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(Circulation. 2000;102:1490.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Flow Cytometric Monitoring of Glycoprotein IIb/IIIa Blockade and Platelet Function in Patients With Acute Myocardial Infarction Receiving Reteplase, Abciximab, and Ticlopidine
Continuous Platelet Inhibition by the Combination of Abciximab and Ticlopidine
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-250).
From Internal Medicine III (K.P., B.K., T.N., C.B.) and Medical Biometry (M.O.), University of Freiburg, Freiburg, Germany; Internal Medicine III (A.S., J.R., M.M., W.K.), University of Heidelberg, Heidelberg, Germany; and Duke Clinical Research Institute (M.E.O.), Durham, NC.
Correspondence to Karlheinz Peter, MD, Internal Medicine III, Albert-Ludwigs-Universität, Hugstetter Str. 55, 79106 Freiburg, Germany. E-mail peter{at}med1.ukl.uni-freiburg.de
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Abstract |
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Background—Improvement of thrombolysis may be achieved by concomitant strong platelet inhibition. To monitor platelet function in patients with myocardial infarction (n=46) who were treated with the fibrinolytic agent reteplase, the glycoprotein (GP) IIb/IIIa blocker abciximab, and the ADP receptor antagonist ticlopidine, we developed a flow cytometric assay.
Methods and Results—Binding of abciximab to platelets was directly monitored as the percentage of platelets stained by a goat anti-mouse antibody. Blood drawn 10 minutes and 2 hours after the start of therapy with reteplase and abciximab and during the 12-hour infusion of abciximab demonstrated a maximal blockade of GP IIb/IIIa (10 minutes, 86.2±10.3%; 12 hours, 85.8±7.1%). Starting at 24 hours, abciximab binding gradually decreased (24 hours, 74.6±16.2%; 48 hours, 66.8±14.9%; 72 hours, 60.5±16.7%; 96 hours, 49.4±17.8%; 120 hours, 35.8±16.4%; and 144 hours, 29.9±15.3%). Binding of a chicken anti-fibrinogen antibody to platelets, indicating the level of functional blockade of GP IIb/IIIa, was inversely correlated with the binding of abciximab (r=-0.72, P<0.0001). In blood drawn at 10 minutes, platelet aggregation was maximally inhibited but recovered within 48 hours even if the majority of GP IIb/IIIa receptors were still blocked by abciximab. Reteplase did not influence abciximab binding and did not activate platelets, as measured by P-selectin expression, fibrinogen binding, and platelet aggregation. Platelet inhibition that was achieved during the first 24 hours by abciximab was directly maintained by additional treatment with ticlopidine.
Conclusions—Flow cytometric monitoring of platelet function allows differentiation of the effects of reteplase, abciximab, and ticlopidine. The combination of abciximab and ticlopidine is an attractive therapeutic strategy that provides a fast and continuous platelet inhibition.
Key Words: platelets • thrombolysis • inhibitors
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Introduction |
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Limited success in the restoration of coronary blood flow and in the reduction of reocclusion in thrombolysis has been attributed to platelet activation.1 2 3 4 Maximal platelet inhibition can be achieved by the blockade of the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa.5 6 In early experimental studies in animals, the combination of fibrinolysis and GP IIb/IIIa blockade resulted in the enhancement of thrombolysis and reduced reocclusion after recanalization of coronary arteries.1 7 8 9 Only very recently have the clinical benefits of this combinatorial therapy been demonstrated in clinical trials.10 11 12 Within one of these trials, the Global Utilization of Strategies for Total Occlusion (GUSTO)-IV pilot trial (Strategies for Patency Enhancement in the Emergency Department [SPEED]),11 we evaluated platelet function of patients with acute myocardial infarction who received various combinations of 3 drugs: the fibrinolytic agent reteplase, the GP IIb/IIIa blocker abciximab, and the ADP receptor antagonist ticlopidine. For the measurement of platelet function during this complex combinatorial drug therapy, we developed a monitoring strategy that is based on flow cytometry. Thereby, we could address the following issues: (1) the pharmacodynamic profile of the GP IIb/IIIa blockade by abciximab in patients with acute myocardial infarction and potential influences by the comedication with reteplase and ticlopidine, (2) the influence of reteplase on platelet function, and (3) the time course of platelet inhibition by the combination of abciximab and ticlopidine.
