Frequency and Management of Thrombocytopenia With the

Glycoprotein IIb/IIIa Receptor Antagonists

Lindsay M. Huxtable, PharmD, BCPSa,*, Mohammad J. Tafreshi, PharmD, BCPSa,
and Amol N. S. Rakkar, MDb
Glycoprotein IIb/IIIa receptor antagonists (GPRAs) are widely used in the manage-
ment of a variety of patients with acute coronary syndromes. Major adverse reactions
to these agents include bleeding and thrombocytopenia. Immune mechanisms respon-
sible for severe thrombocytopenia seen with GPRAs have been hypothesized for all 3
agents currently available in the United States, although specific laboratory tests are
not available for use in routine practice. A review of published research for GPRA-
induced thrombocytopenia (GIT) is provided. Although the incidence of severe GIT
is relatively low, the implications for patients are potentially life threatening. Prompt
recognition of severe thrombocytopenia is essential to facilitate the necessary care of
patients. Treatment strategies include the modification of drug regimens and other
interventions targeting the reduction of immediate bleeding risk and the provision of
supportive care measures. A review of published research supporting the conservative
use of corticosteroids and intravenous gamma globulin in this syndrome is provided.
Clinicians identifying severe thrombocytopenia after GPRA exposure are encouraged
to report these events, following national and institutional guidelines. © 2006
Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:426 – 429)

Three glycoprotein IIb/IIIa receptor antagonists (GRPAs)
are currently available for intravenous administration in
the United States: abciximab, eptifibatide, and tirofiban.
Although these agents differ in their pharmacologic pro-
files, they have all been reported to cause thrombocyto-
penia.1–3 In severe GPRA-induced thrombocytopenia
(GIT), several immune-mediated mechanisms have been
postulated: the GPRA may act as the antigen itself, the
GPRA may cause a conformational change resulting in
the exposure of a ligand-induced binding site that either
binds directly to the antibody or to the GPRA-antibody
complex, or direct platelet activation on binding of the
GPRA to the glycoprotein IIb/IIIa receptor may occur.4 – 8
Individual Agents
Abciximab: Abciximab is the Fab fragment of the chi-
meric human-murine monoclonal antibody 7E3 that binds
to glycoprotein IIb/IIIa, vitronectin, and Mac-1 receptors
in humans.1 Thrombocytopenia, defined as a platelet
count ⬍100 ⫻ 109/L, associated with abciximab occurred
in 2.5% to 6% of patients, while severe thrombocytope-
nia (platelet count ⬍50 ⫻ 109/L) occurred in 0.4% to
1.6% of patients in clinical trials. Platelet transfusions
a
Midwestern University College of Pharmacy–Glendale, Glendale, Ar-
izona; and bPalo Verde Hematology-Oncology, Ltd., Glendale, Arizona.
Manuscript received July 11, 2005; revised manuscript received and ac-
cepted August 22, 2005.
* Corresponding author: Tel: 623-572-3557; fax: 623-572-3550.
E-mail address: lhuxta@midwestern.edu (L.M. Huxtable).
were administered to 0.9% to 6% of patients in these
trials.9 –14
Although the Fc portion of the antibody is removed
during synthesis, it was originally thought that abciximab
would potentially act as an antigen on readministration,
thereby stimulating an immune-mediated response to the
drug. The results of the ReoPro Readministration Registry
suggested that the risk for developing any thrombocytope-
nia after the readministration of abciximab was no different
from the risk during primary exposure (n ⫽ 23 of 499,
4.6%).15 It was discovered that the severity appeared to be
greater in those patients reexposed to abciximab who de-
veloped thrombocytopenia, particularly those with shorter
time lapses between exposures. After reexposure, 50% of all
patients with thrombocytopenia (n ⫽ 12 of 23) experienced
more profound thrombocytopenia (platelet count ⬍20 ⫻
109/L). The platelet nadirs in 2 of these 12 patients were
reached at approximately 96 and 144 hours after exposure,
which again emphasizes the importance of platelet moni-
toring after abciximab administration.15
Eptifibatide: Eptifibatide is a cyclic heptapeptide that
reversibly inhibits platelet aggregation through the binding
of the glycoprotein IIb/IIIa receptor.2 Cases of thrombocy-
topenia (platelet count ⬍100 ⫻ 109/L) associated with ep-
tifibatide occurred in 1.2% to 6.8% of patients, while severe
thrombocytopenia (platelet count ⬍50 ⫻ 109/L) was re-
ported to occur in 0.2% of patients in the Platelet Glycop-
rotein IIb/IIIa in Unstable Angina: Receptor Suppression
Using Integrilin Therapy trial.16,17 Platelet transfusions were
reportedly administered to 1.3% to 1.5% of patients in 1 epti-

0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. www.AJConline.org
doi:10.1016/j.amjcard.2005.08.066
 Review/Thrombocytopenia and Glycoprotein Inhibitors
fibatide trial.18 Because this product is not derived from an
antibody source, one could hypothesize that eptifibatide would
not be likely to induce an immune-mediated response; how-
ever, postmarketing experience may indicate the contrary.
