ANAEMIAS DUE TO EXCESSIVE DESTRUCTION OF RBC’S- HAEMOLYTIC ANAEMIAS
The haemolytic anemias are characterised by
- premature destruction of red cells
- accumulation of the products of haemoglobin catabolism
- a marked increase in erythropoiesis in the bone
Intravascular haemolysis is manifested as
When haemoglobin escapes into the plasma it is bound to to an alpha 2 globulin called
haptoglobin. The heme-haptoglobin complex is not excreted into urine. A decrease
in serum haptoglobin is characteristic of intravascular haemolysis. When the haptoglobin
is depleted the unbound or free haemoglobin is oxidized to methaemoglobin and both
haemoglobin and metahemoglobin are excreted through the kidney imparting a reddish
brown colour to the urine. When the excretory capacity of the kidney is exceeded
the free methomoglobin complexes with albumin to form methaemoalbuminaemia which
imparts a reddish brown colour to the blood. Within the tubular cells of the kidney
iron released form heme produces haemosiderosis of the renal cells. When the cells
are shed into the urine they stain with special iron stains producing haemosiderinuria.
In haemolytic anemias excessive breakdown of heme leads to a unconjugated bilirubinaemia.
Hemoglobinaemia and haemoglobinuria do not occur with extra vascular haemolysis.
Excessive destruction of Red Blood Cells occurs both as a hereditary condition or
as a hereditary condition or as an acquired disorder.
This increased red cell destruction results in an increased level of bilirubin in
the blood leading to jaundice. Bilirubin is a breakdown product of haemoglobin.To
compensate for the increased destruction of red cells the bone marrow increases
the production of red cells which results in the appearance of some immature cell
forms in the peripheral blood- reticulocytosis.
Increased bone marrow expansion when present in early childhood produces bony deformities
which are most commonly seen in the cranial bones, ribs and facial bones.
Haemolytic anaemias can be classified into two groups-
The common hereditary causes for haemolysis result from the abnormalities of Red
blood cell membrane, defects in the enzymes of red blood cells, abnormal Haemoglobins
and quantitative reductions in Globin chain synthesis. Membrane abnormalities include
The red cells assume a globular shape in hereditary sphaerocytosis as a result of
Which they easily get destroyed –“ bruised “ while passing through the sinusoids
of the liver and spleen. These cells have an increased influx and efflux of Sodium.
This disease is inherited in an autosomal dominant pattern. The sphaerocytes are
densely staining without a central pallor.
Sphaerocytes are not conclusive for the diagnosis of hereditary sphaerocytosis as
they could also occur in autoimmune haemolytic anemias and allo immune haemolytic
anemia ( heamolytic disease of the newborn or delayed transfusion reactions ).
Patients are usually anaemic and jaundiced as well. The spleen is usually enlarged.
The disease could manifest anytime either in early childhood or in old age. The
manifestations of the disease process also tend to be variable.
Associated infections can produce HAEMOLYTIC crises resulting in both an increased
anaemia and jaundice or an APLASTIC crisis with marked anaemia. Patients tend to
develop pigment gall stones.The treatment depends on the severity of the condition
and ranges from the administration of Folic acid, blood transfusion and Splenectomy.
In severe crisis splenectomy is done early after the age of six years.
After a splenectomy the child is especially prone to infection with capsulated organisms
like Pneumococci, H. Influenzae and Meningococci and should be protected by way
of vaccination against these organisms at least three weeks prior to the splenectomy.
Microsphaerocytes are cells that are both small in size and hyperchromic and are
seen with hereditary sphaerocytosis and is characteristic of burns and MAHA- microangiopathic
haemolytic anemia which could occur with a number of conditions like DIC, pregnancy
induced hypertension, disseminated cancer, Haemolytic uremic syndrome, Thrombotic
thrombocytopenic purpura etc.
Other Membrane disorders are Hereditary Ovalocytosis wherein the red cells have
an oval shape and Hereditary Elliptocytosis where the red cells are elliptical.
