ANAEMIAS AND CLASSIFICATIONS and characters.pptx

ANAEMIAS AND CLASSIFICATIONS 2: MP;201 1
ANAEMIAS AND CLASSIFICATIONS 2
MP : 201
BY
DR CHUKWUMA OKAFOR MSc, MPH, PhD, FMLSCN
SCHOOL OF HEALTH AND MEDICAL SCIENCES
STATE UNIVERSITY OF ZANZIBAR
22/1/2024

HAEMOLYTIC ANAEMIAS AND ANAEMIA DUE
TO BLOOD LOSS
Haemolytic anaemias are defined as anaemias resulting from an
increase in the rate of red cell destruction.
The red cell lifespan is shortened in haemolytic anaemia i.e. there is
accelerated haemolysis.
The premature destruction of red cells in haemolytic anaemia may
occur at either of the following 2 sites:
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Firstly, the red cells undergo lysis in the circulation and release their
contents into plasma (intravascular haemolysis). In these cases the
plasma haemoglobin rises substantially and part of it may be excreted
in the urine (haemoglobinuria) .
Secondly, the red cells are taken up by cells of the RE system where
they are destroyed and digested (extravascular haemolysis) . In
extravascular haemolysis, plasma haemoglobin level is, therefore,
barely raised.
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Extravascular haemolysis is more common than the former.
Clinically, haemolytic anaemias may be acute or chronic, mild to
severe, hereditary or acquired.
Haemolytic anaemias are broadly classified into 2 main categories:
I. Acquired haemolytic anaemias caused by a variety of extrinsic
environmental factors (i.e. extracorpuscular) .
II. Hereditary haemolytic anaemias which are usually the result of
intrinsic red cell defects (i.e. intracorpuscular )
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I. ACQUIRED
 A. Antibody: Immunohaemolytic anaemias
1. Autoimmune haemolytic anaemia (AIHA)
i) Warm antibody AIHA
ii) Cold antibody AIHA
2. Drug-induced immunohaemolytic anaemia
3. Isoimmune haemolytic anaemia
 B. Mechanical trauma: Microangiopathic haemolytic anaemia (involving the small blood vessels)
 C. Direct toxic effects: Malaria, bacterial, infection and other agents
 D. Acquired red cell membrane abnormalities: Paroxysmal nocturnal haemoglobinuria (PNH)
 E. Splenomegaly
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II. HEREDITARY
 A. Abnormalities of red cell membrane
1. Hereditary spherocytosis
2. Hereditary elliptocytosis (hereditary ovalocytosis)
3. Hereditary stomatocytosis
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 B. Disorders of red cell interior
1. Red cell enzyme defects (Enzymopathies)
i) Defects in the hexose monophosphate shunt: G6PD deficiency
ii) Defects in the Embden-Meyerhof (or glycolytic) pathway: pyruvate
kinase deficiency
2. Disorders of haemoglobin (Haemoglobinopathies)
i) Structurally abnormal haemoglobins: sickle syndromes, other
haemoglobinopathies
ii) Reduced globin chain synthesis: thalassaemias
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GENERAL CLINICAL FEATURES
1. Presence of pallor of mucous membranes.
2. Positive family history with life-long anaemia in patients with
congenital haemolytic anaemia.
3. Mild fluctuating jaundice due to unconjugated hyperbilirubinaemia.
4. Urine turns dark on standing due to excess of urobilinogen in urine.
5. Splenomegaly is found in most chronic haemolytic anaemias, both
congenital and acquired.
6. Pigment gallstones are found in some cases
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LABORATORY EVALUATION OF HAEMOLYSIS
 I. TESTS OF INCREASED RED CELL BREAKDOWN
 1. Serum bilirubin—unconjugated (indirect) bilirubin is raised.
 2. Urine urobilinogen is raised but there is no bilirubinuria.
 3. Faecal stercobilinogen is raised.
 4. Serum haptoglobin (a-globulin binding protein) is reduced or absent.
 5. Plasma lactic dehydrogenase is raised.
 6. Evidences of intravascular haemolysis in the form of
haemoglobinaemia, haemoglobinuria, methaemoglobinaemia and
haemosiderinuria
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II. TESTS OF INCREASED RED CELL PRODUCTION
 1. Reticulocyte count reveals reticulocytosis.
 2. Routine blood film shows macrocytosis, polychromasia and
presence of normoblasts.
 3. Bone marrow shows erythroid hyperplasia with usually raised iron
stores.
