Download Acute haemolytic anaemia

HAEMOLYTIC ANAEMIAS I
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Dr. Zeki Ali Mohamed
MRCP UK ( Edinburgh & London )
FIBMS - Haematology
Consultant Physician & Haematologist
Azadi Teaching Hospital
• Lecturer / Departmeent of Medicine
• Duhok University – Faculty of Medical Sciences
• School of Medicine
Normal Red Cell Destruction
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Being anucleate, red cell metabolism gradually deteriorates as
enzymes are degraded and not replaced >> non-viable.
After a mean lifespan of about 120 days, red cell destruction
normally occurs by the macrophages of the
reticuloendothelial system (RES): (Bone Marrow , Liver
and Spleen) , the breakdown of haem from red cells
liberates:
• Iron: for recirculation via plasma transferrin mainly to BM
erythroblasts.
• Protoporphyrin: is broken down to bilirubin.
• Bilirubin: circulates to the liver where it is conjugated to
glucuronides which are excreted into the duodenum via bile
and converted to stercobilinogen and stercobilin (excreted in
faeces)
• Stercobilinogen and stercobilin: are partly
reabsorbed and excreted in urine as urobilinogen and urobilin.
• Globin chains: are broken down to amino acids which
are reutilized for general protein synthesis in the body.
(a) Normal (RBC) breakdown. Extravascularly
in the macrophages of the RES
(b) Intravascular haemolysis occurs in
some pathological disorders.
Haemolytic anaemias - Definition
 Haemolytic anaemias are defined as:
 Anaemias resulting from increased rate of
RBC destruction >> Shortened life span.
 After full expansion, the normal adult
marrow, is able to produce red cells at 6–8
times its normal rate.
 Because of this (Erythropoietic hyperplasia)
and anatomical extension of bone marrow,
red cell destruction may be increased
several-fold before the patient becomes
anaemic (compensated haemolytic disease).
 Haemolytic anaemia may not be seen until
the red cell lifespan is less than 30 days.
CLASSIFICATION
•Hereditary haemolytic anaemias are
the result of ‘intrinsic’ red cell defects
•Acquired HAs are usually the result of an
‘extracorpuscular’ or ‘environmental’ change.
•(PNH) is exception : an acquired disorder, with
intrinsic defect.
Clinical features
Patients with HA may commonly show:
 pallor of the mucous membranes,
 mild fluctuating jaundice and splenomegaly.
 urine may turn dark on standing because of excess
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urobilinogen not bilirubin.
Pigment (bilirubin) gallstones may complicate the
condition
some patients (particularly with sickle cell disease)
develop ulcers around the ankle.
Aplastic crises may occur, usually precipitated by
infection with parvovirus which ‘switches off
erythropoiesis, and are characterized by a sudden
increase in anaemia and drop in reticulocyte count
folate deficiency may cause a megaloblastic crisis in
the bone marrow .
Laboratory findings: The laboratory findings are
divided into three groups.
1- Features of Increased red
cell breakdown :
 Serum bilirubin raised,
unconjugated ( Indirect ) and
bound to albumin
 Urine urobilinogen increased
 Serum haptoglobins absent
because the haptoglobins
become saturated with
haemoglobin and the complex
is removed by RE cells.
2 - Features of increased red cell
production:
 Reticulocytosis;
 Bone marrow erythroid
hyperplasia; the normal marrow
myeloid: erythroid ratio of 2:1 to
12:1 is reduced to 1:1 or reversed.
3 – Features of damaged red
cells:
 Morphology (e.g.
microspherocytes,
elliptocytes, fragments);
 Osmotic fragility,
autohaemolysis, etc.;
 Specific enzyme, protein or
DNA tests.
Intravascular and extravascular
haemolysis
There are two mechanisms whereby red cells are destroyed
in haemolytic anaemia:
 There may be excessive removal of red cells by
macrophages of the RES (Extravascular haemolysis)
 or they may be broken down directly in the circulation
(Intravascular haemolysis)
 Whichever mechanism dominates will depend on the
pathology involved. In intravascular haemolysis, free
haemoglobin is released which rapidly saturates plasma
haptoglobins and the excess free haemoglobin is filtered
by the glomerulus. If the rate of haemolysis saturates the
renal tubular reabsorptive capacity, free haemoglobin
enters urine and, as iron is released, the renal tubules
become loaded with haemosiderin. Methaemalbumin is
also formed from the process of intravascular
haemolysis.
