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HEREDITARY HAEMOLYTIC ANAEMIAS
HEREDITARY SPHEROCYTOSIS
BY
DR. KAMAL E. HIGGY
CONSULTANT HAEMATOLOGIST
HEREDITARY HAEMOLYTIC ANAEMIA

MEMBRANE DEFECTS
* Hereditary Spherocytosis
* Hereditary Elliptocytosis
* Hereditary Stomatocytosis
etc….
HEREDITARY HAEMOLYTIC ANAEMIA

METABOLIC DEFECTS:
Deficiency of:
* Glucose-6-phosphate dehydrogenase
* Pyruvate kinase
* Triose phosphate isomerase
* Pyrimidine-5-nucleotidase
* Glutathione synthetase
etc….
HEREDITARY HAEMOLYTIC ANAEMIA

HAEMOGLOBIN DEFECTS:
* Defective synthesis
e.g. Thalassaemia (Alpha or Beta)
* Abnormal variants
e.g. Hb S, Hb C, Unstable Hb
GENETIC ABNORMALITIES
OF
THE RED CELL MEMBRANE

Hereditary Spherocytosis

Hereditary Elliptocytosis
Hereditary Stomatocytosis
Hydrocytosis (high MCV, low MCHC)
Xerocytosis (low MCV, high MCHC shrunken RBCs
due to K loss)
Acanthocytosis – Abeta-lipoproteinaemia




GENETIC ABNORMALITIES
OF THE RED CELL MEMBRANE
HEREDITARY SPHEROCYTOSIS (HS)
Electrophoretic
NAME
Band*
Molecular
weight
(kd)
Number
Location / function
of
molecules
Chromosomal
Assignment
Gene
cloned
/ RBC
( x 105 )
α
Yes
1
2
240
220
2
2
CS: form heterodimers,
tetramers
1 q22 – 1 q25
5
42
5
Cs: forms protofilaments
of 10-13 monomers
7 pter – q22
Yes
‘ Band ‘
4.1
78
2
Crosslinks spectrin
heterodimers
1 p32 – 1 pter
Yes
Ankyrin
2.1
210
1
Links spectrin to band 3
‘ Band ‘
3
95
10
IMP: anion transport:
links to ankyrin
29
4
IMP: sialoglycoprotein
4 q28
Yes
Spectrin
β
Actin
Glycophorin A
PASI, 2
IMP = integral membrane protein
CS = cytoskeleton
Yes
* as currently numbered on SDS – gels
PATHOGENESIS
OF
HEREDITARY SPHEROCYTOSIS (HS)
? Spectrin
genes
Abnormal
spectrin
Decreased
Synthesis
of spectrin
? Gene for
other membrane
protein
Spherocytes
OF
Decreased
binding of
spectrin
Decreased
spectrin in
membrane
Glucose
requirement
Decreased
deformability
HEREDITARY SPHEROCYTOSIS
(HS)

DEFINITION:
A congenital disorder which is characterized by:
*
*
*
*
spherocytes
increased osmotic fragility
autosomal dominant inheritance ( ! recessive )
beneficial response to splenectomy
HEREDITARY SPHEROCYTOSIS
(HS)
The diagnosis of HS is not always easy since:
* The degree of spherocytosis is variable
* The changes in osmotic fragility are not always clear cut
* Sporadic cases can occur
* Other haemolytic anaemias may respond to splenectomy
HEREDITARY SPHEROCYTOSIS
(HS)

