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Drug-Induced Aplastic Anaemia and Agranulocytosis

Incidence and Mechanisms

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Summary

Aplastic anaemia and agranulocytosis are uncommon but serious adverse effects of drug therapy. They result from an adverse interaction between the drug and the haemopoietic pathway in certain susceptible individuals. The nature of this idiosyncratic interaction differs for diffefent drugs and possibly for different individuals. In some instances an immune mechanism might be implicated, in others the patient’s cells might carry a genetic susceptibility to the drug, while yet other patients might metabolise the drug abnormally. The idiosyncratic nature of these effects has made their investigation difficult, but experimental studies have allowed some progress in our understanding. In a practical sense, however, responsibility for preventing these problems will remain with clinicians, who should be alert to the risks and revise their prescribing habits accordingly.

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References

  • Alter BP, Potter NU, Li FP. Classification and aetiology of the aplastic anaemias. Clinics in Haematology 7: 431–465, 1978

    PubMed  CAS  Google Scholar 

  • Arneborn P, Palmblad J. Drug induced neutropenia in the Stockholm region 1976–77. Acta Medica Scandinavica 206: 241–243, 1979

    Article  PubMed  CAS  Google Scholar 

  • Australian Drug Evaluation Committee: report of suspected adverse drug reactions, No. 5, Australian Government Publishing Service, Canberrs 1981

    Google Scholar 

  • Barrett AJ, Faille A, Balitrand N, Ketels F, Najean Y. Bone marrow culture in aplastic anaemia. Journal of Clinical Pathology 32: 660–665, 1979

    Article  PubMed  CAS  Google Scholar 

  • Baumelou E, Najean Y. Why still prescribe chloramphenicol in 1983? Comparison of the clinical and biological hematologic effects of chloramphenicol and thiamphenicol. Blut 47: 317–320, 1983

    Article  PubMed  CAS  Google Scholar 

  • Bilezikian SB, Laleli Y, Tsan MF, Hodkinson BA, Ice S, et al. Immunological reactions involving leukocytes: III. agranulocytosis induced by antithyroid drugs. Johns Hopkins Medical Journal 138: 124–129, 1976

    PubMed  CAS  Google Scholar 

  • Boggs DR, Boggs SS. The pathogenesis of aplastic anemia: A defective pluripotent hematopoietic stem cell with inappropriate balance of differentiation and self-replication. Blood 48: 71–76, 1976

    PubMed  CAS  Google Scholar 

  • Böttinger LE, Furhoff AK, Holmberg L. Drug-induced blood dycrasias. Acta Medica Scandinavica 205: 457–461, 1979

    Article  Google Scholar 

  • Böyum A, Lövhaug D, Boecker WR. Regulation of bone marrow cell growth in difusion chambers. The effect of adding normal and leukemic (CML) polymorphonuclear granulocytes. Blood 48: 373–383, 1976

    PubMed  Google Scholar 

  • Böyum A, Lövhaug D, Viken KE, Kristiansen T. Medium conditioned for 24 hours by mononuclear human blood cells contains an inducer of granulopoiesis lacking colony stimulating activity. Scandinavian Journal of Haematology 25: 385–393, 1980

    Article  PubMed  Google Scholar 

  • Brimblecombe RW, Duncan WAM, Durant GJ, Emmett JC, Ganellin CR, et al. Characterisation and development of Cimetidine as a histamine H2 receptor antagonist. Gastroenterology 74: 339–347, 1978

    PubMed  CAS  Google Scholar 

  • Broxmeyer HE, Moore MAS, Ralph P. Cell-free granulocyte colony inhibiting activity derived from human polymorphonuclear neutrophils. Experimental Hematology 5: 87–102, 1977

    PubMed  CAS  Google Scholar 

  • Byron JW. Evidence for the association of a histamine H2 receptor with the haematopoietic stem cell. Pharmacologist 18: 217, 1976

    Google Scholar 

  • Camitta BM, Storb R, Thomas ED. Aplastic anemia. Pathogenesis, diagnosis, treatment and prognosis. New England Journal of Medicine 306: 645–652, 712-718, 1982

    Article  PubMed  CAS  Google Scholar 

  • Chikkappa G, Carsten AL, Cronkite EP. Kinetics of proliferation and differentiation of human hemopoietic cells in a diffusion chamber system. Experimental Hematology 5: 533–540, 1980

