Professional Documents
Culture Documents
review article
current concepts
D
From the Department of Medicine, Medi- rug-induced thrombocytopenia can be caused by dozens, per-
cal College of Wisconsin (R.H.A.), and the haps hundreds, of medications. Because thrombocytopenia can have many
Blood Research Institute, BloodCenter of
Wisconsin (R.H.A., D.W.B.) — both in other causes, the diagnosis of drug-induced thrombocytopenia can easily
Milwaukee. Address reprint requests to be overlooked. On occasion, outpatients with drug-induced thrombocytopenia are
Dr. Aster at the Blood Research Institute, treated for autoimmune thrombocytopenia and can have two or three recurrences
BloodCenter of Wisconsin, 8727 Water-
town Plank Rd., Milwaukee, WI 53226-3548, before the drug causing the disorder is identified.1 In acutely ill, hospitalized pa-
or at richard.aster@bcw.edu. tients, drug-induced thrombocytopenia can be overlooked because thrombocytope-
nia is attributed to sepsis, the effect of coronary-artery bypass surgery, or some other
N Engl J Med 2007;357:580-7.
Copyright © 2007 Massachusetts Medical Society.
underlying condition. Although drug-induced thrombocytopenia is uncommon, it can
have devastating, even fatal consequences that can usually be prevented simply by
discontinuing the causative drug. It is therefore important that clinicians have a
general understanding of this condition and the drugs that can cause it.
In this review, we focus on conditions in which exposure to a drug leads to the
destruction of circulating platelets, often accompanied by bleeding symptoms. We
do not consider thrombocytopenia resulting from dose-dependent hematosuppres-
sion, which often occurs after treatment with chemotherapeutic and immunosup-
pressive agents such as cisplatin and cyclophosphamide.2 Although heparin-induced
thrombocytopenia is the most common drug-related cause of a drop in the platelet
count, we do not discuss this condition because of its complexity and because
thrombosis, rather than thrombocytopenia, is the major threat to an affected pa-
tient. Because heparin is often given together with certain drugs that are likely to
cause drug-induced thrombocytopenia (platelet inhibitors and vancomycin), it is
important to distinguish between heparin-induced thrombocytopenia and drug-
induced thrombocytopenia. Heparin-induced thrombocytopenia was recently re-
viewed in the Journal.3
Drug-induced platelet destruction is usually caused by drug-induced antibodies,
but this can be difficult to prove. In this review, we include many conditions for
which an immune cause has not yet been fully documented. Although platelets are
the preferred targets of drug-induced antibodies, drugs can also cause immune
hemolytic anemia4 and neutropenia5 through similar mechanisms.
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
current concepts
Platelets (×10−5/mm3)
2.0
who may have preexisting, perhaps naturally oc- Platelet
transfusion
curring, antibodies.7 Systemic symptoms such as
1.5
lightheadedness, chills, fever, nausea, and vom-
Petechiae and
iting often precede bleeding symptoms. Severely 1.0 oral and urinary
affected patients have florid purpura and bleed- bleeding
ing from the nose, gums, and gastrointestinal 0.5
or urinary tract (“wet purpura”). In such cases,
thrombocytopenia is invariably severe (<20,000 0.0
platelets per cubic millimeter). 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
If the causative medication is stopped, symp- Days
toms usually resolve within 1 or 2 days, and the
Figure 1. Course of Immune Thrombocytopenia in a Patient Treated
platelet count returns to normal in less than a
with Sulfamethoxazole.
week. For reasons that are poorly understood,
Trimethoprim–sulfamethoxazole was prescribed for treatment of a urinary
patients with drug-induced thrombocytopenia oc tract infection in a 29-year-old woman. On day 7 of treatment, petechiae
AUTHOR: Aster RETAKE 1st
casionally present with disseminated intravascu- and ecchymoses,ICM
buccal hemorrhage,
FIGURE: 1 of 2
and gross urinary bleeding developed,
2nd
REG F
lar coagulation8 or renal failure and other find- and the antibiotic treatment was stopped. Her platelet count was 3rd 4000 per
CASE
ings indicative of the hemolytic–uremic syndrome cubic millimeter. A platelet transfusion given on day 9 Revisedhad little effect on
Line 4-C
EMail
the platelet count. Sustained
ARTIST: recovery
ts occurred during theSIZE next few days.
