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HEREDITARY SPHEROCYTOSIS. HEREDITARY HAEMOLYTIC ANAEMIAS. BY DR. KAMAL E. HIGGY CONSULTANT HAEMATOLOGIST. HEREDITARY HAEMOLYTIC ANAEMIA. MEMBRANE DEFECTS * Hereditary Spherocytosis * Hereditary Elliptocytosis * Hereditary Stomatocytosis etc …. - PowerPoint PPT Presentation
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HEREDITARY HAEMOLYTIC ANAEMIAS
BY
DR. KAMAL E. HIGGY
CONSULTANT HAEMATOLOGIST
HEREDITARY SPHEROCYTOSIS
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 ABNORMALITIESOF
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)NAME Electrophoretic
Band*Molecular
weight (kd)
Number of
molecules /RBC
(x 105 )
Location / function ChromosomalAssignment
Gene cloned
αSpectrin
β
1 240 22
CS: form heterodimers, tetramers
1 q22 – 1 q25Yes
2 220 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, 229 4 IMP: sialoglycoprotein 4 q28 Yes
IMP = integral membrane protein CS = cytoskeleton * as currently numbered on SDS – gels
PATHOGENESIS OF
HEREDITARY SPHEROCYTOSIS (HS)
? Spectrin
genes
? Gene for
other membrane protein
Abnormal
spectrin
Decreased
Synthesis
of spectrin
Decreased
binding of
spectrin
Decreased
spectrin in
membrane
Spherocytes
OF
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
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
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 – 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 Remarks Example of
known molecular lesion
Degree of haemolysis
Genetic status
Sub type of hereditary
elliptocytosis (HE)
One parent has similar picture Structurally abnormal α–
spectrin
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 α–
spectrin
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
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