- James N George, MD
James N George, MD
- Professor of Medicine
- University of Oklahoma Health Sciences Center
The clinician is frequently faced with the problem of a patient presenting with a low platelet count (thrombocytopenia) of uncertain cause. One important and reversible cause of thrombocytopenia is drugs. Drug-induced thrombocytopenia is frequently associated with drug-induced antibodies that cause platelet destruction or clearance by the reticuloendothelial system. This form of drug-induced thrombocytopenia is also called drug-induced immune thrombocytopenia (DITP). Immune-mediated thrombocytopenia may also be caused by other substances, such as herbal remedies, foods, and beverages, in addition to approved drugs. All of these causes are described by the term DITP. Less common mechanisms of drug-induced thrombocytopenia include bone marrow suppression by drugs other than known cytotoxic (eg, chemotherapy) agents (often dose-dependent), and an immune thrombocytopenia (ITP)-like syndrome in which autoimmune platelet destruction continues in the absence of the implicated agent. In most cases, thrombocytopenia is the only hematologic manifestation of drug toxicity. However, there are exceptions to this general rule:
●Heparin-induced thrombocytopenia (HIT) is associated with a hypercoagulable state and thrombosis rather than bleeding. HIT is discussed separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
●Some drug-induced disorders, such as aplastic anemia and thrombotic microangiopathy (DITMA), result in thrombocytopenia along with other cytopenias and organ involvement. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis", section on 'Drugs' and "Drug-induced thrombotic microangiopathy".)
The pathogenesis, diagnosis, and clinical management of patients with suspected drug-induced thrombocytopenia will be reviewed here. The general diagnostic approach to the patient with thrombocytopenia is presented separately. (See "Approach to the adult with unexplained thrombocytopenia".)
Accelerated platelet destruction — The usual mechanism of thrombocytopenia caused by drugs is accelerated platelet destruction caused by drug-dependent, platelet reactive antibodies. This is referred to as drug-induced immune thrombocytopenia (DITP). Following the observation that drug-dependent antibodies bind to platelets via their Fab regions , subsequent studies have documented the various different mechanisms of drug-dependent antibody formation [2,3].
- 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.
- Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost 2009; 7:911.
- Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007; 357:580.
- 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.
- Bougie DW, Wilker PR, Aster RH. Patients with quinine-induced immune thrombocytopenia have both "drug-dependent" and "drug-specific" antibodies. Blood 2006; 108:922.
- Aster RH. Drug-induced immune thrombocytopenia: an overview of pathogenesis. Semin Hematol 1999; 36:2.
- Greinacher A, Fuerll B, Zinke H, et al. Megakaryocyte impairment by eptifibatide-induced antibodies causes prolonged thrombocytopenia. Blood 2009; 114:1250.
- Perdomo J, Yan F, Ahmadi Z, et al. Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro. Blood 2011; 117:5975.
- 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.
- Burgess JK, Lopez JA, Gaudry LE, Chong BH. Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX-specific quinine-dependent antibodies. Blood 2000; 95:1988.
- Pereira J, Hidalgo P, Ocqueteau M, et al. Glycoprotein Ib/IX complex is the target in rifampicin-induced immune thrombocytopenia. Br J Haematol 2000; 110:907.
- Newman PJ. Switched at birth: a new family for PECAM-1. J Clin Invest 1999; 103:5.
- 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.
- Warkentin TE. Drug-induced immune-mediated thrombocytopenia--from purpura to thrombosis. N Engl J Med 2007; 356:891.
- Curtis BR, McFarland JG, Wu GG, et al. Antibodies in sulfonamide-induced immune thrombocytopenia recognize calcium-dependent epitopes on the glycoprotein IIb/IIIa complex. Blood 1994; 84:176.
- 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.
- Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010; 116:2127.
- Bougie DW, Nayak D, Boylan B, et al. Drug-dependent clearance of human platelets in the NOD/scid mouse by antibodies from patients with drug-induced immune thrombocytopenia. Blood 2010; 116:3033.
- Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr 2010; 156:623.
- Cuker A, Coles AJ, Sullivan H, et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 2011; 118:6299.
- Coblyn JS, Weinblatt M, Holdsworth D, Glass D. Gold-induced thrombocytopenia. A clinical and immunogenetic study of twenty-three patients. Ann Intern Med 1981; 95:178.
- Adachi JD, Bensen WG, Kassam Y, et al. Gold induced thrombocytopenia: 12 cases and a review of the literature. Semin Arthritis Rheum 1987; 16:287.
- Garner SF, Campbell K, Metcalfe P, et al. Glycoprotein V: the predominant target antigen in gold-induced autoimmune thrombocytopenia. Blood 2002; 100:344.