 4. X-ray of bones shows evidence of expansion of marrow space
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III. TESTS OF DAMAGE TO RED CELLS
 1. Routine blood film shows a variety of abnormal morphological appearances of red cells.
 2. Osmotic fragility is increased or decreased.
 3. Autohaemolysis test with or without addition of glucose. (This test measures the degree to which
patients red cells lyse without additives, with glucose and with ATP (Adenosine Tri-phosphate).
Interpretation : Glucose by itself can induce autohaemolysis is spherocytosis )
 4. Coombs’ antiglobulin test .
 5. Electrophoresis for abnormal haemoglobins.
 6. Estimation of HbA 2 .
 7. Estimation of HbF .
 8. Tests for sickling. (Sodium metabisulphite reduces the oxygen tension and induces sickling on RBCs)
 9. Screening test for G6PD deficiency and other enzymes (e.g. Heinz bodies test)
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IV. TESTS FOR SHORTENED RED CELL LIFESPAN
A shortened red cell survival is best tested by 51Cr labelling method.
Normal RBC lifespan of 120 days is shortened to 20-40 days in
moderate haemolysis and to 5-20 days in severe haemolysis.
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I. ACQUIRED HAEMOLYTIC ANAEMIAS
A. IMMUNOHAEMOLYTIC ANAEMIAS
 Immunohaemolytic anaemias are a group of anaemias occurring due to
antibody production by the body against its own red cells.
AUTOIMMUNE HAEMOLYTIC ANAEMIA (AIHA)
‘WARM’ ANTIBODY AIHA
PATHOGENESIS
Warm antibodies reactive at body temperature and coating the red cells are
generally IgG class antibodies and occasionally they are IgA. The spleen is
particularly efficient in trapping red cells coated with IgG antibodies. It is,
thus, the major site of red cell destruction in warm antibody AIHA.
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CLINICAL FEATURES
 Warm antibody AIHA may occur at any age and in either sex. The
disease may occur without any apparent cause (idiopathic) but about
a quarter of patients develop this disorder as a complication of an
underlying disease affecting the immune system.
 The usual clinical features are as follows:
1. Chronic anaemia of varying severity with remissions and relapses.
2. Splenomegaly.
3. Occasionally hyperbilirubinaemia.
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LABORATORY FINDINGS
 These are as under:
 1. Mild to moderate chronic anaemia.
 2. Reticulocytosis.
 3. Prominent spherocytosis in the peripheral blood film.
 4. Positive direct Coombs’ (antiglobulin) test for presence of warm antibodies on the red cell, best detected
at 37°C. (direct ab identification in eg in neonates for haemolysis)
 5. A positive indirect Coombs’ (antiglobulin) test at 37°C (invitro ab identification-eg mothers against HDN,
in crossmatching )- The indirect Coombs test looks for antibodies that are floating in the blood. These
antibodies could act against certain red blood cells. This test is most often done to determine if you may
react to a blood transfusion. ( serum of patient + cell of donor + AHG)
 6. Unconjugated (indirect) hyperbilirubinaemia.
 7. Co-existent immune thrombocytopenia along with occasional venous thrombosis may be present.
 8. In more severe cases, haemoglobinaemia and haemoglobinuria may be present
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• ‘COLD’ ANTIBODY AIHA
PATHOGENESIS
Antibodies which are reactive in the cold (4°C) may induce haemolysis under
2 conditions:
1. Cold agglutinin disease
The antibodies are IgM type which bind to the red cells best at 4°C. These
cold antibodies are usually directed against the I antigen (on the fetal and
infant RBCs –IgM specific) on the red cell surface. The etiology of cold
antibody remains unknown. It is seen in the course of certain infections (e.g.
Mycoplasma pneumonia, infectious mononucleosis) and in lymphomas
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2. Paroxysmal cold haemoglobinuria (PCH)
In PCH, cold antibody is an IgG antibody (Donath-Landsteiner
antibody) which is directed against P blood group antigen and brings
about complement-mediated haemolysis. Attacks of PCH are
precipitated by exposure to cold. PCH is uncommon and may be seen
in association with tertiary syphilis or as a complication of certain
infections such as Mycoplasma pneumonia, flu, measles and mumps.
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 CLINICAL FEATURES
 These are as under:
1. Chronic anaemia which is worsened by exposure to cold.
2. Raynaud’s phenomenon (causes decreased blood flow to the fingers.
In some cases, it also causes less blood flow to the ears, toes, nipples,
knees, or nose- on exposure to cold)
3. Cyanosis affecting the cold exposed regions such as tips of nose, ears,
fingers and toes.
