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320 Part IV / Practical Issues and Future Applications
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 321
321
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
15 Platelet Monitoring and Interaction
of Glycoprotein IIb/IIIa Antagonists
with Other Antiplatelet Agents
CONTENTS
INTRODUCTION
PLATELET MONITORING
METHODS OF MONITORING OF PLATELET INHIBITION
INTERACTION OF GPIIb/IIIa ANTAGONISTS WITH OTHER
ANTIPLATELET AGENTS
REFERENCES
Steven R. Steinhubl, MD
INTRODUCTION
Unlike other available antiplatelet agents, a clear dose-effect relationship for the plate-
let glycoprotein (GP) IIb/IIIa antagonists was well established in animal models prior to
study in humans. Based on these early studies, a specific level of blockade of platelet
GPIIb/IIIa receptors was identified as that necessary to prevent intraarterial thrombus
formation, and this target level was carried forward into clinical trials. Subsequently, the
efficacy of these agents in preventing thrombotic events has been confirmed in placebo-
controlled trials involving nearly 50,000 patients (1,2). Despite these overall positive
findings with GPIIb/IIIa receptor-blocker therapy, several large individual studies, in
specific patient populations or with suboptimal dosing regimens, have found a lack of
effect in preventing thrombotic complications (3,4). These results raise the question as to
whether a specific dose of a GPIIb/IIIa antagonist, adjusted only by patient weight, can pro-
vide the same level of platelet inhibition across all clinical syndromes and across all indi-
viduals. If there is interindividual variability in response to standard dosing of GPIIb/IIIa
antagonists, monitoring of platelet inhibition would allow for individualization of therapy
and might improve the efficacy and safety of these agents.
PLATELET MONITORING
One barrier to the routine monitoring and titrating of GPIIb/IIIa antagonists has been
the lack of a convenient, reproducible, clinically relevant measure of platelet function.
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322 Part IV / Practical Issues and Future Applications
Platelet aggregometry and receptor binding assays, the methods utilized in initial dose-
finding studies, require specialized technical expertise, involve substantial time delays, and
are unable to be performed in patient care areas. Today, however, there are several simple,
whole-blood, point-of-care monitoring devices available, making monitoring of platelet
inhibition convenient and clinically relevant.
In this chapter the data demonstrating the clinical relevance of achieving a specific level
of platelet function inhibition with GPIIb/IIIa antagonists, and therefore supporting the
need for monitoring, are reviewed as well as the multiple monitoring methods available.
Level of Platelet Inhibition to Prevent Thrombotic Events
ANIMAL STUDIES
Early studies performed in animals involving arterial injury and thrombus formation
demonstrated a strong correlation between the level of GPIIb/IIIa receptor blockade and
prevention of luminal thrombus formation, with a steep dose response. One of the earliest
studies to evaluate the clinical dose response of the monoclonal antiplatelet GPIIb/IIIa
antibody 7E3 utilized a post-thrombolysis reocclusion dog model (5). Reocclusion was
completely prevented in this model with only the highest (0.8 mg/kg) dose of 7E3. At this
dose, platelet aggregation induced by 9 µM ADP was completely inhibited, >80% of the
GPIIb/IIIa receptors on the platelet surface were blocked, and bleeding time was pro-
longed to > 30 min in most animals. Lower doses were associated with some reocclusion,
but less inhibition of aggregation and shorter prolongations of bleeding time. In a second
study, the same monoclonal antibody was evaluated in the less thrombogenic Folts model
in the monkey carotid artery (6). In this model, only 0.2 mg/kg of 7E3 was required to inhibit
thrombus formation completely, a dose that only rarely prolonged bleeding time beyond
10 min, inhibited ADP-induced aggregation by approx 70%, and blocked approx 70% of
GPIIb/IIIa receptors. Although it is possible that the marked difference in doses needed to
prevent thrombus formation in these two models may have been related to an interspecies
difference in effects of the monoclonal antibody, it is more probable that the disparate
results suggest that in the setting of a more thrombogenic stimulus a greater level of recep-
tor blockade is required to prevent the formation of an arterial thrombus (Fig. 1).
