J Clin Pathol: first published as 10.1136/jcp.s3-9.1.46 on 1 January 1975. Downloaded from J. clin. Path., 28, Suppl. (Roy. Coll. Path.), 9, 46-49 Immunological mechanisms in drug-induced blood dyscrasias URS NYDEGGER AND PETER A. MIESCHER From the Division of Haematology, Department of Medicine, University of Geneva, Geneva, Switzerland Drugs can produce blood disorders in many ways. age in Sedormid-(allylisopropylcarbamide)-induced At one end of the spectrum are dose-dependent thrombocytopenia might be mediated by Sedormid/ effects which can be explained in pharmacological antibody complexes, although at that time he came terms as 'toxic' reactions. At the other end of the to a different conclusion. Soon after, Moeschlin and spectrum are dose-independent effects which cannot Wagner (1952) observed analogous in-vitro pheno- be predicted. With the discovery of the causal rela- mena with the serum of a patient suffering from tionship between amidopyrine intake and agranulo- amidopyrine-induced agranulocytosis, but again the cytosis in certain patients, increasing attention has pathogenesis underlying this observation was inter- been paid to the latter phenomena and a number of preted in a different way. Shulman's studies (1958), distinct immune mechanisms have been elucidated as well as our own (Miescher, 1955), have suggested in drug-induced blood dyscrasias. that formation of immune complexes and their sub- The first mechanism is similar to that encountered sequent deposition on the cells are most likely to be in experimental serum sickness (Cochrane and operative in this type of cytopenia although a Koffler, 1973). The thrombocytopenia and leuco- number of pertinent questions are stilJ unanswered: penia in this condition is probably due to the effect 1 Why should one particular drug always pro- of immune complexes on the cells: platelets and duce thrombocytopenia when complexed with an leucocytes, coated with antigen-antibody complexes, antibody and another drug always produce agranu- are eliminated from the circulating blood, pre- locytosis ? sumably through phagocytosis by the reticuloendo- 2 Why is the disappearance of platelets or leuco- thelial system (Miescher, 1955; Mannick cytes from the peripheral blood almost complete, as- Haakenstad, and Arend, 1974). A similar immune- whereas experimental serum sickness is only http://jcp.bmj.com/ complex type mechanism is likely to be operative in sociated with a slight degree of thrombocytopenia many cases of drug-induced thrombocytopenia and and leucopenia? leucopenia. 3 Why are the precursor cells within the bone The second mechanism has been used for many marrow affected so greatly in this type of agranulo- years as a serological tool for the detection of anti- cytosis ? bodies and is the agglutination of antigen-coated red Various observations might help to answer the cells by antibody (passive hemagglutination). fiist question. In the case of Sedormid, it was shown Damage to drug-coated cells by drug-specific anti- that the drug concentrated around platelets without on October 2, 2021 by guest. Protected copyright. bodies is today a well recognized mechanism in being strongly attached. Furthermore, it was shown certain drug-induced cytopenias. that the drug could be washed off the platelets very A third mechanism emerged from the clinical easily. This affinity of Sedormid for platelets may observation that certain drugs lead to the develop- favour the attachment of the drug-antibody-com- ment of autoantibodies, ie, antibodies directed to plexes to the cells. In the case of drugs shown to autologous antigenic determinants. induce thrombocytopenia in some patients and im- In this review, these three mechanisms are dis- mune haemolytic anaemia in others, Shulman (1963) cussed first and serological methods available for was able to demonstrate that thrombocytopenia was diagnosis of immune drug-induced blood dyscrasias usually mediated by IgG antidrug antibodies where- will be discussed later. as immune haemolytic anaemia was usually mediated by IgM antidrug antibodies. From this observation Inmune-complex-mediated Cell Damage it was suggested that the type of antibody involved in the formation of immune complexes may also be In 1949, Ackroyd (1964, review) discovered a number relevant for the cell specificity of the reaction and it of in-vitro reactions suggesting that platelet dam- might be postulated that this specificity is related to 46 J Clin Pathol: first published as 10.1136/jcp.s3-9.1.46 on 1 January 1975. Downloaded from Immunological mechanisms in drug-induced blood dyscrasias 47 the cell surface receptors (Nussenzweig, Lay, and antibodies are involved in this type of immune Miescher, 1969). However, this question is still haemolytic anaemia (Levine et