AUTO IMMUNE HAEMOLYTIC ANEMIA

ACQUIRED HAEMOLYTIC ANAEMIA
AUTOIMMUNE HAEMOLYTIC ANAEMIA
This results from increased red cell destruction due to red cell autoantibodies. The antibodies may be IgG or M, or more rarely IgE or A. If an antibody avidly fixes complement, it will result in intravascular haemolysis, but if complement activation is weak, the haemolysis will be extravascular. Antibody-coated red cells lose membrane to macrophages in the spleen and hence spherocytes are present in the blood. The optimum temperature at which the antibodc is active (thermal specificity) is used to classify immune haemolvsis:
• Warm antibodies bind best at 37°C and account for 80% of cases. The majority are IQG and usually react against Rhesus antigens.
• Cold antibodies bind best at 4`C but can bind up to 37°C in some cases. They are usually IgM and bind complement. They account for the other 20% of cases.
Warm autoimmune haemolysis
The incidence of warm autoimmune haemolysis is approximately 1/100 000 population per annum; it occurs at all ages but is more common in middle age and there is a female excess. No underlying cause is identified in up to 50% of cases. The remainder are secondary to a wide variety of other conditions:
 
15%. The deficiency in Caucasian and Oriental populations is more severe, with enzyme levels as low as I%.
Clinical features and investisational findings are shown in Box 24.32.
Management aims to stop any precipitant drugs and treat any underlying infection. Acute transfusion support may be life-saving.
• lymphoid neoplasms: lymphoma, chronic lymphocytic leukaemia, myeloma
• solid tumours: lung, colon, kidney. ovary. thymoma • connective tissue disease: SLE, rheumatoid arthritis • drugs: methyldopa, mefenamic acid, penicillin, quinine
• miscellaneous: ulcerative colitis, HIV.
Pyruvate kinase deficiency
This is the second most common red cell enzyme defect and affects thousands of people world-wide. It results in deficiency of ATP production and a chronic haemolytic anaemia. It is inherited as an autosomal recessive trait. The extent of anaemia is variable; the blood film shows characteristic `prickle cells which resemble holly leaves. Enzyme activity is only 5-20% of normal. Transfusion support may be necessary.
Pyrimidine 5 nucleotidase deficiency
This enzyme catalyses the dephosphorylation of nucleoside monophosphates and is important during the degradation of RNA in reticulocytes. It is inherited as an autosomal recessive trait and is as common as pyruvate kinase defi¬ciency in Mediterranean, African and Jewish populations. The accumulation of excess ribonucleoprotein results in coarse basophilic stippling associated with a chronic haemolytic state. The enzyme is very sensitive to inhibition
Investigations
There is evidence of haemolysis and spherocytes on the blood film. The diagnosis is confirmed by the direct Coombs or antiglobulin test (Fig. 24.22). In this, red cells are mixed with Coombs reagent which contains antibodies against human IgG/M/complement. If the red cells have been coated by antibody in vivo, the Coombs reagent will induce their agglutination and this can be detected visually. The relevant antibody can be eluted from the red cell surface and tested against a panel of typed red cells to determine which red cell antigen it is directed against. The most common specificity is Rhesus and most often anti-e; this is helpful when choosing blood to cross-match. The direct Coombs test can be negative in the presence of brisk haemolysis; a positive test requires about 200 antibody molecules to attach to each red cell; with a very avid complement-fixing antibody, haemolysis may occur at lower levels of antibody-binding. The standard Coombs reagent will miss IgA or IgE antibodies.
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BLOOD DISORDERS
A
Direct antiglobulin test (DAT) (Coombs test)
Detects the presence of antibody bound to the red cell surface, e.g.
1. autoimmune haemolytic anaemia
2. haemolytic disease of newborn (HDN) 3. transfusion reactions
B
Indirect antiglobulin test (IAT) (indirect Coombs test) Detects antibodies in the plasma, e.g. antibody screen in pre-transfusion testing
 
 
Key
 
Fig. 24.22 Direct and indirect antiglobulin tests.
 