or thrombotic thrombocytopenic purpura.9 Enon
H/T H/T 22p3
A strong sulfamethoxazole-dependent, platelet-reactive antibody
Combo was detect-
ed in a blood sample obtained on day 9 and was
AUTHOR, PLEASE NOTE: still present after 3 months
Incidence and after 5 years. Figure
No trimethoprim-dependent antibodies
has been redrawn and type has were detected.
been reset.
Please check carefully.
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
* For a more extensive list, see Aster,2 Warkentin,12 and George et al.13 and the University of Oklahoma Web site (http://
moon.ouhsc.edu/jgeorge/DITP.html).
Table 2. Criteria and Level of Evidence for Establishing a Causative Relationship in Drug-Induced Thrombocytopenic
Purpura.*
penia after injection of iodinated contrast medi- severe, usually self-limited thrombocytopenia has
um for radiographic studies.12,13 Whether immune been described in patients treated with recently
mechanisms are involved is unknown. developed monoclonal antibodies such as inflix-
Severe thrombocytopenia and other signs and imab (anti–tumor necrosis factor-α antibody),
symptoms of thrombotic thrombocytopenic pur- efalizumab (anti-CD11a antibody), and rituximab
pura develop in approximately 1 of every 2500 (anti-CD20 antibody).2 No causative mechanism
patients treated with the platelet inhibitor ticlopi- has yet been identified.
dine and a much smaller fraction of those given Certain drugs, such as the antiepileptic agent
the closely related drug clopidogrel, usually after valproate,20 the cardiac agent amrinone,21 and the
1 to 2 weeks of treatment.19 The responsible antibiotic linezolid,22 induce low-grade thrombo-
mechanisms have not yet been defined. Acute, cytopenia in up to 30% of patients receiving long-
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
current concepts
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
platelets and cause their destruction.31 However, these antibodies can occur naturally, creating the
these hypothetical drug–antibody complexes were possibility that thrombocytopenia will arise with-
never demonstrated experimentally, and it was in a few hours after the patient’s first exposure to
later found that drug-dependent antibodies, like the drug.7
other antibodies, react with platelets through
their Fab domains rather than through their Fc Thrombocytopenia Induced by Abciximab
domains, as would be expected of immune com- Abciximab is a widely used chimeric (human–
plexes.32,33 Other possibilities considered were mouse) Fab fragment that is specific for β3 inte-
that the drug reacts with the target protein to grin (glycoprotein IIIa). Like the fibans, it blocks
produce a compound epitope (part drug, part pro platelet–fibrinogen interaction. Abciximab itself
tein) for which the antibody is specific34,35 and does not cause thrombocytopenia because it lacks
that the drug induces a conformational change the Fc domain required for recognition of anti-
in the protein, creating a new target epitope else- body-coated platelets by phagocytes. However, in
where in the molecule.2,36 about 1% of patients given abciximab for the
A recently proposed model aimed at reconcil- first time, and in more than 10% of those treated
ing several of these hypotheses37 suggests that a second time, acute thrombocytopenia develops
drug-dependent antibodies are derived from a within a few hours of starting an infusion.39 In
pool of naturally occurring antibodies with weak some patients the onset of thrombocytopenia is
affinity for self antigens,38 residing in this case delayed until 5 to 8 days after the initial 24- to
on certain platelet membrane glycoproteins. Ac- 48-hour period of exposure to the drug.40 Abcixi
cording to this model, the interaction between mab-induced thrombocytopenia is often mild, but
these low-affinity antibodies and their target fatalities have been recorded.41,42
antigens is too weak to affect blood cells under Acute thrombocytopenia after first exposure
normal circumstances. However, certain drugs to abciximab appears to be caused by preexisting
affect both antibody and antigen in such a way antibodies specific for murine structural elements
that the strength of the interaction is greatly in- in the abciximab molecule.40,42 Antibodies that
creased (Fig. 2). When a B cell expressing such cause delayed thrombocytopenia are newly induced