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Methods |
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Antibodies and Reagents for Flow Cytometric Monitoring
Abciximab binding to platelets was monitored by a dichlorotriacinylamino fluorescein (DTAF)-labeled polyclonal goat anti-mouse IgG+IgM (H+L) antibody (Jackson Immuno Research Laboratory). Platelet-bound fibrinogen was detected by a polyclonal fluorescein isothiocyanate (FITC)-labeled chicken antibody to human fibrinogen (Biopool) as described in detail.13 The anti–P-selectin monoclonal antibody was obtained from Becton Dickinson. ADP (Sigma Chemical Co) was used at a final concentration of 10 µmol/L. Modified Tyrode’s buffer (50 mmol/L NaCl, 2.5 mmol/L KCl, 1.2 mmol/L NaHCO3, 2 mmol/L CaCl2, 2 mmol/L MgCl2, 1 mg/mL BSA, and 1 mg/mL glucose) was used for predilution of the whole blood samples.
Blood Sampling
Blood was collected by venipuncture with a 21-gauge
butterfly needle from an antecubital vein. Five milliliters of blood
was drawn and discarded before blood samples were drawn for
analysis in a second syringe and anticoagulated with 0.106
mol/L citrate. Samples were processed within 15 minutes.
Flow Cytometry
Samples for flow cytometric analysis were prepared by a
whole blood assay. Twenty microliters of whole blood anticoagulated
with citrate was added to 980 µL of modified Tyrode’s buffer. Fifty
microliters was then added to 10 µL of appropriate antibody and
agonist solution. After the samples were gently mixed, they were
incubated at room temperature for 20 minutes and then diluted with 500
µL of 1x CellFix (Becton Dickinson) to achieve a stable
fixation and to avoid further activation. Fixation after incubation
with antibodies was chosen because fixation before the incubation
resulted in a decrease of fluorescence staining. Flow cytometry
was performed on a FACScan cytometer (Becton Dickinson)
within 2 hours after the fixation step. The instrument was aligned
daily by using CaliBrite beads (Becton Dickinson). Blood
cells were examined with Lysis II software (Becton
Dickinson), and platelets were identified by light-scatter
characteristics. A gate was set around the platelet population, and
platelet identity was confirmed by using the anti–GP IIb antibody
SZ22. A total of 10 000 platelets were analyzed within
this gate. When 10 blood samples in 5 replicates each were assayed, the
coefficient of variation was 10.4%.
Platelet Aggregation
The measurement of ex vivo platelet aggregation was
performed with platelet-rich plasma by the turbidimetric method in
a 4-channel aggregometer (PAP-4, Biodata Corp). Platelet-rich
plasma was obtained as a supernatant after
centrifugation of citrated blood at 160g for
10 minutes. Platelet-poor plasma was obtained by a second
centrifugation step at 2500g for 10 minutes.
For aggregation, the platelet count was adjusted with
platelet-poor plasma to 250/nL. Light transmission was adjusted to
0% for platelet-rich plasma and to 100% for platelet-poor
plasma for each measurement. Platelet aggregation was determined as
maximal change of light transmission after the addition of ADP.
Study Population and Enrollment Criteria for Patients With
Myocardial Infarction
Patients (n=46) were enrolled from October 1997 until November
1998 at the intensive care unit of the Department of
Cardiology, University of Heidelberg, Germany, within a
substudy of the SPEED trial (a multicenter, open-labeled, parallel
group trial). The enrolled patients were randomized to receive either
weight-adjusted abciximab (ReoPro, Centocor) with a bolus
of 0.25 mg/kg body wt, followed by a 12-hour infusion of 0.125
µg · kg-1
· min-1 to a maximum (at
80 kg body weight) of 10 µg/min, or 2x 10 U reteplase
(Boehringer-Mannheim) or the combination of weight-adjusted
abciximab combined with reduced doses of reteplase (5, 7.5, and 10 U,
single bolus each; 5 plus 2.5 U or 2x 5 U, 2 injections 30 minutes
apart). Patients admitted within 6 hours of onset of chest pain that
lasted at least 30 minutes and with significant ST-segment elevation in
2 contiguous ECG leads were randomized to one of the treatment arms.
Before administration of the study medication, all patients received
aspirin (500 mg IV and continuing with 100 mg given orally, starting
the second day) and heparin (low dose with 60 IU/kg, 
4000 IU IV
bolus). Further heparin administration was titrated by the
activated clotting time. With one exclusion, coronary
angiography was performed in all patients between 60 and 90 minutes
after the start of study medication. If stent placement was necessary,
patients further received 2x 250 mg ticlopidine per day starting with
the first dose immediately after placement and lasting for 3 weeks.
None of the patients developed reocclusion. One patient who developed
thrombocytopenia is reported separately.14 Patency data of
the SPEED trial are reported elsewhere.11 The study
protocol was approved by the ethics committee of the University of
Heidelberg, and written informed consent was obtained from each
patient.
