Haemolytic Anaemia :-

Introduction :-
 Haemolytic means breaking down of Red Blood
Cells.
 It is a disorder in which red blood cells are
destroyed faster than they can be made. The
destruction of red blood cells is called
Haemolysis.
 Various abnormalities either in the erythrocyte
may shorten the normal life span of 120 days.
Anaemia develops when marrow output no
longer compensates. The increased output of
new erythrocytes is reflected in a raised
reticulocyte count which gives an indication of
the severity of the process. Normoblast may be
released under extreme stress.
 The Catabolic Pathways for Haemoglobin
degradation are overloaded and there is modest
increased in Unconjugated Bilirubin in the blood
and increased reabsorption of Urobilinogen from
the gut, which is then excrete in the urine in
increased amounts. Bile does not appear in the
urine. Jaundice is mild.
Types Of Haemolysis :-
1. Intravascular Haemolysis :- Haemoglobin is
liberated into the plasma where it is bound
mainly by the Alpha- 2 Globulin, Hapatoglobulin
to form a complex too large to be lost in the
urine. It is taken up by the liver and degraded.
Some Haemoglobin is Partially degraded and
bound to albumin to form Methemalbumin. This
is the basis of the Schumm’s Test for
Haemoglobin in the Plasma.
 Extravascular Haemolysis :- This occurs in the
Phagocytic cells of the Spleen, Liver, Bone
Marrow and other organs and there may be little
or no depletion of Haptoglobin. Estimation of
Haptoglobin level in the blood is not always easily
interpreted. Inflammatory disease and steroid
therapy both increase Haptoglobin levels.
Ahaptoglobinaemia may occur as in inherited
disorder. Nevertheless absence of Haptoglobin is
usually a strong indicator of Haemolytic disease.
Its presence does not exclude Haemolysis.
 Hemolytic anaemia due to
intraerythrocytic causes :-
The principal disorders are hereditary
spherocytosis, glucose-6-phosphate dehydrogense
(G6PD) deficiency, hemoglobinopathies (e.g. sickle-
cell disease and thalassemia), G6PD deficiency and
hemoglobinopathies are most common in African
Blacks and thalassemia in the Mediterranean area.
There has been a rise in incidence of these
disorders in other countries including Britain
because of immigration.
 Hereditary spherocytosis :-
This is an autosomal dominant disorder in which
the principle abnormality appears to be a deficiency
of spectrin, a red cell membrane protein. The
erythroctye envelope is abnormally permeable and
the sodium pumps are overworked. The eryth-
rocytes lose their biconcave shape, become
spherical and are ore susceptible to osmotic lysis.
These spherocytic are destroyed almost exclusively
by the spleen. The severity of the disorder is very
variable even within an affected family. Haemolysis
is mainly extravascular.
 Clinical features :-
 Symptoms vary from none to those of severe
anaemia.
 Episodic jaundice may be noted.
 The spleen is often but not always palpably
enlarged. The severity of the disorders tends to
 vary in any one patient with episodes of
increased hemolysis (homolytic crises) at times.
 The transient hypoplasia of red cell production,
which can occur in normal persons in
association with parvovirus infections, presents
as aplastic crises in these patients becuase of
the greatly increased red cell turnover.
 There is a libility to form pigment gallstones
and cholecystitis may be the presenting event.
 Leg Ulcers sometimes occur.
 Investigations :-
 The diagnosis is made by demonstrating a
hemolytic state together with spherocytic in the
blood film, increased osmotic fragility due to the
spherocytes and the demonstration of the same
disorder in other members of the family. The
Coomb's test is negative.
 There is an increased loss of urobilinogen in the
urine. Red cells survival studies with "Cr show
destruction of red cells almost exclusively in the
spleen.
 The differential diagnosis is from other causes of
speherocytosis, particularly the various forms of
immune hemolysis.
 Management :-
Splenectomy results in striking and usually permanent
improvement both in the symptoms and in the
anaemia and should be advised when :
1. The anaemia causes persistent impairment of
health
2. When severe homolytic or aplastic crises have
occurred
3. When other members of the family have died from
the disease
4. Where evidence of cholecystitis and cholelithiasis is
present.
 Glucose-6-Phosphate dehydrogenase
deficiency :-
Glucose-6-phosphate dehydrogenase (G6PD) is the
first enzyme in the hexose monophosphate shunt of
the Embden Myerhof glycolytic pathway from which