Causes of intravascular haemolysis
The main laboratory features of intravascular haemolysis are:
1 - Haemoglobinaemia and haemoglobinuria;
2 - Haemosiderinuria (iron storage protein in the spun deposit of urine
3 - Methaemalbuminaemia (detected spectrophotometrically by
Schumm’s test).
Hereditary haemolytic anaemias
Membrane defects
Hereditary spherocytosis
Hereditary Spherocytosis (HS) is the most common hereditary haemolytic
anaemia in northern Europeans.
It is usually caused by defects in the proteins involved in the vertical
interactions between the membrane skeleton and the lipid bilayer of the
red cell. The loss of membrane may be caused by the release of parts of the
lipid bilayer that are not supported by the skeleton.
In HS, the marrow produces red cells of normal biconcave shape but these
lose membrane and become increasingly spherical (loss of surface area
relative to volume) as they circulate through the spleen and the rest of the
RES. Ultimately, the spherocytes are unable to pass through the splenic
microcirculation where they die prematurely.
Clinical features
The inheritance is Autosomal Dominant with variable expression;
rarely it may be Autosomal Recessive.
The anaemia can present at any age from infancy to old age.
Jaundice is typically fluctuating.
Splenomegaly occurs in most patients.
Pigment gallstones are frequent
Aplastic crises, usually precipitated by parvovirus infection, may
cause a sudden increase in severity of anaemia
Haematological findings
Anaemia is usual but not invariable; its severity tends to be
similar in members of the same family.
Reticulocytes are usually 5–20%.
The blood film shows Microspherocytes that are densely staining
with smaller diameters than normal red cells.
Eosin-5-maleimide staining in hereditary
spherocytosis (HS) showing reduced mean
channel fluorescence due to membrane band
3 protein deficiency.
Investigation and treatment
A rapid fluorescent flow analysis of eosin-maleimide bound to red cells
is used as a test for HS and membrane band 3 protein deficiency (This has
replaced the classic osmotic fragility test which showed the HS red cells to
be excessively fragile in dilute saline solution.
The identification of the exact molecular defect is NOT NEEDED for
management.
The direct antiglobulin (Coombs) test is, Negative, excluding an
autoimmune cause of spherocytosis and haemolysis.
The principal form of treatment is Splenectomy, preferably laparoscopic.
Indications:
symptomatic anaemia,
gallstones,
leg ulcers or
growth retardation.
NB: (Splenectomy should not be performed Unless cCinically Indicated )
This is because of the risk of post-splenectomy sepsis, particularly in early
childhood. There is also evidence for late vascular complications.
Cholecystectomy should be performed with splenectomy if symptomatic
gallstones are present. Splenectomy should always produce a rise in the
haemoglobin level to normal, even though microspherocytes formed in the rest
of the RE system will remain.
Hereditary elliptocytosis
This usually a clinically milder disorder with similar clinical and laboratory
features to HS except for the appearance of the blood film. Usually
discovered incidentally on a blood film and there may be no evidence of
haemolysis.
Occasional patients require splenectomy. The basic defect is a failure of
spectrin heterodimers to self-associate into heterotetramers. Patients with
homozygous or doubly heterozygous elliptocytosis present with a severe
haemolytic anaemia with microspherocytes, poikilocytes and splenomegaly
(hereditary pyropoikilocytosis).
Hereditary elliptocytosis. Peripheral blood smears representative of different hereditary elliptocytosis syndromes are
shown. A: Micropoikilocytes and elliptocytes in a neonate with transient poikilocytosis and an α-spectrin gene
mutation. B: Same child at 7 months of age, now exhibiting morphology of common hereditary elliptocytosis. C:
Compound heterozygous hereditary elliptocytosis due to two α-spectrin self-association–site structural mutations.
Note distorted red cell shapes, elliptocytes, and fragments. D: Hereditary pyropoikilocytosis. Red cell abnormalities
are similar to those in (A) and (C) with prominent budding and fragmentation.
Defective red cell metabolism
Glucose-6-phosphate dehydrogenase
deficiency
Glucose-6-phosphate
dehydrogenase (G6PD)
functions to reduce
nicotinamide adenine
dinucleotide phosphate
(NADP). It is the only
source of NADPH that is
needed for the production of
reduced glutathione.