4. Haemoglobinaemia and haemoglobinuria occur on exposure to cold.
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 These are as follows:
1. Chronic anaemia.
2. Low reticulocyte count since young red cells are affected more.
3. Spherocytosis is less marked.
4. Positive direct Coombs’ test.
5. The cold antibody titre is very high at 4°C and very low at 37°C
(DonathLandsteiner test)
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DRUG-INDUCED IMMUNOHAEMOLYTIC ANAEMIA
Drugs may cause immunohaemolytic anaemia by 3 different
mechanisms:
1. a-methyl dopa type antibodies
2. Penicillin-induced immunohaemolysis
3. Innocent bystander immunohaemolysis (tissues are destroyed by
immune reactions caused by cells that act as “innocent bystanders )
 In each type of drug-induced immunohaemolytic anaemia,
discontinuation of the drug results in gradual disappearance of
haemolysis
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ISOIMMUNE HAEMOLYTIC ANAEMIA
 Isoimmune haemolytic anaemias are caused by acquiring
isoantibodies or alloantibodies by blood transfusions, pregnancies
and in haemolytic disease of the newborn.
 These antibodies produced by one individual are directed against red
blood cells of the other.( NON-SELF REACTING ANTIBODIES)
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B. MICROANGIOPATHIC HAEMOLYTIC ANAEMIA
Microangiopathic haemolytic anaemia is caused by abnormalities in
the microvasculature.
It is generally due to mechanical trauma to the red cells in circulation
and is characterized by red cell fragmentation (schistocytosis).
There are 3 different ways by which microangiopathic haemolytic
anaemia results:
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1. EXTERNAL IMPACT e.g. in prolonged marchers, joggers, karate
players etc.
These patients develop haemoglobinaemia, haemoglobinuria (march
haemoglobinuria- after marching or running on hard surfaces), and
sometimes myoglobinuria as a result of damage to muscles
2. CARDIAC HAEMOLYSIS
A small proportion of patients who receive prosthetic cardiac valves
or artificial grafts develop haemolysis.
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3. FIBRIN DEPOSIT IN MICROVASCULATURE e.g.
i) Abnormalities of the vessel wall
ii) Thrombotic thrombocytopenic purpura (blood clots form in small blood
vessels throughout the body. The clots can limit or block the flow of oxygen-
rich blood to the body's organs, such as the brain, kidneys, and heart).
iii) Haemolytic-uraemic syndrome.(small blood vessels in your kidneys
become damaged and inflamed and clots clog the filtering system in the
kidneys and lead to kidney failure)
iv) Disseminated intravascular coagulation (DIC).
v) Vasculitis in collagen diseases
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C. HAEMOLYTIC ANAEMIA FROM DIRECT TOXIC EFFECTS
Haemolysis may result from direct toxic effects of certain agents e.g.
1. Malaria
2. Bartonellosis (Bartonella spp of bacteria from cat scratch)
3. Septicaemia with Clostridium welchii
4. Other microorganisms
5. Copper
6. Lead poisoning
7. Snake and spider bites
8. Extensive burns.
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D. PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH)
PNH is a rare acquired disorder of red cell membrane in which there is
chronic intravascular haemolysis due to undue sensitivity of red blood cells
to complement due to defective synthesis of a red cell membrane protein.
PATHOGENESIS
PNH is considered as an acquired clonal disease of the cell membrane
while normal clone also continues to proliferate. The defect is a mutation
in the stem cells affecting myeloid progenitor cells that is normally
required for the biosynthesis of glycosyl phosphatidyl inositol (GPI)
essential for anchoring of the cell.
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CLINICAL AND LABORATORY FINDINGS
These are as under:
i) Haemolytic anaemia.
ii) Pancytopenia (mild granulocytopenia and thrombocytopenia frequent).
iii) Intermittent clinical haemoglobinuria; acute haemolytic episodes occur at night
identified by passage of brown urine in the morning.
iv) Haemosiderinuria is very common.
v) Venous thrombosis is a common complication. The presence of inordinate sensitivity
of red blood cells, leucocytes and platelets to complement in PNH can be demonstrated
in vitro by Ham’s test using red cell lysis at acidic pH or by sucrose haemolysis test. (In
Ham’s test - RBCs are placed in mild acid; a positive result (increased RBC fragility)
indicates PNH or congenital dyserythropoietic anemia)
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E. HAEMOLYTIC ANAEMIA IN SPLENOMEGALY
Splenomegaly exaggerates the damaging effect to which the red cells
are exposed.
Besides haemolytic anaemia, splenomegaly is usually associated with
pancytopenia (low levels of red blood cells, white blood cells, and
platelets )
Splenectomy or reduction in size of spleen by appropriate therapy
relieves the anaemia as well as improves the leucocyte and platelet
counts.