    Google Scholar 

  • Cline MJ, Golde DW. Controlling the production of blood cells. Blood 53: 157–165, 1979

    PubMed  CAS  Google Scholar 

  • Cronkite EP. Erythropoietic cell proliferation in man. Medicine 43: 635–637, 1979

    Google Scholar 

  • Cronkite EP, Vincent PC. Granulocytopoiesis. Series Haemato-logica 4(II): 3–43, 1969

    Google Scholar 

  • Cronkite EP, Burlington H, Chanan AD, Joel DD, Reincke U, et al. Concepts and observations on the regulation of granulocyte production. In Baum & Ledney (Eds) Experimental hematology today, pp. 41–49, Springer-Verlag, New York, 1977

    Chapter  Google Scholar 

  • Cunningham JL, Leyland MJ, Delamore IW, Price Evans DA. Acetanilide oxidation in phenylbutazone-associted hypoplastic anaemia. British Medical Journal 3: 313–317, 1974

    Article  PubMed  CAS  Google Scholar 

  • Dexter TM, Allen TD, Lajtha LG. Conditions controlling the proliferation of haemopoietic stem cells in vitro. Journal of Cell Physiology 91: 335–344, 1977

    Article  CAS  Google Scholar 

  • Eisner EV, Carr RM, Mackinney AA. Quinidine-induced agranulocytosis. Journal of the American Medical Association 238: 884–886, 1977

    Article  PubMed  CAS  Google Scholar 

  • Firkin FC, Sumner MA, Bradley TR. The influence of chloramphenicol on the bone marrow haemopoietic stem cell compartment. Experimental Hematology 2: 264–268, 1974

    PubMed  CAS  Google Scholar 

  • Firkin FC, Moore MAS. Atypical phenylbutazone sensitivity of marrow colony forming units in phenylbutazone-induced aplastic anaemia. In Hibino, Takaku and Shahidi (Eds) Aplastic anemia. Proceedings of the First International Symposium on Aplastic Anemia, September 3–4, 1976, Kyoto, pp. 335–342, University of Tokyo Press, Tokyo, 1976

    Google Scholar 

  • Freston JW. Cimetidine and granulocytopenia. Annals of internal medicine 90: 264–265, 1979

    PubMed  CAS  Google Scholar 

  • Fried W. Progress in erythropoiesis and megakaryocytopoiesis. In Baum and Ledney (Eds) Experimental hematology today, pp. 75–77, Springer-Verlag, New York, 1979

    Google Scholar 

  • Gartner S, Kaplan HS. Long-term culture of human bone marrow cells. Proceeding of the National Academy of Sciences 77: 4756–4759, 1980

    Article  CAS  Google Scholar 

  • Gordon MY. Relevance of colony forming assays to bone marrow transplantation with particular reference to grafting for aplastic anaemia. British Journal of Haematology 42: 61–71, 1979

    Article  PubMed  CAS  Google Scholar 

  • Haak HL. Experimental drug-induced aplastic anaemia. Clinics in Haematology 9: 621–639, 1980

    PubMed  CAS  Google Scholar 

  • Hara H, Kai S, Fushimi M, Taniwaki S, Okamoto T, et al. Pluripotent hemopoietic precursors in vitro (CFUmix) in aplastic anemia. Experimental Hematology 8: 1165–1171, 1980

    PubMed  CAS  Google Scholar 

  • Heimpel H, Heit W. Drug-induced aplastic anaemia: clinical aspects. Clinics in Haematology 9: 641–662, 1980

    PubMed  CAS  Google Scholar 

  • Heit W, Kern P, Heimpel H, Kubanek, B. Granulocytic colony forming cells in vitro: 1. Patients with drug induced agranulocytosis. Blut 34: 403–405, 1977

    Article  PubMed  CAS  Google Scholar 

  • Hoppin EC, Greenberg BR, Walter RM. Agranulocytosis secondary to pentazocine therapy. Archives of Internal Medicine 138: 533–534, 1978

    Article  PubMed  CAS  Google Scholar 

  • Howell A, Andrews TM, Watts RWE. Bone marrow cells resistant to chloramphenicol-induced aplastic anaemia. Lancet 1: 65–69, 1975a

    Article  CAS  Google Scholar 

  • Howell A, Gumpel JM, Watts RWE. Depression of bone marrow colony formation in gold-induced neutropenia. British Medical Journal 1: 432–434, 1975b