The first case reported in published research involving
eptifibatide occurred after the readministration of the med-
ication ⬍3 months after its initial use.19 A platelet nadir of
29 ⫻ 109/L occurred 2 hours after the second exposure.
Although this patient had received unfractionated heparin,
antibody testing for heparin and platelet factor 4 complexes
was negative. Fortunately, this patient was treated at an insti-
tution that routinely obtains a complete blood count 2 hours
after any GPRA is used. This allowed the rapid recognition of
the thrombocytopenia and the discontinuation of the eptifi-
batide infusion and other antiplatelet medications.19
Bougie et al20 described GIT associated with eptifibatide
and tirofiban that was dependent on an immune process, as
detected by functional and antigenic assays. Nine patients
with severe thrombocytopenia (platelet count ⬍25 ⫻ 109/L)
were evaluated for previous exposure to the offending
agent, cross reactivity of antibodies to the 2 agents, and
cross sensitivity to abciximab. This yielded 5 patients with
no previous exposure to the GPRA, 1 patient with eptifi-
batide-associated antibodies that reacted weakly with tiro-
fiban-associated antibodies, and no in vitro cross sensitivity
to platelets treated with abciximab.20 The primary implica-
tion of this study is that patients may develop severe GIT
after primary exposure.
Tirofiban: Tirofiban is a nonpeptide molecule that re-
versibly inhibits platelet aggregation through binding of the
glycoprotein IIb/IIIa receptor.3 Thrombocytopenia (platelet
count ⬍100 ⫻ 109/L) associated with tirofiban occurred in
1.1% to 1.9% of patients, while severe thrombocytopenia
(platelet count ⬍50 ⫻ 109/L) occurred in 0.2% to 0.5% of
patients in clinical trials.21–23 Again, one might postulate
that an immune mechanism would be unlikely with tirofi-
ban, but preceding evidence as described by Bougie et al20
demonstrate the possibility for this to occur.
Pseudothrombocytopenia: Although rare, pseudothrom-
bocytopenia can be dangerous when treated as true thrombo-
cytopenia, because a clinician’s reaction to severe thrombocy-
topenia may be to discontinue the offending agent and, in some
cases, administer platelets. The discontinuation of antiplatelet
agents, in this case abciximab, limits the benefit known to be
provided by administration of this agent. The administration of
platelets in patients with pseudothrombocytopenia may also
result in an increased risk for acute thrombosis, exposure to
known risks associated with the transfusion of blood products,
and the excess consumption of precious resources.4,24,25
Pseudothrombocytopenia occurs as a result of artifactual
platelet clumping in vitro, generating a falsely decreased
platelet count. It has been reported to occur with various
anticoagulants used in platelet assays, including citrate, eth-
ylenediaminetetraacetic acid, and nonchelating anticoagu-
lants.26 The incidence of pseudothrombocytopenia in 4 ma-
427
jor trials with abciximab was 2.1%, compared with 0.6%
with placebo. In a review by Sane et al,24 approximately 1/3
of severe thrombocytopenia cases seen after abciximab ad-
ministration may be related to pseudothrombocytopenia. In
our search of available studies, no reports of pseudothrom-
bocytopenia related to tirofiban or eptifibatide were found.
To reduce the chance of misdiagnosing thrombocytope-
nia, it is recommended to draw 3 separate samples of blood for
monitoring platelet counts: 1 each in tubes containing citrate,
ethylenediaminetetraacetic acid, and heparin.1 To decrease the
volume of blood required from a patient, a clinician may
reserve this option as secondary testing if the initial platelet
count is decreased significantly. A peripheral blood smear to
detect the presence of clumped platelets to assist in the diag-
nosis of pseudothrombocytopenia is also recommended.4,25,27
Prevalence
A major limiting factor to determining the prevalence of
severe GIT related to immune mechanisms is the lack of
readily attainable and validated assays. Although several
laboratory techniques have been used for years for the
detection of specific antibodies, no gold standard for the
detection of drug-dependent antibodies has been developed
for GPRAs. The concomitant administration of other agents
known to cause thrombocytopenia may also complicate the
identification of the causative agent. The proactive testing of
patients for preformed antibodies to the glycoprotein IIb/
IIIa receptor complex cannot be recommended on the basis
of the probability of low yield, the lack of reliable data to
indicate that positive antibody test results would accurately
predict a negative outcome, and the lack of standardized
testing. Clinicians are faced with the need to establish di-
agnoses solely on the basis of the clinical presentations of
and interviews with patients, including detailed histories of
previous exposures to the suspected agent or agents.
