(Circulation. 2000;101:1122.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Abciximab, Ticlopidine, and Combined Abciximab/Ticlopidine Therapy on Platelet and Leukocyte Function in Patients Undergoing Coronary Angioplasty
From the Department of Bioengineering, Rice University (B.J.F., N.A.T., L.V.M.); the Department of Medicine, Baylor College of Medicine (N.S.K., N.G., K.M.), Houston, Tex; Eli Lilly & Co (M.B.E.), Indianapolis, Ind; and Centocor, Inc (M.A.M.), Malverne, Pa.
Correspondence to Larry V. McIntire, PhD, Department of Bioengineering, Rice University, PO Box 1892, Houston, TX 77251. E-mail mcintire{at}rice.edu
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Abstract |
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Background—Abciximab and ticlopidine reduce adverse cardiovascular events after percutaneous transluminal coronary angioplasty (PTCA). The goal of the current study was to determine if combined abciximab/ticlopidine therapy inhibits arterial thrombosis more effectively than either treatment alone. The effect of each therapy on platelet-leukocyte interactions was also investigated.
Methods and Results—Whole blood samples from 14 patients
undergoing PTCA who received abciximab therapy, ticlopidine therapy, or
both treatments were evaluated using dynamic experimental systems.
Mural thrombus formation under arterial shear conditions
(1500 s-1) was determined in a parallel plate flow
chamber. Shear-induced platelet aggregation was evaluated using a
cone-and-plate viscometer at a shear rate of 3000 s-1. Of
the 3 treatments, combined abciximab/ticlopidine therapy produced the
most consistent reduction in shear-induced platelet
aggregation and the most prolonged inhibition of mural thrombosis.
Three days after PTCA, abciximab/ticlopidine treatment decreased mural
thrombus formation to 
50% of baseline values. Abciximab treatment
alone inhibited mural thrombosis for only 1 day after PTCA, whereas
ticlopidine treatment alone had no significant effect. Two hours after
PTCA, abciximab therapy significantly decreased the number of
circulating platelet-neutrophil aggregates but significantly
enhanced P-selectin–mediated leukocyte adhesion on the collagen/von
Willebrand factor–platelet surface.
Conclusions—Combined therapy with abciximab and ticlopidine has a prolonged inhibitory effect on mural thrombosis formation relative to either treatment alone. Further, we demonstrated an unexpected effect of abciximab in enhancing P-selectin–mediated leukocyte adhesion.
Key Words: platelets • leukocytes • thrombosis • abciximab • ticlopidine • angioplasty
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Introduction |
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Pathological arterial thrombosis limits the success of percutaneous transluminal coronary angioplasty (PTCA) by causing short-term ischemic episodes and contributing to vessel restenosis.1 The molecular mechanisms that support pathological thrombosis depend on the local fluid mechanical environment in the vessel.2 3 4 Under arterial shear conditions, platelet adhesion to the exposed subendothelium of vessels injured by PTCA is supported by the integrin glycoprotein (GP) IIb-IIIa receptor.5 Subsequent platelet aggregation on the vessel wall is mediated by soluble von Willebrand factor (vWf) bridging GP IIb-IIIa receptors on adjacent platelets.2 6 7 8 Under shear conditions characteristic of stenotic vessels, platelet aggregates also form as a direct result of shear-induced platelet activation. This high shear–induced platelet aggregation depends on vWf binding to GP IIb-IIIa receptors.9 10 Although platelets are the primary mediators of arterial thrombosis, leukocytes are activated by PTCA and contribute to the vascular response.11 12 13
To reduce the clinical complications of PTCA, a number of
antithrombotic agents have been developed. One of the most successful
compounds is abciximab, a murine/human chimeric monoclonal antibody
fragment directed against the human platelet GP IIb-IIIa
(
IIbß3)
receptor.14 15 Abciximab also binds to the integrin
Vß316 17 and Mac-1
(Mß2)
receptors.18 The phase III Evaluation of IIb-IIIa platelet
receptor antagonist 7E3 in Preventing Ischemic Complications
(EPIC) study demonstrated that abciximab decreased acute
ischemic events after PTCA by 35% and that it decreased
restenosis 6 months after PTCA by 23%.19
Ticlopidine has also been successful in reducing adverse cardiac events
after PTCA with stent implantation.20 21
Although the effects of abciximab on platelet aggregation occur within a matter of minutes, the effects of ticlopidine are not seen until several days after administration.22 Therefore, the simultaneous administration of these drugs may be beneficial. The objective of the current study was to compare combined abciximab and ticlopidine therapy with either treatment alone by monitoring platelet and leukocyte function in patient whole blood samples before PTCA and up to 14 days after PTCA. This was done using dynamic experimental systems that model 2 distinct molecular mechanisms that lead to pathological arterial thrombosis. Shear-induced platelet aggregation (SIPA) was evaluated using patient whole blood in a cone-and-plate viscometer. Mural thrombus formation from patient whole blood was detected in a parallel plate flow chamber. Combined abciximab/ticlopidine therapy provided the most extended and consistent reduction of thrombosis. In the presence of abciximab, we observed an unexpected interaction between leukocytes and platelets in mural thrombosis.