    Article  PubMed  CAS  Google Scholar 

  • Kaneko S, Motomura S, Ibayashi H. Differentiation of human bone marrow-derived fibroblastoid colony forming cells (CFU-F) and their roles in haemopoiesis in vitro. British Journal of Haematology 51: 217–225, 1982

    PubMed  CAS  Google Scholar 

  • Kelton JG, Huang AT, Mold N, Logue G, Rosse WF. The use of in vitro technics to study drug-induced pancytopenia. New England Journal of Medicine 301: 621–624, 1979

    Article  PubMed  CAS  Google Scholar 

  • Kern P, Heimpel H, Heit W, Kubanek B. Bone-marrow cells resistant to chloramphenicol in chloramphenicol-induced aplastic anaemia. Lancet 1: 1190, 1975

    Article  PubMed  CAS  Google Scholar 

  • Kern P, Heimpel, H, Heit W, Kubanek B. Granulocytic progenitor cells in aplastic anaemia. British Journal of Haematology 35: 613–623, 1977

    Article  PubMed  CAS  Google Scholar 

  • Klassen LW, Birks J, Allen E, Gurney CW. Experimental medullary aplasia. Journal of Laboratory and Clinical Medicine 80: 8–17, 1972

    PubMed  CAS  Google Scholar 

  • Knospe WH, Crosby WH. Aplastic anaemia: a disorder of the bone-marrow sinusoidal microcirculation rather than stem-cell failure? Lancet 1: 20–22, 1971

    Article  PubMed  CAS  Google Scholar 

  • Kurland J, Moore MAS. The regulatory role of the macrophage in normal and neoplastic hemopoiesis. In Baum & Ledney (Eds) Experimental hematology today, pp. 51–64, Springer-Verlag, New York, 1977

    Chapter  Google Scholar 

  • Lajtha LG. Haemopoietic stem cells. British Journal of Haematology 29: 529–535, 1975

    Article  PubMed  CAS  Google Scholar 

  • Lind DE, Levi JA, Vincent PC. Amodiaquine-induced agranulocytosis: toxic effect of amodiaquine in bone marrow cultures in vitro. British Medical Journal 1: 458–460, 1973

    Article  PubMed  CAS  Google Scholar 

  • Lord BI. Proliferation regulators in haemopoiesis. Clinics in Haematology 8: 435–451, 1979

    PubMed  CAS  Google Scholar 

  • Mangan KF, Desforges JF. The role of T-lymphocytes and monocytes in the regulation of human erythropoietic peripheral blood burst forming units. Experimental Hematology 8: 717–727, 1980

    PubMed  CAS  Google Scholar 

  • Messner HA, Fauser AA. Culture studies of human pluripotent hemopoietic progenitors. Blut 41: 327–333, 1980

    Article  PubMed  CAS  Google Scholar 

  • Metcalf D, Merchav S, Wagemaker G. Commitment by GM-CSF or M-CSF of bipotential GM progenitor cells to granulocyte or macrophage formation. In Baum, Ledney and Thierfelder (Eds) Experimental Hematology Today, pp. 3–9, S. Karger, Basel, 1982

    Google Scholar 

  • Moeschlin S, Wagner K. Agranulocytosis due to the occurrence of leucocyte-agglutinins. Acta Haematologica 8: 29–41, 1952

    Article  PubMed  CAS  Google Scholar 

  • Morley A. Residual marrow damage from cytotoxic drugs. Australian and New Zealand Journal of Medicine 10: 569–571, 1980

    Article  PubMed  CAS  Google Scholar 

  • Morley A, Blake J. Haemopoietic precursor cells in experimental hypoplastic marrow failure. Australian Journal of Experimental Biology and Medical Science 52: 909–914, 1974

    Article  PubMed  CAS  Google Scholar 

  • Morley A, Furness M, Higgs D. Inhibition of growth of marrow cells by chloramphenicol. Australian Journal of Experimental Biology and Medical Science 52: 847–850, 1974

    Article  PubMed  CAS  Google Scholar 

  • Morley A, Trainor K, Blake J. A primary stem cell lesion in experimental chronic hypoplastic marrow failure. Blood 45: 681–688, 1975

    PubMed  CAS  Google Scholar 

  • Morley A, Trainor K, Remes J. Residual Imarrow damage: possible explanation for idiosyncrasy to chloramphenicol. British Journal of Haematology 32: 525–531, 1976

