Immune Thrombocytopenia Caused by

Glycoprotein IIb/IIIa Inhibitors *

Richard H. Aster

Chest 2005;127;53S-59S
DOI 10.1378/chest.127.2_suppl.53S

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Immune Thrombocytopenia Caused by
Glycoprotein IIb/IIIa Inhibitors*
Richard H. Aster, MD

Agents that react with the platelet glycoprotein (GP) IIb/IIIa complex (␣IIb/␤3 integrin) to block
fibrinogen binding and platelet-platelet aggregation have been proved to be effective in reducing
the incidence of complications following coronary angioplasty and are now widely used for this
purpose. Acute thrombocytopenia, which is sometimes severe and life-threatening, is a recog-
nized side effect of this class of drugs. In contrast to other types of drug-induced thrombocyto-
penia, this complication can occur within a few hours of a patient’s first exposure to the
medication. Accumulating evidence has indicated that drug-dependent antibodies, which can be
naturally occurring, are the cause of platelet destruction in such individuals. In this review, we
will consider the clinical aspects of thrombocytopenia resulting from sensitivity to GPIIb/IIIa
inhibitors and will review evidence that the platelet destruction is antibody-mediated.
(CHEST 2005; 127:53S–59S)

Key words: abciximab; eptifibatide; glycoprotein IIb/IIIa inhibitors; thrombocytopenia; tirofiban

Abbreviations: DITP ⫽ drug-induced immune thrombocytopenia; EDTA ⫽ ethylendiaminetetraacetic acid;

GP ⫽ glycoprotein; RGD ⫽ Arg-Gly-Asp

T henewglycoprotein (GP) IIb/IIIa inhibitors are a

class of antithrombotic agents that are ef-
fective because they block the binding of fibrinogen
to activated GPIIb/IIIa, thereby inhibiting platelet-
platelet interaction and thrombus formation.1–3
GPIIb/IIIa inhibitors have been shown to reduce
secondary complications following coronary angio-
plasty and are now being evaluated for their ability to
prevent thrombosis in patients with other conditions.
Three GPIIb/IIIa inhibitors, abciximab, tirofiban,
and eptifibatide, have been approved for clinical use
in the United States and other countries. All are
given by IV administration, usually for 12 to 18 h
after the patient undergoes angioplasty. Agents de-
signed for oral administration are in various stages of
development.4
Drug-induced immune thrombocytopenia (DITP)
is an unpredictable and sometimes serious side effect
of many medications, including heparin, quinine,
sulfonamides, and other antibiotics, especially van-
comycin, rifampicin, cephalosporins, other sulfon-
*From the Blood Research Institute, The Blood Center of
Southeastern Wisconsin, Milwaukee, WI.
Supported in part by grants HL-44612 and HL-13629 from the
National Heart, Lung, and Blood Institute.
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Richard H. Aster, MD, Blood Research
Institute, The Blood Center of Southeastern Wisconsin, PO Box
2178, Milwaukee, WI 53201-2178; e-mail: rhaster@bcsew.edu
amide compounds, and nonsteroidal antiinflamma-
tory drugs.5,6 It has been recognized7,8 that DITP is
a relatively common side effect of GPIIb/IIIa inhib-
itors. The mechanisms by which GPIIb/IIIa inhibi-
tors induce thrombocytopenia differ from those
thought to be responsible for thrombocytopenia
induced by drugs such as quinine and certain anti-
biotics. This review will consider the clinical features
and pathogenetic mechanisms of thrombocytopenia
induced by the GPIIb/IIIa inhibitors.
Immune Thrombocytopenia in Patients
Treated With Abciximab
Clinical Presentation
Acute Thrombocytopenia After First or Second
Exposure to Abciximab: Abciximab (ReoPro; Eli
Lilly; Indianapolis, IN) is a chimeric (human/mouse)
Fab fragment that is derived from a murine mono-
clonal antibody, 7E3, that binds to an epitope on the
GPIIb/IIIa complex close to a critical binding site for
fibrinogen, thereby inhibiting its reaction with the
activated integrin.1 To create abciximab, N-terminal
sequences in 7E3 that control its specificity were
incorporated into a human IgG1 framework. The
intact chimeric IgG molecule then was cleaved by
papain to produce the Fab fragment abciximab.1 In
clinical trials8,9 of abciximab and in subsequent
experience, it was found that about 1% of patients