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Methods |
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Compounds
Abciximab (c7E3, Reo-Pro, Centocor, Inc/Eli Lilly & Co) is a murine/human chimeric monoclonal antibody fragment directed against the human platelet GP IIb-IIIa receptor.14 15 Ticlopidine (Ticlid, Syntex) is an orally active agent that inhibits ADP-induced platelet aggregation.20 The antiplatelet effects of ticlopidine become maximal 5 to 7 days after long-term administration and continue 4 to 8 days after the cessation of therapy.
HuEP5C7.g4 was prepared by Dr Ellen Berg of Protein Design Labs, Inc, Mountain View, Calif. HuEP5C7.g4 is a humanized monoclonal antibody (IgG1) that binds both P- and E-selectin.23 PSL-275 is a monoclonal antibody (IgG1) directed against P-selectin glycoprotein ligand-1 (PSGL-1, CD162).24 Both the whole PSL-275 antibody and the Fab fragment were used. S12 binds P-selectin but does not block function.25 These compounds were added to normal donor blood for 10 minutes immediately before parallel plate flow chamber and flow cytometry experiments in the following concentrations: 20 µg/mL HuEP5C7.g4, 10 µg/mL PSL-275, 20 µg/mL S12, and 5 µg/mL abciximab.
Patients
A total of 14 patients undergoing high-risk PTCA who were
scheduled to receive abciximab, ticlopidine, or both treatments were
enrolled in the study. Patients included both men and women aged 40 to
72. None of the patients had received prior abciximab treatment, and no
patient had received ticlopidine within the 2 months before PTCA.
Additionally, no patient had a known bleeding or platelet disorder
in the 6 months before PTCA, and none of the patients had a known
hyperactivity to murine proteins or an evolving myocardial infarction.
Patients were selected for each group according to the anatomical
propriety of the target coronary lesion for stent placement.
The study was approved by the Institutional Review Board for Human
Subject Research for Baylor College of Medicine and Affiliated
Hospitals, and all patients signed informed consent documents.
Medical Treatment
Of the 14 patients enrolled in the study, 5 received abciximab
therapy, 5 received ticlopidine therapy, and 4 received both
treatments. Standard abciximab therapy includes a 0.25 mg/kg bolus
injection immediately before PTCA, which is followed by a 12-hour, 10
µg/min infusion. Standard ticlopidine therapy begins with a 500-mg
initial dose 12 to 36 hours before PTCA, which is followed by 250 mg
BID for 30 days and includes stent placement during PTCA. All patients
who received ticlopidine or abciximab/ticlopidine also received a JJIS
stent. Patients who received abciximab alone did not receive a stent.
All patients received 325 mg of aspirin daily beginning 
24 hours
before PTCA.
Blood Collection
Patient whole blood samples were collected at 7 time points.
Collection points from before PTCA included a baseline sample 12 to 36
hours before PTCA and a sample <1 hour before PTCA. Other samples were
collected 2 hours, 24 hours, 3 days, 7 days, and 14 days after
treatment. The sample taken <1 hour before PTCA was obtained from the
femoral arterial sheath. At all other time points, patient
samples were obtained by venipuncture. All samples were
anticoagulated with sodium citrate (0.38% wt/vol). Patient hematocrits
were monitored at each time point, and they remained nearly constant
throughout the study. The fluorescent dye mepacrine (quinacrine
dihydrochloride, Sigma) was added to the blood used in parallel plate
experiments at a concentration of 10 µmol/L.
