Skip to main content
SpringerLink
Log in

Drugs and Blood Cells

  • Chapter
  • First Online:
Hematologic Problems in the Critically Ill

  • 1308 Accesses

Abstract

Many therapeutic drugs have been associated with adverse drug reactions (ADRs) affecting circulating blood cells and blood forming tissues. The most common drug-induced hematologic disorders are blood cytopenias, including anemia, thrombocytopenia, neutropenia, and aplastic anemia. These reactions occur rarely in the general population, but they can be of great concern in the critically ill patient, in whom polytherapy is frequent and the pharmacokinetic of many drugs may be altered. From a pathophysiological point of view, drug-induced cytopenia results from nonimmune or immune mechanisms. Nonimmune mechanisms may be due to direct toxicity against one or more blood cell lines (e.g., myelosuppression by chemotherapeutic agents), while immune mechanisms involve mainly antibodies (and seldom the complement) that may react with blood cells leading to peripheral destruction. The onset of symptoms is generally not abrupt, as immune reactions need time to mount, and span from few days to months. Nevertheless, clinical complications such as intense bleeding or intracranial hemorrhage from drug-induced thrombocytopenia and sepsis from prolonged neutropenia could be life-threatening. In most cases, clinical diagnosis is supported by laboratory findings of reactive immunoglobulins, in particular for heparin-induced thrombocytopenia and drug-induced hemolytic anemia. Discontinuation of the suspected medication is mandatory in all cases, with subsequent recovery occurring frequently thereafter. Supportive therapy is only sometimes required.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Benichou C (1994) Adverse drug reactions: a practical guide to diagnosis and management. Wiley, New York

    Google Scholar 

  2. Hine LK, Gerstman BB, Wise RP, Tsong Y (1990) Mortality resulting from blood dyscrasias in the United States, 1984. Am J Med 88(2):151–153

    Article  PubMed  CAS  Google Scholar 

  3. Reis AM, Cassiani SH (2011) Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol 67(6):625–632. doi:10.1007/s00228-010-0987-y

    Article  PubMed  Google Scholar 

  4. Park S, In Y, Suh GY, Sohn K, Kim E (2013) Evaluation of adverse drug reactions in medical intensive care units. Eur J Clin Pharmacol 69(1):119–131. doi:10.1007/s00228-012-1318-2

    Article  PubMed  CAS  Google Scholar 

  5. Vandendries ER, Drews RE (2006) Drug-associated disease: hematologic dysfunction. Crit Care Clin 22(2):347–355, viii. doi:10.1016/j.ccc.2006.02.002

  6. Heimpel H (1996) When should the clinician suspect a drug-induced blood dyscrasia, and how should he proceed? Eur J Haematol Suppl 60:11–15

    PubMed  CAS  Google Scholar 

  7. van den Bemt PM, Meyboom RH, Egberts AC (2004) Drug-induced immune thrombocytopenia. Drug Saf 27(15):1243–1252

    Article  PubMed  Google Scholar 

  8. Priziola JL, Smythe MA, Dager WE (2010) Drug-induced thrombocytopenia in critically ill patients. Crit Care Med 38(6 Suppl):S145–S154. doi:10.1097/CCM.0b013e3181de0b88

    Article  PubMed  Google Scholar 

  9. Everds NE, Tarrant JM (2013) Unexpected hematologic effects of biotherapeutics in nonclinical species and in humans. Toxicol Pathol 41(2):280–302. doi:10.1177/0192623312467400

    Article  PubMed  CAS  Google Scholar 

  10. George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S, Vondracek T (1998) Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 129(11):886–890

    Article  PubMed  CAS  Google Scholar 

  11. Reese JA, Li X, Hauben M, Aster RH, Bougie DW, Curtis BR, George JN, Vesely SK (2010) Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 116(12):2127–2133. doi:10.1182/blood-2010-03-276691

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Garbe E, Andersohn F, Bronder E, Salama A, Klimpel A, Thomae M, Schrezenmeier H, Hildebrandt M, Spath-Schwalbe E, Gruneisen A, Meyer O, Kurtal H (2012) Drug-induced immune thrombocytopaenia: results from the Berlin Case-control Surveillance Study. Eur J Clin Pharmacol 68(5):821–832. doi:10.1007/s00228-011-1184-3