Statistical Analysis
Outcome measures over time were analyzed by
repeated-measures ANOVA. If overall intergroup differences were
significant (P<0.05), relevant differences at specific time
points were tested by the Mann-Whitney rank sum test. To test for the
strength of association, the Pearson product moment correlation
coefficient was determined.
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Results |
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Direct Monitoring of Abciximab Binding to Platelets by Flow Cytometry
Abciximab binding to platelets was monitored by flow cytometry with use of a goat anti-mouse antibody. Typical histograms are given in Figure 1
. The extent of abciximab
binding is measured as the percentage of platelets within a gate
(M1) that allows for an unspecific binding of the goat anti-mouse
antibody of 1.3% of platelets in all patients (see pretreatment,
Figure 1). The linearity of the flow cytometric detection of
abciximab binding is shown in a representative example
(Figure 2A). The concentration at which
maximal binding of abciximab to platelets is achieved varies
between individuals. However, saturation of abciximab binding is
reached with all individuals tested at 3 µg/mL (Figure 2A).
This in vitro saturation characteristic is in agreement with a blockade
of 
80% of the platelet GP IIb/IIIa receptors at a concentration
of 
3.5 µg/mL, which is reported to be reached in vivo with the
dosage regimen applied in the SPEED trial.15 16 17 18 19 20
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, typical binding curve in one
individual depicted as mean±SD of 5 determinations each. B, Fibrinogen
binding to ADP-stimulated platelets was detected by using
FITC-labeled chicken anti-human fibrinogen antibody. C, Platelet
aggregation was initiated by the addition of ADP to platelet-rich
plasma and quantified as maximal change of light transmission. Mean±SD
values are given for 7 individuals in panels B and C.
Beginning with the blood samples that were drawn 10 minutes after
abciximab bolus and during the 12-hour infusion, a maximal blockade of
GP IIb/IIIa (pretreatment, 0.6±0.6%; 10 minutes, 86.2±10.3%; 2
hours, 84.7±7.9%; and 12 hours, 85.8±7.1%) was achieved. Starting
at 24 hours, abciximab binding gradually decreased (24 hours,
74.6±16.2%; 48 hours, 66.8±14.9%; 72 hours, 60.5±16.7%; 96 hours,
49.4±17.8%; 120 hours, 35.8±16.4%; and 144 hours, 29.9±15.3%).
Representative histograms are shown in Figure 1
.
All histograms revealed a unimodal pattern of abciximab binding to
platelets. Unimodal patterns of platelet staining were also
present when samples were fixed immediately after blood drawing
(also at the 10-minute time point of blood drawing), arguing against a
significant redistribution of abciximab on platelets during the in
vitro incubation and preparation steps.
Inhibition of Ligand Binding to GP IIb/IIIa by Abciximab
To evaluate the functional effect of the blockade of GP IIb/IIIa
by abciximab, binding of fibrinogen and the monoclonal antibody
PAC-1 (specific for activated GP IIb/IIIa) was monitored. The
binding of an FITC-conjugated chicken polyclonal anti-fibrinogen
antibody was determined as percentage of ADP-stimulated platelets
within the gate M2 (see Figure 1). In vitro incubation of
platelets with various concentrations of abciximab revealed
saturation with maximal inhibition of fibrinogen binding reached
between 2 and 3 µg/mL. Abciximab binding and inhibition of fibrinogen
binding to platelets are inversely correlated with each other
(r=-0.72, P<0.0001). In blood of patients that
was drawn 10 minutes after the abciximab bolus, fibrinogen binding to
platelets already reached minimal binding levels that remained
stable at 2 and 12 hours (Figure 1 and 3B). Beginning at 24 hours, fibrinogen
binding to platelets gradually recovered (Figure 1 and
3B). As for the binding of fibrinogen to platelets, similar
results were obtained with the activation-specific FITC-conjugated
mouse IgM monoclonal antibody PAC-1 (data not shown).
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Effects of Abciximab on Platelet Aggregation
A widely used functional evaluation of platelets is
ADP-induced platelet aggregometry. In vitro evaluation of various
abciximab concentrations revealed saturation of the
inhibitory effect of abciximab at 2 µg/mL in platelet
aggregometry (Figure 2C). Ten minutes after administration of
the abciximab bolus, platelet aggregation was reduced to a minimal
level in the blood of patients (Figure 1 and 3C).