SIPA
SIPA was evaluated using whole blood and a cone-and-plate
viscometer (Ferranti-Shirley 781, Ferranti Electric, Inc). Whole blood
samples were sheared for 30 s at a shear rate of 3000
s-1 (shear stress=140
dynes/cm2) at room temperature. Aliquots of pre-
and post-shear samples measuring 5 µL were taken and immediately
fixed with 5 µL of 2% formaldehyde in Dulbecco’s PBS (Sigma). The
fixed samples were combined with saturating concentrations of
CD42a-FITC (antiplatelet GP IX-FITC, Becton Dickinson
Immunocytometry Systems) at room temperature in the dark for 20 minutes
and then diluted with 1% formaldehyde in PBS. The number of single
(unaggregated) platelets in pre- and post-shear samples was then
measured using a FACScan flow cytometer (Becton Dickinson
Immunocytometry Systems), as previously described.26 The
number of large platelet aggregates (bigger than a leukocyte) was
also quantified in post-shear samples.26
Flow Cytometric Studies
P-selectin expression on circulating platelets and the
number of circulating platelet-leukocyte aggregates were quantified
using flow cytometry, as previously described.26 27 28 To
determine P-selectin expression on platelets, 5 µL of patient or
normal donor whole blood was incubated with saturating concentrations
of CD62-PE (anti–P-selectin-PE, Becton Dickinson Immunocytometry
Systems) and CD42a-FITC. Background fluorescence was measured
using saturating concentrations of IgG-PE and CD42a-FITC. To measure
the number of circulating platelet-leukocyte aggregates, 5 µL of
patient or normal donor whole blood was incubated for 20 minutes with
saturating concentrations of CD42a-FITC and CD45-PerCP (leukocyte
anti–HLe-1, Becton Dickinson Immunocytometry Systems). Background
fluorescence was determined using saturating concentrations of
CD45-PerCP but no CD42a-FITC. Fixed samples were analyzed using
the FACScan flow cytometer. The number of platelet-leukocyte
aggregates was determined by identifying the leukocytes by
PerCP-fluorescence, gating on each leukocyte
subpopulation,29 30 and measuring the amount of
FITC-fluorescence above background in each leukocyte
subpopulation (Figure 1
).
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Parallel Plate Flow Chamber and Digital Image Processing
Mural thrombus formation was determined using a parallel plate
flow chamber and epifluorescent video microscopy, as previously
described.2 31 32 33 34 Glass coverslips were coated with 200
µL of a suspension of type I acid-insoluble collagen (1100 µg/mL),
which was prepared from a bovine Achilles’ tendon
(Sigma).31 Whole blood was drawn through the chamber for 1
minute at a constant flow rate, producing a wall shear rate of 1500
s-1.
Mural leukocyte-platelet interactions were determined by counting the total number of leukocytes rolling on the collagen/vWf–platelet surface in a single field of view over the 1-minute flow period. Leukocytes that contacted the surface but were immediately carried back to the center of the flow stream without even transiently rolling were not included in the numbers reported.
Statistics
Results are reported as mean±SEM. The significance of the
difference between means was determined by ANOVA using Fischer’s
protected least significant difference test.
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Results |
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SIPA
SIPA was significantly reduced 2 hours after PTCA with abciximab/ticlopidine therapy or abciximab treatment alone (Figure 2
, A and B). In both cases, the number of
pre-shear single platelets that remained unaggregated was more than
twice the number in baseline samples. Relative to ticlopidine treatment
alone, the extent of SIPA was significantly lowered with
abciximab/ticlopidine treatment 2 hours, 24 hours, and 3 days after
PTCA (Figure 2, A and C). Additionally, in samples from patients
receiving abciximab/ticlopidine treatment, SIPA was significantly less
than that in samples from patients receiving abciximab treatment alone
3 days and 7 days after PTCA (Figure 2, A and B).
Abciximab/ticlopidine was the only treatment to significantly reduce
the formation of large platelet aggregates relative to baseline
values (Figure 3). This reduction was
observed 2 hours and 3 days after PTCA (Figure 3A). At 14 days
after PTCA, the formation of large platelet aggregates
significantly increased relative to baseline in samples from patients
receiving abciximab treatment alone (Figure 3B). This increase
was not observed in samples from patients receiving ticlopidine alone
or combined abciximab/ticlopidine treatment (Figure 3, A and
C).
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Platelet Activation
Abciximab/ticlopidine treatment significantly decreased the
activation of circulating platelets relative to baseline 2 hours, 7
days, and 14 days after PTCA (Figure 4A).