 
Antibodies to human globulin
Red cell agglutination
Stage 1
Patient s plasma
 
 
Red cells with Red cells with
known antigen Ag-Alb complex
expression on cell surface
 
 
Antibodies to Red cell
human globulin agglutination
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Management
0 If the haemolysis is secondary to an underlying cause, this must be treated and any offending drugs stopped. 0 It is usual to treat patients initially with prednisolone
1 mg/kg orally. A response is seen in 70-80% of cases but this may take up to 3 weeks; a rise in haemoglobin will be matched by a fall in bilirubin and LDH levels. Once the haemoglobin has reached 100 g/1, the corticosteroid dose can be reduced by 5 mg per week to 10 mg daily, then reduced slowly to nothing over a further 10 weeks. Steroids work by decreasing macrophage destruction of antibody-coated red cells and reducing antibody production.
Transfusion support may be required for life-threatening problems. The least incompatible blood should be used but may still give rise to transfusion reactions or the development of further alloantibodies.
0 If the haemolysis fails to respond to corticosteroids or can only be stabilised by large doses, then splenectomy should be considered. This removes a main site of red cell destruction and antibody production with a good response in 50-60% of cases. The operation can be performed laparoscopically with reduced morbidity.
~ For patients who fail to respond to corticosteroids or for whom splenectomy is not appropriate, alternative immunosuppressive therapy may be considered. This is least suitable for young patients, for whom long-term therapy may carry a risk of secondary neoplasms. The choice of drug is between azathioprine 1-2 mg/kg and cyclophosphamide 2 mg/kg, both orally; induction of a response usually takes 2-3 months.
Cold agglutinin disease
This is due to antibodies, usually IgM, which bind to the red cells at 4°C and cause them to agglutinate. It may cause intravascular haemolysis if complement fixation occurs. This can be chronic when the antibody is monoclonal, or acute or transient when the antibody is polyclonal.
Chronic cold agglutinin disease
This affects elderly patients and may be associated with an underlying low-grade B-cell lymphoma. It causes a low¬grade intravascular haemolysis with cold, painful and often blue fingers, toes, ears or nose (so-called acrocyanosis). The latter is due to red cell agglutination in the small vessels in these exposed areas. The blood film shows red cell agglutination and the MCV may be spuriously raised because the automated analysers count aggregates as single cells. The monoclonal IgM usually has specificity against the I or, more rarely, i antigen and is present in a very high titre. Treatment is directed at any underlying lymphoma but if the disease is idiopathic, then patients must keep extremities warm, especially in winter. Some patients respond to corticosteroid therapy and blood transfusion may be considered, but the cross-match sample must be placed in a transport flask at a temperature of 37°C and blood administered via a blood-warmer.
Other causes of cold agglutination
Cold agglutination can occur in association with Mycoplasma pneumoniae or with infectious mononucleosis. Paroxysmal cold haemoglobinuria is a very rare cause seen in children in association with congenital syphilis. An IgG antibody binds to red cells in the peripheral circulation but
lysis occurs in the central circulation when complement fixation takes place. This antibody is termed the Donath¬Landsteiner antibody and has specificity against the P antigen on the red cells.
NON-IMMUNE HAEMOLYTIC ANAEMIA
Physical trauma
Physical disruption of red cells may occur in a number of conditions and is characterised by the presence of red cell fragments on the blood film and markers of intravascular haemolysis:
• Mechanical heart valves. High flow through incompetent valves or periprosthetic leaks through the suture ring holding a valve in place result in shear stress damage.
• March haemoglobinuria. Vigorous exercise such as prolonged marching or marathon running can cause red cell damage in the capillaries in the feet.
• Thermal injury. Severe burns cause thermal damage to red cells characterised by fragmentation and the presence of microspherocytesin the blood.
v Microangiopathic haemolytic anaemia. Fibrin deposition in capillaries can cause severe red cell disruption. It may occur in a wide variety of conditions: disseminated carcinomatosis, malignant or pregnancy-induced hypertension, haemolytic uraemic syndrome (p. 498), thrombotic thrombocytopenic purpura (p. 1057) and DIC (p. 1060).
Infection
Plasmodium falciparum malaria (p. 342) may be associated with intravascular haemolysis; when severe this is termed blackwater fever due to the associated haemoglobinuria. Clostridium perfringens septicaemia (p. 326), usually in the context of an ascending cholangitis, may cause severe intravascular haemolysis with marked spherocytosis due to bacterial production of a lecithinase which destroys the red cell s membrane.
Chemicals or drugs
These agents cause haemolysis by oxidant denaturation of haemoglobin. Dapsone and sulfasalazine can produce haemolysis associated with the presence of Heinz bodies in the red cells on supravital staining with brilliant cresyl blue. Heinz bodies contain denatured haemoglobin. Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives may all cause haemolysis.