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© 2005 American College of Chest Physicians
given this drug experienced acute, often severe
thrombocytopenia. After a second exposure to the
drug, the rate for this complication rises to about
4%.10 In some instances, the onset of thrombocyto-
penia was accompanied by fever, dyspnea, hypoten-
sion, and even frank anaphylaxis, occurring soon
after starting the drug.11–13 Although most patients
with abciximab-associated thrombocytopenia re-
cover uneventfully, life-threatening bleeding has
been described,13 and several patients have experi-
enced intracranial hemorrhage.14,15
Delayed Thrombocytopenia After Abciximab: Al-
though abciximab-induced thrombocytopenia usu-
ally occurs within a few hours of starting therapy with
the drug, a subgroup of patients has been described
in whom the drop in platelet levels occurred 5 to 8
days after the drug was administered.16,17 Recent
studies have provide an explanation for this type of
presentation (see below).
Abciximab-Associated Pseudothrombocytopenia:
A subset of patients with abciximab-induced
“thrombocytopenia” actually will have a circulating
platelet count in the normal range. In such cases,
low platelet counts obtained with automated count-
ing instruments were found to be a consequence of
the in vitro clumping of platelets in blood samples
anticoagulated with ethylenediaminetetraacetic acid
(EDTA).18,19 Pseudothrombocytopenia in patients
who have received abciximab can usually be distin-
guished from true thrombocytopenia by repeating a
platelet count in blood that has been anticoagulated
with citrate and/or by estimating the platelet levels in
a peripheral blood smear prepared from a finger-
stick. The mechanism by which abciximab promotes
the in vitro clumping of platelets in blood anticoag-
ulated with EDTA is not known.
was provided by studies13 showing that a group of
patients who developed severe thrombocytopenia after
a second exposure to the drug all had strong IgG and/or
IgM antibodies that reacted with abciximab-coated
platelets in a flow cytometric assay (Fig 1). The speci-
ficity of this finding was called into question by the
observation that some healthy individuals (both those
who were exposed to the drug and those unexposed)
have similar types of antibodies, although they are
generally weaker than those found in patients with
abciximab-induced thrombocytopenia.13 However, it
was found that most antibodies from patients with
abciximab-induced thrombocytopenia can be distin-
guished from the antibodies commonly found in
healthy individuals in two ways. First, the antibodies
found in healthy subjects recognize the papain cleavage
site at the C-terminus of the abciximab molecule13,26
and can thus be inhibited by Fab fragments, whereas
patient antibodies are resistant to this treatment. Sec-
ond, the antibodies from patients react preferentially
with platelets coated with the intact monoclonal anti-
body 7E3, from which the specificity-determining se-
quences incorporated into abciximab were derived,
whereas antibodies from nonthrombocytopenic indi-
viduals do not13 (Fig 2). It has been known for many
years that healthy individuals can have naturally occur-
ring antibodies that recognize enzymatic cleavage sites
in human Igs.27,28 It appears that antibodies found in
healthy individuals that react with abciximab-coated

Pathogenesis
The development of severe thrombocytopenia
within hours of a patient’s first exposure to abciximab
is in distinct contrast to most types of DITP, which
occurs in patients who have previously been exposed
to the sensitizing drug or have received it for a
number of days. Accordingly, nonimmune mecha-
nisms were initially considered as a possible expla-
nation for the acute platelet destruction that is
typical of this condition. Some reports20 –23 were
consistent with this possibility, but others24,25 argued
against it, leaving this question unresolved.
Figure 1. Reactions of strong IgG antibodies (top) and weak IgG
Thrombocytopenia After Second Exposure to Ab- antibodies (bottom) from patients with abciximab-induced
thrombocytopenia with abciximab (Drug)-coated platelets. No
ciximab: Direct evidence for the immune destruction reaction was obtained with uncoated (No Drug) platelets. From
of platelets in patients who have received abciximab Curtis et al,13 with permission.

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© 2005 American College of Chest Physicians