Based on the results of these animal models, early dosing of GPIIb/IIIa antagonists was
designed to achieve blockade of approx 80% of platelet GPIIb/IIIa receptors and inhibit
ADP-induced platelet aggregation to approx 20% of baseline (7–9). This dose was consid-
ered necessary to prevent ischemic complications in response to severe thrombotic provo-
cations but was also recognized as being “highly speculative” (10).
I
NDIRECT DATA FROM CLINICAL TRIALS
Indirect evidence from several placebo-controlled trials of GPIIb/IIIa antagonists in
percutaneous coronary intervention (PCI) has suggested the importance of achieving and
maintaining a specific level of platelet inhibition in order to minimize thrombotic com-
plications. In the EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications)
trial, patients undergoing a high-risk PCI were randomized to receive either a bolus and
infusion of placebo, a bolus of abciximab and an infusion of placebo, or a bolus and infu-
sion of abciximab (11). Patients receiving placebo started to require urgent interventions
immediately after the initial percutaneous transluminal coronary angioplasty (PTCA),
whereas patients receiving a bolus alone of abciximab were nearly completely protected
for the first 4–6 h (during which time receptor blockade was likely to be ≥ 80% in most
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 323
patients), and patients treated with a bolus and 12-h infusion of abciximab were protected
from ischemic complications almost throughout the infusion period. At 30 d, patients
who received a bolus and infusion of abciximab had almost a one-third reduction in ische-
mic events compared with those treated with a bolus alone. This benefit of a bolus and infu-
sion of abciximab vs a bolus alone was maintained for at least 3 yr (12).
The importance of achieving a high level of receptor blockade with eptifibatide at the
time of a PCI is suggested by the discrepant results of two trials utilizing significantly dif-
ferent doses of this agent. In the IMPACT-II (Integrilin to Minimize Platelet Aggregation
and Coronary Thrombosis) trial, randomization to a 135 µg/kg bolus and a 0.5 µg/kg/
min infusion of eptifibatide at the time of PCI led to an 18% relative decrease in the com-
posite endpoint compared with placebo (9.2% vs 11.4%, p = 0.063) (3). Later, this dosing
regimen was found to produce only approx 50% receptor blockade (13). In the ESPIRIT
(Enhanced Suppression of Platelet Receptor IIb/IIIa Using Integrilin Therapy) trial, a much
higher dose of eptifibatide was evaluated, with two 180 µg/kg boluses and a 2 µg/kg/min
infusion. In a pilot study, this dose was estimated to provide >90% inhibition of 20 µM ADP-
induced aggregation, approx 80% GPIIb/IIIa receptor occupancy, and bleeding times of
at least 30 min (14). Clinically, this increased dosing regimen was associated with twice
the relative benefit of eptifibatide treatment compared with the results in IMPACT-II, with
a 35% reduction in the 30-d composite clinical endpoint of death, myocardial infarction
(MI), or urgent revascularization (6.8% vs 10.4%, p = 0.003).
D
IRECT EVIDENCE CORRELATING THE LEVEL OF PLATELET
INHIBITION WITH EFFICACY OUTCOMES FROM CLINICAL TRIALS
Several clinical trials have utilized some measure of platelet inhibition and linked these
results with efficacy outcomes. In the PARAGON-A (Platelet IIb/IIIa Antagonism for
the Reduction of Acute Coronary Syndrome Events in a Global Organization Network)
trial, 2282 patients with a non-ST-elevation acute coronary syndrome were randomized to
either a low- or high-dose lamifiban regimen, with or without heparin (15). In an attempt
Fig. 1. Relationship between dose of the GPIIb/IIIa antagonist 7E3-F(ab)
2
and inhibition of thrombo-
sis formation in two different animal models, suggesting that the correct antithrombotic dose may be
dependent on the thrombogenic stimulus (5,6).
