Haemolytic anaemia II – Acquired disorders

Published on 03/04/2015 by admin

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Haemolytic anaemia II – Acquired disorders

Autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) is an example of an acquired form of haemolysis with a defect arising outside the red cell. The bone marrow produces structurally normal red cells and premature destruction is caused by the production of an aberrant autoantibody targeted against one or more antigens on the cell membrane. Once an antibody has attached itself to the red cell, the exact nature of the haemolysis is determined by the class of antibody and the density and distribution of surface antigens. IgM autoantibodies cause destruction by agglutination or by direct activation of serum complement. IgG class antibodies generally mediate destruction by binding of the Fc portion of the cell-bound immunoglobulin molecule by macrophages in the spleen and liver. The disparate behaviour of different types of autoantibody provides the explanation for a number of different clinical syndromes.

Table 15.1 shows a simple approach to the classification of autoimmune haemolytic anaemia. The disease can be divided into ‘warm’ and ‘cold’ types depending on whether the antibody reacts better with red cells at 37°C or 0–5°C. For each of these two basic types of autoimmune haemolysis there are a number of possible causes and these can be incorporated into the classification. A diagnosis of autoimmune haemolysis may precede diagnosis of the causative underlying disease.

Table 15.1

Classification of the autoimmune haemolytic anaemias

Warm AIHA (usually IgG)
Primary (idiopathic)
Secondary	Lymphoproliferative disorders
	Other neoplasms
	Connective tissue disorders
	Drugs
	Infections
Cold AIHA (usually IgM)
Primary (cold haemagglutinin disease)
Secondary	Lymphoproliferative disorders
	Infections (e.g. mycoplasma)
	Paroxysmal cold haemoglobinuria¹

¹ Caused by a biphasic polyclonal IgG antibody (Donath–Landsteiner).

Clinical presentation and management

Warm autoimmune haemolytic anaemia

Warm AIHA (Figs 15.1 and 15.2) is the most common form of the disease. The red cells are coated with either IgG alone, IgG and complement, or complement alone. Premature destruction of these cells usually takes place in the reticuloendothelial system. Approximately half of all cases are idiopathic but in the other half there is an apparent underlying cause (Table 15.1). The autoantibody is produced by polyclonal B-cells and is usually non-specific with reactivity against basic membrane constituents present on virtually all red cells. Patients present with the clinical and laboratory features of haemolysis discussed in the last section. Splenomegaly is a frequent examination finding in severe cases. The most characteristic laboratory abnormality in warm AIHA is a positive direct antiglobulin test (DAT) sometimes known as the Coombs’ test (p. 83). A major priority in management is the identification and treatment of any causative disorder. It is particularly important to stop an offending drug – cephalosporin antibiotics are most commonly implicated. Where the haemolysis itself requires treatment, steroids are normally used (e.g. prednisolone 1–2 mg/kg daily). In idiopathic AIHA most patients will respond to steroids with a significant rise in haemoglobin and diminished clinical symptoms. However, the disease is usually controlled rather than cured and relapses often occur when steroids are reduced or stopped. Where refractoriness to steroids develops, splenectomy is usually indicated. Other immunosuppressive drugs (e.g. azathioprine, ciclosporin), intravenous immunoglobulin, cytotoxic agents and the monoclonal antibody rituximab may all be helpful in difficult cases.

Fig 15.1 Blood film in warm AIHA.
Spherocytes and polychromasia are present.

Fig 15.2 Increased reticulocytes in warm AIHA.
The reticulocyte ribosomal RNA is stained supravitally by brilliant cresyl blue.

Cold autoimmune haemolytic anaemia

In cold AIHA the antibody is generally of IgM type with specificity for the I red cell antigen. It attaches best to red cells in the peripheral circulation where the blood temperature is lower. As is seen in Table 15.1, this kind of haemolysis can occur in the context of a monoclonal (i.e. malignant) proliferation of B-lymphocytes in the so-called ‘idiopathic cold haemagglutinin syndrome’ or in a variety of lymphomas. The other major cause is infection.