red cells derive most of their metabolic energy. The
function of this shunt is to service the enzyme
glutathione reductase and glutathione peroxidase
which protect the red cells against damage but to
oxidation. In the absence of G6PD this protective
mechanisms is crippled and certain drugs in sufficient
concentration can seriously injure the erythrocyte.
The deficiency is inherited as a X-linked disorder with
a high frequency among African Blacks among whom
there is an electrophoretic enzyme polymorphism
with A and B type enzymes. The enzymes is A type
(A-) in deficient Africian Blacks. In Caucasians only the
normal B type enzyme is found and the deficient type
is also B (B-). In West and East Africa about 20% of
male (homozygotes) and about 4% of about 20% of
male (homozygotes) and about 4% of females
(homozygous for the abnormal gene) are affected and
the enzyme activity is about 15% of normal. Het-
erozygous females have two population of red cells,
one deficient and the other nor- mal. 100 million
persons are affected by this disorder world wide.
 Clinical features :-
 Persons with G6PD deficiency normally enjoy
good health but are liable to hemolysis if any of
the incriminated drugs or foods are ingested.
However the haemolytic effect is dose related
and will not be clinically detectable if the amount
does not exceed a critical level. It is often possible
to employ doses which are not toxic.
 The anaemia, when it occurs, may be rapid in
onset, becoming obvious between 2 and 10 days
after exposure to the precipitating agent and may
be sufficiently severe to cause hemoglobinuria as
 well as the other classical signs of hemolysis. In
the relatively mild type of deficiency prevalent in
Blacks only older cells which have lost enzyme
activity are involved so that the hemolysis is to
some extent self-limiting even when the
offending agent is continued.
 Young red cells have some G6PD activity and
remain viable until their enzyme complement
decays.
 The enzyme deficiency is much more severe in
the B-variety, and destruction tends to be
greater.
 Anuria is an infrequent but serious complication.
 Investigation :-
 The diagnosis can be confirmed by estimating the
G6PD activity of the red cell but this may not be
entirely accurate if there is a considerable
reticulocytosis.
 A number of screening tests are also available.
The characteristics of intravascular hemolysis are
usually present:-
 Hemoglobinemia, Methaemalbuminaemia,
Hemoglobinuria, Ahaptoglobinemia and later
Haemosiderinuria.
 Management :-
This is by removal of the toxic agent. Recovery is
usually rapid but if the anemia is severe transfusion of
red cells with a normal enzyme complement may be
required. Thereafter the patient should be advised to
avoid drugs which may precipitate the disorder.
Splenectomy is valueless.
 Sickle Cell Anaemia :-
In sickle-cell anaemia most of the red cells
contain haemoglobin S and anaemia most of
the red cells contain haemoglobin S and little
else and are very prone to sickle even in vivo
under normal conditions. This happens
particularly in those parts of the
microvasculature which are sinusoidal and
where the flow is sluggish. Sickled cells
increase blood viscosity, traverse capillaries
poorly and tend to obstruct flow, thereby
increasing the sickling of other cells and
eventually stopping the flow. Thrombosis
follows and an area of tissue infraction
results causing severe pain, swelling and
tenderness (infarction crisis). In addition
these cells are phagocytosed in large
numbers by the mononuclear-phagocyte
system, reducing their life span considerably
and giving rise to Haemolysis.
 Clinical features :-
The two major problems are chronic
anaemia due to reduced erythrocyte survival
and episodes of tissue infarction.
 Anaemia :-
Problems do not arise until about the fourth
month of life when haemoglobin F
containing cells give way to haemoglobin S
containing cells. The anaemia is hemolytic in
type and severe, the haemoglobin seldom
rising above 100 g/l and averaging ap-
proximately 80 g/l. Secondary folate
deficiency is common and exacerbates the
anaemia. When folate deficiency is chronic,
growth may be retarded and puberty
delayed. Episodes of increased sequestration
and destruction of red cells (hemolytic crises)
occur, sometimes for no apparent reason
and may lead to a swift fall in haemo-globin
with rapidly enlarging spleen and liver.
Aplastic crises occur in association with
parvovirus infections as in hereditary
spherocytosis but the effect of the tempo-
rary cessation of erythropoiesis my be more
dramatic as the hemolysis is severe.
