Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2835-2840
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2835.)
© 1999 American Heart Association, Inc.
Platelet Glycoprotein IIb/IIIa Inhibitors
Basic and Clinical Aspects
Alan T. Nurden;
Christel Poujol;
Catherine Durrieu-Jais;
Paquita Nurden
From the UMR 5533 CNRS and the Unité des Soins Intensifs
(C.D.-J.), Institut Fédératif de Recherche
"C
ur-Vaisseaux-Thrombose," Hôpital Cardiologique,
Pessac, France.
Correspondence to Alan T. Nurden, Director, UMR 5533 CNRS, Hôpital Cardiologique, 33604 Pessac, France. E-mail Alan.Nurden{at}cnrshl.u-bordeaux2.fr
Key Words: glycoproteins abciximab platelet aggregation antithrombotic drugs
 |
Introduction
|
|---|
Glycoprotein IIb/IIIa (GPIIb-IIIa) complexes (integrin
IIbß
3)
mediate
platelet aggregation by binding fibrinogen or von
Willebrand
factor (vWF), protein cofactors that form bridges
between adjacent
platelets. The cross-linked adhesive proteins
assemble platelets
into the aggregate. Agents that block the
function of the GPIIb-IIIa
complex of platelets constitute a
powerful new generation of
antithrombotic drugs.
1 Among
the short- and long-term aims
of such drugs are (1) to provide
immediate relief in the case
of ongoing arterial thrombosis
and (2) to eliminate excessive
platelet reactivity in diseased
vessels so that occlusive thrombi
and restenosis do not occur,
while allowing sufficient hemostasis
to prevent spontaneous bleeding.
It should be emphasized that
stenosis and partial occlusion are
both prothrombotic, with
increased shear stress promoting platelet
activation. Under
these conditions, vWF plays a major role in the
mediation of
thrombus formation, interacting with GPIIb-IIIa and the
adhesion
receptor GPIb.
2 Otherwise, fibrinogen is the
major cofactor
of platelet aggregation, essentially binding through
a dodecapeptide
sequence (aa400 to aa411) present at the carboxy
terminus of
each

chain. Binding of vWF and other adhesive proteins,
such
as fibronectin, to GPIIb-IIIa is mediated by the Arg-Gly-Asp
(RGD)
sequence, a universal mediator of cellular interactions
with the
extracellular matrix.
1 2 3 AntiGPIIb-IIIa drugs
block
this final step of the platelet aggregation process. They
also
block the "outside-in" signaling that follows the binding
of
adhesive proteins to activated GPIIb-IIIa and the onset of
platelet
aggregation.
3 This signaling may promote
events such as secretion,
clot retraction, and the expression of
procoagulant activity;
therefore, its inhibition extends the influence
of antiGPIIb-IIIa
drugs beyond the blocking of
platelet-to-platelet cohesion.
 |
GPIIb-IIIa Inhibitors Constitute a Wide Class of
Drugs
|
|---|
The present review will mostly be illustrated by results
obtained
with abciximab (c7E3 Fab, ReoPro), a chimeric antibody
fragment
that is the most widely used of the new
inhibitors.
1 Abciximab
acts rapidly; >80% of
platelet receptors are blocked within
2 hours of the administration
of a 0.25 mg/kg bolus in humans.
4 Saturation is maintained
during a 10-µg/min infusion
(mostly between 12 and 24 hours), and
recovery of platelet function
is gradual after the infusion is
stopped. Whereas plasma levels
quickly fall, platelet-bound
abciximab can be detected for up
to 15 days after treatment. Flow
cytometry shows that histograms
representing bound drug
within the total platelet population
remain homogeneous
while decreasing in intensity.
5 EPIC
6 and
EPILOG
7 trials, among others, showed a beneficial effect
of sustained
blockade of the GPIIb-IIIa receptor by abciximab in
patients
undergoing high-risk percutaneous transluminal
coronary angioplasty
(PTCA) or directional coronary
atherectomy. The effect was defined
in EPIC as a 35% relative risk
reduction of death, myocardial
infarction, or urgent
revascularization within 30 days. An extended
follow-up
has since shown that abciximab also improves the probability
of
event-free survival over a long period.