At these time points, the percentage of circulating, activated
platelets was reduced to 50% of baseline values. Abciximab or
ticlopidine treatment alone had no effect on circulating platelet
activation at any time point (Figure 4, B and C).
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Leukocyte-Platelet Aggregates
The percentage of circulating neutrophil-platelet aggregates
was decreased by >70% relative to baseline values 2 hours after PTCA
with abciximab/ticlopidine or abciximab treatment alone (Figure 5, A and B). Compared with ticlopidine
treatment alone, abciximab and abciximab/ticlopidine treatment resulted
in significantly fewer circulating neutrophil-platelet aggregates
at this time point (Figure 5). In patients receiving abciximab,
the percentage of circulating neutrophil-platelet aggregates was
significantly greater relative to baseline in the samples taken
immediately before PTCA and 14 days after PTCA. Monocyte-platelet
and lymphocyte-platelet aggregates were also measured. The
percentage of monocyte-platelet aggregates increased by 44%
relative to baseline 7 days and 14 days after PTCA in samples from
patients receiving ticlopidine treatment alone. The addition of
abciximab to whole blood drawn from normal donors did not significantly
change the percentage of leukocyte-platelet aggregates measured by
flow cytometry (Table). However, relative to patient
whole blood samples, the percentage of circulating
leukocyte-platelet aggregates was much lower in the control samples
from normal donors.
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Mural Thrombus Formation
Mural thrombus formation was significantly decreased relative to
baseline patient samples 3 days after PTCA with abciximab/ticlopidine
treatment and 1 day after PTCA with abciximab treatment alone (Figure 6, A and B). One day after PTCA,
treatment with both abciximab/ticlopidine and abciximab alone decreased
the total number of platelets deposited by 84% and 58%,
respectively, relative to baseline samples. In contrast, ticlopidine
treatment alone had no effect (Figure 6C). Three days after
PTCA, abciximab/ticlopidine treatment effectively reduced the total
number of platelets deposited to 45% of baseline values, whereas
either treatment alone had no effect (Figures 6 and 7). The total area of the collagen
surface covered by platelets was also significantly reduced 3 days
after PTCA with abciximab/ticlopidine treatment (Figure 8A); at this time point, the total
surface area covered by platelets was 50% that of baseline
coverage. Abciximab treatment alone significantly reduced the total
surface coverage by platelets to 66% of baseline values 2 hours
after PTCA (Figure 8B). Ticlopidine treatment alone did not
significantly reduce the total surface area covered by platelets at
any time point (Figure 8C).
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P-Selectin/PSGL-1–Mediated Leukocyte Rolling
During parallel plate experiments, high numbers of leukocytes
rolling on the collagen surface were observed with
abciximab/ticlopidine or abciximab treatment 2 hours after PTCA
(Figures 9 and 10). No significance differences
between the numbers of rolling leukocytes were observed between
treatment with abciximab/ticlopidine or abciximab alone. Rolling
leukocytes were not observed immediately after the initiation of flow;
they were seen after a monolayer of platelets had been deposited on
the collagen coverslip. Firm adhesion of leukocytes was not observed.
When ticlopidine was administered alone, rolling leukocytes were not
observed in significant numbers; instead, rather large thrombi
developed on the collagen/vWf surface (Figures 9 and 10).
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and 
) were only observed to roll after
formation of platelet monolayer, which is designated by 
in A.
Platelet monolayers formed when whole blood samples from patients
receiving either abciximab/ticlopidine treatment (A) or abciximab
treatment alone (B) were perfused. Ticlopidine (C) treatment resulted
in platelet thrombi with essentially no leukocyte involvement.
Experimental conditions were identical to those in Figure 6
To confirm the specificity of leukocyte rolling on the
collagen/vWf–platelet surface, flow chamber experiments using
normal donor blood were performed in the presence of abciximab and
monoclonal antibodies against P-selectin and PSGL-1. As observed in
patient samples, leukocytes from normal donors rolled in significant
numbers on the collagen/vWf–platelet surface in the presence of
abciximab. When HuEP5C7.g4 or PSL-275 was added to the whole blood
samples containing abciximab, leukocyte rolling was reduced by >80%
(Figure 11). When HuEP5C7.g4, PSL-275,
or S12 was added to whole blood without abciximab, leukocyte rolling
was not significant (data not shown).