an antibody is induced to proliferate and undergo but recognize the same target; they cause throm-
affinity maturation in a patient taking the medi- bocytopenia because abciximab-coated platelets
cation, the resulting antibody can destroy the are still present in the circulation 10 to 14 days
targeted blood cell if the drug is present.37 This after treatment.40
model suggests that whether the drug binds first
to the antibody or to the targeted membrane pro- Thrombocytopenia Due to Drug-Induced
tein depends simply on its relative affinity for Autoantibodies
one component or the other. In rare cases, drugs induce true autoantibodies
that are capable of destroying platelets in the ab-
Thrombocytopenia Induced by Platelet sence of the sensitizing agent.43 About 1% of pa-
Inhibitors tients treated with gold salts for rheumatoid ar-
Acute thrombocytopenia, usually mild but occa- thritis have this complication.44 Autoantibodies
sionally life-threatening, is a common complica- induced by gold may be unique in having specific-
tion of treatment with the platelet inhibitors tiro- ity for platelet membrane glycoprotein V.45 Other
fiban and eptifibatide, which are widely used to drugs that are probably capable of inducing auto-
prevent restenosis after coronary angioplasty.7 immune thrombocytopenia include procainamide,
These ligand-mimetic drugs (“fibans”) inhibit sulfonamide antibiotics, and interferons alfa and
thrombosis by binding to a specific site on the beta.2,12,13,43 Acute, sometimes severe, but usual
platelet αIIb/β3 integrin (glycoprotein IIb/IIIa) and ly transient thrombocytopenia can occur several
competitively inhibiting platelet–fibrinogen inter- weeks after the vaccination of children or adults
action.7 Antibodies causing thrombocytopenia in for various infectious diseases, but it is rare.46,47
patients given these agents probably recognize This condition resembles acute idiopathic throm-
structural changes (neoepitopes) induced in the bocytopena, which sometimes develops in chil-
αIIb/β3 integrin when a fiban binds to it, but this dren after a viral infection, but its cause has not
theory has not been formally proved. Curiously, been established.
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
current concepts
Drug-dependent
H antibody CDR Drug
Drug-dependent
H antibody CDR
+
+ H
+
+
+ +
Figure 2. Model for the Binding of a Drug-Dependent Antibody to an Epitope on a Platelet Glycoprotein.
Antibodies capable of causing drug-dependent thrombocytopenia react weakly with an epitope on a target glycoprotein. The binding affinity
COLOR FIGURE
Draft 5 06/15/07
(K A) for this interaction is too low to allow a sufficient number of antibody molecules to bind in the absence of the drug (“low-affinity
Author Aster
fit”). The drug contains structural elements that are complementary to a negatively charged site on the glycoprotein
Fig # and2
a hydrophobic
site (H) on the complementarity-determining region (CDR) of the antibody. The drug interacts with these sites toTitle
improve the fit between
Drug-dependent antibody binding
the two proteins, increasing the K A to a value that permits binding to occur at levels of antibody, antigen, and ME
drug achieved in the cir
culation after ingestion of the drug (“high-affinity fit”). Adapted from Bougie et al.37 DE Campion
Artist KMK
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
tial drop in platelet levels,51 and a conventional platelet transfusions because of the risk of fatal
dose can cause severe thrombocytopenia and intracranial or intrapulmonary hemorrhage.2,53,54
bleeding.52 Therefore, it is important to start with Corticosteroids are often given, but there is no
a few milligrams of the drug and to monitor evidence that they are helpful if the thrombocyto-
platelet counts closely for 24 hours. Antibodies penia is drug-induced. Intravenous immune glob-
sometimes become undetectable after a few ulin55 and plasma exchange56 have been used in
months, in which case the drug may initially acutely ill patients, but the benefit of these treat-
have no effect on the platelet count. ments is uncertain.2
Once established, drug sensitivity probably per
T r e atmen t a nd Pro gnosis sists indefinitely. Therefore, patients should be
advised to avoid permanently the medication
Many patients with drug-induced thrombocyto- thought to be the cause of thrombocytopenia.
