Abstract
Thrombocytopenia can have several causes, including the use of certain drugs. The mechanism behind drug-induced thrombocytopenia is either a decrease in platelet production (bone marrow toxicity) or an increased destruction (immune-mediated thrombocytopenia). In addition, pseudothrombocytopenia, an in vitro effect, has to be distinguished from true drug-induced thrombocytopenia. This article reviews literature on drug-induced immune thrombocytopenia, with the exception of thrombo-haemorrhagic disorders such as thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia and thrombosis.
A literature search in PubMed combined with a check of the reference lists of all the retrieved articles resulted in 108 articles relevant to the subject. The drug classes that are most often associated with drug-induced immune thrombocytopenia are cinchona alkaloid derivatives (quinine, quinidine), sulfonamides, NSAIDs, anticonvulsants, disease modifying antirheumatic drugs and diuretics. Several other drugs are occasionally described in case reports of thrombocytopenia; an updated review of these case reports can be found on the internet. A small number of epidemiological studies, differing largely in the methodology used, describe incidences in the magnitude of 10 cases per 1 000 000 inhabitants per year. No clear risk factors could be identified from these studies. The underlying mechanism of drug-induced immune thrombocytopenia is not completely clarified, but at least three different types of antibodies appear to play a role (hapten-dependent antibodies, drug-induced, platelet-reactive auto-antibodies and drug-dependent antibodies). Targets for drug-dependent antibodies are glycoproteins on the cell membrane of the platelets, such as glycoprotein (GP) Ib/IX and GPIIb/IIIa.
Diagnosis of drug-induced immune thrombocytopenia may consist of identifying clinical symptoms (bruising, petechiae, bleeding), a careful evaluation of the causal relationship of the suspected causative drug, general laboratory investigation, such as total blood count and peripheral blood smear (to rule out pseudothrombocytopenia), and platelet serology tests. The sensitivity of these tests is dependent on factors such as the concentration of the drug in the test and the potential sensitisation of the patient by metabolites instead of the parent drug.
Drug-induced immune thrombocytopenia can be treated by withholding the causative drug and, in severe cases associated with bleeding, by platelet transfusion.
Although drug-induced thrombocytopenia is a relatively rare adverse drug reaction, its consequences may be severe. Therefore it is important to extend our knowledge on this subject. Future research should focus on the identification of potential risk factors, as well as the exact mechanism underlying drug-induced thrombocytopenia.
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References
Fung M, Thornton A, Mybeck K, et al. Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets - 1960 to 1999. Drug Inf J 2001; 35: 293–317
The International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anemia: a first report of their relation to drug use with special reference to analgesics. JAMA 1986; 256: 1749–57
Patnode NM, Gandhi PJ. Drug-induced thrombocytopenia in the coronary care unit. J Thromb Thrombolysis 2000; 10: 155–67
Majhail NS, Lichtin AE. What is the best way to determine if thrombocytopenia in a patient on multiple medications is drug-induced? Cleve Clin J Med 2002; 69: 259–62
George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for The American Society of Hematology. Blood 1996; 88: 3–40
Wazny LD, Ariano RE. Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient. Pharmacotherapy 2000; 20: 292–307