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Discussion |
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Of the 3 treatments, combined abciximab/ticlopidine therapy produced the most consistent reduction in SIPA (Figures 2
and 3). The effect of abciximab/ticlopidine was most
pronounced 2 hours after PTCA, when SIPA was reduced by 50% relative
to baseline samples. At this time point, patients were still receiving
a 10 µg/min abciximab infusion, and abciximab treatment alone
produced a similar reduction in SIPA. Combined abciximab/ticlopidine
therapy also produced the most prolonged reduction in mural thrombus
formation (Figures 6 and 8). Three days after PTCA,
abciximab/ticlopidine treatment decreased mural thrombus formation to
50% of baseline values. Abciximab treatment alone effectively
inhibited mural thrombosis for only 1 day after PTCA, whereas
ticlopidine treatment alone did not decrease mural thrombus formation
significantly at any time point studied. These results suggest that the
sustained clinical benefit of abciximab treatment alone may be a direct
effect of inhibiting mural thrombus growth during the critical period
before vessel wall passivation, thereby reducing the local
concentration of platelet-derived products, including ADP,
thrombin, and platelet-derived growth factor, which stimulate the
neointimal hyperplasia.35 In most patients,
the vessel wall becomes passivated in 2 days. However, in some
patients, passivation may not occur for up to 8 days.35
Therefore, the prolonged reduction in mural thrombus formation produced
by combined abciximab/ticlopidine treatment may further decrease
clinical events after PTCA relative to abciximab treatment alone.
Two hours after PTCA, treatment with abciximab/ticlopidine or abciximab
alone resulted in significant numbers of leukocytes rolling on the
collagen surface (Figures 9 and 10). The high number of
leukocytes rolling on the platelet monolayer 2 hours after PTCA
could be a result of the increased availability of free leukocytes
circulating in the blood stream, because both abciximab/ticlopidine and
abciximab treatment alone decreased the number of
leukocyte-platelet aggregates in the circulation (Figure 5).
This is unlikely, however, because the addition of abciximab to normal
donor blood did not decrease the number of leukocyte-platelet
aggregates but did promote leukocyte rolling on the platelet
monolayer (Figure 11). A more likely hypothesis is that
the platelet monolayer forms using the GP Ib-IX-V complex and
creates a reactive carpet of P-selectin that enhances the recruitment
of leukocytes to the surface by binding leukocyte PSGL-1. In support of
this, we showed that leukocyte rolling is almost completely
inhibited by anti-P-selectin or PSGL-1 monoclonal antibodies (Figure 11).
Adhesion of leukocytes to sites of arterial injury after PTCA may aggravate the endothelial damage through the release of proteolytic enzymes and other toxic substances.11 13 Additionally, leukocyte secretory products may potentiate platelet activation and amplify the thrombotic process. The effects of increased P-selectin–mediated leukocyte adhesion may be offset by the cross-reactivity of abciximab with the integrin Mac-1. Mac-1 supports monocyte and neutrophil adhesion to intercellular adhesion molecule-1 and fibrinogen, which are both present in the subendothelial matrix. Abciximab significantly reduces Mac-1–mediated binding to both of these ligands.18 Therefore, on a denuded vessel, abciximab may enhance P-selectin–mediated adhesion while diminishing adhesion supported by intercellular adhesion molecule-1 and fibrinogen.
In summary, we demonstrated that combined abciximab/ticlopidine therapy significantly inhibits mural thrombus formation, as assessed in a parallel plate flow chamber, for 3 days after PTCA. This is a significant increase over the effective duration of either treatment alone. The antiplatelet effects of the combined therapy are still evident 7 and 14 days after PTCA, as indicated by the reduction in the percentage of circulating, activated platelets relative to baseline values. Additionally, we found that abciximab treatment decreases the percentage of circulating leukocyte-platelet aggregates but promotes leukocyte-platelet interactions on a collagen/vWf–platelet surface.
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Acknowledgments |
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This work was supported by the National Institutes of Health (grants HL-18672 and NS-23327), the Robert A. Welch Foundation (grant C-938), a grant from Eli Lilly and Company, and a Graduate Fellowship from the Whitaker Foundation.
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Footnotes |
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Guest Editor for this article was Barry S. Coller, MD, Mount Sinai School of Medicine, New York.
Received November 2, 1998; revision received September 20, 1999; accepted October 7, 1999.
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