al, 1966). The anti- wide open to further investigation, particularly when bodies thus appear not to react with antigenic deter- drugs are the antigen or the hapten involved. minants on the red cell. Very similar pathogenetic The question of why granulocytes and/or platelets events seem to be operative in cephalothin-(Keflin) almost totally disappear from the peripheral blood in induced haemolytic anaemia (Gralnick, McGinnis, drug-induced agranulocytosis and/or thrombocyto- Elton, and McCurdy, 1971). The red cell appears to penia and are frequently associated with a gradual be damaged by cephalothin bound onto its surface disappearance of the precursor cells is equally diffi- and is then destroyed following the union of circulat- cult to answer. In this context, one should bear in ing anticephalothin antibody with the antigen. For mind that agents which raise the intracellular level clinical purposes it is important to know that the of cyclic AMP, such as theophyllin or prostaglandin incidence of penicillin-induced haemolytic anaemia El, have been implicated in additional damage to is much commoner than that of cephalothin-induced subcellular organelles (Gillespie, 1971). Thus drug/ anaemia and ranks at the top of a series of some 15 antibody complexes might be harmful to blood cells drugs incriminated in immune red cell damage through at least two pathways, first because the (review in Miescher, 1973). complex coats the cells and secondly because of the More recently, it has been shown that cephalothin potentiated toxic effect of the antigen. can lead to thrombocytopenia. Gralnick, McGinnis, The removal of large quantities of cells from the and Halterman (1972) were able to detect a cephalo- circulating blood with special procedures (leuco- thin-specific antibody in a well studied patient suffer- pheresis, thrombocytopheresis) does not lead to ing from cephalothin-induced thrombocytopenia. damage to the precursor cells and, in experimental When cephalothin was added to the patient's plate- serum sickness, neutropenia is not accompanied by lets, her serum agglutinated her in-vitro cephalothin- damage to the cells in the bone marrow. However, in coated platelets but not her own uncoated platelets. many drug-induced leucopenias, drug-mediated This activity could be neutralized by prior incuba- damage is not limited to circulating cells but affects tion of the serum with cephalothin. This latter precursor cells as well. The pathogenesis of the bone experiment distinguishes this type of mechanism marrow damage has not yet been elucidated but a from the immune complex type of damage in which number of differing mechanisms may be operative. a preformed complex produces agglutination The recovery time of agranulocytosis not only varies (Pfueller and Luischer, 1972). with the extent of cell damage in the bone marrow (injury to myelocytes, promyelocytes or myelo- Drug-induced Autoimmune Phenomena blasts), but also with the pharmacological variety of http://jcp.bmj.com/ drugs involved, ie, being relatively short with amido- The association of certain drugs, eg, hydralazine, pyrine and much longer with phenothiazines. procainamide, with antinuclear antibodies has lead to the assumption that the two events are causally Damage to Drug-coated Cells by Drug-specific related (Perry and Schroeder, 1954; Blomgren, Antibodies Condemi, Bignall, and Vaughan, 1969). Indeed, when procainamide medication is discontinued in This mechanism was first demonstrated in penicillin- patients taking this drug and exhibiting an SLE-like induced immune haemolytic anaemia. Evidence has syndrome, antinuclear antibody and clinical symp- on October 2, 2021 by guest. Protected copyright. been provided that part of the immunogenicity of toms and signs of SLE gradually disappear benzylpenicillin is due to a rearrangement of its (Blomgren et al, 1969). Subsequently, this observa- isomer D-benzylpenicillenic acid, a compound which tion was extended to other autoantibodies as well is chemically highly reactive with proteins. Levine and in particular to antibodies directed against and Redmond (1967) could demonstrate that 30% antigenic determinants located on the membrane of of patients taking 1-2-2-4 million units of penicillin red cells. had some detectable drug on their red cells and all Indeed, with the introduction of methyldopa into patients taking 10 or more million units had large the treatment of hypertension, this mechanism was amounts of the drug on their cells. In patients who firmly established. In fact, about 20% of patients have developed a high titre of IgG antibodies to receiving this drug for many months have been benzylpenicilloyl haemolytic anaemia occurs as a shown to develop a positive IgG Coombs test which consequence of the reaction