Haemolytic anaemia is rare in these conditions.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY-
The most common of the red cell enzyme deficiency leading to haemolysis is Glucose-6-Phosphate
dehydrogenase deficiency. This is an X-linked recessive disorder seen in male children
with the defective X chromosome and in female children with the homozygous state.
About 3% of the world population has this defect and is more common in the Mediterranean
region, South East Asia and in blacks.
The activity of the enzyme could be normal in young cells and falls rapidly with
ageing of the red cells. Subjects taking drugs like anti-malarials, sulpha drugs,
analgesics including aspirin, phenacetin, viral infections, consumption of fava
beans could all precipitate a haemolytic episode. During periods of haemolysis the
diagnosis could be difficult as newly formed red cells contain normal enzyme levels.
A repeat study after about a month would show the enzyme deficiency then.
Features of haemolysis are – Jaundice, reticulocytosis, circulating nucleated red
cells. Special staining techniques would show up “ HEINZ” bodies which would help
establish the diagnosis. Heinz bodies are precipitated globin chains seen in the
Treatment consists of stopping the offending drug and administration of Folate.
Keratocytes or bite cells and Blister cells which are cells with an irregular Contour
is characteristic of acute haemolysis induced by oxidant stress. These irregularly
contracted cells share with sphaerocytes the lack of central pallor but differ in
that they have an irregular outline.
PYRUVATE KINASE DEFICIENCY- Is a rare condition but produces severe haemolysis.
HAEMOGLOBINOPATHIES AND THALASSAEMIA-
Among the haemoglobinopathies the most common disease is sickle cell disease- Hb
This condition is largely seen among African blacks, residents of the Mediterranean
region and in certain pockets in India.
Subjects who are homozygous for the condition suffer from the disease and heterozygous
individuals have lesser amounts of Hb S and correspondingly do not suffer from the
problems related to the disease.
Hb S results form a single amino acid substitution in the beta chain wherein Glutamic
acid is replaced by Valine. Red cells containing excessive amounts of Hb S get distorted
with hypoxaemia and undergo lysis. A sickle shaped cell is formed due to the rod
like structure of less soluble Hb S. The sickle shaped cells clog up small blood
vessels which worsens hypoxia leading to further sickling. Clogging up of small
blood vessels results in the “ painful “ or “ vaso-occlusive crisis “ Symptoms start
from childhood. Abdominal pain, bone pain, chest pain, haematuria and neurological
syndromes could occur.
The three crises associated with Sickle Cell disease are
- Infarction producing painful crisis. Dehydration
and hypoxia resulting from infections like pneumonia precipitate these attacks
- Haemolytic crisis associated with infections.
- Aplastic crisis results from bone marrow failure
resulting from infections commonly due to the Parvo B 19 strain.
DIAGNOSIS- An examination of the peripheral smear would show sickled cells
in the homozygous state. Haemoglobin electrophoresis would reveal the slow migration
of Hb S as compared to Hb A.
TREATMENT- Prevention of dehydration, adequate analgesia, treatment of inter
current infections, Folic acid supplementation, avoidance of hypoxic states are
the main stay of treatment.
In emergency situations like CNS crises, priaprism, aplastic crisis, and acute coronary
syndromes exchange transfusions could be given.
Anti sickling agents largely have not been found useful in preventing the various
crises. It has been observed that some of the Mediterranean patients have an increased
level of HbF and correspondingly the crisis rate has been seen to be low in them.
So Hydroxyurea which helps in switching to an increased HbF production has been
found to be useful in reducing crisis rates among patients with the sickle cell
Subjects with the Sickle Cell Trait are usually aymptomatic. They may occasionally
have haematuria. Painful crises are rare except when severe hypoxaemia develops.
The HbS trait can be diagnosed by doing a Haemoglobin electrophoresis. It can also
be tested for by inducing sickling with reducing agents like sodium metabisulphite.
Other haemoglobinopathies like HbC,HbE,HbD are seen but are not clinically very
This is one of the commoner genetic conditions with a world wide distribution. Thalassaemia
too is more common in the Mediterranean belt.
