Review

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Glycoprotein IIb/IIIa inhibitors: an update on the

mechanism of action and use of functional testing
methods to assess antiplatelet efficacy
The human glycoprotein (GP)IIb/IIIa belongs to a large family of cation-dependent adhesion molecules
known as integrins, which share a common heterodimeric structure. The primary function of GPIIb/IIIa is
to aid platelet aggregation by transmitting bidirectional signals across the plasma membrane. Since the
GPIIb/IIIa receptor is among the key integrins involved in platelet aggregation and, therefore, thrombus
formation, the development of GPIIb/IIIa antagonists (e.g., abciximab, eptifibatide and tirofiban) has
become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. All
three drugs are administered intravenously, and large-scale clinical trials have demonstrated a clear clinical
benefit and good safety profile in high-risk patients, especially those undergoing percutaneous coronary
intervention. However, the adverse events related to thrombosis or bleeding are still reported in patients
undergoing therapy with GPIIb/IIIa antagonists and reflect a variable interindividual responsiveness.
Therefore, some form of laboratory monitoring is required to optimize the effects of a drug or to indicate
that it needs replacing with other antithrombotic agents, as well as for identifying and enhancing the
platelet inhibition in this subgroup of patients to improve the clinical outcome and reduce bleeding
complications. As such, the aim of this article is to provide an update on the mechanism of action and
use of functional testing methods to assess antiplatelet efficacy in patients undergoing therapy with
GPIIb/IIIa antagonists.

KEYWORDS: glycoprotein IIb/IIIa n monitoring n platelets n therapy n thrombosis Giuseppe Lippi†1,

Biochemistry of glycoprotein IIb/IIIa
The human glycoprotein (GP)IIb/IIIa (also
known as integrin aIIbb3) is one of the best
characterized inducible type  I membrane-
spanning receptors present on the surface of
platelets [1] . GPIIb/IIIa belongs to the large
family of cation-dependent adhesion mole­cules
called integrins, which share a common het-
erodimeric structure. GPIIb/IIIa was initially
identified in 1974 by Nurden and Caen  [2] ,
who found an abnormal migration pattern of
platelet-associated glycoproteins from three
thrombasthenic patients compared with that
obtained from normal patients. Two of these
glycoproteins were undetectable on platelets
from thrombasthenic patients, and were indi-
vidually designated GPIIb and -IIIa [2] . In the
early 1980s, Jennings and Phillips purified
these glycoproteins and demonstrated that the
association between the two subunits to form
the heterodimer complex is calcium or man-
ganese dependent [3] . In 1992, the ana­lysis of
the primary structure of the subunit aIIb indi-
cated the presence of four stretches of amino
acid residues that were highly conserved among
various integrin a‑subunits and these have
been suggested to be putative calcium-binding
Martina Montagnana2,
Elisa Danese2,
sites. These findings also indicated that opti- Emmanuel J Favaloro3
mal fibrinogen binding occurs when the four & Massimo Franchini4
calcium-binding sites are occupied [4] . 1
UO di Diagnostica Ematochimica,
The mature aIIb subunit consists of a Dipartimento di Patologia e Medicina
large extracellular domain (partially made di Laboratorio, Azienda
Ospedaliero-Universitaria di Parma,
up of the four calcium-binding sites), a single Italy
trans­membrane-spanning region and a short 2
Sezione di Chimica Clinica,
Dipartimento di Scienze della Vita e
cytoplasmic tail [5] . The aIIb cytoplasmic and della Riproduzione, Università di
transmembrane domains, and a small portion of Verona, Italy
the extracellular domain form the 137-amino-
3
Servizio di Immunoematologia e
Trasfusione, Azienda
acid-long light chain while the majority of the Ospedaliero-Universitaria di Parma,
aIIb extracellular domain, including the four Italy
4
Department of Haematology,
calcium-binding sites, is associated with the Institute of Clinical Pathology &
871-amino-acid-long heavy chain  –  the two Medical Research (ICPMR), Westmead
Hospital, Westmead, Australia
chains are linked by a disulfide bond. The b3 †
Author for correspondence:
subunit is a single polypeptide (762  amino UO Diagnostica Ematochimica,
acids) and, along with the cytoplasmic, trans- Azienda Ospedaliero-Universitaria di
Parma, Strada Abbeveratoia 14,
membrane and extracellular domains, which 43126, Parma, Italy
are common domains of integrin subunits, con- Tel.: +39 052 170 3050
Fax: +39 052 170 3054
tains two other functional domains; an Arg- glippi@ao.pr.it
Gly-Asp (RGD) ligand-binding domain (which giuseppe.lippi@univr.it
allows the binding to RGD-containing mole-
cules such as fibronectin, von Willebrand factor
and vitronectin) and a region associated with
calcium-dependent stabilization of the aIIbb3
fibrinogen-binding pocket. The b3 subunit
also possesses five extracellular cysteine-rich