    Article  PubMed  CAS  Google Scholar 

  • Morley A, Trainor K, Seshadri RS. Chronic hypoplastic marrow failure and residual injury. Blood Cells 4: 253–266, 1978

    PubMed  CAS  Google Scholar 

  • Morris TCM, Vincent PC, Sutherland R, Hersey P. Inhibition of normal human granulopoiesis in vitro by non-B non-T lymphocytes. British Journal of Haematology 45: 541–550, 1980

    Article  PubMed  CAS  Google Scholar 

  • Morris TCM, Vincent PC, Young GAR, Sutherland R, Forrest PR, et al. CUF-C inhibitors in aplastic anaemia. Blut 48: 1–14, 1984

    Article  Google Scholar 

  • Nagao T, Mauer AM. Concordance for drug-induced aplastic anemia in identical twins. New England Journal of Medicine 281: 7–11, 1969

    Article  PubMed  CAS  Google Scholar 

  • Nieweg HO. Aplastic anemia (panmyelopathy). In Girdwood (Ed.) Blood disorders due to drugs and other agents, pp. 84–106, Excerpta Medica, Amsterdam, 1974

    Google Scholar 

  • Pelus LM, Broxmeyer HE, Kurland JI, Moore MAS. Regulation of macrophage and granulocyte proliferation. Journal of Experimental Medicine 150: 277–292, 1979

    Article  PubMed  CAS  Google Scholar 

  • Petz LD, Fudenberg HH. Immunologic mechanisms in drug-induced cytopenias. Progress in Hematology 9: 185–206, 1975

    PubMed  CAS  Google Scholar 

  • Pisciotta AV. Immune and toxic mechanisms in drug-induced agranulocytosis. Seminars in Hematology 10: 279–310, 1973

    PubMed  CAS  Google Scholar 

  • Ratzan R, Moore MAS, Yunis AA. Effect of chloramphenicol and thiamphenicol on the in vitro colony-forming cell. Blood 43: 363–369, 1974

    PubMed  CAS  Google Scholar 

  • Samsom JP, Hulstaert CE, Molenaar I, Nieweg HO. Fine structure of the bone marrow sinusoidal wall in idiopathic and drug-induced panmyelopathy. Acta Haematologica 48: 218–226, 1972

    Article  PubMed  CAS  Google Scholar 

  • Singer JW, Brown JE. In vitro marrow culture techniques in aplastic anaemia and related disorders. Clinics in Haematology 7: 487–499, 1978

    PubMed  CAS  Google Scholar 

  • Smith CS, Chinn S, Watts RWE. The sensitivity of human bone marrow granulocyte/monocyte precursor cells to phenylbutazone, oxyphenbutazone and gamma-hydroxyphenylbutazone in vitro, with observations on the bone marrow colony formation in phenylbutazone-induced granulocytopoenia. Biochemical Pharmacology 26: 847–852, 1977

    Article  PubMed  CAS  Google Scholar 

  • Stohlman F, Ebbe S, Morse B, Howard D, Donovan J. Regulation of erythropoiesis XX kinetics of red cell production. Annals of the New York Academy of Sciences 149: 156–172, 1968

    Article  PubMed  Google Scholar 

  • Strieker BH, Oei TT. Agranulocytosis caused by spironolactone. British Medical Journal 289: 731, 1984

    Article  Google Scholar 

  • Sutherland R, Vincent PC, Raik E, Burgess K. Quinine-induced agranulocytosis: toxic effect of quinine bisulphate on bone marrow cultures in vitro. British Medical Journal 1: 605–607, 1977

    Article  PubMed  CAS  Google Scholar 

  • Taetle R, Lane TA, Mendelsohn J. Drug-induced agranulocytosis: in vitro evidence for immune suppression of granulopoiesis and a cross-reacting lymphocyte antibody. Blood 54: 501–512, 1979

    PubMed  CAS  Google Scholar 

  • Till JE, McCulloch EA, Siminovitch L. A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proceeding of the National Academy of Sciences 51: 29–36, 1964

    Article  CAS  Google Scholar 

  • Trainor KJ, Seshadri RS, Morley AA. Residual marrow injury following cytotoxic drugs. Leukemia Research 3: 205–210, 1979

    Article  PubMed  CAS  Google Scholar 

  • Trainor KJ, Morley AA, Seshadri RS. A proliferative defect of marrow cells in experimental chronic hypoplastic marrow failure (aplastic anaemia). Experimental Hematology 8: 674–682, 1980

