2. Haemolytic anaemias
• Haemolytic anaemias are defined as those anaemias that result
from an increase in the rate of red cell destruction.
• Because of 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, as normal adult marrow is able to produce red
cells at 6 – 8 times the normal rate.
• It leads to a marked reticulocytosis, particularly in the more
anaemic cases.
3. Normal red cell destruction:
• Red cell destruction normally occurs after a mean lifespan of 120 days when
the cells are removed extravascularly by the macrophages of the
reticuloendothelial (RE) system, especially in the marrow but also in the liver
and spleen.
• The breakdown of haem from red cells liberates iron for recirculation via
plasma transferrin mainly to marrow erythroblasts, and protoporphyrin which
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.
• Haptoglobins are proteins present in normal plasma capable of binding
haemoglobin. The haemoglobin – haptoglobin complex is removed from
plasma by the RE system.
4. (a) Normal red blood cell (RBC) breakdown.
This takes place extravascularly in the macrophages
Of the reticuloendothelial system.
7. • Clinical features:
• The patient may show pallor of the mucous membranes, mild
fluctuating jaundice and splenomegaly.
• There is no bilirubin in urine but this may turn dark on standing
because of excess urobilinogen.
• 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.
8. • Laboratory findings:
1- Features of increased red cell breakdown:
(a) Serum bilirubin raised, unconjugated and bound to albumin;
(b) Urine urobilinogen increased;
(c) 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:
(a) Reticulocytosis;
(b) Bone marrow erythroid hyperplasia; the normal marrow myeloid :
erythroid ratio of 2 : 1 to 12 : 1 is reduced to 1 : 1 or reversed.
3- Damaged red cells:
(a) Morphology (e.g. microspherocytes, elliptocytes, fragments)
(b) Osmotic fragility, autohaemolysis, etc.
(c) Specific enzyme, protein or DNA tests.
9. 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 RE system (extravascular haemolysis) or they may
be broken down directly in the circulation (intravascular haemolysis).
• In intravascular haemolysis, free haemoglobin is released which rapidly
saturates plasma haptoglobins and the excess free haemoglobin is
filtered by the glomerulus.
• 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).
10.
11. Hereditary haemolytic anaemias:
• Membrane defects
1. Hereditary spherocytosis
2. Hereditary elliptocytosis
3. South - East Asian ovalocytosis
• Defective red cell metabolism
1. Glucose - 6 - phosphate dehydrogenase deficiency
2. Glutathione deficiency and other syndromes
3. Pyruvate kinase deficiency
12.
13. Blood fi lm in G6PD
deficiency with acute
haemolysis after an oxidant
stress. Some of the cells show
loss of cytoplasm with
separation of remaining
haemoglobin from the cell
membrane ( ‘ blister ’ cells).
There are also numerous
contracted and deeply staining
cells. Supravital staining (as
for reticulocytes) showed the
presence of Heinz bodie
14. Acquired haemolytic anaemias
• Immune haemolytic anaemias
1. Autoimmune haemolytic anaemias
2. Alloimmune haemolytic anaemias
3. Drug - induced immune haemolytic anaemias
• Red cell fragmentation syndromes
• March haemoglobinuria
• Infections
• Chemical and physical a gents
• Secondary haemolytic a naemias
• Paroxysmal nocturnal haemoglobinuria
15. Autoimmune HemolyticAnemia (AIHA)
▪ Caused by antibody production by the body against its
• own RBC
▪ Characterized by positive Direct Agglutination Test (DAT) Coombs test
▪ Divided into 2 main types:
1. Warm Autoimme hemolytic anemia at which the reaction of Antibody
with RBC occurs strongly at 37C
2. Cold Autoimme hemolytic anemia at which the reaction of Antibody
with RBC occurs strongly at 4 C
16. WarmAutoimmune HemolyticAnemia
▪ RBC coated with IgG or IgG and complement
▪ Coated RBC taken by Macrophages in RES
▪ Part of membrane lost, and cells become spherical
▪ Coated cells destroyed in the spleen
▪ The spleen is often enlarged
▪ Occurs at any age or sex
17. 26
26
Cold Autoimmune Hemolytic Anemia
▪ Antibody attached to RBC mainly in the peripheral
circulation where the blood temp is cooled
▪ The antibody is usually IgM associated with intravascular
hemolysis
▪ IgM efficient in complement fixing so RBC damage may
occur intra and extravasclar
Blood film in cold autoimmune hemolytic anemia
Shows RBC agglutination
18. 227
7
Alloimmune Hemolytic Anemias
▪ In this anemia, Antibody produced by one individual reacts
with others RBC
▪ Two important situations:
1. Incompatible blood transfusion
2. Rhesus disease of the newborn
▪ Increases in cases of allogeneic transplantation
19. 228
8
Mechanisms of drug induced hemolytic anemia
Drug Induced Hemolytic Anemia
▪ Drug may induce hemolytic anemias via three different
mechanisms:
1. Antibody directed a drug-RBC membrane complex
(e.g penicillin etc)
2. Deposition of complement via drug-protein-antibody complex
onto RBC surface
3. True autoimmune HA at which the role of drug is not clear
▪ In each case the anemias disappears when the drug is
discontinued
20. Red Cell Fragmentation Syndromes
29
▪ These arise through physical damage to RBCs either on
abnormal surfaces (e.g. artificial heart valves or arterial
grafts), arteriovenous malformations or as a
microangiopathic haemolytic anaemia.