10.2217/BMM.10.119 © 2011 Future Medicine Ltd Biomarkers Med. (2011) 5(1), 63–70 ISSN 1752-0363 63
Review Lippi, Montagnana, Danese, Favaloro & Franchini
regions that facilitate disulfide bond forma-
tion and  confer a globular conformation to
the subunit.
The genes that encode the aIIb and b3 sub-
units (known as GP2B and GP3A, respectively)
have been found to have a close physical loca-
tion, mapping to the q21–23 band of chromo-
some 17. In fact, Bray et al. demonstrated that
the GP2B gene is located 3´ to the GP3A gene, in
the same 260‑kb pulsed field gel electrophoresis
fragment [6] . The GP2B gene consists of approx-
imately 17.2 kbp and contains 30 exons – des-
ignated 1–30 – that range in size from 45 to
249  bp [7] . The human b3 gene is 63  kb in
length and is composed of 14 exons – desig-
nated A to N – that range in length from 87
to 430 bp [8] . Platelets possess 40,000–80,000
molecules of aIIbb3 per cell, mainly distrib-
uted on the membrane surface [9,10] . However,
after platelet activation, the aIIbb3 molecules
located in the internal pool, as in the membrane
of a‑granules and in the canalicular system, are
translocated to the platelet surface [11] .
The primary function of GPIIb/IIIa is to aid
platelet aggregation by transmitting bi­directional
signals across the plasma membrane [12] . Nearly
20 years ago, Savage et al. demonstrated that the
GPIIb/IIIa on the membrane of nonactivated
platelets serves as a specific receptor for surface-
bound fibrinogen  [13] but, after platelet and
GPIb-IX activation [14] , this receptor acquires
the ability to interact with other adhesive pro-
teins, such as vitro­nectin, fibronectin and von
Willebrand factor [13] . Platelet activation by vari-
ous agonists, including ADP, collagen or throm-
bin, leads to a conformational change in plate-
let GPIIb/IIIa receptors (inside-out signaling),
which induces binding to fibrino­gen [15] . The
inside-out signaling mechanism is controlled
by the transmembrane–cytoplasmic domains
of integrin, a right-handed coiled-coil confor-
mation with two helices intertwined throughout
the trans­membrane region [16] . The consequence
is a cyto­skeletal reorganization and structural
changes in proteins that are directly or indirectly
linked to the cytoplasmic tails. Accordingly,
the affinity for ligands is regulated by tertiary
and quaternary conformational changes during
the transition from the inactive to the active
state [17] .
Multiple peptide motifs in fibrinogen have
been described. The main fibrinogen–plate-
let interaction site is the carboxyl-terminal
chain dodecapeptide sequence His-His-
Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val
(HHLGGAKQAGDV) between residues 400
64 Biomarkers Med. (2011) 5(1)
and 411; although two other fibrinogen sites
are involved: the sequences Arg-Gly-Asp-Phe
(RGDF) and Arg-Gly-Asp-Ser (RGDS) [18] . The
activation of GPIIb/IIIa by fibrinogen involves a
change in a redox site, located within the extra-
cellular cysteine-rich domain of the b‑subunit
of the receptor [19] . Both aIIb and b3 integrin
subunits contain these highly conserved cyste-
ine residues, which form disulfide bonds, thus
modifying the receptor from a low‑affinity to a
high-affinity state [20] .
The existence of constitutively active aIIb3
receptors has been recently demonstrated; these
are characterized by a high-affinity ligand
binding state caused by the presence of muta-
tions, one being the S527F mutagen in the b3