Measurements at later time points revealed a continuous recovery of
platelet aggregation. In the patient group without ticlopidine,
platelet aggregation returned to normal as early as 48 hours after
the start of treatment. At this time point, 70% of platelets
demonstrated fluorescence intensity within gate M1 (Figure
3A). Thus, ADP-induced platelet aggregation demonstrated
recovery even if the majority of GP IIb/IIIa receptors on the
platelets were still occupied and blocked by abciximab.
Effects of Reteplase on Abciximab Binding and on Platelet
Function
Reteplase did not influence the time course of abciximab binding
to platelets as demonstrated in the comparison of the patients with
and without fibrinolytic therapy (Figure 4A). Effects of reteplase on the
platelet activation status can be measured by the expression of
P-selectin on the platelet surface.21 The comparison
of patients treated with reteplase only, abciximab only, and the
combination of reteplase and abciximab did not reveal a significant
influence of these drugs, either alone or in combination, on the
platelet activation status (Figure 4B). Furthermore,
reteplase did not affect the functional blockade of GP IIb/IIIa, which
is a consequence of the binding of abciximab. No statistically
significant difference was obtained in the comparison of fibrinogen
binding to platelets in patients treated with abciximab alone or
the combination of abciximab and reteplase (Figure 4C). In
addition, application of reteplase alone did not cause an increase in
fibrinogen binding to GP IIb/IIIa (Figure 4C). Platelet
aggregation was inhibited by abciximab independent of the comedication
with reteplase (Figure 4D). Treatment of patients with reteplase
alone did not result in an increased platelet aggregation (Figure
4D).
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, reteplase only (n=7). A, Abciximab
binding to platelets (goat anti-mouse antibody). B, Platelet
activation (anti–P-selectin antibody). C, Fibrinogen binding (chicken
anti-human fibrinogen antibody). D, Platelet aggregation
(ADP-induced). Mean±SD values are given. No significant differences
were obtained between patients treated with abciximab and reteplase and
patients treated with abciximab alone (ANOVA for repeated
measures).
Effects of Ticlopidine
Patients who required stent placement were additionally treated
with ticlopidine. The gradual loss of abciximab binding to
platelets did not differ between the patients treated with or
without ticlopidine (Figure 3A). However, recovery of the
binding of fibrinogen and PAC-1 (not shown) and platelet
aggregation differed significantly in both groups (Figure 3B and 3C). In ticlopidine-treated patients, platelet inhibition reached a
plateau 24 hours after the onset of treatment that was maintained
thereafter, independent of further decrease in abciximab binding.
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Discussion |
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Monitoring of Abciximab Binding to Platelets
Despite the widespread use of GP IIb/IIIa blockers, limited pharmacodynamic data on this new group of antiplatelet agents is available.16 20 Furthermore, the few strategies to monitor platelet function that have been described so far are discussed controversially.22 In the present study, a direct flow cytometric monitoring of the binding of the GP IIb/IIIa blocker abciximab to platelets is reported. In contrast to radiometric measurements that only allow the determination of the average binding of abciximab to all platelets, flow cytometry allows direct monitoring of abciximab binding to the individual platelet. This methodological advantage of flow cytometry is the basis for an important conclusion drawn from the presented data. At each time point evaluated during the present study, abciximab was evenly distributed to all platelets, as demonstrated in a unimodal fluorescence pattern. Because newly generated platelets must have entered the circulation during our 7-day monitoring period, there had to be a continuous redistribution and, thus, equilibration of the number of abciximab molecules bound to the individual circulating platelet. The pharmacodynamic profile of abciximab binding was identical in patients receiving abciximab in combination with reteplase or abciximab alone with or without the additional administration of ticlopidine. In healthy volunteers19 and in patients with stable angina,16 similar profiles of abciximab binding to platelets have been obtained.
Monitoring of GP IIb/IIIa Blockers: Flow Cytometry Versus
Aggregometry
Flow cytometry allows the direct measurement of the binding of
abciximab and the direct determination of the extent of blockade of the
GP IIb/IIIa receptors on the individual platelet. Furthermore, the
activation state of the individual platelet can be evaluated by
activation-specific epitopes.21 In contrast, platelet
aggregometry determines the overall aggregatory function of the mixture
of all platelets in the sample. Platelet aggregometry has some
practical limitations. The necessary centrifugation of
blood samples may activate platelets. Whereas only 1 µL
blood per sample is needed in flow cytometry, 500 µL blood per
sample is needed for standard aggregometry. Platelet aggregation is
dependent on plasma factors, especially fibrinogen. Thus, in patients
treated with fibrinolytics, which result in the degradation of
fibrinogen, platelet aggregation may be influenced without change
in platelet function. Furthermore, platelet aggregometry cannot
be used in patients with severe thrombocytopenia. In contrast, flow
cytometry allows monitoring of platelet function at low
platelet counts and has even been useful in the evaluation of
mechanisms of GP IIb/IIIa blocker–induced
thrombocytopenia.14 In platelet aggregometry, the
sensitivity for the detection of partial GP IIb/IIIa blockade is
limited and depends on the stimulus used.19 Our data
demonstrated a return to normal platelet aggregation even with the
majority of GP IIb/IIIa receptors being blocked. Overall, flow
cytometry and platelet aggregometry are 2 methods, both with
specific limitations, describing platelet function on different
levels, but both techniques are a useful combination in the monitoring
of platelet function during GP IIb/IIIa blocker therapy.