8 Although the
risk
of excessive bleeding was highlighted in the EPIC trial,
weight-adjusted
heparin dosing and early sheath removal in subsequent
trials
led to improved safety.
7 9 The occasional need for
emergency
coronary bypass surgery is helped by the rapid
clearance of
abciximab from plasma, and platelet transfusion will
provide
functional platelets, lower the free plasma levels of the
drug
further, and promote the antibody exchange that has been suggested
to
occur between circulating platelets.
5 Abciximab
also substantially
improves the safety of coronary stenting,
now used in >60%
of percutaneous
revascularization procedures in the United
States.
10 Stenting can itself promote GPIIb-IIIa complex
activation and
predispose to coronary thrombus formation. The
combination of
aspirin and ticlopidine inhibits the
thromboxane A
2 and ADP-dependent
pathways
of platelet activation
11 (Figure

). However,
multiple intracellular
pathways appear to be involved in platelet
activation, and these
include serine and threonine
phosphorylation of proteins by
protein kinase C and
phosphorylation of tyrosine residues on
proteins by
tyrosine kinase enzymes.
3 However, different agonists
use
different pathways, and by blocking the end step of platelet
aggregation
common to all physiological agonists,
antiGPIIb-IIIa
drugs provide a theoretically wider range of
protection. GPIIb-IIIa
inhibition is also now often considered as part
of a last resort
"rescue" therapy in the case of abrupt
coronary occlusion or
the failure of PTCA to restore the
circulation.
12 The concept
is that this facilitates the
dispersion of platelet-rich thrombi
in difficult cases by tissue
plasminogen activator or even by
PTCA by
halting the incorporation of incoming platelets. However,
the
association of abciximab or other antiGPIIb-IIIa
agents with powerful
anticoagulants or with thrombolytics increases
the risk
of bleeding.

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Figure 1. Schematic diagram showing the target for GPIIb-IIIa
inhibitors. Platelet activation can be initiated by
adhesion to immobilized substrates in the vessel wall or to
a fibrin clot or by soluble agonists such as ADP and thrombin.
Antiplatelet therapies can target individual receptor-linked
activation pathways. For example, ticlopidine and clopidogrel act on an
ADP-induced activation pathway. Aspirin dampens the platelet
response by inactivating cyclooxygenase enzyme
(Cox-1) and preventing thromboxane A2
(TXA2) formation. GPIIb-IIIa inhibitors block
the final step of platelet aggregation common to all agonists, the
binding of fibrinogen or vWF to activated GPIIb-IIIa complexes.
Such inhibitors include an antibody, abciximab (c7E3 Fab
fragments), a cyclic peptide (eptifibatide), and 2 peptidomimetics
(lamifiban and tirofiban), all of which require intravenous
injection (left side of Figure). Orally bioavailable
inhibitors include xemilofiban, DMP 802, and SR 121787
(right side of Figure). These are just selected examples of the
anti-integrin therapies being tested.
|
|
The fabrication of synthetic small-molecule inhibitors
(some are called peptidomimetics because they mimic RGD peptides)
designed for intravenous administration, such as
eptifibatide (integrelin), lamifiban, and tirofiban, means that
alternative antiGPIIb-IIIa therapies are now
available.13 14 15 Eptifibatide is a small cyclic
heptapeptide, and lamifiban and tirofiban are nonpeptide
peptidomimetics. These compounds, which circulate for shorter times
than does abciximab, have also been found to be beneficial in acute
situations, such as after PTCA or stenting. Another family of synthetic
inhibitors, such as xemilofiban, DMP 802, and SR 121787,
may be taken orally and are being assessed for long duration use in
patients with coronary artery disease who are considered
vulnerable for major thrombotic episodes.16 17 18 This
latter group consists mostly of prodrugs that are biologically
transformed into active metabolites. However, it remains to be seen
whether safety parameters will allow their use chronically,
in view of the fact that some compounds have already been withdrawn
because of a higher than acceptable bleeding risk and/or
thrombocytopenia (see below). Another concern is that the apparent
potency of some small-molecular-mass GPIIb-IIIa antagonists
can be enhanced by citrate and that microaggregates can still often be
detected by platelet counting, thus hampering the interpretation of
drug efficacy in in vitro tests.19
 |
Effects on Circulating Platelet Count
|
|---|
Thrombocytopenia is an often-cited complication of the use of
GPIIb-IIIa
receptor antagonists. In one study, it has
recently been estimated
that profound thrombocytopenia
(<20
x10
9/L) during abciximab
therapy affects

0.5% of patients.