Deficiency of G6PD renders
the red cell susceptible to
oxidant stress
Haemoglobin and red blood cell (RBC)
membranes are usually protected from
oxidant stress by reduced glutathione
(GSH). In G6PD deficiency, NADPH and
GSH synthesis is impaired. F6P fructose6-phosphate; G6P glucose-6-phosphate;
G6PD, glucose-6-phosphate
dehydrogenase; GSSG, glutathione
(oxidized form); NADP nicotinamide
adenine dinucleotide phosphate
Epidemiology
There is a wide variety of normal genetic variants of the enzyme G6PD,
the most common being type B (Western) and type A in Africans. In
addition, more than 400 variants caused by point mutations or deletions
of the enzyme G6PD have been characterized that show less activity
than normal and worldwide over 400 million people are G6PD deficient
in enzyme activity
Clinical features
G6PD deficiency is Usually Asymptomatic. Although G6PD is present in
all cells, the main syndromes that occur are as follow:
1 - Acute haemolytic anaemia in response to oxidant stress, e.g.
drugs, fava beans or infections. The acute haemolytic anaemia is
caused by rapidly developing intravascular haemolysis with
haemoglobinuria (The anaemia may be self-limiting as new young red
cells are made with near normal enzyme levels.
2 - Neonatal jaundice.
3 - Rarely, a Congenital Non-Spherocytic Haemolytic Anaemia.
These syndromes may result from different types of severe enzyme
deficiency.
Agents that cause haemolysis in (G6PD) deficiency:
Infections and other acute illnesses (e.g. diabetic ketoacidosis)
Drugs
Antimalarials (e.g. primaquine, pamaquine, chloroquine,
Fansidar®, Maloprim®)
Sulphonamides and sulphones (e.g. co-trimoxazole,
sulfanilamide, dapsone, Salazopyrin®)
Other antibacterial agents (e.g. nitrofurans, chloramphenicol)
Analgesics (e.g. aspirin), moderate doses are safe
Antihelminths (e.g. β-naphthol, stibophen)
Miscellaneous (e.g. vitamin K analogues, naphthalene
(mothballs), probenecid)
Fava beans (possibly other vegetables)
NB. Many common drugs have been reported to precipitate
haemolysis in G6PD deficiency in some patients (e.g. aspirin,
quinine and penicillin) but not at conventional dosage.
Diagnosis
Between crises the blood count is normal.
The enzyme deficiency is detected by one of a number of screening tests or
direct enzyme assay on red cells.
 During a crisis the blood film may show contracted and fragmented cells, ‘bite’
cells and ‘blister’ cells which have had Heinz bodies removed by the spleen.
Heinz bodies (oxidized, denatured haemoglobin) may be seen in the
reticulocyte preparation, particularly if the spleen is absent.
There are also features of intravascular haemolysis. Because of the higher
enzyme level in young red cells, red cell enzyme assay may give a (False
Normal) level in the phase of acute haemolysis with a reticulocyte response.
Subsequent assay after the acute phase reveals the low G6PD level when the red
cell population is of normal age distribution.
Treatment
The offending drug is stopped,
The underlying infection is treated,
High urine output should be maintained
Blood transfusion undertaken where necessary for severe anaemia.
G6PD-deficient babies are prone to neonatal jaundice and in severe cases
phototherapy and exchange transfusion may be needed.
The jaundice is usually not caused by excess haemolysis but by deficiency of
G6PD affecting neonatal liver function.
Pyruvate kinase deficiency
This is inherited as an autosomal recessive, the affected patients being
homozygous or doubly heterozygous. Over 100 different mutations
have been described.
The red cells become rigid as a result of reduced (ATP) formation.
Clinically:
The severity of the anaemia varies widely (haemoglobin 4–10 g/dL)
and causes relatively mild symptoms because of a shift to the right
in the oxygen (O2) dissociation curve caused by a rise in
intracellular 2,3-diphosphoglycerate (2,3-DPG).
jaundice is usual and gallstones frequent.
Frontal bossing may be present.
The blood film shows poikilocytosis and distorted ‘prickle’ cells,
particularly post-splenectomy.
Direct enzyme assay is needed to make the diagnosis.
Splenectomy may alleviate the anaemia but does not cure it and is
indicated in those patients who need frequent transfusions.