Role of spleen:
* Results post splenectomy
- Decrease in the rate of haemolysis (ameliorates the degree of anaemia)
- Decrease in the number of spherocytes
(but can not cure the red cell abnormality)
* Spleen is the major site of red cell destruction
* RBCs retained for long time in the splenic pulp as a result of decreased deformability
+
Unfavorable environmental conditions in the splenic pulp (acid pH & decreased glucose)
Failure of the cation pump
Loss of water
Loss of RBCs discoid shape
Vicious circle
HEREDITARY SPHEROCYTOSIS
(HS)
Clinical Manifestations:
•
Most of the cases present in childhood or as teenagers
•
HS has been rarely diagnosed at:
* Neonatal period (persistent jaundice)
* The age of 60 (asymptomatic)
•
The disease has a wide spectrum of severity
•
The most consistent findings according to frequency are:
* Jaundice
* Splenomegaly
* Anaemia
HEREDITARY SPHEROCYTOSIS
(HS)
Clinical Manifestations (cont…):
•
Haemolysis can be compensated for, with normal
haemoglobin in about 1/3 of the patients
•
Patients may be more yellow than sick
•
Cholelithiasis is a complication of HS
•
HS as any other congenital haemolytic anaemia has a
STEADY STATE and EPISODIC CHANGES
HEREDITARY SPHEROCYTOSIS (HS)
Laboratory Tests and Findings:
* Peripheral blood film\
> 1-2% spherocytes in significant
* MCHC is increased or in the upper limit of normal range (due to decreased water
content)
* Increased osmatic fragility (O.F)
Shift to the right of the entire curve or only part of it
Draw backs of this test:
Laborious test
Needs fresh defibrinated blood
Not specific for HS (can be increased in AIHA)
Insufficiently sensitive
(10-25%) of patients genetically proven to have HS have normal O.F)
* Acidified glycerol lysis time. The rate of haemolysis (The time required for 50%
lysis). Normal values > 1800 seconds)
* Auto haemolysis (Screening test). 48 hours incubation under sterile conditions
HEREDITARY SPHEROCYTOSIS (HS)
Spherocytes
HEREDITARY ELLIPTOCYTOSIS (HE)
Elliptocytes
HEREDITARY STOMATOCYTOSIS (HST)
Stomatocytes
HEREDITARY SPHEROCYTOSIS
HEREDITARY SPHEROCYTOSIS (HS)
Autohaemolysis Test
Condition
Lysis in a typical case (%)
No addition
Normal
+ 27 mmol glucose
1.7
0.15
10.1
1.3
Pyruvate kinase deficiency
5.5
6.1
G6PD deficiency with
CNSHA*
2.9
1.8
Hereditary spherocytosis
* In the more common forms of G6PD deficiency without chronic non spherocytic haemolytic anaemia
(CNSHA) the autohaemolysis test is normal
HEREDITARY SPHEROCYTOSIS (HS)
Differential diagnosis

IF SPHEROCYTOSIS is prominent:
Acquired haemolytic anaemia
DAT
FAMILY DATA
Red cell fragmentation
poikilocytosis
Fever

favours
microangiopathic process
may favor rare infectious cause for haemolysis (Clostridium welchii)
IF SPHEROCYTOSIS is not prominent with chronic course:
PNH ---- Ham test – flowcytometry – molecular genetic
Enzymopatheis ---- O.F. usually normal or decreased
Autohaemolysis not corrected by glucose
HEREDITARY SPHEROCYTOSIS (HS)
Complications



Leg ulcers
Gall stones (Often asymptomatic)
Aplastic crises
HEREDITARY SPHEROCYTOSIS (HS)
Management

No cure

The aim is to minimize the consequences of the
genetic abnormality
Splenectomy
Avoid below the age of 5 years unless haemolytic
anaemia is very severe (rare is HS)
Pneumococcal vaccination – (regular penicillin for at
least 2 years)
Treatment of complication’s as arises



Different forms of elliptocytosis
Sub type of
hereditary
elliptocytosis
(HE)
Genetic
status
Degree of
haemolysis
Example of
known
molecular lesion
Remarks
Common Nonhaemolytic
Heterozygote
Absent
Structurally
abnormal α–
spectrin
One parent has similar picture
Mild
Heterozygote
Minimal
Glycoprotein C
deficiency
One parent has similar picture
Intermediate
Heterozygote
Moderate
One parent has similar picture
Severe
Heterozygote
Severe
One parent has HE: some times
both
Pyropoikilocyt
osis
Homozygote
Severe
Structurally
abnormal α–
spectrin
Usuallybot parents
asymptomatic. Or one has HE
Spherocytic
Heterozygote
Homozygote
Mild
Severe
Absence of
protein 4.1
Deletion revealed at DNA level
(Conoboy et al., 1986)
Stomatocytic
Not well
defined
Absent or
mild
Common in Melanesians ?
Protects against malaria