penia have only petechial hemorrhages and occa- Fortunately, drug-induced antibodies tend to be
sional ecchymoses and require no specific treat- specific for the sensitizing drug,57 and patients
ment other than discontinuation of the sensitizing usually tolerate pharmacologic equivalents, even
medication. When there is uncertainty about the those with quite similar structures.
causative drug, all medications should be discon- Supported by grants from the National Heart, Lung, and Blood
tinued, and pharmacologic equivalents with differ Institute (HL-13629 and HL-44612) and the Northland affiliate
of the American Heart Association (0235419Z).
ent chemical structures substituted as necessary. No potential conflict of interest relevant to this article was
Patients who have severe thrombocytopenia and reported.
“wet purpura” should be aggressively treated with
References
1. Reddy JC, Shuman MA, Aster RH. et al. Acute thrombocytopenic purpura in atric patients taking valproate. Am J Psy-
Quinine/quinidine-induced thrombocyto- relation to the use of drugs. Blood 1993; chiatry 2001;158:128-30.
penia: a great imitator. Arch Intern Med 82:2714-8. 21. Ross MP, Allen-Webb EM, Pappas JB,
2004;164:218-20. 12. Warkentin TE. Thrombocytopenia due McGough EC. Amrinone-associated throm
2. Aster R. Drug-induced thrombocyto- to platelet destruction and hypersplenism. bocytopenia: pharmacokinetic analysis.
penia. In: Michelson AD, ed. Platelets. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al., Clin Pharmacol Ther 1993;53:661-7.
New York: Academic Press, 2007:887-902. eds. Hematology: basic principles and prac 22. Attassi K, Hershberger E, Alam R,
3. Arepally GM, Ortel TL. Heparin- tice. 4th ed. Philadelphia: Elsevier, 2005: Zervos MJ. Thrombocytopenia associated
induced thrombocytopenia. N Engl J Med 2305-25. with linezolid therapy. Clin Infect Dis
2006;355:809-17. 13. George JN, Raskob GE, Shah SR, et al. 2002;34:695-8.
4. Arndt PA, Garratty G. The changing Drug-induced thrombocytopenia: a sys- 23. Curtis BR, Kaliszewski J, Marques MB,
spectrum of drug-induced immune hemo- tematic review of published case reports. et al. Immune-mediated thrombocytope-
lytic anemia. Semin Hematol 2005;42: Ann Intern Med 1998;129:886-90. nia resulting from sensitivity to oxalipla-
137-44. 14. Roujeau JC, Kelly JP, Naldi L, et al. tin. Am J Hematol 2006;81:193-8.
5. Stroncek DF. Drug-induced immune Medication use and the risk of Stevens– 24. Von Drygalski A, Curtis BR, Bougie
neutropenia. Transfus Med Rev 1993;7:268- Johnson syndrome or toxic epidermal DW, et al. Vancomycin-induced immune
74. necrolysis. N Engl J Med 1995;333:1600- thrombocytopenia. N Engl J Med 2007;
6. Vipan W. Quinine as a cause of pur- 7. 356:904-10.
pura. Lancet 1865;2:37. 15. Li X, Hunt L, Vesely SK. Drug-induced 25. Belkin GA. Cocktail purpura: an un-
7. Aster RH. Immune thrombocytopenia thrombocytopenia: an updated systematic usual case of quinine sensitivity. Ann In-
caused by glycoprotein IIb/IIIa inhibitors. review. Ann Intern Med 2005;142:474-5. tern Med 1967;66:583-6.
