HEREDITARY HAEMOLYTIC ANAEMIAS

1
HEREDITARY HAEMOLYTIC ANAEMIAS
HEREDITARY SPHEROCYTOSIS

• BY
• DR. FATMA ALQAHTANI
• CONSULTANT HAEMATOLOGIST

2

3
HEREDITARY HAEMOLYTIC ANAEMIA

• MEMBRANE DEFECTS
• Hereditary Spherocytosis
• Hereditary Elliptocytosis
• Hereditary Stomatocytosis
• etc.

4
HEREDITARY HAEMOLYTIC ANAEMIA

• METABOLIC DEFECTS
• Deficiency of
• Glucose-6-phosphate dehydrogenase
• Pyruvate kinase
• Triose phosphate isomerase
• Pyrimidine-5-nucleotidase
• Glutathione synthetase
• etc.

5
HEREDITARY HAEMOLYTIC ANAEMIA

• HAEMOGLOBIN DEFECTS
• Defective synthesis
• e.g. Thalassaemia (Alpha or
  Beta)
• Abnormal variants
• e.g. Hb S, Hb C, Unstable Hb
  

6
GENETIC ABNORMALITIESOFTHE 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

7
(No Transcript)
8
GENETIC ABNORMALITIES OF THE RED CELL MEMBRANE
HEREDITARY SPHEROCYTOSIS (HS)
NAME Electrophoretic Band Molecular weight (kd) Number of molecules / RBC ( x 105 ) Location / function Chromosomal Assignment Gene cloned
a Spectrin ß 1 240 2 2 CS form heterodimers, tetramers 1 q22 1 q25 Yes
a Spectrin ß 2 220 2 2 CS form heterodimers, tetramers 1 q22 1 q25 Yes
Actin 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
Glycophorin A PASI, 2 29 4 IMP sialoglycoprotein 4 q28 Yes
IMP integral membrane protein CS
cytoskeleton as currently numbered on
SDS gels
9
PATHOGENESIS OFHEREDITARY SPHEROCYTOSIS (HS)
Spherocytes
Abnormal spectrin
OF
? Spectrin genes
Decreased spectrin in membrane
Decreased Synthesis of spectrin
Glucose requirement
? Gene for other membrane protein
Decreased binding of spectrin
Decreased deformability
10
HEREDITARY SPHEROCYTOSIS (HS)

• DEFINITION
• A congenital disorder which is characterized
  by
• spherocytes
• increased osmotic fragility
• autosomal dominant
  inheritance ( ! recessive )
• beneficial response to
  splenectomy

11
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

12
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

13
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

14
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

15
HEREDITARY SPHEROCYTOSIS (HS)

• Laboratory Tests and Findings
• Peripheral blood film\
• gt 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 gt 1800 seconds)
• Auto haemolysis (Screening test). 48 hours
  incubation under sterile conditions

16
HEREDITARY SPHEROCYTOSIS (HS)
Spherocytes
17
HEREDITARY ELLIPTOCYTOSIS (HE)
Elliptocytes
18
HEREDITARY STOMATOCYTOSIS (HST)
Stomatocytes
19

HEREDITARY SPHEROCYTOSIS
20
HEREDITARY SPHEROCYTOSIS (HS)Autohaemolysis Test

Lysis in a typical case () No addition 27 mmol glucose Lysis in a typical case () No addition 27 mmol glucose Condition
0.15 1.7 Normal
1.3 10.1 Hereditary spherocytosis
6.1 5.5 Pyruvate kinase deficiency
1.8 2.9 G6PD deficiency with CNSHA
In the more common forms of G6PD deficiency
without chronic non spherocytic haemolytic
anaemia (CNSHA) the autohaemolysis test is
normal
21
HEREDITARY SPHEROCYTOSIS (HS)

• Differential diagnosis
• IF SPHEROCYTOSIS is prominent
• Acquired haemolytic anaemia
• DAT
• FAMILY DATA
• Red cell fragmentation favours
• poikilocytosis microangiopathic process
• Fever may favor rare infectious
  cause for haemolysis (Clostridium welchii)
• IF SPHEROCYTOSIS is not prominent with chronic
  course
• PNH ---- Ham test
• Enzymopatheis ---- O.F. usually normal
  or decreased
• Autohaemolysis not corrected by
  glucose

22
HEREDITARY SPHEROCYTOSIS (HS)

• Complications
• Leg ulcers
• Gall stones (Often asymptomatic)
• Aplastic crises

23
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 complications as arises

24
Different forms of elliptocytosis

Remarks Example of known molecular lesion Degree of haemolysis Genetic status Sub type of hereditary elliptocytosis (HE)
One parent has similar picture Structurally abnormal aspectrin Absent Heterozygote Common Non-haemolytic
One parent has similar picture Glycoprotein C deficiency Minimal Heterozygote Mild
One parent has similar picture Moderate Heterozygote Intermediate
One parent has HE some times both Severe Heterozygote Severe
Usuallybot parents asymptomatic. Or one has HE Structurally abnormal aspectrin Severe Homozygote Pyropoikilocytosis
Deletion revealed at DNA level (Conoboy et al., 1986) Absence of protein 4.1 Mild Severe Heterozygote Homozygote Spherocytic
Common in Melanesians ? Protects against malaria Absent or mild Not well defined Stomatocytic