    Article  PubMed  CAS  Google Scholar 

  13. Arnold DM, Kukaswadia S, Nazi I, Esmail A, Dewar L, Smith JW, Warkentin TE, Kelton JG (2013) A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 11(1):169–176. doi:10.1111/jth.12052

    Article  PubMed  CAS  Google Scholar 

  14. Martel N, Lee J, Wells PS (2005) Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 106(8):2710–2715. doi:10.1182/blood-2005-04-1546

    Article  PubMed  CAS  Google Scholar 

  15. Acharya S, Bussel JB (2000) Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol 22(1):62–65

    Article  PubMed  CAS  Google Scholar 

  16. ten Berg MJ, Huisman A, Souverein PC, Schobben AF, Egberts AC, van Solinge WW, van den Bemt PM (2006) Drug-induced thrombocytopenia: a population study. Drug Saf 29(8):713–721

    Article  PubMed  Google Scholar 

  17. Wright RO, Lewander WJ, Woolf AD (1999) Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med 34(5):646–656

    Article  PubMed  CAS  Google Scholar 

  18. Von Drygalski A, Curtis BR, Bougie DW, McFarland JG, Ahl S, Limbu I, Baker KR, Aster RH (2007) Vancomycin-induced immune thrombocytopenia. N Engl J Med 356(9):904–910. doi:10.1056/NEJMoa065066

    Article  Google Scholar 

  19. Pea F, Viale P, Cojutti P, Del Pin B, Zamparini E, Furlanut M (2012) Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J Antimicrob Chemother 67(8):2034–2042. doi:10.1093/jac/dks153

    Article  PubMed  CAS  Google Scholar 

  20. Aster RH, Bougie DW (2007) Drug-induced immune thrombocytopenia. N Engl J Med 357(6):580–587. doi:10.1056/NEJMra066469

    Article  PubMed  Google Scholar 

  21. Aster RH (2010) Adverse drug reactions affecting blood cells. Handb Exp Pharmacol 196:57–76. doi:10.1007/978-3-642-00663-0_3

    Article  PubMed  CAS  Google Scholar 

  22. Aster RH, Curtis BR, McFarland JG, Bougie DW (2009) Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost 7(6):911–918. doi:10.1111/j.1538-7836.2009.03360.x

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Chong BH, Choi PY, Khachigian L, Perdomo J (2013) Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 27(3):521–540. doi:10.1016/j.hoc.2013.02.003

    Article  PubMed  Google Scholar 

  24. Visentin GP, Liu CY (2007) Drug-induced thrombocytopenia. Hematol Oncol Clin North Am 21(4):685–696, vi. doi:10.1016/j.hoc.2007.06.005

  25. Kenney B, Stack G (2009) Drug-induced thrombocytopenia. Arch Pathol Lab Med 133(2):309–314. doi:10.1043/1543-2165-133.2.309

    PubMed  Google Scholar 

  26. Reilly RF (2003) The pathophysiology of immune-mediated heparin-induced thrombocytopenia. Semin Dial 16(1):54–60

    Article  PubMed  Google Scholar 

  27. Warkentin TE, Kelton JG (2001) Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 344(17):1286–1292. doi:10.1056/nejm200104263441704

    Article  PubMed  CAS  Google Scholar 

  28. Kelton JG (2002) Heparin-induced thrombocytopenia: an overview. Blood Rev 16(1):77–80. doi:10.1054/blre.2001.0189

    Article  PubMed  CAS  Google Scholar 

  29. Warkentin TE (1999) Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost 82(2):439–447

    PubMed  CAS  Google Scholar 

  30. George JN, Aster RH (2009) Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology Am Soc Hematol Educ Program 153–158. doi:10.1182/asheducation-2009.1.153

  31. Bougie D, Aster R (2001) Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 97(12):3846–3850

    Article  PubMed  CAS  Google Scholar 

  32. Jang I-K, Hursting MJ (2005) When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation 111(20):2671–2683. doi:10.1161/circulationaha.104.518563

    Article  PubMed  Google Scholar 

  33. Arepally GM, Ortel TL (2006) Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 355(8):809–817. doi:10.1056/NEJMcp052967

    Article  PubMed  CAS  Google Scholar 

  34. Garratty G (2009) Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 73–79. doi:10.1182/asheducation-2009.1.73

  35. Weinblatt ME (1985) Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol Suppl 12(Suppl 12):35–39

    PubMed  Google Scholar 

  36. Hynicka LM, Heil EL (2013) Anemia management in patients with chronic viral hepatitis C. Ann Pharmacother 47(2):228–236. doi:10.1345/aph.1R513