Chest 2005;127:Suppl 2:53S-59S. 16. Arnold J, Ouwehand WH, Smith GA, 26. Visentin GP, Newman PJ, Aster RH.
8. Knower MT, Bowton DL, Owen J, Du- Cohen H. A young woman with petechiae. Characteristics of quinine- and quinidine-
nagan DP. Quinine-induced disseminated Lancet 1998;352:618. induced antibodies specific for platelet
intravascular coagulation: case report and 17. Azuno Y, Yaga K, Sasayama T, Kimoto glycoproteins IIb and IIIa. Blood 1991;77:
review of the literature. Intensive Care Med K. Thrombocytopenia induced by Jui, a tra- 2668-76.
2003;29:1007-11. ditional Chinese herbal medicine. Lancet 27. Asvadi P, Ahmadi Z, Chong BH. Drug-
9. Kojouri K, Vesely SK, George JN. Qui- 1999;354:304-5. induced thrombocytopenia: localization of
nine-associated thrombotic thrombocyto- 18. Lavy R. Thrombocytopenic purpura the binding site of GPIX-specific quinine-
penic purpura–hemolytic uremic syndrome: due to lupinus termis bean. J Allergy Clin dependent antibodies. Blood 2003;102:
frequency, clinical features, and long-term Immunol 1964;35:386-9. 1670-7.
outcomes. Ann Intern Med 2001;135:1047- 19. Bennett CL, Connors JM, Carwile JM, 28. Parker CW. Hapten immunology and
51. et al. Thrombotic thrombocytopenic pur- allergic reactions in humans. Arthritis
10. van den Bemt PM, Meyboom RH, Eg- pura associated with clopidogrel. N Engl J Rheum 1981;24:1024-36.
berts AC. Drug-induced immune thrombo- Med 2000;342:1773-7. 29. Garratty G. Immune cytopenia asso-
cytopenia. Drug Saf 2004;27:1243-52. 20. Trannel TJ, Ahmed I, Goebert D. Oc- ciated with antibiotics. Transfus Med Rev
11. Kaufman DW, Kelly JP, Johannes CB, currence of thrombocytopenia in psychi- 1993;7:255-67.
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
current concepts
30. Salamon DJ, Nusbacher J, Stroupe T, et al. Abciximab readministration: results 48. Reid DM, Shulman NR. Drug purpura
Wilson JH, Hanrahan JB. Red cell and of the ReoPro Readministration Registry. due to surreptitious quinidine intake.
platelet-bound IgG penicillin antibod- Circulation 2001;104:870-5. Ann Intern Med 1988;108:206-8.
ies in a patient with thrombocytopenia. 40. Curtis BR, Divgi A, Garritty M, Aster 49. Bougie DW, Wilker PR, Wuitschick ED,
Transfusion 1984;24:395-8. RH. Delayed thrombocytopenia after treat- et al. Acute thrombocytopenia after treat-
31. Shulman NR. A mechanism of cell ment with abciximab: a distinct clinical ment with tirofiban or eptifibatide is asso
destruction in individuals sensitized to entity associated with the immune re- ciated with antibodies specific for ligand-
foreign antigens and its implications in sponse to the drug. J Thromb Haemost occupied GPIIb/IIIa. Blood 2002;100:
auto-immunity: combined Clinical Staff 2004;2:985-92. 2071-6.
Conference at the National Institutes of 41. McCorry RB, Johnston P. Fatal de- 50. Bougie D, Aster R. Immune thrombo-
Health. Ann Intern Med 1964;60:506-21. layed thrombocytopenia following abcix- cytopenia resulting from sensitivity to me-
32. Christie DJ, Mullen PC, Aster RH. imab therapy. J Invasive Cardiol 2006;18: tabolites of naproxen and acetaminophen.
Fab-mediated binding of drug-dependent E173-E174. Blood 2001;97:3846-50.