The chronic anaemia is responsible for
fatigue, reduced exercise tolerance,
increased susceptibility to infection,
cardiomegaly, leg ulcers and cholelithiasis.
Hyperplasia of the marrow in the first year of
life expands the marrow cavity producing
bossing of the skull, prominent malar bones
and protuberant teeth.
 Infarction crises :-
 These are characterised by episodes of
severe pain and these punctuate the
patients lives. They occur commonly in
 bones and spleen but no tissue is
exempt.
 In the infant they classically affect the
fingers and toes, the infant they
classically affect the fingers and toes,
producing large fusiform swellings
(dactylitis). Metacarpal and tar- sal bones
may be affected and shortened digits due
to epiphyseal involvement may occur.
Mesenteric infarction may produce an
acute abdominal emergency any age. The
renal papilla is another site of damage
and infarction may give rise to painless
hematuria. In adults aseptic necrosis of
the head of the femur is a disabling
complication. An acute chest syndrome
can occur resemblling penumonia but is
probably due to pulmonary infartcion.
 Precipitating factors include
dehydration, chilling and infection, but
sometimes the attacks occur
spontaneously The onset is usually rapid
 and the pain excruciatingly severe (pain
crisis) in in the first 24 hours, thereafter
abating over the next few days. Fever,
increasing jaundice and malaise are
frequent and, if persistent, may sug- gest
the establishment of infecting in he
infarcted site. Salmonella osteomyelitis is
common.
 Pregnancy is hazardous unless careful
antenatal care is provided and as full-
term approaches, infarctive crises in he
bones may liberate large amounts of fat
and bone marrow emboli which cause
diffuse microembolism of he lungs with
pulmonary inf arction, corpulmonale and
even death. A pseudo-toxaemia
syndrome may develop. These
complications may also be seen in the
less severe haemoglobin SC disease.
 Sickle-cell anaemia should always be
suspected in a patient who has had
symptoms of anaemia and ‘Rheumatism’
 since infancy and who belongs to a race
which is often affected. In areas where
sickle-cell anaemia is common, it should
be considered in the differential
diagnosis of many disorders. Patients
must be adequately screened before
major surgery and bloodless field surgery
should never be employed because
infarction of the entire limb below the
tourniquet may occur.
 Investigations :-
 Diagnosis is based on the patient's race,
history, clinical findings and investigation
which demonstrate the presence of Hb S
and no other major haemoglobin in the
blood. These include solubility screening
tests and haemoglobin electrophoresis.
 A family study should reveal that both
parents carry the abnormal gene for Hb
S. In this way true sickle-cell anaemia can
be differentiated from other diseases in
which Haemoglobin S is combined with
 thalassemia or some other abnormal
haemoglobin such as C or D.
 Management :-
 There is no method of changing the
genetic constitution of an individual and
therefore no means of curing this
diseases other than by bone marrow
transplantation. Management is aimed at
alleviation of the symptomatology and
the promotion of a way of life that will
minimise the ill effects of the disorder.
Regular folic acid supple Blood vessels
source vision causes, symptoms and
general treatment ments (5 mg. daily)
are prescribed to support the greatly
increased erythropoietic Activity.
 Exacerbation of the chronic homolytic
anaemia is commonly associated with
infections and these should be treate
promptly and prevented, e.g. life-long
antimalarial taken where appropriate.
Young patients with hyposplenism
 should be given phenoxymethylpenicillin,
one 250 mg tablet daily, and
pneumococcal vaccine. Patients should
avoid becoming chilled, dehydrated or
exposed to hypoxia, e.g. at high
altitudes.
 An acute exacerbation of the anaemia
may have not obvious precipitating
cause. The spleen and liver may enlarge
rapidly and the haemoglobin drops,
sometimes with alarming speed
(sequestration crisis). Transfusion with
red cell concentrate is urgently required.
 In less severe illness the patient should
be adequately hydrated but transfusion
with red cell concentrate is used only if
essential because of the risk of allo-
antibody formation and subsequent
retains.
 In pain crises, powerful, potentially
addictive, analgesics may be necessary in
the early stages; after 24-48 hours they
 should be replaced by mild nonaddictive
preparations.
 Haemolytic disease due to
Extraerythrocytic causes :-