    Article  PubMed  Google Scholar 

  37. Bernstein WB, Trotta RF, Rector JT, Tjaden JA, Barile AJ (2003) Mechanisms for linezolid-induced anemia and thrombocytopenia. Ann Pharmacother 37(4):517–520

    Article  PubMed  Google Scholar 

  38. Shander A, Javidroozi M, Ashton ME (2011) Drug-induced anemia and other red cell disorders: a guide in the age of polypharmacy. Curr Clin Pharmacol 6(4):295–303

    Article  PubMed  CAS  Google Scholar 

  39. Snapper I, Marks D, Schwartz L, Hollander L (1953) Hemolytic anemia secondary to mesantoin. Ann Intern Med 39(3):619–623

    Article  PubMed  CAS  Google Scholar 

  40. Garratty G, Arndt PA (2007) An update on drug-induced immune hemolytic anemia. Immunohematology 23(3):105–119

    PubMed  CAS  Google Scholar 

  41. Mintzer DM, Billet SN, Chmielewski L (2009) Drug-induced hematologic syndromes. Adv Hematol 2009:495863. doi:10.1155/2009/495863

    Article  PubMed  PubMed Central  Google Scholar 

  42. Weinberg RS, Chusid ED, Galperin Y, Thomson JC, Cheung T, Sacks HS (1998) Effect of antiviral drugs and hematopoietic growth factors on in vitro erythropoiesis. Mt Sinai J Med 65(1):5–13

    PubMed  CAS  Google Scholar 

  43. Tseng A, Conly J, Fletcher D, Keystone D, Salit I, Walmsley S (1998) Precipitous declines in hemoglobin levels associated with combination zidovudine and lamivudine therapy. Clin Infect Dis 27(4):908–909

    Article  PubMed  CAS  Google Scholar 

  44. Arndt PA, Garratty G (2005) The changing spectrum of drug-induced immune hemolytic anemia. Semin Hematol 42(3):137–144

    Article  PubMed  CAS  Google Scholar 

  45. Salama A (2009) Drug-induced immune hemolytic anemia. Expert Opin Drug Saf 8(1):73–79. doi:10.1517/14740330802577351

    Article  PubMed  CAS  Google Scholar 

  46. Pierce A, Nester T (2011) Pathology consultation on drug-induced hemolytic anemia. Am J Clin Pathol 136(1):7–12. doi:10.1309/ajcpbvljzh6w6rqm

    Article  PubMed  Google Scholar 

  47. Dhaliwal G, Cornett PA, Tierney LM Jr (2004) Hemolytic anemia. Am Fam Physician 69(11):2599–2606

    PubMed  Google Scholar 

  48. Jarvis SM, Thorn JA, Glue P (1998) Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. Br J Pharmacol 123(8):1587–1592. doi:10.1038/sj.bjp.0701775

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Ruscin JM, Page RL 2nd, Valuck RJ (2002) Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother 36(5):812–816

    Article  PubMed  Google Scholar 

  50. Filioussi K, Bonovas S, Katsaros T (2003) Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust Fam Physician 32(5):383–384

    PubMed  Google Scholar 

  51. Ash-Bernal R, Wise R, Wright SM (2004) Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore) 83(5):265–273

    Article  Google Scholar 

  52. Zantek ND, Koepsell SA, Tharp DR Jr, Cohn CS (2012) The direct antiglobulin test: a critical step in the evaluation of hemolysis. Am J Hematol 87(7):707–709. doi:10.1002/ajh.23218

    Article  PubMed  CAS  Google Scholar 

  53. Andersohn F, Konzen C, Garbe E (2007) Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 146(9):657–665

    Article  PubMed  Google Scholar 

  54. Strom BL, Carson JL, Schinnar R, Snyder ES, Shaw M (1992) Descriptive epidemiology of agranulocytosis. Arch Intern Med 152(7):1475–1480

    Article  PubMed  CAS  Google Scholar 

  55. Benichou C, Solal Celigny P (1991) Standardization of definitions and criteria for causality assessment of adverse drug reactions. Drug-induced blood cytopenias: report of an international consensus meeting. Nouv Rev Fr Hematol 33(3):257–262

    PubMed  CAS  Google Scholar 

  56. Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, Young NS, Leaverton P, Levy M, Shapiro S (1996) Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl 60:23–30