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II. HEREDITARY HAEMOLYTIC ANAEMIAS
A. HEREDITARY ABNORMALITIES OF RED CELL MEMBRANE
There are 3 important types of inherited red cell membrane defects:
hereditary spherocytosis,
hereditary elliptocytosis (hereditary ovalocytosis) and
hereditary stomatocytosis.
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HEREDITARY SPHEROCYTOSIS
Hereditary spherocytosis is a common type of hereditary haemolytic anaemia
of autosomal dominant inheritance in which the red cell membrane is
abnormal.
PATHOGENESIS
The molecular abnormality in hereditary spherocytosis is a defect in proteins
which anchor the lipid bilayer to the underlying cytoskeleton. These are:
1. Spectrin deficiency (loss of erythrocyte surface area, which produces
spherical RBCs)
2. Ankyrin abnormality (An erythrocyte membranal protein that binds spectrin)
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Inherited mutation in spectrin or ankyrin causes defect in anchoring of lipid bilayer
cell membrane.
This results in formation of spheroidal contour and smaller size of red blood cells,
termed microspherocytes.
 CLINICAL FEATURES
 The family history may be present.
1. Anaemia is usually mild to moderate.
2. Splenomegaly is a constant feature.
3. Jaundice occurs due to increased concentration of unconjugated (indirect)
bilirubin.
4. Pigment gallstones are frequent
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1. Anaemia of mild to moderate degree.
2. Reticulocytosis, usually 5-20%
3. Blood film shows the characteristic abnormality of erythrocytes in the form of
microspherocytes.
4. MCV is usually normal or slightly decreased but MCHC is increased.
5. Osmotic fragility is increased.
6. Autohaemolysis test shows increased spontaneous autohaemolysis.
7. Direct Coombs’ (antiglobulin) test is negative.
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HEREDITARY ELLIPTOCYTOSIS (HEREDITARY OVALOCYTOSIS)
Hereditary elliptocytosis or hereditary ovalocytosis is another autosomal
dominant disorder involving red cell membrane protein spectrin.
Acquired causes of elliptocytosis include iron deficiency and
myeloproliferative disorders
HEREDITARY STOMATOCYTOSIS
Stomatocytes are cup-shaped RBCs having one surface concave and the
other side as convex.
The underlying defect is in membrane protein, stomatin, having
autosomal dominant pattern of inheritance.
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B. HEREDITARY DISORDERS OF RED CELL INTERIOR
RED CELL ENZYME DEFECTS (ENZYMOPATHIES) G6PD DEFICIENCY
Among the defects in hexose monophosphate shunt, the most
common is G6PD deficiency.
G6PD gene is located on the X chromosome and its deficiency is,
therefore, a sex (X)-linked trait affecting males, while the females are
carriers and are asymptomatic.
Several variants of G6PD (upto 400) have been described. The most
common and significant clinical variant is A– (negative) type found in
black males
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PATHOGENESIS
Individuals with inherited deficiency of G6PD, an enzyme required for
hexose monophosphate shunt for glucose metabolism, fail to develop
adequate levels of reduced glutathione in their red cells.
This results in oxidation and precipitation of haemoglobin within the
red cells forming Heinz bodies
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CLINICAL FEATURES
1. Acute haemolytic anaemia: This develops in males, being X-linked
disorder, within hours of exposure to oxidantive stress such as drugs like
primaquin, infection, favism (vicine and convicine, found within fava beans)
and metabolic acidosis. It affects the older red cells only.
2. Chronic haemolytic anaemia: Cases having severe enzyme deficiency have
chronic persistent haemolysis throughout life
3. Neonatal jaundice: Infants born with G6PD deficiency may continue to
have unconjugated hyperbilirubinaemia and may even develop kernicterus.
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1. During the period of acute haemolysis, there is rapid fall in
haematocrit by 25-30%, features of intravascular haemolysis such as
rise in plasma haemoglobin, haemoglobinuria, rise in unconjugated
bilirubin and fall in plasma haptoglobin.
2. Formation of Heinz bodies is visualized by means of supravital stains
such as crystal violet, also called Heinz body haemolytic anaemia
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2. Between the crises, the affected patient generally has no anaemia.
The red cell survival is, however, shortened. The diagnosis of G6PD
enzyme deficiency is made by one of the screening tests (e.g.
methaemoglobin reduction test or MRT, fluorescent screening test,
ascorbate cyanide screening test), or by direct enzyme assay on red
cells.
PK DEFICIENCY
Pyruvate kinase (PK) deficiency is the only significant enzymopathy of
the Embden-Meyerhof glycolytic pathway. The disorder is inherited as
an autosomal recessive pattern.
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THE END
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