 Autoimmune Haemolytic disease :-

 In this disorder antibodies are formed

against red cell antigens and cause
inappropriate destruction of the cells.
There are two main types categorised on
the basis of the thermal characteristics of
the antibody.
 “Warm” antibodies. These have a
thermal optimum of 37°C, this being
characteristic of most acquired
antibodies. The majority are IgG. Warm
type autoimmune haemolytic anaemia
has antibodies of this type and can
almost always be shown to have Rhesus
specificity.
  “Cold” antibodies. These have a thermal
optimum of 4°C, but sometimes a
thermal range of up to 37°C. Naturally
occurring antibodies tend to be of this
type, most are IgM and bind complement
strongly. About 50% of 'warm' type
antibodies are also seen to bind
complement but less strongly.
Warm type autoimmune haemolytic
anaemia

 Many cases are idiopathic but some

occur in association with chronic
lymphatic leukemia, lymphoma, systemic
lupus erythematosus or certain drugs
( e.g. :- methyldopa ).

 Clinical features :-
Patients of all ages are affected. Symptoms
vary with the severity of the disease and its
cause and are mainly those of anaemia. In
addition, in severe cases there may be fever,
vomiting and prostration. Splenomegaly and
sometimes hepatomegaly is present.
 Investigations :-

 The diagnosis is established by

demonstrating evidence of antibody on
the red Cells by the direct antiglobulin
test (Coomb's test). This test detects the
presence of antibodies on the surface of
erythrocytes using an antihuman globulin
antiserum (AHG). Antibodies being
human globulin are recognised by the
AHG which attacks them and causes
agglutination of the erythrocytes. This is
the “Direct Test”.
 When antibodies are present in serum
they must first be attached to red cells
 with the appropriate antigen before their
presence can be detected as described
above. This is known as the “Indirect
Test”. Elution of antibody from the red
cells allows investigation of specificity
against a panel of cells. The majority of
these antibodies can be shown to have
anti-Rhesus specificity. Of these, anti-e is
the commonest. If possible, identification
of specificity is useful as blood for
transfusion which does not carry the
specific antigen can be chosen. The blood
film almost always shows polychromasia,
spherocytosis and nucleated red cells.
 Management :-
 This is with prednisolone 60 mg daily for
3-4 weeks, if after 6 months of steroid
therapy the patient still has active
haemolytic disease, splenectomy should
be considered.
  If splenectomy fails, immune suppression
with drugs such as azathioprine, 100 mg
daily, may be tried.
 Haemolytic Anaemia Due to Other
Abnormalities :-
 Physical trauma to red cells:-
This is seen in:
1. Prosthetic heart valves
2. Bacteriemia with certain organisms e.g.
[Link];
[Link] fibrin formation
(disseminated intravascular coagulation).
Fragmented cells may be seen in the blood
film.
 Drugs Such as :-

1. Sulphasalazine or dapsone stress the

erythrocyte metabolism
2. antigen-antibody reactions (drugs
acting as happens).
  Malaria:-
Haemolysis always accompanies malaria
and in severe or prolonged attacks very
considerable anaemia may ensure. The
destruction of erythrocytes is al- ways
greater than can be explained by
parasitisation and may be due to an immune
mechanism.

 Inflammatory and neoplastic disease:-

This shortens the life span of erythroncyte.
The mechanisms are complex and not
completely understood. Excessive eryth-
rophagocytosis by macrophages occurs.
Erythrocytes are damaged as they pass
thought affected tissue and drugs used in
treatment may also harm them.
 Paroxysmal Nocturnal
Haemoglobinuria:-
This is a very rare disease in which a clone of
erythrocytes with an acquired defect is
abnormally sensitive to lysis by complement
in the blood causing intermit- tent
haemolytic anaemia, hemoglobinuria and
thrombotic episodes.
 Transfusion with incompatible blood :-
 Clerical or checking errors, usually at the
bed side, leading to the wrong blood
being given.
 Infused red cells are of the wrong main
blood group due to careless typing of the
blood.
 The blood of the recipient and donor are
of compatible main groups but contain
incompatible subgroups. Direct cross-
matching of recipient's serum against
donor cells greatly reduces the risk .
From the transfusion of Rh-positive
blood to a sensitised Rh-negative
recipient cells greatly reduces the risk .
 From the transfusion of Rh-positive
blood to a sensitised Rh-negative
recipient.
 Clinical Features :-
 Symptoms usually begin after only a few
milliliters of blood have been give, and if
the transfusion is immediately stopped
there may be no serious consequences.
 In severe reactions the patient complains
of shivering and restlessness, nausea and
vomiting, precordial and lumbar pain.
 Pulse and respiration rates increase.
 The blood pressure falls and the patient
passes into a state of shock.
 Jaundice appears after a few hours.
 There is hemoglobinemia, and possibly
even hemoglobinuria; oliguria may occur
with renal failure due to acute tubular
necrosis.
 In severe cases anuria persists and
uraemia develops, from which the
patient may die. In others diuresis occurs
 even after several days and the patient
recovers. In the majority the acute
features subside in 24-48 hours.
 Problems may arise later from immune
complexes causing renal damage.
 Management :-
 Treatment of the established reaction
involves :-
1. Giving Hydrocortisone (100 mg i.v.)
2. Inducing a Diuresis with Mannitol
3. Treating the patient for Shock. If acute
Tubular necrosis occurs the measures
recommended on must be instituted at once.