gene  [21,22] . It has also been demonstrated that
the physical properties of fibrinogen, which
might be at a high (as a multilayered material)
or low density, influence the integrin’s outside-
in signaling, thus altering cellular signaling
and adhesion [23] . Outside-in integrin aIIb3
signaling involves a series of tyrosine kinase
reactions that conclude in platelet spreading
on fibrinogen [24] .
Mechanisms of action & clinical
relevance of GPIIb/IIIa antagonists
Platelet activation occurs in response to vari-
ous agonists that act via independent metabolic
pathways that converge toward a common final
effect: GPIIb/IIIa activation and consequen-
tial platelet aggregation [25] . The consequent
change in the shape of the GPIIb/IIIa recep-
tor engenders greater affinity for binding to
soluble fibrinogen (through the RGD ligand-
binding tri­peptide sequence site), as well as
other adhesion molecules that also contain this
RGD-binding domain (e.g., von Willebrand
factor, vitronectin and fibronectin). Notably,
platelet aggregation is the final stage of pri-
mary hemostasis and is key to the formation of
a stable thrombus. While platelet aggregation
and thrombus formation is a natural defence
mechanism enacted to prevent loss of blood fol-
lowing tissue injury, excessive thrombus forma-
tion may occur in a variety of disease states and
lead to adverse, potentially fatal clinical events
such as thrombosis. Furthermore, excess or
uncontrolled platelet aggregation or thrombo-
sis formation may arise during some surgical
procedures that would normally lead to a high
level of platelet activation [26] .
As the GPIIb/IIIa receptor is among the
key integrins involved in platelet aggrega-
tion and, therefore, thrombus formation, the
future science group
 Glycoprotein IIb/IIIa inhibitors: mechanism of action & monitoring
development of GPIIb/IIIa antagonists has
become an attractive strategy for antiplatelet
therapy with an expected strong and specific
effect [27] . GPIIb/IIIa inhibitors are currently
based on monoclonal antibodies that irrevers-
ibly block the fibrinogen binding site (abcix-
imab), or small synthetic molecules that com-
petitively and reversibly block the binding site
for the RGD sequence (eptifibatide and tiro-
fiban)  [28] . All three drugs are administered
intravenously, and large-scale clinical trials
have demonstrated their clear clinical benefit
and good safety profile in high-risk patients
undergoing percutaneous coronary intervention
(PCI) [29] . In particular, Ernst et al. assessed
the extent of platelet aggregation inhibition in
patients with ST-segment elevation myocar-
dial infarction undergoing PCI, treated with
different antiplatelet agents and dosages  [30] .
Interestingly, although mean periprocedural
platelet aggregation inhibition only exceeded
80% with high-dose tirofiban, the angiographic
parameters after PCI did not significantly differ
among the groups. Furthermore, no relation-
ship was found between the level of platelet
aggregation and parameters of PCI success
after combining the data from all four groups
studied. Therefore, it could be concluded that
platelet aggregation inhibition in ST-segment
elevation myocardial infarction patients under­
going PCI and treated with antiplatelet agents
is variable and suboptimal for all agents and
dosages studied [30] .
Abciximab irreversibly binds to the
GPIIb/IIIa receptor and blocks the binding
of fibrinogen and other adhesion molecules