Figure 2. Reactions of IgG antibodies from patients who
experienced thrombocytopenia after a second exposure to abcix-
imab (left) and antibodies found in healthy persons (right) against
platelets coated with the murine IgG1 monoclonal antibodies 7E3
and AP3. 7E3 contains peptide sequences that were incorporated
into the chimeric abciximab molecule to endow it with specificity
for the GPIIb/IIIa complex. AP3 is specific for GPIIIa and does
not block fibrinogen binding. The results are expressed as the
ratio of the fluorescence intensity obtained using 7E3-coated
platelets as targets to that obtained with AP3-coated platelets.
Antibodies from patients who developed thrombocytopenia re-
acted preferentially with 7E3-coated platelets (high 7E3/AP3
ratio), whereas antibodies found in healthy subjects did not.
From Curtis et al,13 with permission.
platelets recognize the papain cleavage site at the C
terminus of the abciximab molecule and are probably
not capable of causing thrombocytopenia in patients
who have received the drug.13 In contrast, antibodies
from patients with abciximab-induced thrombocytope-
nia recognize either murine sequences incorporated
into abciximab or conformational changes induced by
abciximab in GPIIb/IIIa when abciximab binds (Fig 3).
Why such antibodies cause platelet destruction,
whereas antibodies found in many healthy individuals
that recognize a different target on abciximab-coated
platelets apparently do not is unresolved.
Thrombocytopenia After First Exposure to Abcix-
imab: There are no published reports characteriz-
ing antibodies in patients who developed thrombo-
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© 2005 American College of Chest Physicians
Figure 3. Model illustrating the apparent binding sites on
abciximab-coated platelets for antibodies commonly found in
normal persons (“normal abs”) and antibodies identified in
patients who developed severe thrombocytopenia after treatment
with abciximab (“patient abs”).
cytopenia after a first exposure to abciximab,
although our unpublished observations suggest that
antibodies similar to those found in patients given
abciximab a second time are responsible for platelet
destruction in most cases. These antibodies can be
found in pretreatment blood samples, indicating that
they are naturally occurring.
Delayed Thrombocytopenia After Abciximab
Treatment: Abciximab remains bound to circulating
platelets for several weeks after its infusion.29,30 As
noted, some patients who have received abciximab
have a normal or near-normal platelet count for the
first few days after treatment starts but develop
thrombocytopenia 5 to 7 days later. Recent studies31
have indicated that “delayed thrombocytopenia” oc-
curring in such individuals is caused by newly
formed antibodies or weak preexisting antibodies
stimulated to a high titer by abciximab exposure.
Thrombocytopenia Following Treatment
With Ligand-Mimetic GPIIb/IIIa Inhibitors
Clinical Presentation
A second class of GPIIb/IIIa inhibitors, the ligand-
mimetic agents, act by binding specifically to the
Arg-Gly-Asp (RGD) recognition site on GPIIb/IIIa,
thereby rendering the integrin incapable of binding
fibrinogen.2– 4 Two drugs of this class, tirofiban (Ag-
grastat; Merck; Whitehouse Station, NJ) and eptifi-
batide (Integrelin; COR Therapeutics Inc; South San
Francisco, CA) are currently approved for clinical
use by IV infusion (Fig 4). Other IV and oral agents
CHEST / 127 / 2 / FEBRUARY, 2005 SUPPLEMENT 55S
 Figure 4. Chemical structures of the ligand-mimetic GPIIb/IIIa inhibitors tirofiban and eptifibatide.
Eptifibatide is a cyclic heptapeptide containing an RGD sequence. Tirofiban is a completely synthetic
compound that is designed to mimic the conformation and charge distribution of RGD. From Aster et
al,54 with permission.

of this class are in development. Like abciximab,
tirofiban and eptifibatide have been shown32,33 to
reduce the incidence of secondary complications
following coronary angioplasty.
As with abciximab, a subset of patients treated
with ligand-mimetic GPIIb/IIIa inhibitors will de-
velop acute, severe thrombocytopenia.32–35 In some
reported cases,36 –39 the onset of thrombocytopenia
was accompanied by systemic symptoms such as
chills, fever, and hypotension. The various ligand-
mimetic GPIIb/IIIa inhibitors appear to differ in
their tendency to cause thrombocytopenia. In trials
of the oral inhibitors xemilofiban and orbofiban,
about 0.6% of 12,000 patients who received one of
these drugs, but only 0.03% of patients who received
placebo, experienced thrombocytopenia that was
judged by a blinded review committee to be “possi-
bly drug-induced.”40 A second oral drug, roxifiban,
caused drug-induced thrombocytopenia in about 2%
of treated individuals.41 The incidence of drug-
induced thrombocytopenia in patients who received
tirofiban or eptifibatide has not been rigorously
defined but is probably less than either of these
estimates. The fact that oral inhibitors are adminis-
tered daily for an extended period of time, whereas
IV drugs are usually infused for less than a day,
probably explains the greater tendency of the former
to cause thrombocytopenia.
Pathogenesis
The onset of acute thrombocytopenia within hours
of the first exposure of a ligand-mimetic GPIIb/IIIa
inhibitor suggested that nonimmune factors might
be responsible. Several reports42,43 were consistent
with this possibility, but observations to the contrary
have also been described,44,45 and no convincing
nonimmune mechanisms have yet been advanced to
explain acute platelet destruction following drug
administration. Recent reports36,38,46 have indicated
that patients with thrombocytopenia induced by
tirofiban, eptifibatide, and several other oral inhibi-
tors40,41,47 often have antibodies that recognize
GPIIb/IIIa in the presence of the agent being ad-
ministered. As in some patients with abciximab-
induced thrombocytopenia,13 such antibodies can be
identified in blood samples obtained prior to treat-
ment with the drug, indicating that they can be
naturally occurring36 (Fig 5). Antibodies of this type
were not found in patients who received the same
drugs and did not experience thrombocytopenia,
although weaker tirofiban-dependent and eptifi-
batide-dependent antibodies were found in about
3% of healthy persons.36
Although accumulating evidence indicates that
thrombocytopenia associated with the administration
of ligand mimetic GPIIb/IIIa inhibitors is caused by
antibodies that recognize ligand-occupied GPIIb/
IIIa, the sites on the integrin for which these anti-
bodies are specific have not yet been defined. By
several criteria, the antibodies appear to recognize
more than one and perhaps many target epitopes.
First, the binding of some antibodies is totally
blocked by precoating drug-treated platelets with
abciximab, whereas the binding of others is unaf-
fected. Second, the antibodies differ from one an-
other in respect to the levels of ionized calcium
required for drug-dependent binding to their targets
(Fig 6).36 It is known that ligand-mimetic com-
pounds such as tirofiban and eptifibatide induce
conformational changes in the GPIIb/IIIa complex