20 Often, though, administration
of
the drug is interrupted before such low counts are reached.
The
mechanisms responsible for the thrombocytopenia are not
known, although
different causes may be evoked. With abciximab,
one possible
explanation involves naturally occurring antibodies
that recognize
epitopes on mouse IgG still present on the chimeric
Fab fragments.
The binding of immune complexes to platelets
will be followed by
their clearance by way of the reticuloendothelial
system
and the spleen. The pressure for the repeated use of abciximab
will
increase as the previously treated patient is confronted with
more
problems later, and anaphylaxis could yet become a more
important
worry. Another explanation for the thrombocytopenia
is that host
immunoglobulins could recognize neoepitopes expressed
on GPIIb-IIIa
after a drug has bound (the so-called ligand-induced
binding
sites).
21 Such a mechanism could explain the rapid
thrombocytopenia
induced by small-molecular-mass inhibitors
of GPIIb-IIIa, including
the orally bioavailable drugs.
Another relevant question is whether antiGPIIb-IIIa drugs can
penetrate into the marrow and interfere with thrombopoiesis. We have
looked for abciximab in the sternal marrow aspirate of a patient who
received a bolus followed by a 10-µg/mL infusion for 3 hours before
the stopping of therapy because of bleeding. Thrombocytopenia was
noted, and this continued to develop (C. Poujol, C.
Durrieu-Jais, B. Larrue, A.T. Nurden, P. Nurden, unpublished data,
1999). At 15 hours, the time at which the marrow cells were obtained,
proplatelet fragments in the vascular sinuses were heavily labeled
with abciximab, but megakaryocytes within the marrow were only weakly
labeled. Thus, it would seem unlikely that abciximab penetrates into
the marrow in such quantities to interfere with megakaryocyte
maturation and stem cell proliferation, and certainly, this would not
bring about major falls in platelet count within 24 hours.
Nevertheless, marrow-related changes must remain a major concern for
prolonged therapy with small-molecular-mass inhibitors.
There is abundant evidence pointing to a role for RGD-binding integrins
during hematopoiesis and angiogenesis. Recently, accutin, a 5-kDa snake
venom disintegrin that blocks GPIIb-IIIa and binds competitively with
c7E3 for
vß3 on human
umbilical cord endothelial cells, has been shown to
inhibit angiogenesis and to induce apoptotic fragmentation of
endothelial cells.22 Similar results have
been obtained for other RGD peptides.23 These findings
imply caution in the long-term use of RGD-based drugs, while confirming
a potential role for them as antimetastatic agents.
 |
Effect on Platelet Activation
|
|---|
Platelet activation is known to occur episodically in
coronary
syndromes, and elevated levels of circulating
activated platelets,
as detected by flow cytometry, have
been said to be predictive
for increased risk of acute ischemic
events after PTCA or stenting,
although the interpretation of such
measurements remains controversial.
24 25 We have recently
compared the expression of activation-dependent
markers on
platelets during abciximab therapy given according
to the CAPTURE
protocol
9 to patients with unstable angina undergoing
PTCA.
26 Before the onset of therapy, the percentage of
platelets positive
for one or more of the monoclonal antibodies
directed against
GPIIb-IIIa complexes that are "activated and
unoccupied" (PAC-1)
or "activated and occupied with
fibrinogen" (AP6 and F26) were
elevated for 5 of 6 patients studied.
Abciximab therapy reduced
these levels appreciably, presumably through
the blockade of
the active site of GPIIb-IIIa. Testing of samples taken
after
the bolus and 3 hours into the infusion confirmed that for most
patients
near-maximal inhibition of platelet aggregation was
already
achieved. This inhibition continued during the duration of the
abciximab
infusion (up to 24 hours). However, for one patient, a
residual
irreversible aggregation response was seen with ADP.
Interestingly,
it was for this patient that activation-dependent
markers on
GPIIb-IIIa continued to be detected, suggesting continued
platelet
hyperactivity and a resistance to abciximab. Peter et
al
27 have recently shown that the binding of abciximab
itself induced
conformation changes in GPIIb-IIIa and, in so doing,
mimicked
the changes previously shown for some RGD peptides. According
to
these authors, the changes were such that when abciximab dissociated
from
the complex, a process facilitated in their experimentation
by the
large-scale dilution of the platelet suspensions, fibrinogen
was
able to bind without the normal requirement for platelet
stimulation
by an agonist. Peter et al
27 also showed that
2 small-molecular-mass
inhibitors were able to
activate GPIIb-IIIa but that aspirin
prevented
"aggregation" induced by the antiGPIIb-IIIa
drugs. Further
studies are required to confirm that such events
occur in vivo and to
determine whether this can lead to clinical
drawbacks. In our previous
study,
26 activated platelets progressively
reappeared
in the circulation after the stopping of the abciximab, but
this
can be due to the fact that the cause of increased platelet
stimulation
had not been removed (eg, fissured atherosclerotic plaques,
stenosis,
and resistant fibrin-rich thrombi).
Intersubject heterogeneity in the extent and duration
of inhibition of platelet aggregation has been previously shown in
patients with coronary artery disease receiving
abciximab.4 9 26 Among the other factors that may
influence the recovery rate after antiGPIIb-IIIa therapy are (1)
variations in the plasma levels of free drug, (2) the rate at which
surface-bound drug dissociates from circulating
platelets,5 and (3) the extent to which GPIIb-IIIa
receptors are exchanged between surface and internal
pools.28 Therefore, it is reasonable to suggest
that biological surveillance, with testing of platelet function and
flexibility with regard both to the doses used and the duration of
therapy, may help to improve the success rate with antiGPIIb-IIIa
inhibitors in acute situations. This may also be so with
orally bioavailable drugs that are used chronically and for which the
degree of sustained receptor inhibition may be
lower.16 17 18
 |
Internal Pools of GPIIb-IIIa and Trafficking of Abciximab
|
|---|
Although ADP-induced platelet aggregation was extensively
inhibited
by abciximab in our previous study,
26
platelet responses to
thrombin receptoractivating peptide
(14mer) during abciximab
infusion ranged from 28% to 71% of
pretreatment levels. Similar
results have previously been reported for
patients after a single
bolus injection of abciximab.
29
Estimates suggest that between
35 000 and 100 000 copies of
GPIIb-IIIa are to be found on the
surface of resting platelets and
that a pool of similar proportions
is to be found inside the
platelet (data reviewed in Reference
30
30 ). Using the monoclonal
antibody AP-2, competitive for
GPIIb-IIIa with c7E3, in flow cytometry
or immunoelectron microscopy,
we have shown that unblocked (with
abciximab) GPIIb-IIIa receptors
from the internal pool do indeed become
exposed after thrombin
stimulation of platelets taken from patients
during abciximab
infusion.
26 A residual aggregation with
thrombin receptoractivating
peptide during the infusion and after the
administration of
the abciximab bolus suggests that the concentration
of free
abciximab in plasma is insufficient to block these newly
exposed
receptors within the time scale of platelet aggregation,
which
will occur in seconds. The ability of peptides, peptidomimetics,
and
orally bioavailable drugs to inhibit aggregation with strong
agonists
will therefore depend on their affinity for GPIIb-IIIa and
their
sustained concentration in plasma. Furthermore, some GPIIb-IIIa
complexes
of the internal pool may be surface-expressed with the
already
active site occupied with fibrinogen being secreted from

-granules,
as has been shown for platelets stimulated in vitro
with thrombin.
21
The ability of antiGPIIb-IIIa drugs to gain access to internal pools
of GPIIb-IIIa complexes of circulating platelets is therefore an
important question to address. We have examined the trafficking of
abciximab within platelets at different time points during
therapeutic infusion by immunoelectron microscopy using a rabbit
antibody specific for c7E3.31 It appears that abciximab
gains access to the internal membrane subpopulations of GPIIb-IIIa by 2
mechanisms: (1) through thin channels of the surface-connected
canalicular system and (2) by way of clathrin-coated
pits and endocytosis. However, there is not a continuous accumulation
and storage of the antibody within
-granules as is seen, for
example, for fibrinogen.28 This means that internal pools
of GPIIb-IIIa do not become saturated with the drug. Furthermore, the
fact that abciximab is a Fab fragment and monovalent raises the
possibility that we are visualizing natural recycling of GPIIb-IIIa
between the surface and internal pools. Such recycling has previously
been implied from studies performed with an RGD-based
peptide28 ; thus, small-molecular-mass
inhibitors of GPIIb-IIIa may be expected to behave
similarly. The difference in the functional response between
platelets from patients receiving abciximab and those from patients
with Glanzmanns thrombasthenia is important to emphasize. In the
latter, an inherited GPIIb-IIIa deficiency extends to all membrane
systems,32 whereas at the present therapeutic doses of
abciximab, a residual pool of functional GPIIb-IIIa complexes can be
expressed after a strong hemostatic challenge. Whether this limits the
efficacy of abciximab or provides a protective backup to limit the
tendency for hemorrhage is an essential question to address
both for abciximab and for other antiGPIIb-IIIa drugs.
 |
Interindividual Variability in the Response to Treatment
|
|---|
The inhibition provided by abciximab continues at various levels
for
several days after the infusion has stopped. Possible explanations
for
its durability include the combined effects of a high affinity
for
GPIIb-IIIa and a frequent association/dissociation cycle,
which means
that the c7E3 Fab fragments simply move from one
platelet to
another and are not cleared.
5 Smaller
inhibitors
of GPIIb-IIIa are eliminated from the
bloodstream more rapidly
than is abciximab. This can be considered to
be a safety benefit
in the case of untoward bleeding but may lead to a
lower efficacy
unless the drugs are infused for longer periods. Such
factors
are critical in that at 80% receptor occupancy, ADP-induced
platelet
aggregation is severely reduced, whereas at 50%
occupancy, aggregation
can be more or less normal.
4 5
Thus, the "window" for successful
therapy is fairly narrow, and for
some donors, recovery of platelet
function after the drug has been
stopped can be quick, even
with abciximab.
26 The
additional inhibition of thromboxane
A
2 synthesis by aspirin can influence
platelet aggregate stability
and permit a more rapid dissolution of
thrombi in vivo, a potentially
important factor in "rescue"
therapy.
12 33
It is plausible that some individuals possess GPIIb-IIIa complexes,
where abciximab (or other antiGPIIb-IIIa drugs) bind with an altered
affinity or where there is an increased propensity for fibrinogen to
bind (Table
). Polymorphisms in the cytoplasmic domains of
GPIIb and GPIIb, implicated in controlling the activation state of the
complex,3 are a potential field for study here.
Furthermore, a higher than usual density of GPIIb-IIIa complexes could
render a standard dose of drug unsuccessful. Variations in patient
reactivity to heparin or other medications received by patients with
unstable angina (nitrates, calcium antagonists, and/or
ß-blockers) may also influence the end result. The activating
potential of heparin on platelets is well known, and its ability to
potentiate the expression of activation-dependent markers has recently
been reported.34 Whereas there is a standard dose of drug,
there is no such thing as a standard patient. Thus, increased
biological testing to assess whether platelet function is
adequately inhibited might improve the success rate with all
antiGPIIb-IIIa drugs. Although platelet aggregometry or flow
cytometry are of proven use, simple and rapid point-of-care tests may
provide the answer. Among such tests is an automated and quantitative
cartridge-based method assessing the competence of the GPIIb-IIIa
receptor, as reflected in the ability of platelets to agglutinate
fibrinogen-coated beads.35 An alternative system looks at
the activated clotting time of whole blood.36
 |
Other Potential Actions of GPIIb-IIIa Inhibitors That
Influence Their Activity
|
|---|
Abciximab not only reacts with GPIIb-IIIa but also demonstrates
equivalent
affinity and functional blockade of the
vß
3
integrin.
37 This latter integrin is widespread, being
found on endothelial
cells, osteoclasts, and smooth
muscle cells, among others. We
have recently confirmed the reactivity
of this drug with the
luminal surface of endothelial
cells lining the vascular sinuses
in the bone marrow (C. Poujol, C.
Durrieu-Jais, B. Larrue, A.T.
Nurden, P. Nurden, unpublished data,
1999). Abciximab also interacts
with an activation-dependent neoantigen
present on the leukocyte
integrin Mac-1.
38 These
findings are explained through the
presence of subunit structural
homology and a common epitope
recognized by the antibody, which blocked
the binding of Mac-1bearing
cells to fibrinogen and intercellular
adhesion molecule-1, both
ligands of Mac-1.
38 The
implication is that the drug can interfere
with the recruitment of
monocytes to sites of vessel injury
and inflammation. Although whether
these properties provide
an additional in vivo benefit of abciximab
therapy remains controversial,
an inhibitory action of
antiplatelet drugs on Mac-1 and
vß
3 may potentially
reduce neointimal hyperplasia after vessel injury
and
participate in the long-term benefits of their use. In this
respect,
abciximab contrasts, for example, with eptifibatide,
which is specific
for GPIIb-IIIa.
13
The finding by Reverter et al39 that abciximab has a
dampening effect on platelet-mediated thrombin generation may also
help explain its antithrombotic efficacy. In that study, the evidence
from in vitro experiments suggested that blocking ligand binding to
GPIIb-IIIa and
vß3 on
platelets can inhibit tissue factorinduced thrombin generation by
up to 50%. This was caused by inhibition of the expression of
procoagulant activity on platelets and the release of procoagulant
microparticles (surface exposure of aminophospholipids is followed by a
Ca2+-dependent binding of factor Va, factor Xa,
and prothrombin and a process of microvesiculation). This unexpected
dampening of platelet reactivity may be due to the inhibition of
"outside-in" signaling promoted by GPIIb-IIIa occupancy and
platelet aggregation.3 Prothrombin has also been shown
to bind to GPIIb-IIIa directly but by a mechanism different from that
of fibrinogen.40 Reduced thrombin generation in the area
of vessel injury may also mean less smooth muscle migration and
hyperplasia (and restenosis), and less fibrin-bound thrombin
within the clot can reduce resistance to thrombolysis
via activation of factor XIII. Finally, there is evidence that fibrin
can also interact with additional sites on GPIIb-IIIa complexes
compared with soluble fibrinogen.41 Because fibrin is a
component of most thrombi, the ability of drugs to inhibit platelet
attachment to fibrin may be another factor in controlling their
antithrombotic potential. Thus, there is a great deal yet to learn
about the mode of action of antiGPIIb-IIIa drugs, and new
inhibitors must be tested as comprehensively as possible.
Not least, our understanding of the mechanisms underlying those
ischemic events that continue despite the use of the
antiGPIIb-IIIa inhibitors must be increased, because
these drugs, although representing a major step forward in
the control of arterial thrombosis, do not provide a total
protection.
 |
Acknowledgments
|
|---|
This study was financed by funding from the CNRS,
Université
de Bordeaux II (DRED), the Conseil Régional
dAquitaine.
Received February 25, 1999;
accepted April 28, 1999.
 |
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