that would otherwise lead to platelet aggrega-
tion [31] . Unlike other GPIIb/IIIa antagonists,
abciximab is not specific for this receptor and
can also bind to vitronectin and leukocyte
integrin Mac‑1 [32] . Platelet inhibition occurs
with abciximab in a dose-dependent manner.
Following administration of a 0.25  mg/kg
intravenous bolus abciximab, there is an almost
complete reduction in platelet function, with
more than 80% receptor occupancy. A con-
tinuous weight-adjusted infusion is required to
maintain this degree of inhibition. The half-life
of abciximab is between 6 and 12 h. In addition,
owing to its irreversible binding with the recep-
tor, the recovery of platelet function after stop-
ping infusion is gradual and occurs 4–6 days
after treatment. Drug-related adverse effects
include a bleeding risk, caused by abciximab’s
great inhibitory potency and prolonged effect,
and thrombocytopenia can occur in up to 5%
future science group
Review
of treated patients [33] . Abciximab is currently
recommended as adjunct therapy in patients
with acute coronary syndrome (ACS) requiring
PCI, with and without stent implantation. A
meta-ana­lysis of the three major clinical tri-
als, Evaluation of Platelet IIb/IIIa Inhibitor
for Stenting (EPISTENT), Evaluation of c7E3
to Prevent Ischemic Complications (EPIC)
and Evaluation in Percutaneous Transluminal
Coronary Angioplasty to Improve Long-
term Outcome with Abciximab GP IIb/IIIa
Blockade (EPILOG), on the use of abciximab
in PCI demonstrated that abciximab treat-
ment resulted in a 20% decrease in all-cause
mortality during long-term follow-up [34] . By
contrast, its clinical efficacy in patients with
unstable angina, who were not scheduled for
PCI is less clear. Although several clinical tri-
als have demon­s trated a clear benefit [35,36] ,
differing results were obtained in the Global
Utilization of Strategies To open Occluded
arteries (GUSTO) IV study [37] . The differ-
ent outcomes can be explained by the fact
that abciximab is indicated for use down-
stream before PCI, but is not indicated for
upstream use.
Eptifibatide and tirofiban are small synthetic
molecules that reversibly and competitively
bind to the fibrinogen receptor. Both have a
short half-life (2 h) and, owing to the revers-
ibility of their effect, their antithrombotic
properties rapidly disappear after cessation of
treatment [38] . Several clinical trials have docu-
mented their efficacy in the treatment of ACS
without PCI and in high-risk patients with
diabetes mellitus or high troponin concentra-
tions [39] . In patients with ACS undergoing the
PCI Efficacy of Vasopressin Antagonism in
Heart Failure Outcome Study with Tolvaptan
(EVEREST) trial, upstream tirofiban was also
associated with improved tissue-level perfu-
sion and attenuated myocardial damage as
compared with abciximab [40] .
„„ Oral GPIIb/IIIa inhibitors
In contrast to the observed efficacy of intra­
venous GPIIb/IIIa inhibitors in the manage-
ment of ACS and as adjunctive therapy in PCI,
trials with oral GPIIb/IIIa inhibitors have, to
date, failed to demonstrate any benefit [41–44] .
In a pooled ana­lysis of over 33,000 patients, the
use of oral GPIIb/IIIa inhibitors was associated
with a significant increase in mortality (odds
ratio: 1.37; 95% CI: 1.13–1.67; p = 0.001) [45] .
Accordingly, oral GPIIb/IIIa inhibitors are not
available for clinical use.
www.futuremedicine.com 65
Review Lippi, Montagnana, Danese, Favaloro & Franchini