antibodies to platelets in quinidine- and 42. Curtis BR, Swyers J, Divgi A, McFar- 51. Shulman NR. Immunoreactions involv
quinine-induced thrombocytopenia. J Clin land JG, Aster RH. Thrombocytopenia ing platelets. IV. Studies on the pathogen-
Invest 1985;75:310-4. after second exposure to abciximab is esis of thrombocytopenia in drug purpura
33. Smith ME, Reid DM, Jones CE, Jordan caused by antibodies that recognize ab- using test doses of quinidine in sensitized
JV, Kautz CA, Shulman NR. Binding of ciximab-coated platelets. Blood 2002;99: individuals; their implications in idio-
quinine- and quinidine-dependent drug 2054-9. pathic thrombocytopenic purpura. J Exp
antibodies to platelets is mediated by the 43. Aster RH. Can drugs cause autoim- Med 1958;107:711-29.
Fab domain of the immunoglobulin G and mune thrombocytopenic purpura? Semin 52. Schmitt SK, Tomford JW. Quinine-
is not Fc dependent. J Clin Invest 1987;79: Hematol 2000;37:229-38. induced pancytopenia and coagulopathy.
912-7. 44. von dem Borne AE, Pegels JG, van der Ann Intern Med 1994;120:90-1.
34. Mueller-Eckhardt C, Salama A. Drug- Stadt RJ, van der Plas-van Dalen CM, Hel- 53. Freiman JP. Fatal quinine-induced
induced immune cytopenias: a unifying merhorst FM. Thrombocytopenia associ- thrombocytopenia. Ann Intern Med 1990;
pathogenetic concept with special empha- ated with gold therapy: a drug-induced 112:308-9.
sis on the role of drug metabolites. Trans- autoimmune disease? Br J Haematol 1986; 54. Fireman Z, Yust I, Abramov AL. Lethal
fus Med Rev 1990;4:69-77. 63:509-16. occult pulmonary hemorrhage in drug-
35. Shulman NR, Reid DM. Mechanisms 45. Garner SF, Campbell K, Metcalfe P, induced thrombocytopenia. Chest 1981;
of drug-induced immunologically mediat- et al. Glycoprotein V: the predominant 79:358-9.
ed cytopenias. Transfus Med Rev 1993;7: target antigen in gold-induced autoim- 55. Ray JB, Brereton WF, Nullet FR. Intra-
215-29. mune thrombocytopenia. Blood 2002;100: venous immune globulin for the treatment
36. Aster RH. Drug-induced immune cyto- 344-6. of presumed quinidine-induced thrombo-
penias. Toxicology 2005;209:149-53. 46. Neau D, Bonnet F, Michaud M, et al. cytopenia. DICP 1990;24:693-5.
37. Bougie DW, Wilker PR, Aster RH. Immune thrombocytopenic purpura after 56. Pourrat O. Treatment of drug-related
Patients with quinine-induced immune recombinant hepatitis B vaccine: retro- diseases by plasma exchanges. Ann Med
thrombocytopenia have both “drug-depen spective study of seven cases. Scand J In- Interne (Paris) 1994;145:357-60.
dent” and “drug-specific” antibodies. Blood fect Dis 1998;30:115-8. 57. Christie DJ, Weber RW, Mullen PC,
2006;108:922-7. 47. Nieminen U, Peltola H, Syrjala MT, Cook JM, Aster RH. Structural features of
38. Pillai S. Two lymphoid roads diverge Makipernaa A, Kekomaki R. Acute throm- the quinidine and quinine molecules nec-
— but does antigen bade B cells to take bocytopenic purpura following measles, essary for binding of drug-induced anti-
the road less traveled? Immunity 2005;23: mumps and rubella vaccination: a report bodies to human platelets. J Lab Clin Med
242-4. on 23 patients. Acta Paediatr 1993;82:267- 1984;104:730-40.
39. Tcheng JE, Kereiakes DJ, Lincoff AM, 70. Copyright © 2007 Massachusetts Medical Society.
Downloaded from www.nejm.org on February 15, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.