Kojouri K, Perdue JJ, Medina PJ, et al. Occult quinine-induced thrombocytopenia. J Okla State Med Assoc 2000; 93: 519–21
Sane DC, Damaraju LV, Topol EJ, et al. Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy. J Am Coll Cardiol 2000; 36: 75–83
Poskitt TR, Poskitt PKF. Spurious thrombocytopenia produced by the interaction of rheumatoid factor with antiplatelet antibody. Am J Hematol 1985; 18: 207–11
Cunningham VL, Brandt JT. Spurious thrombocytopenia due to EDTA-independent cold-reactive agglutinins. Am J Clin Pathol 1992; 97: 359–62
Warkentin TE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol 1998; 35Suppl. 5: 9–16
George JN, Raskob GE, Rizvi Shah S, et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 1998; 129: 886–90
Pedersen-Bjergaard U, Andersen M, Hansen PB. Thrombocytopenia induced by noncytotoxic drugs in Denmark 1968-91. J Intern Med 1996; 239: 509–15
Pedersen-Bjergaard U, Andersen M, Hansen PB. Drug-induced thrombocytopenia: clinical data on 309 cases and the effect of corticosteroid therapy. Eur J Clin Pharmacol 1997; 52: 183–9
Rizvi MA, Kojouri K, George JN. Drug-induced thrombocytopenia: an updated systematic review [letter]. Ann Intern Med 2001; 134: 346
Pedersen-Bjergaard U, Andersen M, Hansen PB. Drug-specific characteristics of thrombocytopenia caused by non-cytotoxic drugs. Eur J Clin Pharmacol 1998; 54: 701–6
Böttiger LE, Westerholm B. Thrombocytopenia. II: drug-induced thrombocytopenia. Acta Med Scand 1972; 191: 541–8
Böttiger LE, Böttiger B. Incidence and cause of aplastic anemia, hemolytic anemia, agranulocytosis and thrombocytopenia. Acta Med Scand 1981; 210: 475–9
Böttiger LE, Westerholm B. Thrombocytopenia. I: incidence and aetiology. Acta Med Scand 1972; 191: 535–40
Danielson DA, Douglas SW, Herzog P, et al. Drug-induced blood disorders. JAMA 1984; 252: 3257–60
Kaufman DW, Kelly JP, Johannes CB, et al. Acute thrombocytopenic purpura in relation to the use of drugs. Blood 1993; 82: 2714–8
Hibbard AB, Medina PJ, Vesely SK. Reports of drug-induced thrombocytopenia [letter]. Ann Intern Med 2003; 138: 239
Jaffe IA. Adverse effects profile of sulfhydryl compounds in man. Am J Med 1986; 80: 471–6
Steen VD, Blair S, Medsger TA. The toxicity of d-penicillamine in systemic sclerosis. Ann Intern Med 1986; 104: 699–705
Bensen WG, Moore N, Tugwell P, et al. HLA antigens and toxic reactions to sodium aurothiomalate in patients with rheumatoid arthritis. J Rheumatol 1984; 11: 358–61
Magnus JH, Gran JT, Mikkelsen K, et al. Toxicity to d-penicillamine in rheumatoid arthritis. Scand J Rheumatol 1987; 16: 441–4
Kean WF, Lock CJL, Howard-Lock HE, et al. Prior gold therapy does not influence the adverse effects of d-penicillamine in rheumatoid arthritis. Arthritis Rheum 1982; 25: 917–22
Christiansen K. Fusidic acid adverse drug reactions. Int J Antimicrob Agents 1999; 12: S3–9
Kean WF, Anastassiades TP. Long term chrysotherapy. Incidence of toxicity and efficacy during sequential time periods. Arthritis Rheum 1979; 22: 495–501
Miescher PA. Blood dyscrasias secondary to non-steroidal anti-inflammatory drugs. Med Toxicol 1986; 1Suppl. 1: 57–70
Hong JC, Kahan BD. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 2000; 69: 2085–90
Farr M, Tunn E, Crockson AP, et al. The long term effects of sulphasalazine in the treatment of rheumatoid arthritis and a comparative study with penicillamine. Clin Rheumatol 1984; 3: 473–82
Dahlqvist SR, Strom H, Bjelle A, et al. HLA antigens and adverse drug reactions to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis. Clin Rheumatol 1985; 4: 55–61
Frisch JM. Clinical experience with adverse reactions to trimethoprim-sulfamethoxazole. J Infect Dis 1973; 128: S607–11
Schell DA, Ganti AK, Levitt R, et al. Thrombocytopenia associated with c7E3 Fab (abciximab). Ann Hematol 2002; 81: 76–9