Laboratory monitoring of Function Analyzer (PFA)‑100 and VerifyNow ®

GPIIb/IIIa inhibitors
Although laboratory monitoring of antiplatelet
drugs cannot be considered a mainstay of such
therapy as yet, support for monitoring might
be proposed for a variety of reasons, including
the identification of patients with platelet non-
and hyporesponsiveness (potential treatment
failure), and the characterization of the peri-
operative bleeding risk in patients undergoing
surgical antiplatelet therapy. Platelet non- and
hypo­responsiveness has long been overlooked in
this setting and, even now, is potentially under-
estimated, with recent data suggesting that cur-
rent estimates might reflect the classical ‘tip of
the iceberg’. Furthermore, although relevant
epidemiological data are now available for other
antiplatelet agents, such as aspirin and clopido-
grel, much less is known regarding the burden
of hyporesponsiveness to GPIIb/IIIa inhibitors.
Whilst antiplatelet therapy with GPIIb/IIIa
inhibitors, and other agents such as aspirin and
clopidogrel, comprise important strategies dur-
ing and following PCI, adverse events related
to thrombosis or bleeding still occur, suggest-
ing variable responsiveness among patients.
Therefore, the lack of measurement in clini-
cal practice to assess the presence of platelet
responsiveness to these agents, based on a mis-
conception that ‘one size fits all’, would favor
some form of laboratory testing. At present,
there are a variety of methodologies and tech-
niques available to investigate platelet func-
tion, including platelet aggregometry, Platelet
(Table 1) . These methodologies and techniques
can also be utilized to assess the effectiveness
of antiplatelet agents [46,47] .
Galeote et al. assessed the degree of platelet
inhibition (with platelet aggregometry using 5
and 20 µmol/l concentrations of ADP), closure
time (measurement of platelet hemostatic capac-
ity using the PFA‑100) and platelet activation
markers in 15 patients undergoing basal coro-
nary angioplasty and abciximab treatment [48] .
Although up to 80% platelet aggregation inhi-
bition was observed in 13 patients (87%) dur-
ing the procedure, residual inhibition was only
observed in two (13%) after 24 h. Similarly, the
closure time during the procedure was markedly
prolonged (>300 s) in 13 patients (87%), but
six (17%) returned to normal values after 24 h.
Notably, no platelet inhibition or closure time
changes were observed in two patients (13%)
throughout the study period, reflecting inter-
patient variability [48] . In a similar investiga-
tion, Madan et  al. prospectively investigated
platelet function at baseline, 10 min, and 4, 12
and 24 h after the bolus by platelet-rich plasma
aggregometry, receptor occupancy studies (D3
assay) and PFA‑100 in 27  patients receiving
abciximab during PCI  [49] . The closure time
was maximally prolonged (>300  s) in 96%
of the patients immediately after abciximab
bolus and this prolongation persisted through-
out the infusion, whereas a variable recovery
from platelet inhibition was observed at 24 h
(in 72% of patients the closure time returned

Table 1. Advantages and limitations of laboratory techniques for monitoring

platelet function.
Technique Advantages Limitations
LTA Reference assay for evaluating High degree of technical
platelet responsiveness expertise required
Operator dependent
Specific requirements for
sample preparation
Length of assay time
Poor reproducibility
High sample volume
PFA-100 and Modest degree of technical expertise required Not universally recognized as gold
VerifyNow® Nonoperator dependent standard for evaluating platelet
Simple responsiveness as yet
Rapid availability of results (even at
the bedside)
Low sample volume
Good reproducibility
Impedance aggregometry has demonstrated a good correlation with optical aggregometry when testing the
glycoprotein IIb/IIIa inhibitors and thienopyridines. Sample preparation takes approximately 2 min and results are available
within 10 min after initiating the test. However, there are no prospective studies evaluating the predictive value of the
results obtained with impedance aggregometry.
LTA: Light transmission aggregometry; PFA: Platelet function analyzer.

