Drugs have been classically thought to cause immune haemolytic anaemia by the following mechanisms:
IMMUNE COMPLEX. The formation of drug-antibody immune complexes that become attached to red cells, activating complement and resulting in cell destruction. Example: quinine.
MEMBRANE ADSORPTION. An antigenic drug-red cell complex is formed. Production of IgG antibodies results in cell destruction. Example: penicillin.
AUTOANTIBODY. The drug induces the production of a red cell autoantibody. Example: methyldopa. New data suggest that the mechanisms involved in druginduced haemolytic anaemia may be simpler than indicated above. The interaction between a drug and red cell membrane is now thought to cause a composite antigenic structure (or neoantigen), which provokes two types of antibodies:

1 Drug-dependent antibodies, which bind to both the drug and the cell membrane but not to either separately. Clinically there is usually severe complementmediated intravascular haemolysis, which resolves quickly after withdrawal of the drug.
2 Drug-independent antibodies, which are induced by a subtle alteration of the red cell membrane. Such antibodies react with red cells in vitro in the absence of the drug and are indistinguishable from ‘true’ autoantibodies. There is extravascular haemolysis and the clinical course tends to be more protracted.
This new concept for drug-induced immune haemolytic anaemia probably also applies to drug-induced thrombocytopenia and neutropenia.



Antibodies produced in one individual react with the red cells of another. This situation occurs in haemolytic disease of the newborn, haemolytic transfusion reactions  and after allogeneic bone marrow, renal, liver or cardiac transplantation when donor lymphocytes transferred in the allograft may produce red cell antibodies against the recipient and cause haemolytic anaemia.

Haemolytic disease of the newborn (HON)

HDN is due to fetomaternal incompatibility for red cell antigens; maternal alloantibodies against fetal red cell antigens pass from the maternal circulation via the placenta into the fetus, where they destroy the fetal red cells. Only IgG antibodies are capable of transplacental passage from mother to fetus.
The commonest type of HDN is that due to ABO incompatibility, where the mother is usually group 0 and the fetus group A.
HDN due to ABO incompatibility is usually mild and exchange transfusion is rarely needed. HDN due to RhD incompatibility has become much less common following the introduction of anti-D prophylaxis . HDN may be caused by antibodies against antigens in many blood group systems, e.g. other Rh antigens such as c and E, and Kell, Duffy and Kidd.
Sensitization occurs due to passage of fetal red cells into the maternal circulation which most readily occurs at the time of delivery, so that first pregnancies are rarely affected. However, sensitization may occur at other times, for example after a miscarriage, ectopic pregnancy or blood transfusion, or due to episodes during pregnancy which cause transplacental bleeding such as amniocentesis, chorionic villus sampling and threatened miscarriage.


These vary from a mild haemolytic anaemia of the newborn to intrauterine death from 18 weeks’ gestation with the characteristic appearance of hydrops fetalis (hepatosplenomegaly, oedema and cardiac failure).
Kernicterus occurs due to severe jaundice in the neonatal period, where the unconjugated (lipid-soluble) bilirubin exceeds 250 urnol litre”! and bile pigment deposition occurs in the basal ganglia. This results in mental deficiency, deafness, epilepsy and spasticity.


Routine antenatal serology

All mothers should have their ABO and RhD groups determined and their serum tested for atypical antibodies after attending the antenatal booking clinic. The serum should be tested again for antibodies at 26 and 34 weeks of gestation.
If an antibody is detected, its blood group specificity should be determined and the mother’s serum should be tested more frequently. A rising antibody titre is an indication or amniocentesis to assess the level of bilirubin in the amniotic fluid which gives an indication of the severity of HDN.
At the birth of an affected infant A sample of cord blood is obtained. This shows:
• Anaemia with a high reticulocyte count
• A positive direct antiglobulin test
• A raised serum bilirubin