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 Figure 5. Reactions of serum samples from patients who developed acute thrombocytopenia after a
first exposure to tirofiban (patient T2) and eptifibatide (patient E1) against normal platelets (flow
cytometry). Drug-dependent antibodies were present in serum samples obtained before and after
exposure in each case. From Bougie et al,36 with permission. Rx ⫽ treatment.

that are recognized by certain murine monoclonal
antibodies.48,49 Possibly, tirofiban-dependent and
eptifibatide-dependent antibodies recognize similar
epitopes (ie, ligand-induced binding sites) on GPIIb/
IIIa. If so, it would appear that certain healthy
individuals have strong, naturally occurring antibod-
ies that recognize the GPIIb/IIIa complex that are
Figure 6. Drug-dependent reactions of serum samples from
patients who developed acute thrombocytopenia after treatment
with tirofiban at various concentrations of ionized calcium.
Antibody T3 reacted at all concentrations of calcium employed
and even in the presence of the strong calcium chelator EDTA.
In contrast, antibody T1 reacted optimally only when the calcium
concentration was close to the physiologic range (1.0 mM). No
reactions were obtained in the absence of tirofiban (not shown).
From Bougie et al,36 with permission.
“activated” by ligand-mimetic drugs, and are capable
of causing severe and sometimes life-threatening
thrombocytopenia following drug administration.
Treatment of Thrombocytopenia Induced
by GPIIb/IIIa Inhibitors
A platelet count should be performed routinely
before and within 2 to 6 h after starting treatment in
any patient given a GPIIb/IIIIa inhibitor to enable
the early diagnosis of drug-induced thrombocytope-
nia. Some patients who develop thrombocytopenia
are asymptomatic or exhibit only scattered petechial
hemorrhages. Others experience bleeding from sites
of catheterization, GI hemorrhage, or hematoma
formation. Because the function of platelets remain-
ing in the circulation is impaired by the inhibitor, all
patients with this complication should be considered
to be at risk for bleeding, and those with significant
hemorrhage should be given platelet transfusions.
Because tirofiban and eptifibatide are cleared from
the circulation within hours of discontinuing their
infusion,50,51 the duration of thrombocytopenia and
hemorrhagic risk in patients who have received these
drugs is of short duration. Patients who have re-
ceived abciximab are at risk for a longer period of
time because platelet function is impaired for up to
1 week,30 and thrombocytopenia sometimes persists

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© 2005 American College of Chest Physicians
for 3 to 5 days.13 On the basis of limited experience,
it appears that patients who are sensitive to abcix-
imab can safely receive tirofiban or eptifibatide at a
later time.52,53 It is likely that the converse is true,
but this has not yet been documented.
Can Thrombocytopenia After Treatment
With GPIIb/IIIa Inhibitors Be Prevented by
Pretreatment Screening?
Since thrombocytopenia in patients who have
received GPIIb/IIIa inhibitors is usually caused by
preexisting antibodies, it seems possible that pre-
treatment screening to detect such antibodies might
prevent this complication. In studies of patients who
have been treated with the oral, ligand-mimetic
GPIIb/IIIa inhibitor roxifiban, Seiffert et al41 re-
ported that the incidence of thrombocytopenia can
be reduced by about ten fold by screening for
antibodies before the drug is administered, and for
newly formed antibodies about 1 week later.
Whether it is practical and feasible to perform such
screening remains to be determined.
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CHEST / 127 / 2 / FEBRUARY, 2005 SUPPLEMENT 59S
Immune Thrombocytopenia Caused by Glycoprotein IIb/IIIa Inhibitors*
Richard H. Aster
Chest 2005;127; 53S-59S
DOI 10.1378/chest.127.2_suppl.53S
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