Platelet Function in Relation to GP IIb/IIIa Blockade
Within 48 hours, ADP-induced platelet aggregation returned to
normal. This early recovery despite the blockade of the majority of GP
IIb/IIIa receptors on circulating platelets is consistent
with pharmacodynamic data published until now.16 19 20 23
However, there is a caveat in the interpretation of these findings.
Platelets may still be functionally inhibited; thus,
platelet aggregation may be induced by weak
physiological stimuli, and the stability of
aggregates and platelet adhesion may be impaired even if only a low
percentage of GP IIb/IIIa receptors are blocked by abciximab.
Clinical Implications
Few data are available on the lack of time between the start of
ticlopidine medication and the onset of platelet inhibition. Time
periods between 2 and 5 days are reported.24 The
present study adds the finding that the platelet
inhibitory effect of ticlopidine is complete within 48
hours. Furthermore, we describe a continuous platelet inhibition
that starts after application of the abciximab bolus, is maintained
throughout the abciximab infusion for 12 hours, and finally continues
on a plateau level of platelet inhibition caused by the daily
administration of ticlopidine. The continuity of this platelet
inhibition makes the combination of abciximab-mediated GP IIb/IIIa
blockade and ticlopidine very attractive.
A potential activation of platelets by fibrinolytic agents in general but especially by reteplase has been discussed.25 P-selectin expression on the platelet surface is a measure of the platelet activation status. It was not increased on the platelets of patients treated with reteplase. Furthermore, patients treated with reteplase alone did not demonstrate an increase in fibrinogen binding to GP IIb/IIIa, which also reflects the platelet activation status.21 And finally, platelet aggregability was not increased by the treatment with reteplase. Therefore, none of the parameters examined reported platelet activation by reteplase.
Limitations of the Flow Cytometric Monitoring of Platelet
Function
Preparation of blood samples for flow cytometry, data acquisition,
and data analysis requires time (15 to 30 minutes).
Furthermore, trained personnel and an expensive flow cytometer are
necessary. Therefore, flow cytometry is not suitable for a rapid
bedside monitoring of platelet function. A recently described rapid
platelet-function assay26 based on coagglutination of
fibrinogen-coated beads and platelets may be one of the potential
assays that may provide a fast evaluation of GP IIb/IIIa blocker
effects directly in the catheter laboratory. However, for dosing
decisions outside the acute situation, eg, for the monitoring of oral
GP IIb/IIIa blocker therapy, flow cytometry demonstrates the advantage
of the direct evaluation of the blockade of the GP IIb/IIIa receptors
on the individual platelet. Because of their versatile
applications, flow cytometers are available in many clinical
laboratories, and the determination of the extent of GP IIb/IIIa
blockade could be established as a regular laboratory test. During the
preparation steps in flow cytometry and also in platelet
aggregometry, GP IIb/IIIa blockers may dissociate or redistribute, and
the in vitro measurements may not reflect the in vivo situation.
Therefore, especially at early time points after drug administration
(eg, 10 minutes) and with GP IIb/IIIa blockers that have a low affinity
to GP IIb/IIIa, short incubation times or immediate fixation of the
blood samples may be necessary.
Conclusions
We describe a strategy for the direct monitoring of platelet
function by flow cytometry and demonstrate its use in patients with
acute myocardial infarction treated by various combinations of
reteplase, abciximab, and ticlopidine. The pharmacodynamics of
abciximab binding in these patients could be defined, and it was not
influenced by reteplase or ticlopidine. Administration of reteplase did
not result in platelet activation. The administration of
ticlopidine results in a continuous platelet inhibition with a
direct transition of the inhibition caused by abciximab bolus and then,
after infusion, to a plateau of platelet inhibition caused by
ticlopidine.
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Acknowledgments |
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This study was supported by the German Research Foundation (SFB 320) and the Medical Faculty of the University of Heidelberg with grants to Drs Peter, Moser, and Bode.
Received January 7, 2000; revision received May 1, 2000; accepted May 5, 2000.
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