Immune Haemolytic Anaemia

Abstract

The immune haemolytic anaemias comprise a set of diseases characterised by shortened red blood cell survival (haemolysis) mediated by the action of antibodies and serum complement. The haemolysis is evidenced by a raised reticulocyte count in the absence of blood loss. Activity of the immune system is diagnosed by the presence of antibody or fragments of complement components (mainly C3 and C4) on the red blood cell surfaces by means of the direct antiglobulin test. Pathogenic antibodies may bind optimally at either 37°C (warm autoimmune haemolytic anaemia) or at 4°C (cold agglutinin disease). Drugs may also cause immune haemolysis either by induction of drug‐dependent antibodies to red blood cells or by induction of autoantibodies.

Key Concepts:

  • The immune haemolytic anaemias are characterised by shortened red blood cell survival mediated by the action of antibodies and complement.

  • The key laboratory finding is the demonstration of antibody or complement on red blood cells by means of the direct antiglobulin (Coombs) test.

  • Antibodies may bind optimally at body temperature (37°C; warm antibody autoimmune haemolytic anaemia) or at 4°C (cold agglutinin disease).

  • Autoimmune haemolytic anaemia is most often idiopathic, but some cases occur in association with other diseases, most commonly a lymphoma or systemic lupus erythematosus.

  • Drugs may cause antibody binding to red blood cells by three distinct mechanisms. Nowadays, the most common offending drugs are second and third generation cephalosporins.

  • Treatment options include glucocorticoids and splenectomy (warm antibody autoimmune hemolysis); rituximab (warm antibody autoimmune haemolysis and cold agglutinin disease); and removal of the offending drug (drug‐immune haemolytic anaemia).

  • Transfusion should not be withheld from patients with symptomatic anaemia while awaiting a response to other treatments.

Keywords: antibody; haemolysis; anaemia; reticulocyte; complement

Figure 1.

Saline agglutinins and the antiglobulin test. (a) Saline agglutination. Antibodies that can agglutinate RBCs are termed saline agglutinins. Most such antibodies are of IgM class and are almost always autoantibodies, usually directed towards RBC antigens I or i. These antibodies react with RBC antigens more efficiently at temperatures below normal body temperature (37°C) and are thus termed cold agglutinins. IgM antibodies can agglutinate RBCs more easily than IgG antibodies, primarily because the molecules are pentavalent and large, which allows them to span the intercellular space and bind as many as five RBCs. (b) Direct antiglobulin (Coombs) test. IgG antibodies are in general too small to span between two RBCs, and thus are incapable of causing agglutination. Most patients with acquired haemolytic anaemia have warm antibody autoimmune haemolysis mediated by IgG autoantibodies, with or without complement. IgG autoantibodies and complement components are detected on RBCs by the direct antiglobulin test, often called the Coombs test, after its originator. RBCs taken directly from the patient are washed to remove plasma. Washing does not remove the bound IgG or complement from the RBCs. The antiglobulin reagent, containing antibody to IgG, complement components, or both, is then added to the RBC suspension. The antibodies in the antiglobulin reagent bind to the cell‐bound antibody or complement, and agglutinate the cells. Using monospecific antiglobulin reagents, the patterns of IgG alone, complement alone or IgG plus complement may be detected. In the figure, the cells are coated with IgG alone. In cases of warm antibody autoimmune haemolytic anaemia exhibiting complement alone, there is actually IgG present on the RBCs but in quantities too small to detect (about 400 molecules per cell) by standard antiglobulin reagents. Cold antibodies and drug‐dependent antibodies of the ternary or immune complex type also exhibit a complement alone pattern. (c) Indirect antiglobulin test. The indirect antiglobulin test detects antibody in patient plasma. The test is performed by first incubating patient serum containing free antibody with donor RBCs. Antibody from the serum binds to the RBCs and can now be detected using the antiglobulin reagent. It may be alloantibody formed in response to previous RBC exposure through transfusion or pregnancy, or it may be autoantibody. Alloantibodies do not bind to the patient's own RBCs, thus the direct antiglobulin test will be negative. When autoantibodies are detected by the indirect antiglobulin test, the direct antiglobulin test result must also be positive as well. This is due to overflow: there is more antibody present in the patient's blood than can be absorbed by the patient's own RBCs. The antigen specificity of alloantibodies and autoantibodies can be ascertained by the indirect antiglobulin test using panels of reagent RBCs of defined antigenic phenotype.

Figure 2.

Mechanisms of interaction between drug, antibody and RBC membrane antigen during the effector phase in drug‐immune haemolytic anaemia. (a) Drug adsorption mechanism. The drug is tightly bound to the RBCs, presumably to a protein. This occurs in vitro or in vivo. Antibody directed against the drug may then attach to the membrane‐bound drug. As is typical for haptens (in this case the drug), antibody does not bind to the hapten unless it is attached to a protein carrier (in this case, the RBC membrane protein). There is no evidence that the antidrug antibody recognises any epitope of the membrane protein. A high blood level of the drug is required to achieve RBC membrane coating with the drug (and subsequently antibody) sufficient to cause haemolysis. The direct antiglobulin test is positive for IgG. The indirect antiglobulin test result is also positive if the reagent cells are previously coated with the drug before incubation with patient serum. (b) Ternary (immune) complex mechanism. Drugs that mediate immune haemolysis by this mechanism bind only weakly and in small quantity to RBCs. The mechanism by which the drug‐dependent antibodies form is not known. The antibodies will not bind drug in the absence of RBCs, and the RBCs cannot be coated with the drug in the absence of the antibody. However, if all three components (RBC, drug and antibody) are present together, a stable trimolecular (ternary) complex consisting of drug, RBC membrane protein antigen and antibody is formed. Ternary complexes mediate haemolysis through the complement system. The direct antiglobulin test is positive for complement, mainly fragments of C3. (c) True autoantibody mechanism. Certain drugs elicit autoantibodies against RBCs. The mechanism of antibody induction is unknown. The antibodies, mostly IgG class, are indistinguishable from RBC autoantibodies that arise de novo. The likelihood of haemolysis increases with increasing drug dosage, but the antibodies are not drug dependent in that their attachment to RBCs occurs equally well in the presence or absence of the drug.

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Further Reading

Dacie JV (ed.) (1992) The haemolytic anaemias. In: The Autoimmune Haemolytic Anaemias, 3rd edn, vol. 3. New York: Churchill Livingstone.

Leddy JP (1996) Immune hemolytic anemia. In: Rich RR, Strober W, Fleisher TA, Schwartz BD and Shearer WT (eds) Clinical Immunology, Principles and Practice, pp. 1273–1288. St Louis: Mosby.

Packman CH (2010) Hemolytic anemia resulting from immune injury, Chapter 53. In: Kaushansky K, Lichtman M, Beutler E et al. (eds) Williams Hematology, 8th edn. New York: McGraw‐Hill.

Petz LD and Garratty G (2004) Immune Hemolytic Anemias. Philadelphia: Churchill Livingstone.

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Packman, Charles H(Apr 2011) Immune Haemolytic Anaemia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002148.pub3]