66 Biomarkers Med. (2011) 5(1) future science group

 Glycoprotein IIb/IIIa inhibitors: mechanism of action & monitoring
to normal values). The results of PFA‑100 test-
ing were similar to those obtained with platelet
aggregometry and receptor occupancy measure-
ments [49] . In a following investigation, the same
authors assessed platelet function by PFA‑100
at baseline, 10 min, and 4, 12 (abciximab-only)
and 24 h after the bolus in 250 patients receiv-
ing abciximab or eptifibatide during PCI. A
profound inhibition of platelet function was
recorded in most patients (98%) shortly after
receiving the drug bolus, regardless of which
GPIIb/IIIa inhibitor was used for the proce-
dure. Recovery of platelet function was observed
12 h after discontinuation of abciximab despite
a high degree of interpatient variability, whereas
ongoing platelet inhibition could be demon-
strated 4–6 h after the discontinuation of eptifi-
batide. The failure to achieve maximal platelet
inhibition (nonclosure) at 10 min was also asso-
ciated with a threefold higher rate of adverse
clinical events after 6 months of follow-up.
Interestingly, obese patients treated with abcix-
imab displayed an earlier recovery from platelet
inhibition, whereas elderly patients recovered
later [50] . A variability in platelet responsiveness
(expressed as the proportion of patients achiev-
ing 80% inhibition of 20 µmol/l ADP-induced
platelet aggregation after 15 min of therapy) was
also described by Batchelor et al., the frequency
of nonresponsiveness being higher for tirofiban
(20–30%) than for eptifibatide and abciximab
(both <10%). However, after 12 h of therapy,
fewer abciximab-treated patients maintained
80% inhibition (~25%) than with eptifibatide
or tirofiban (both <10%) [51] .
Several hypotheses were formulated on
the mechanisms influencing the response of
platelets to GPIIb/IIIa antagonists, including
an enhanced platelet aggregability caused by
concomitant risk factors (e.g., hypertension,
hypercholesterolemia, cigarette smoking, stress
and medications, such as aspirin, which might
enhance platelet thromboxane A2 production
and thus GPIIb/IIIa activity), environmental
interactions, the baseline state of platelet func-
tion before initiation of treatment and genetic
polymorphisms in the genes encoding for the
GPIIb/IIIa complex [52,53] .
The perioperative assessment of drug-induced
platelet inhibition by antiplatelet drugs, includ-
ing GPIIb/IIIa inhibitors, is a further source of
contention, since no official guidelines or recom­
mendations are available thus far. However, it
is now widely acknowledged that the absolute
degree of platelet inhibition is significantly asso-
ciated with perioperative bleeding and the need
future science group
Review
for blood product transfusions, especially plate-
let concentrates, so that laboratory monitoring
of hemostatic function in patients undergoing
major surgery might, ultimately, be advisable for
suspending or tailoring the therapy according
to the individual risk of both thrombosis and
bleeding [54] .
However, the main concerns related to moni-
toring of antiplatelet therapy relate to the vari-
able sensitivity of different methodologies for
different agents, the lack of standardization
of these methods and the lack of large-scale
clinical outcome studies, meaning that current
laboratory monitoring cannot be translated into
any definitive clinical decision-making pro-
cess  [55–57] . In other words, although adverse
events still occur during surgical interventions,
such as PCI, despite the use of antiplatelet
agents, there is recognition that one size does
not fit all when it comes to antiplatelet ther-
apy and it is possible to measure this variabil-
ity in platelet therapy in the laboratory using
various methodologies. This cannot, as yet, be
translated into clinical practice, accordingly.
Conclusion
The administration of GPIIb/IIIa inhibitors is
an effective approach for improving the out-
comes of patients with ACS, including those
undergoing PCI. Recent evidence also attest
that intracoronary bolus administration of
GPIIb/IIIa inhibitors (eptifibatide) during
PCI in patients with ACS results in higher local
platelet GPIIb/IIIa receptor occupancy and
improved microvascular perfusion as well [58] .
However, the currently recommended drugs
and regimens designed to inhibit the platelet
GPIIb/IIIa receptor have heterogeneous phar-
macodynamic profiles that might affect their
relative efficacy in clinical practice. As such,
it might be concluded that the heterogeneous
pattern of platelet inhibition after adminis-
tration of GPIIb/IIIa therapy, along with the
evidence that a significant number of patients
might not achieve the minimal inhibition of
aggregation threshold with the current recom-
mended weight-adjusted dosages of these drugs,
might support the use of laboratory monitor-
ing for optimizing the effects of the drug or
to indicate the need to replace it with other
antithrombotic agents, as well as for identi-
fying and optimizing the absolute degree of
platelet inhibition in this subgroup of patients
to improve the clinical outcome and reduce
bleeding complications [51,59] . Although the
monitoring of GPIIb/IIIa antagonists can be
www.futuremedicine.com 67
Review Lippi, Montagnana, Danese, Favaloro & Franchini