Ferraccioli GF, Nervetti A, Mercadanti M, et al. Serum IgA levels and ANA behaviour in rheumatoid patients with and without toxicity to remission-inducing drugs. Clin Exp Rheumatol 1986; 4: 217–20
Lockie LM, Smith DM. Forty-seven years experience with gold therapy in 1,019 rheumatoid arthritis patients. Semin Arthritis Rheum 1985; 14: 238–46
Gilman RH, Terminel M, Levine MM, et al. Comparison of trimethoprim-sulfamethoxazole and amoxicillin in therapy of chloramphenicol-resistant and chloramphenicol-sensitive typhoid fever. J Infect Dis 1975; 132: 630–6
Isbister JP. Penicillin allergy: a review of the immunological and clinical aspects. Med J Aust 1971; 25: 1067–74
Bocanegra TS, Dicenta C, Carpignano M, et al. Diflunical (’Dolobid’) once-a-day in the treatment of rheumatoid arthritis. Curr Med Res Opin 1985; 9: 568–77
Llevadot J, Coulter SA, Giugliano RP. A practical approach to the diagnosis and management of thrombocytopenia associated with glycoprotein IIb/IIIa receptor inhibitors. J Thromb Thrombolysis 2000; 9: 175–80
Alanis A, Weinstein AJ. Adverse reactions associated with the use of oral penicillins and cephalosporins. Med Clin North Am 1983; 67: 113–29
Jubelirer SJ, Koenig BA, Bates MC. Acute profound thrombocytopenia following C7E3 Fab (abciximab) therapy: case reports, review of the literature and implications for therapy. Am J Hematol 1999; 61: 205–8
Brinker AD, Beitz J. Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to regulatory action. Am J Hematol 2002; 70: 313–7
Wade EE, Rebuck JA, Healey MA, et al. H2-antagonist-induced thrombocytopenia: is this a real phenomenon? Intensive Care Med 2002; 28: 459–65
Giugliano RP. Drug-induced thrombocytopenia: is it a serious concern for glycoprotein IIb/IIIa receptor inhibitors? J Thromb Thrombolysis 1998; 5: 191–202
Berkowitz SD, Harrington RA, Rund MM, et al. Acute profound thrombocytopenia after c7E3 Fab (abciximab) therapy. Circulation 1997; 95: 809–13
Berkowitz SD, Sane DC, Sigmon KN, et al. Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. J Am Coll Cardiol 1998; 32: 311–9
Conley EL, Coley KC, Pollock BG, et al. Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital. Pharmacotherapy 2001; 21: 1325–30
Ko CH, Kong CK, Tse PWT. Valproic acid and thrombocytopenia: cross-sectional study. Hong Kong Med J 2001; 7: 15–21
Trannel TJ, Ahmed I, Goebert D. Occurrence of thrombocytopenia in psychiatric patients taking valproate. Am J Psychiatry 2001; 158: 128–30
May RB, Sunder TR. Hematologic manifestations of long-term valproate therapy. Epilepsia 1993; 34: 1098–101
Blackburn SCF, Oliart AD, Rodriguez LAG, et al. Antiepileptics and blood dyscrasias: a cohort study. Pharmacotherapy 1998; 18: 1277–83
Verrotti A, Greco R, Matera V, et al. Platelet count and function in children receiving sodium valproate. Pediatr Neurol 1999; 21: 611–4
Allarakhia IN, Garofalo EA, Komarynski MA, et al. Valproic acid and thrombocytopenia in children: a case-controlled retrospective study. Pediatr Neurol 1996; 14: 303–7
Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol 2000; 22: 62–5
Delgado MR, Riela AR, Mills J, et al. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol 1994; 9: 311–4
Lerner W, Caruso R, Faig D, et al. Drug-dependent and nondrug-dependent antiplatelet antibody in drug-induced immunologic thrombocytopenic purpura. Blood 1985; 66: 306–11
Christie DJ, Weber RW, Mullen PC, et al. Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets. J Lab Clin Med 1984; 104: 730–40
Visentin GP, Newman PJ, Aster RH. Characteristics of quinineand quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa. Blood 1991; 77: 2668–76
Billheimer JT, Dicker IB, Wynn R, et al. Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated. Blood 2002; 99: 3540–6