    PubMed  CAS  Google Scholar 

  • Tso SC, Chan TK, Todd D. Aplastic anaemia: a study of prognosis and the effect of androgen therapy. Quarterly Journal of Medicine 46: 513–529, 1977

    PubMed  CAS  Google Scholar 

  • Vincent PC, De Gruchy GC. Complications and treatment of acquired aplastic anaemia. British Journal of Haematology 13: 977–999, 1967

    Article  Google Scholar 

  • Vincent PC. Granulocyte kinetics in health and disease. Clinics in Haematology 6: 695–717, 1977

    PubMed  CAS  Google Scholar 

  • Vincent PC. In vitro evidence of drug action in aplastic anemia. Blut 49: 3–12, 1984

    Article  PubMed  CAS  Google Scholar 

  • Weisberger AS, Wolfe S, Armentrout S. Inhibition of protein synthesis in mammalian cell-free systems of chloramphenicol. Journal of Experimental Medicine 120: 161–181, 1964

    Article  PubMed  CAS  Google Scholar 

  • Weitzman SA, Stossel TP, Desmond M. Drug-induced immunological neutropenia. Lancet 1: 1068–1072, 1978

    Article  PubMed  CAS  Google Scholar 

  • Williams N, Jackson H, Rabellino EM. Proliferation and differentiation of normal granulopoietic cells in continuous bone marrow cultures. Journal of Cellular Physiology 93: 435–440, 1977

    Article  PubMed  CAS  Google Scholar 

  • Williams DM, Lynch RE, Cartwright GE. Drug-induced aplastic anemia. Seminars in Hematology 10: 195–223, 1973

    PubMed  CAS  Google Scholar 

  • Williams WJ, Beutler E, Erslev AJ, Lichtman MA. Hematology, 3rd ed, McGraw-Hill, New York, 1983

    Google Scholar 

  • Yataganas X, Gahrton G, Thorell B. DNA, RNA and hemoglobin during erythroblast maturation. Experimental Cell Research 62: 254–261, 1970

    Article  PubMed  CAS  Google Scholar 

  • Young GAR. Drug-induced haematological disorders. Current Therapeutics 25 (No. 8): 61–69, 1984

    Google Scholar 

  • Young GAR, Croaker G, Joyce RM, Forrest P, Vincent PC. In preparation, 1984

  • Young GAR, Forrest P, Deveridge SF, Gates RB, Vincent PC. Mebhydrolin induced agranulocytosis. Australian and New Zealand Journal of Medicine 12: 173–176, 1982

    Article  PubMed  CAS  Google Scholar 

  • Young GAR, Vincent PC. Drug-induced agranulocytosis. Clinics in Haematology 9: 483–504, 1980

    PubMed  Google Scholar 

  • Yunis AA. Chloramphenicol-induced bone marrow suppression. Seminars in Hematology 10: 225–234, 1973

    PubMed  CAS  Google Scholar 

  • Yunis AA. Chloramphenicol toxicity. In Girdwood (Ed.) Blood disorders due to drugs and other agents, pp. 107–126, Excerpta Medica, 1974

    Google Scholar 

  • Yunis AA, Adamson JW. Differential in vitro sensitivity of marrow erythroid and granulocytic colony forming cells to chloramphenicol American Journal of Hematology 2: 355–363, 1977

    Article  PubMed  CAS  Google Scholar 

  • Yunis AA, Miller AM, Salem Z, Arimura GK. Chloramphenicol toxicity: pathogenetic mechanisms and the role of the p-No2 in aplastic anemia. Clinical Toxicology 17: 359–373, 1980

    Article  PubMed  CAS  Google Scholar 

  • Zelkowitz L, Arimura GK, Yunis AA. Chloramphenicol and protein synthesis in mammalian cells. Journal of Laboratory and Clinical Medicine 71: 596–609, 1968

    PubMed  CAS  Google Scholar 

  • Zipori D, Sasson T, Friedman S. Bone marrow resident colony-stimulating factor activity (CSA) produced by stromal cells: In Baum et al. (Eds) Experimental hematology today, pp. 19–26, S. Karger, Basel, 1982

    Google Scholar 

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Vincent, P.C. Drug-Induced Aplastic Anaemia and Agranulocytosis. Drugs 31, 52–63 (1986). https://doi.org/10.2165/00003495-198631010-00004

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