It is commonly called as Cooley’s anaemia in the United States as the condition
was first described by Cooley and Lee in the year 1925.
The severe from of Cooleys anaemia – Thalassaemia major results from the homozygous
state. Heterozygous states produce the milder Thalassaemia minor.
The main content of red blood cells is haemoglobin which carries oxygen from the
lungs to metabolizing tissues in different parts of the body. Haemoglobin contains
Heme the iron containing part of Globin which is the protein part and is made up
of 2 parts of protein chains.
Normal adult haemoglobin HbA consists of two Alpha and two Beta chains.In utero
the globin chains are predominantly two Alpha and two Gamma called the HbF or the
foetal haemoglobin. The conversion of foetal to the adult type of haemoglobin starts
during the late part of gestation and is complete by early infancy. When synthesis
of Alpha chain is reduced it is called Alpha Thalassaemia and when Beta chain synthesis
is deficient it is called Beta Thalassaemia.
There are three main forma of Beta Thalassaemia
- Thalassaemia Major-
This is the severe form with anaemia being present from early infancy. This is associated
with hepatosplenomegaly and the facila bony changes of haemolysis resulting in a
mongoloid facies. The main haemoglobin present is HbF ( the foetal Haemoglobin )
which may range from 50-100%.
- Thalassaemia Intermedia-
In this clinical entity the severity of disease is less than in Thalassaemia Major.
These patients too are anaemic, have splenomegaly and have jaundice.Transfusion
requirements are variable in this group of patients
- Thalassaemia Minor-
This is a heterozygous state in which subjects usually show no symptoms with the
underlying condition usually being picked up during investigation of families with
the Thalassaemia gene.
The clinical features in severe forms are a failure to thrive, microcytic anaemia,
jaundice, mongoloid facies, hepato-splenomegaly and growth retardation.
1. Blood transfusions so as to keep the level of Haemoglobin above 10 gm%. This
type of a hypertransfusion program helps the child attain a normal physical and
mental status for age and also helps lead an active life. This mode of treatment
also results in transfusional haemosiderosis due to the increase in the body iron
stores. Haemosiderosis leads to diabetes, impotence, cirrhosis etc due to deposition
in various organs.
Transfusion haemosiderosis is treated with iron chelation therapy using subcutaneous
infusion of Desferal using a pump for delivery. The pump is attached to the body
using a belt. This is usually transfused during night five days a week. New chealting
agents using oral drugs like Kelfer is now available.
Thalassaemia Trait or Thalassaemia Minor-
Heterozygous state. Anaemia is minimal. Red cells are microcytic with many target
ceels. HbA2 levels are slightly increased
Homozygous state is not compatible with life- Hydrops foetalis. HbH disease is a
heterozygous state with mild haemolysis. The red cells contain HbH inclusion bodies
which give a “ golf ball “ appearance to the red cells.
Alpha thalassaemia trait usually does not produce an anaemia. Detection is by studying
globin chains synthesis. This investigation is limited to only a few established
centres as of now, as the expenses towards this is prohibitive.
ACQUIRED HAEMOLYTIC ANAEMIAS-
This occurs in newborns from the transfer of auto antibodies to blood group antigens-
ABO and Rh systems. In the Rh haemolytic disease when a Rh -ve mother has a Rh+
ve baby the foetal cells enter into the maternal circulation producing antibodies
which gain entry into the foetal circulation producing haemolysis and also increase
the foetal bilirubin levels.
ABO incompatibility can also occur. When the mother is of the blood group O and
the baby is Blood group A or Blood group B group antibodies developed in the mother
enter the foetal circulation producing haemolysis. This is less intense than that
seen in Rh incompatibility. The first baby is usually not affected unless there
was a previous miscarriage.
Haemolytic anaemias also occur following certain infections, immunologicalle mediated
conditions like SLE, in association with lymphoid malignancies and following the
use of certain drugs like penicillin, alpha- methyl dopa and quinine.