The severity of haemolysis varies and agglutination (clumping) of red cells (Fig 15.3) may cause circulatory problems such as acrocyanosis, Raynaud’s phenomenon and ulceration. The haemolysis, where longstanding, is often worse in the winter. On occasion red cell destruction is intravascular due to direct lysis by activated complement. Where this occurs free haemoglobin is released into the plasma (haemoglobinaemia) and may appear in the urine (haemoglobinuria), giving it a dark colour. Cold AIHA arising from infection is usually self-limiting. Where it is chronic the mainstay of treatment is keeping the patient warm, particularly in the extremities. In forms associated with lymphoproliferative disorders, cytotoxic drugs (e.g. chlorambucil) or rituximab may be helpful. Steroids are generally ineffective.

Fig 15.3 Cold agglutination in the blood film of a patient with cold autoimmune haemolytic anaemia.

Isoimmune haemolytic anaemia

Here alloantibodies (isoantibodies) cause haemolysis as a result of transfusion or transfer across the placenta. These antibodies are conventional antibodies specific for foreign antigens on incompatible red cells. Haemolytic blood transfusion reactions are discussed on page 84 and haemolytic disease of the newborn on page 90.

Microangiopathic haemolytic anaemia

Collectively, microangiopathic haemolytic anaemia (MAHA) is one of the most frequent causes of haemolysis. The term describes intravascular destruction of red cells in the presence of an abnormal microcirculation. There are many causes of MAHA (Table 15.2) but common triggers are the presence of disseminated intravascular coagulation (DIC), abnormal platelet aggregation and vasculitis. Characteristic laboratory findings include red cell fragmentation in the blood film (Fig 15.4) and the coagulation changes seen in DIC (see p. 79). Two specific syndromes merit brief description.

Fig 15.4 Blood film in microangiopathic haemolytic anaemia.
Fragmented red cells and thrombocytopenia.

Haemolytic uraemic syndrome (HUS)

HUS mainly affects infants and children. The three main features are MAHA, renal failure and thrombocytopenia. The disease can occur as seasonal epidemics caused by Escherichia coli producing verotoxin; it is then preceded by bloody diarrhoea. Treatment is essentially supportive with dialysis for renal failure. Mortality ranges from 5 to 15%.

Thrombotic thrombocytopenic purpura (TTP)

This rare congenital or acquired disorder has many similarities to HUS. It is characterised by MAHA, thrombocytopenia (often severe), fluctuating neurological symptoms, fever and renal failure. Platelet microvascular thrombi are mediated by ultra-large von Willebrand factor multimers which accumulate due to deficiency of a protease (ADAMTS 13). Daily plasma exchange is the mainstay of treatment; mortality rates are 10–20%.

Other acquired haemolytic anaemias

Haemolysis associated with red cell fragmentation may also occur due to the mechanical effects of defective heart valves or in long distance runners who effectively stamp repeatedly on a hard surface (‘march haemoglobinuria’). Certain drugs (e.g. dapsone and sulfasalazine) can cause oxidative intravascular haemolysis in normal people if taken in sufficient dosage. Many infections can cause haemolysis, either by direct invasion of red cells or via the circulatory changes already discussed. The anaemia of malaria often has a haemolytic component (pp. 98–99).

Paroxysmal nocturnal haemoglobinuria (PNH) (Fig 15.5) is a rare example of acquired haemolysis caused by an intrinsic red cell defect. In this clonal disorder arising from a somatic mutation in the PIG-A gene in a stem cell, the mature blood cells have faulty anchoring of several proteins to membrane glycophospholipids containing phosphatidylinositol. Clinical features are highly variable and include intravascular haemolysis, pancytopenia and recurrent thrombotic episodes, including portal vein thrombosis. There is coexistent marrow damage and PNH is often associated with aplastic anaemia and may even terminate in acute leukaemia. The traditional diagnostic test exploited the cell’s unusual sensitivity to complement lysis (Ham test). Flow cytometry is now used to show the cells’ characteristic lack of certain surface proteins (CD55, CD59) and to quantitate the PNH clone. Management is largely supportive with blood transfusion and anticoagulation. More recently, eculizumab, a monoclonal antibody blocking activation of terminal complement, has been given to reduce haemolysis and the risk of thrombosis. Allogeneic stem cell transplantation is the only curative option but is used very selectively (e.g. in severe marrow failure).