performed by a variety of tests, including light
transmission aggrego­metry, whole blood assays,
flow cytometry, platelet adhesion assays and
radiolabeled antibody binding assays [60,61] , the
use of rapid, simple, cheap and sensitive assays
that identify those patients with an impaired
responsiveness or a heightened platelet reactiv-
ity (PR) is pivotal. VerifyNow and the PFA‑100
are user friendly point-of-care platelet-function
test systems, which allow rapid results and early
decision on the most suited antiplatelet drug
for the individual patient (Table 1) [59,62–63] . The
analytical performances of these systems might
even be optimal for this use, as demonstrated by
Stegnar et al., who observed highly significant
associations between platelet aggregation and
PFA‑100 closure time (correlation coefficients
ranging from 0.97 to 1.00; p < 0.001) [64] .
The suggestion to tailor antiplatelet treat-
ment with these analytical systems is further
supported by clinical evidence. In the study by
Campo et al., PR was measured using PFA‑100
and light transmission aggregometry using
ADP as an agonist for predicting the response
to treatment and outcome in patients with
ST-segment elevation myocardial infarction,
undergoing primary PCI assisted by GPIIb/IIIa
inhibition. The PR was assessed at entry, 10 min
after GP IIb/IIIa bolus and at discharge.
According to both methods, PR at entry was
higher than both PR at discharge and PR in
30 stable angina patients. PR at entry was also
higher in patients with a final Thrombolysis in
Myocardial Infarction flow grade of less than
three. Furthermore, the PR at entry, as assessed
with PFA‑100, significantly correlated with cor-
rected thrombolysis in myocardial infarction
frame count, ST-segment resolution, and cre-
atine kinase-MB. More interestingly, patients
with high PR at entry demonstrated an adjusted
five‑ to 11-fold increase in the risk of death,
reinfarction and target vessel revascularization
after 1 year [65] .
Similar results were obtained by Steinhubl
et al., who evaluated patients undergoing a PCI
with the planned use of a GPIIb/IIIa inhibitor
using the ultegra rapid platelet function assay at
10 min, and 1, 8 and 24 h after the initiation of
therapy [66] . Approximately 25% of all patients
did not achieve 95% inhibition 10 min after the
bolus and experienced a significantly higher inci-
dence of major adverse cardiac events (14.4 vs
6.4%; p = 0.006). Furthermore, those patients
whose platelet function was less than 70% inhib-
ited at 8 h after the start of therapy had a higher
major adverse cardiac event rate compared with
those with a greater than 70% inhibition (25
vs 8.1%, respectively; p = 0.009). Platelet func-
tion inhibition greater than 95% at 10 min after
the start of therapy was also significantly associ-
ated with a decrease in the incidence of a major
adverse cardiac event, displaying an odds ratio of
0.46 (95% CI: 0.22–0.96; p = 0.04) [66] .
Future perspective
There is growing focus and research on rapid,
easy-to-use and cheap techniques for assessing
platelet responsiveness in individual patients
undergoing therapy with GPIIb/IIIa inhibitors.
However, the translation of all of the afore-
mentioned issues into a reliable test process
that would involve all general laboratories still
awaits better standardization of methodologies,
the identification of optimal conditions and the
formulation of evidence-based guidelines.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

Executive summary
ƒƒ The glycoprotein (GP)IIb/IIIa receptor is among the key integrins involved in platelet aggregation and thrombus formation.
ƒƒ The development of GPIIb/IIIa antagonists (e.g., abciximab, eptifibatide and tirofiban) has become an attractive strategy for antiplatelet
therapy with an expected strong and specific effect.
ƒƒ Large-scale clinical trials have demonstrated positive outcomes for all of these drugs, especially in patients undergoing percutaneous
coronary intervention.
ƒƒ The occasional adverse outcomes (i.e., thrombosis and bleeding) reported in some patients undergoing therapy with GPIIb/IIIa
antagonists reflects a variable interindividual responsiveness, which calls for some form of laboratory monitoring.
ƒƒ Although there is growing focus and research on rapid, easy-to-use and cheap techniques (e.g., Platelet Function Analyzer-100 and
VerifyNow®) for assessing platelet responsiveness as a surrogate of the traditional light transmission aggregometry in individual patients,
these point-of-care analyzers still need better standardization of methodologies, identification of optimal conditions and formulation of
evidence-based guidelines.

68 Biomarkers Med. (2011) 5(1) future science group

 Glycoprotein IIb/IIIa inhibitors: mechanism of action & monitoring
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