Kroll H, Sun QH, Santoso S. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a target glycoprotein in drug-induced thrombocytopenia. Blood 2000; 96: 1409–14
Burgess JK, Lopez JA, Gaudry LE, et al. Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX-specific quinine-dependent antibodies. Blood 2000; 95: 1988–92
Gentilini G, Curtis BR, Aster RH. An antibody from a patient with ranitidine-induced thrombocytopenia recognizes a site on glycoprotein IX that is a favored target for drug-induced antibodies. Blood 1998; 92: 2359–65
Christie DJ, Sauro SC, Fairbanks KD, et al. Detection of clonal platelet antibodies in immunologically-mediated thrombocytopenias: association with circulating clonal/oligoclonal B cells. Br J Haematol 1993; 85: 277–84
Connellan JM, Deacon S, Thurlow PJ. Changes in platelet function and reactivity induced by quinine in relation to quinine (drug) induced immune thrombocytopenia. Thromb Res 1991; 61: 501–14
Christie DJ, Mullen PC, Aster RH. Fab-mediated binding of drug-dependent antibodies to platelets in quinidine- and quinine-induced thrombocytopenia. J Clin Invest 1985; 75: 310–4
Conti L, Fidani P, Chistolini A, et al. Detection of drug-dependent IgG antibodies with antiplatelet activity by the antiglobulin consumption assay. Haemostasis 1984; 14: 480–6
Burgess JK, Lopez JA, Berndt MC, et al. Quinine-dependent antibodies bind a restricted set of epitopes on the glycoprotein Ib-IX complex: characterization of the epitopes. Blood 1998; 92: 2366–73
Claas FHJ. Immune mechanisms leading to drug-induced blood dyscrasias. Eur J Haematol 1996; 57Suppl.: 64–8
McFarland JG. Laboratory investigation of drug-induced immune thrombocytopenias. Transfus Med Rev 1993; 7: 275–87
Karpatkin M, Siskind GW, Karpatkin S. The platelet factor 3 immunoinjury technique re-evaluated: development of a rapid test for antiplatelet antibody. Detection in various clinical disorders, including immunologic drug-induced and neonatal thrombocytopenias. J Lab Clin Med 1977; 89: 400–8
Aster RH. Can drugs cause autoimmune thrombocytopenic purpura? Semin Hematol 2000; 37: 229–38
Aster RH. Drug-induced immune thrombocytopenia: an overview of pathogenesis. Semin Hematol 1999; 36: 2–6
McCrae KR, Bussel JB, Mannucci PM, et al. Platelets: an update on diagnosis and management of thrombocytopenic disorders. Hematology 2001; 6: 282–305
Greinacher A, Eichler P, Lubenow N, et al. Drug-induced and drug-dependent immune thrombocytopenias. Rev Clin Exp Hematol 2001; 5: 166–200
Parker CW. Allergic reactions in man. Pharmacol Rev 1982; 34: 85–104
Rizvi MA, Rizvi Shah S, Raskob GE, et al. Drug-induced thrombocytopenia. Curr Opin Hematol 1999; 6: 349–53
Burgess JK. Molecular mechanisms of drug-induced thrombocytopenia. Curr Opin Hematol 2001; 8: 294–8
Christie DJ. Specificity of drug-induced immune cytopenias. Transfus Med Rev 1993; 7: 230–41
Kreithen H. Allergy in adverse drug reactions. Semin Drug Treat 1973; 2: 431–44
Pochedly C, Ente G. Adverse hematologic effects of drugs. Pediatr Clin North Am 1972; 19: 1095–111
Parker CW. Drug allergy. N Engl J Med 1975; 292: 511–4
Drug-induced thrombotic thrombocytopenic purpura. Prescrire Int 2001; 10: 50–1
Cawley MJ, Wittbrodt ET, Boyce EG. Potential risk factors associated with thrombocytopenia in a surgical intensive care unit. Pharmacotherapy 1999; 19: 108–13
Stephan F, Hollande J, Richard O, et al. Thrombocytopenia in a surgical ICU. Chest 1999; 115: 1363–70
Baughman RP, Lower EE, Flessa HC, et al. Thrombocytopenia in the intensive care unit. Chest 1993; 104: 1243–7
Wong PC, Yew WW, Wong CF, et al. Ethambutol-induced pulmonary infiltrates with eosinophilia and skin involvement. Eur Respir J 1995; 8: 866–8