Patient Management
The approach to managing patients who develop severe GIT
has not been clearly defined. Laboratory confirmation of the
platelet count should be obtained, and antibody testing may
be requested to determine if unfractionated heparin is the
causative agent in patients receiving concomitant unfrac-
tionated heparin. Testing for antibodies to the glycoprotein
receptor complexes may support the clinical suspicion of
the causative agent, but neither the sensitivity nor specificity
of these tests has been established to confirm a clinical
diagnosis, so measures to provide supportive care and min-
imize blood loss should be applied. Patients with platelet
counts of ⬍100 ⫻ 109/L should be considered to have a
greater risk for bleeding, potentially necessitating the discon-
tinuation of the GPRA, anticoagulant, and other antiplatelet
agents (e.g., aspirin, clopidogrel). The presence of active bleed-
428 The American Journal of Cardiology (www.AJConline.org)
ing at any time, or a platelet count of ⬍20 ⫻ 109/L, should
warrant consideration for platelet transfusion.28,29 Designating
an absolute platelet count transfusion trigger of 20 ⫻ 109/L is
controversial because a lower threshold (⬍10 ⫻ 109/L) has
been proved safe for patients without clinical signs of bleed-
ing30 –33 and was used by the Thrombolysis In Myocardial
Infarction Study Group during trials of the GPRAs.29
Corticosteroids and intravenous immunoglobulin (IVIG)
have been considered standard treatments for idiopathic
thrombocytopenic purpura and immune thrombocytopenia
related to various causes for many years.34 Although data to
specifically advocate for or against the use of either agent in
suspected immune-mediated severe GIT are extremely lim-
ited, their usefulness related to other causes warrants inves-
tigation.35,36 In 1994, Jacobs et al36 randomized 43 patients
with symptomatic immune thrombocytopenia of undetermined
origin to 3 treatment arms: oral prednisone (1 mg/kg/day),
intravenous gamma globulin (IVIG; 400 mg/kg/day for 5
days), or the 2 regimens of oral prednisone and IVIG given
concomitantly. Patients receiving oral prednisone plus IVIG
had significantly greater complete responses than those receiv-
ing IVIG alone (p ⫽ 0.0365). Patients receiving oral pred-
nisone alone trended toward more favorable responses than
those receiving IVIG alone, but this difference did not reach
statistical significance. Bougie et al20 also reported that 3 of 9
patients in their study received IVIG, but individual doses and
outcomes were not included in this report.
The results of Jacobs et al36 are in contrast to a retro-
spective analysis of 309 cases of drug-induced thrombocy-
topenia by Pedersen-Bjergaard et al.37 Thirty-two percent of
these cases occurred ⬍2 weeks after initiating the offending
agent, and platelet-specific antibodies were found in only 9
of 34 cases actually studied. The investigators found no
significant impact of the administration of corticosteroids to
53% of the 309 patients, although there was a nonsignificant
trend toward more rapid recovery. Treatment with IVIG
after severe thrombocytopenia related to abciximab was of
no clinical benefit, as reported by Kereiakes et al.38 Com-
paring the results of these studies37,38 with those of Jacobs
et al36 is difficult, because they evaluated patients with
varying causes of thrombocytopenia using different re-
search methods in a limited number of patients.
Summary of recommendations: An inability to deter-
mine with absolute certainty that severe GIT is dependent
on an immune process limits the ability to recommend the
routine use of corticosteroids or IVIG. In severe cases of
GIT accompanied by admission to a critical care unit or
active bleeding suspected to potentially be related to an
immune process, we believe that it may be reasonable to
administer a corticosteroid, given the low risk for compli-
cations and relatively low cost associated with this interven-
tion. Although this may potentially hasten the recovery time,
clinicians should keep in mind that this has not proved to be a
transfusion-sparing intervention. The use of IVIG in severe
GIT has not demonstrated clinical benefit, and the administra-
tion of this agent should not be without a corticosteroid and
consideration to cost. Supportive care and the judicious use of
platelet transfusion remains the cornerstone of treatment.
Platelet counts should be monitored in patients after
exposure to any of the 3 GPRAs. Institutionalized patients
may readily have platelet counts monitored ⬍2 to 4 hours
following administration and again at 24 hours. Monitoring
outpatients after GPRA exposure beyond 24 hours may
seem prudent, but the extremely low incidence of severe
GIT does not clearly support these recommendations. Ab-
ciximab is the only GPRA that currently contains recom-
mendations for monitoring platelet counts up to 24 hours
after administration in its package labeling.1 After multiple
exposures to ⱖ1 GPRA, clinicians should be cognizant that
if thrombocytopenia does develop, the severity may be
increased. This has been particularly demonstrated after
abciximab readministration but may potentially occur with
eptifibatide or tirofiban as well.
Conversely, the duration of time for monitoring platelet
counts after severe GIT has not been clearly established.
With abciximab,15,39,40 platelet counts returned to baseline
over a period of 3 days to 2 weeks.40 With eptifibatide and
tirofiban, platelet counts recovered over a period of 1 to ⬎5
days.19,20 Clinicians should be aware of this associated time
delay, because oral antiplatelet agents should generally be
avoided until a patient is stabilized and the immediate risk
for associated bleeding is minimized. Clinicians encounter-
ing severe GIT in practice should also follow national and
institutional adverse drug event reporting guidelines in an
effort to facilitate future assessment of the incidence and
management of this condition.
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