▪ This is caused by RBCs passing through abnormal small
vessels.
intravascular coagulation (DIC), or platelet adherence as in
thrombotic thrombocytopenic purpura (TTP) or vasculitis
(e.g. polyarteritis nodosa)
▪ The latter may be caused by deposition of
fibrin strands, often associated with disseminated
21. ▪ The peripheral blood contains
many deeply staining red cell
fragments.
▪ When DIC underlies the
hemolysis, clotting abnormalities
and a low platelet count are also
present.
Red Cell Fragmentation Syndromes
22. March Hemoglobinuria
▪ This is caused by damage to red cells between the small
bones of the feet, usually during prolonged marching or
running.
▪ The blood film does not show fragments.
23. Infections
Infections can cause hemolysis in a variety of ways.
▪ They may precipitate an acute hemolytic crisis in G6PD
deficiency or cause microangiopathic hemolytic anemia
(e.g. with meningococcal or pneumococcal septicemia).
▪ Malaria causes hemolysis by extravascular destruction of
parasitized RBCs as well as by direct intravascular lysis.
▪ Blackwater fever is an acute intravascular hemolysis
accompanied by acute renal failure caused by Falciparum
malaria.
▪ Clostridium perfringens septicemia can cause intravascular32
hemolysis with marked microspherocytosis.
24. Chemical and Physical Agents
▪ Certain drugs (e.g. dapsone and sulfasalazine) in high
doses cause oxidative intravascular hemolysis with Heinz
body formation in normal subjects.
▪ In Wilson’s disease an acute hemolytic anemia can occur
as a result of high levels of copper in the blood.
▪ Chemical poisoning (e.g. with lead, chlorate or arsine) can
cause severe hemolysis.
▪ Severe burns damage red cells causing acanthocytosis or
spherocytosis.
25. 34
34
Paroxysmal nocturnal hemoglobinuria (PNH)
▪ Rare acquired syndrome
▪ Clonal disorder of stem cells in which
there is deficient synthesis
glycosylphosphatydlinistol
anchor
▪ GPI anchor attaches several
proteins to the RBC membrane
of the
(GPI)
surface
26. 35
35
Paroxysmal nocturnal hemoglobinuria (PNH)
▪ The net result in GPI deficiency is that GPI linked proteins
such as CD55 and CD59 are absent from the RBC surface
of all cells derived from the abnormal stem cells
▪ Lack of CD55 and CD59 renders cells sensitive to lysis by
complement
▪ Intravascular hemolysis
27. 336
6
Special tests:
1. Hams test:
▪ RBC lysis in the serum at low pH.
▪ Low pH activates the alternative pathway of the
complement system which leads to RBC lysis
2. Flow cytometry:
looking for loss of expression of GPI-linked proteins such as CD55
and CD59 sensitive test
Paroxysmal nocturnal hemoglobinuria (PNH)
28.
29. (a) Blood fi lm in warm autoimmune haemolytic anaemia. Numerous microspherocytes are present and larger
polychromatic cells (reticulocytes). (b) Blood fi lm in cold autoimmune haemolytic anaemia. Marked red cell agglutination
is present in films made at room temperature. The background is caused by the raised plasma protein concentration.
(a) (b)