    PubMed  CAS  Google Scholar 

  57. Bhatt V, Saleem A (2004) Review: drug-induced neutropenia–pathophysiology, clinical features, and management. Ann Clin Lab Sci 34(2):131–137

    PubMed  Google Scholar 

  58. Fibbe WE, Claas FH, Van der Star-Dijkstra W, Schaafsma MR, Meyboom RH, Falkenburg JH (1986) Agranulocytosis induced by propylthiouracil: evidence of a drug dependent antibody reacting with granulocytes, monocytes and haematopoietic progenitor cells. Br J Haematol 64(2):363–373

    Article  PubMed  CAS  Google Scholar 

  59. Palmblad J, Papadaki HA, Eliopoulos G (2001) Acute and chronic neutropenias. What is new? J Intern Med 250(6):476–491

    Article  PubMed  CAS  Google Scholar 

  60. Williams DP, Pirmohamed M, Naisbitt DJ, Uetrecht JP, Park BK (2000) Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. Mol Pharmacol 58(1):207–216

    PubMed  CAS  Google Scholar 

  61. Tesfa D, Keisu M, Palmblad J (2009) Idiosyncratic drug-induced agranulocytosis: possible mechanisms and management. Am J Hematol 84(7):428–434. doi:10.1002/ajh.21433

    Article  PubMed  CAS  Google Scholar 

  62. Dettling M, Cascorbi I, Roots I, Mueller-Oerlinghausen B (2001) Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA subtyping in a non-jewish caucasian sample. Arch Gen Psychiatry 58(1):93–94

    Article  PubMed  CAS  Google Scholar 

  63. Andres E, Federici L, Weitten T, Vogel T, Alt M (2008) Recognition and management of drug-induced blood cytopenias: the example of drug-induced acute neutropenia and agranulocytosis. Expert Opin Drug Saf 7(4):481–489. doi:10.1517/14740338.7.4.481

    Article  PubMed  CAS  Google Scholar 

  64. Andres E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F (2006) Idiosyncratic drug-induced agranulocytosis: update of an old disorder. Eur J Intern Med 17(8):529–535. doi:10.1016/j.ejim.2006.07.012

    Article  PubMed  CAS  Google Scholar 

  65. Crawford J (2002) Clinical uses of pegylated pharmaceuticals in oncology. Cancer Treat Rev 28(Suppl A):7–11

    Article  PubMed  Google Scholar 

  66. Andres E, Maloisel F, Kurtz JE, Kaltenbach G, Alt M, Weber JC, Sibilia J, Schlienger JL, Blickle JF, Brogard JM, Dufour P (2002) Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature. Eur J Intern Med 13(5):324–328

    Article  PubMed  Google Scholar 

  67. Montane E, Ibanez L, Vidal X, Ballarin E, Puig R, Garcia N, Laporte JR, Catalan Group for Study of Agranulocytosis and Aplastic Anemia (2008) Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica 93(4):518–523. doi:10.3324/haematol.12020

    Article  PubMed  Google Scholar 

  68. Young NS, Kaufman DW (2008) The epidemiology of acquired aplastic anemia. Haematologica 93(4):489–492. doi:10.3324/haematol.1285510.3324/haematol.12855

    Article  PubMed  Google Scholar 

  69. Pellock JM, Faught E, Leppik IE, Shinnar S, Zupanc ML (2006) Felbamate: consensus of current clinical experience. Epilepsy Res 71(2–3):89–101. doi:10.1016/j.eplepsyres.2006.06.020

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Medical Sciences, Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia of Udine, University of Udine, Piazzale S. Maria della Misericordia, 15, Udine, 33100, Italy

    Federico Pea & Pier Giorgio Cojutti

Authors
  1. Federico Pea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pier Giorgio Cojutti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Federico Pea .

Editor information

Editors and Affiliations

  1. Anesthesia and Intensive Care, University of Trieste, University Hospital, Trieste, Italy

    Giorgio Berlot

  2. Haematology, University of Trieste, University Hospital, Trieste, Italy

    Gabriele Pozzato

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Italia

About this chapter

Cite this chapter

Pea, F., Cojutti, P.G. (2015). Drugs and Blood Cells. In: Berlot, G., Pozzato, G. (eds) Hematologic Problems in the Critically Ill. Springer, Milano. https://doi.org/10.1007/978-88-470-5301-4_8

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-5301-4_8

  • Published:

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-5300-7

  • Online ISBN: 978-88-470-5301-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation