Download Platelet Glycoprotein IIb/IIIa Inhibitors

Platelet Glycoprotein IIb/IIIa Inhibitors
Basic and Clinical Aspects
Alan T. Nurden, Christel Poujol, Catherine Durrieu-Jais, Paquita Nurden
G
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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 EPIC6 and EPILOG7 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 A2 and ADP-dependent pathways of platelet activation11 (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, anti–GPIIb-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
lycoprotein IIb/IIIa (GPIIb-IIIa) complexes (integrin
aIIbb3) 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 GPIIbIIIa 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 g 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.1–3 Anti–GPIIb-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 anti–GPIIb-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-mg/min infusion (mostly between 12 and 24 hours), and
Received February 25, 1999; revision accepted April 28, 1999.
From the UMR 5533 CNRS and the Unité des Soins Intensifs (C.D.-J.), Institut Fédératif de Recherche “Cœur-Vaisseaux-Thrombose,” Hôpital
Cardiologique, Pessac, France.
Correspondence to Alan T. Nurden, Director, UMR 5533 CNRS, Hôpital Cardiologique, 33604 Pessac, France. E-mail Alan.Nurden@
cnrshl.u-bordeaux2.fr
(Arterioscler Thromb Vasc Biol. 1999;19:2835-2840.)
© 1999 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
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Arterioscler Thromb Vasc Biol.
December 1999
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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.
cases by tissue plasminogen activator or even by PTCA by
halting the incorporation of incoming platelets. However, the
association of abciximab or other anti–GPIIb-IIIa agents with
powerful anticoagulants or with thrombolytics increases the
risk of bleeding.
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 anti–GPIIb-IIIa therapies are now available.13–15
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 –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 smallmolecular-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
(,203109/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 ligandinduced 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 anti–GPIIb-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-mg/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, marrowrelated 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 avb3 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 RGDbased 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 protocol9 to patients with unstable angina undergoing PTCA.26 Before the onset of therapy, the percentage of
Nurden et al
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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 GPIIbIIIa. 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 al27 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 al27 also showed that 2
small-molecular-mass inhibitors were able to activate GPIIbIIIa but that aspirin prevented “aggregation” induced by the
anti–GPIIb-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 anti–GPIIb-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 anti–GPIIb-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 –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 receptor–activating 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
Anti–GPIIb-IIIa Therapy
2837
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). 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 receptor–activating 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 a-granules, as has been shown for platelets stimulated in
vitro with thrombin.21
The ability of anti–GPIIb-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 a-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, smallmolecular-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 Glanzmann’s 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 anti–GPIIb-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/
2838
Arterioscler Thromb Vasc Biol.
December 1999
Some of the Factors That May Influence the Efficacy of
GpIIb-IIIa Inhibitors in Different Individuals
1. Platelet count
High: low level of GPIIb-IIIa occupancy
Low (including enlarged spleen): increased bleeding risk
2. Plasma antibodies
To mouse immunoglobulin determinants (abciximab)
To neonantigens on GPIIb-IIIa (type anti-LIBS)
3. Presence of circulating activated platelets
4. Capacity for the inhibition of the internal pool of GPIIb-IIIa complexes
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 anti–GPIIbIIIa 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
In circulating resting platelets
During secretion and surface expression
5. Interindividual variations in the reactivity of the drug with GPIIb-IIIa
Polymorphisms of GPIIb and/or GPIIIa
Influence of high or low GPIIb-IIIa density
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6. Different rates of drug metabolism or in the rate of elimination from the
blood stream
7. Presence of other thrombotic risk factors (eg, high cholesterol may
influence membrane fluidity; diabetes, factor V Leiden, or prothrombin
gene G 20210 A variants, polymorphisms of other platelet receptors)
8. Degree of atherosclerosis or variations in the size of the PTCA lesion and
the frequency of platelet/vessel wall interactions
9. Variations in the reactivity of platelets with other drugs used during
therapy (eg, aspirin, heparin)
LIBS indicates ligand-induced binding sites.
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 A2 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 anti–GPIIb-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 b-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
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 avb3
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 activationdependent neoantigen present on the leukocyte integrin Mac1.38 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-1–
bearing 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 avb3 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 avb3
on platelets can inhibit tissue factor–induced 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 Ca21-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
Nurden et al
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 anti–GPIIb-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 anti–GPIIb-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.
Acknowledgment
16.
17.
18.
19.
This study was financed by funding from the CNRS, Université de
Bordeaux II (DRED), the Conseil Régional d’Aquitaine.
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KEY WORDS: glycoproteins
drugs
n abciximab n platelet aggregation n antithrombotic
Downloaded from http://atvb.ahajournals.org/ by guest on May 2, 2017
Downloaded from http://atvb.ahajournals.org/ by guest on May 2, 2017
Platelet Glycoprotein IIb/IIIa Inhibitors: Basic and Clinical Aspects
Alan T. Nurden, Christel Poujol, Catherine Durrieu-Jais and Paquita Nurden
Arterioscler Thromb Vasc Biol. 1999;19:2835-2840
doi: 10.1161/01.ATV.19.12.2835
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