- von dem Borne AE, Pegels JG, van der Stadt RJ, et al. Thrombocytopenia associated with gold therapy: a drug-induced autoimmune disease? Br J Haematol 1986; 63:509.
- Rousan TA, Aldoss IT, Cowley BD Jr, et al. Recurrent acute thrombocytopenia in the hospitalized patient: sepsis, DIC, HIT, or antibiotic-induced thrombocytopenia. Am J Hematol 2010; 85:71.
- 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.
- George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 1998; 129:886.
- Pedersen-Bjergaard U, Andersen M, Hansen PB. Drug-specific characteristics of thrombocytopenia caused by non-cytotoxic drugs. Eur J Clin Pharmacol 1998; 54:701.
- Kojouri K, Perdue JJ, Medina PJ, George JN. Occult quinine-induced thrombocytopenia. J Okla State Med Assoc 2000; 93:519.
- Neylon AJ, Saunders PW, Howard MR, et al. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol 2003; 122:966.
- Achterbergh R, Vermeer HJ, Curtis BR, et al. Thrombocytopenia in a nutshell. Lancet 2012; 379:776.
- Royer DJ, George JN, Terrell DR. Thrombocytopenia as an adverse effect of complementary and alternative medicines, herbal remedies, nutritional supplements, foods, and beverages. Eur J Haematol 2010; 84:421.
- Von Drygalski A, Curtis BR, Bougie DW, et al. Vancomycin-induced immune thrombocytopenia. N Engl J Med 2007; 356:904.
- Kaufman DW, Kelly JP, Johannes CB, et al. Acute thrombocytopenic purpura in relation to the use of drugs. Blood 1993; 82:2714.
- Pedersen-Bjergaard U, Andersen M, Hansen PB. Thrombocytopenia induced by noncytotoxic drugs in Denmark 1968-91. J Intern Med 1996; 239:509.
- ten Berg MJ, Huisman A, Souverein PC, et al. Drug-induced thrombocytopenia: a population study. Drug Saf 2006; 29:713.
- Patel N, VanDeWall H, Tristani L, et al. A comparative evaluation of adverse platelet outcomes among Veterans' Affairs patients receiving linezolid or vancomycin. J Antimicrob Chemother 2012; 67:727.
- Search on "Drug-induced thrombocytopenia". www.ouhsc.edu/platelets (Accessed on March 14, 2011).
- Nguyen L, Reese JA, George JN. Drug-induced thrombocytopenia. An updated systematic review, 2010. Drug Saf 2011.
- Höchtl T, Pachinger L, Unger G, et al. Antiplatelet drug induced isolated profound thrombocytopenia in interventional cardiology: a review based on individual case reports. J Thromb Thrombolysis 2007; 24:59.
- Bougie D, Aster R. Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 2001; 97:3846.
- Bougie DW, Benito AI, Sanchez-Abarca LI, et al. Acute thrombocytopenia caused by sensitivity to the glucuronide conjugate of acetaminophen. Blood 2007; 109:3608.
- Scognamiglio F, Corso C, Madeo D, et al. Flow cytometry in the diagnosis of drug-induced thrombocytopenia: two illustrative cases. Am J Hematol 2008; 83:326.
- Leach MF, Cooper LK, AuBuchon JP. Detection of drug-dependent, platelet-reactive antibodies by solid-phase red cell adherence assays. Br J Haematol 1997; 97:755.
- Nieminen U, Kekomäki R. Quinidine-induced thrombocytopenic purpura: clinical presentation in relation to drug-dependent and drug-independent platelet antibodies. Br J Haematol 1992; 80:77.
- Azuno Y, Yaga K, Sasayama T, Kimoto K. Thrombocytopenia induced by Jui, a traditional Chinese herbal medicine. Lancet 1999; 354:304.
- Ray JB, Brereton WF, Nullet FR. Intravenous immune globulin for the treatment of presumed quinidine-induced thrombocytopenia. DICP 1990; 24:693.
- Accelerated platelet destruction
- Decreased platelet production
- Antibody specificity
- Reactivity with drug metabolites
- Special mechanisms
- - Heparin
- - Glycoprotein IIb/IIIa inhibitors
- - Prolonged thrombocytopenia
- CLINICAL PRESENTATION
- INITIAL APPROACH
- Confirm thrombocytopenia
- Establish the temporal relationship
- - History of drug ingestion
- - Commonly implicated drugs
- Laboratory testing
- DIFFERENTIAL DIAGNOSIS
- Immune thrombocytopenia (ITP)
- Heparin-induced thrombocytopenia
- Sepsis and DIC
- Other thrombocytopenic disorders
- SUMMARY AND RECOMMENDATIONS