Yamreudeewong W, Fosnocht BJ, Weixelman JM. Severe thrombocytopenia possibly associated with TMP/SMX therapy. Ann Pharmacother 2002; 36: 78–82
Bougie D, Aster R. Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 2001; 97: 3846–50
Gales BJ, Sulak LB. Severe thrombocytopenia associated with alatrofloxacin. Ann Pharmacother 2000; 34: 330–4
Atali M, Israeli E, Abend Y, et al. Trimethoprim/sulfamethoxazole-induced rash, fever, abnormal liver function tests, leukopenia, and thrombocytopenia. Ann Pharmacother 1993; 27: 1139–40
Burnakis TG. Inaccurate assessment of drug-induced thrombocytopenia: reason for concern. Ann Pharmacother 1994; 28: 726–9
Gottschall JL, Neahring B, McFarland JG, et al. Quinine-induced immune thrombocytopenia with hemolytic uremic syndrome: clinical and serological findings in nine patients and review of literature. Am J Hematol 1994; 47: 283–9
Demirkan K, Fleckenstein JF, Self TH. Thrombocytopenia associated with octreotide. Am J Med Sci 2000; 320: 296–7
Dourakis SP, Deutsch M, Hadziyannis SJ. Immune thrombocytopenia and alfa-interferon therapy. J Hepatol 1996; 25: 972–5
Holtzer CD, Reisner-Keller LA. Phenytoin-induced thrombocytopenia. Ann Pharmacother 1997; 31: 435–7
Hunt PJ, Gibbons SS. Naproxen induced thrombocytopenia: a case report. N Z Med J 1995; 108: 483–4
Nagae S, Hori Y. Immune thrombocytopenia due to tranilast (Rizaben): detection of drug-dependent platelet-associated IgG. J Dermatol 1998; 25: 706–9
Ponte CD. Carbamazepine-induced thrombocytopenia, rash, and hepatic dysfunction. Drug Intell Clin Pharm 1983; 17: 642–4
Tohen M, Castillo J, Cole JO, et al. Thrombocytopenia associated with carbamazepine: a case series. J Clin Psychiatry 1991; 52: 496–8
McKenna KE, McMillan JC. Exacerbation of psoriasis, liver dysfunction and thrombocytopenia associated with mebhydrolin. Clin Exp Dermatol 1993; 18: 131–2
Fraiture de WH, Claas FHJ, Meyboom RHB. Bijwerkingen van ticlopidine; klinische waarneming en immunologisch onderzoek. Ned Tijdschr Geneesk 1982; 126: 1051–4
Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura. Br J Clin Pharmacol 2002; 55: 107–11
Hull RL, Brandon D. Thrombocytopenia possibly caused by structurally related third-generation cephalosporins. DICP: the annals of pharmacotherapy 1991; 25: 135–6
Buzdar AU, Wogan CF. Tamoxifen-induced thrombocytopenia. Am J Clin Oncol 1999; 22: 529–32
Giner V, Rueda D, Salvador A, et al. Thrombocytopenia associated with levodopa treatment. Arch Intern Med 2003; 163: 735–6
Kereiakes DJ, Essell JH, Abbottsmith CW, et al. Abciximab-associated profound thrombocytopenia: therapy with immunoglobulin and platelet transfusion. Am J Cardiol 1996; 78: 1161–3
Claas FHJ, Meer van der JW, Langerak J. Immunological effect of co-trimoxazole on platelets. BMJ 1979; 2: 898–9
Stricker BHC, Barendregt JNM, Claas FHJ. Thrombocytopenia and leucopenia with mianserin-dependent antibodies. Br J Clin Pharmacol 1985; 19: 102–4
Aljitawi OS, Krishnan K, Curtis BR, et al. Serologically documented loracarbef (Lorabid)-induced immune thrombocytopenia. Am J Hematol 2003; 73: 41–3
Drug-induced thrombocytopenia [online]. Available from URL: http://moon.ouhsc.edu/jgeorge/DITP.html [Accessed 2003 Apr 8]
Bénichou C, editor. Adverse drug reactions: a practical guide to diagnosis and management. West Sussex: John Wiley & Sons Ltd, 1994
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No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.
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van den Bemt, P.M.L.A., Meyboom, R.H.B. & Egberts, A.C.G. Drug-Induced Immune Thrombocytopenia. Drug-Safety 27, 1243–1252 (2004). https://doi.org/10.2165/00002018-200427150-00007
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DOI: https://doi.org/10.2165/00002018-200427150-00007