurs:
-Forceful precordial apical impulse
-Systolic & Diastolic flow murmers, as
manifestation of hyperdynamic
circulation.

73. 1. Fever
2. Chest pain
3. Shortness of
Breath
4. Increasing
tiredness
5. Abdominal
swelling
6. Unusual
Danger Signs of a Crisis
7. Any sudden weakness
or loss of feeling
8. Pain that will not go
away with home
treatment .
9. Priapism (painful
erection that will not go
down)
10.Sudden vision change

74. V. OTHER FEATURES:
 Stunted growth:
 A vast majority of children with SCD
will show decline in growth compared
to normal peers.
 Puberty is delayed on an average by
12 to 24 months, as is skeletal age.

75. High risk pregnancy
 One third of patients will have
adverse obstretic outcomes as
defined by Miscarriages, StillBirths
or Ectopic implantation.
 Preterm delivery occurs in 30-50%
of pregnancy in sickle cell disease
patients and 20% of infants have
low birth weight.

76.  A five fold increase in risk for
Thromboembolism is present during
pregnancy.
 Other significant findings include
-higher rates of Caeserian section
-infection
-Gestational hypertension
-Pre-eclampsia or Eclampsia
-IUGR
-asymptomatic bacteruria.