Management of the baby

In mild cases phototherapy may be used to convert bilirubin to water-soluble biliverdin. Biliverdin can be excreted by the kidneys and this therefore reduces the chance of kernicterus.
In more severely affected cases, exchange transfusion may be necessary to replace the infant’s red cells and to remove bilirubin. Indications for exchange transfusion include:
• A cord Hb of <14 g dl?
• A cord bilirubin of >60 urnol litre ”
• A later bilirubin of >300 urnol litre'”
• A rapidly rising bilirubin level
Further exchange transfusions may be necessary to remove the unconjugated bilirubin.
The blood used for exchange transfusions should be ABO compatible with the mother and infant, lack the antigen against which the maternal antibody is directed, be as fresh as possible and seronegative for cytomegalovirus. A fetus severely affected before 33 weeks of gestation may need intrauterine blood transfusions carried out in a special unit.
Prevention of RhD immunization in the mother Anti- D should be given after delivery when all of the following are present:
• The mother is RhD negative
• The fetus is RhD positive
• There is no maternal anti-D detectable in the mother’s serum, i.e. mother not already immunized
The dose is 500 i.u. of IgG anti-D intramuscularly within 48 hours of delivery. The Kleihauer test is used to assess the number of fetal cells in the maternal circulation. A blood film prepared from maternal blood is treated with acid, which elutes Hb A. Hb F is resistant to this treatment and can be seen when the film is stained with eosin. If large numbers of fetal red cells are present in the maternal circulation, a higher dose of anti-D is necessary.
It may be necessary to give prophylaxis to RhD-negative women at other times when sensitization may occur, for example after an ectopic pregnancy, threatened miscarriage or amniocentesis. The dose of anti-D is 500 i.u. after 20 weeks of gestation and 250 i.u. before 20 weeks. Of previously non-immunized RhD-negative women carrying RhD-positive fetuses, 1-2% are immunized by the time of delivery. Antenatal prophylaxis with administration of anti-D to RhD-negative women at 28 and 34 weeks of gestation has been shown to reduce the incidence of immunization in some studies. Antenatal prophylaxis is already used in some centres but further evidence is required before a recommendation for its routine use can be given.


Paroxysmal nocturnal haemoglobinuria (PNH)

This is a rare acquired red cell defect in which a clone of red cells is particularly sensitive to destruction by activated complement. These cells are continually haemolysed intravascularly. Platelets and granulocytes are also affected and there may be thrombocytopenia and neutropenia. The underlying defect is an inability of PNH cells to make glycosyl-phosphatidylinositol (GPI) which anchors proteins such as delay accelerating factor (DAF) and membrane inhibitor of reactive lysis (MIRL) to cell membranes. These and other proteins are involved in complement degradation and in their absence the haemolytic action of complement is not regulated.


Patient, present with haemolysis which may be precipitated by infection, iron therapy or surgery. Characteristically only the urine voided at J.igltt and in the morning on waking is dark in colour although the reason for this phenomenon is not clear. In severe cases all urine samples are dark. Urinary iron loss may be sufficient to cause iron deficiency.
The condition may be complicated by thrombotic episodes, giving acute abdominal pain, myocardial infarction or stroke. The Budd-Chiari syndrome (hepatic vein occlusion) can occur.


HAM’S TEST. Cells from a patient with PNH lyse more readily in acidified serum than do normal cells.
BONE MARROW is sometimes hypoplastic despite haemolysis.


There is no specific treatment for PNH. It is a chronic disorder requiring supportive measures such as blood transfusions, which are necessary for patients with severe anaemia. Leucocyte-depleted blood should be used in order to prevent transfusion reactions resulting in complement activation and acceleration of the haemolysis, Long-term anticoagulation may be necessary for patients with recurrent thrombotic episodes. Bone marrow transplantation has been successfully carried out in a small number of patients.
The course of PNH is variable. It may remain stable for many years and the PNH clone may even disappear. The median survival is 10 years. PNH may transform into aplastic anaemia or acute leukaemia.


Red cells may be injured by physical trauma in the circulation. Direct injury may cause immediate cell lysis or may be followed by resealing of the cell membrane with the formation of distorted red cells or ‘fragments’. These cells may circulate for a short period before being destroyed prematurely in the reticuloendothelial system. The causes of mechanical haemolytic anaemia include damaged artificial heart valves, March haemoglobinuria, where there is damage to red cells in the feet associated with prolonged marching or running, and microangiopathic haemolytic anaemia (MAHA) where fragmentation of red cells occurs in an abnormal microcirculation caused by malignant hypertension, eclampsia, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, vasculitis or disseminated intravascular coagulation.

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