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324 Part IV / Practical Issues and Future Applications
to establish a dose-response relationship, steady-state plasma concentrations of lamifiban
were determined in a subgroup of 810 lamifiban-treated patients. Interestingly, a U-shaped
correlation was found between plasma drug levels and the incidence of death and MI at
6 mo (16). Whereas patients achieving a midrange of concentrations, representing 80–90%
GPIIb/IIIa receptor occupancy, realized a 40% relative reduction in death and MI at 30 d,
and 38% at 6 mo compared with placebo, higher and lower steady-state plasma levels
were associated with no significant benefit over placebo (Fig. 2).
The PARAGON-B trial built on the knowledge gained from the results of the PARAGON-
A study by attempting to target drug levels carefully in a similar patient population (17).
Of the 5225 patients randomized, steady-state plasma concentrations of lamifiban were
available in 1272 patients (18). Interestingly, in contrast to the PARAGON-A results, a
U-shaped dose response was not seen, with a trend toward greater benefit with increasing
plasma levels in the overall PARAGON-B population (Fig. 3). The importance of achiev-
ing an adequate level of inhibition in order to optimize clinical outcomes was highlighted
by the results in the subgroup of troponin-positive patients in which patients with low
plasma levels derived no benefit compared with patients randomized to placebo, whereas
patients with target levels or greater of inhibition experienced a >50% relative decrease
in ischemic events (Fig. 3).
The FROST (Fibrinogen Receptor Occupancy Study) study was a Phase II trial evalu-
ating treatment with the oral GPIIb/IIIa antagonist lefradafiban for 1 mo in 531 patients
with a non-ST-elevation acute coronary syndrome. The minimum fibrinogen receptor occu-
pancy (FRO) was calculated from up to four plasma concentrations per patient and cor-
related with clinical outcomes (19). The incidence of the combined endpoint of death, MI,
and angina pectoris was found to be directly related to the FRO. Only those patients with
an FRO of >70%, correlating with ≥90% inhibition of 20 µM ADP-induced platelet aggre-
gation, achieved outcomes better than the control group.
Fig. 2. Correlation between plasma steady-state lamifiban concentrations in PARAGON-A (Platelet
IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organiza-
tion Network) and the incidence of death and myocardial infarction (MI) at 6 mo in a subgroup of 810
lamifiban-treated patients (16).
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 325
The only study to date to evaluate prospectively the level of platelet inhibition achieved
with GPIIb/IIIa antagonists and clinical outcomes is the GOLD [AU (Assessing Ultegra)]
study (20). In this multicenter study, 500 patients undergoing a PCI with the planned use
of a GPIIb/IIIa inhibitor had platelet inhibition measured using the point-of-care Ultegra-
Rapid Platelet Function Assay (RPFA) (see the RPFA section). The most important find-
ing from this study was that approximately one-fourth of all patients did not achieve ≥95%
inhibition 10 min following the bolus and that this lower level of inhibition was associated
with a significantly higher incidence of major adverse cardiac events (MACE; 14.4% vs
6.4%, p = 0.006). By multivariate analysis, platelet function inhibition ≥95% at 10 min
following the start of therapy was associated with a significant decrease in the incidence
of a MACE (odds ratio 0.46, 95% confidence interval 0.22–0.96, p = 0.04).
Level of Platelet Inhibition and Bleeding Complications
The use of agents that inhibit the platelet GPIIb/IIIa receptor is modeled after the inher-
ited platelet disorder Glanzmann’s thrombasthenia, which is characterized by a total defi-
ciency or abnormality in the GPIIb/IIIa receptor. Interestingly, patients with Glanzmann’s
thrombasthenia, who have essentially infinite bleeding times, only rarely experience
spontaneous major bleeding (21). Most serious hemorrhagic problems occur only when
associated with either physiologic or pathologic processes that would also cause bleeding
in normal individuals. Therefore, it was not surprising that early experience with GPIIb/
IIIa antagonists in the setting of PCI was associated with a higher rate of bleeding compli-
cations (11). However, later trials, utilizing reduced-dose heparin regimens and earlier
arterial sheath removal, led to a marked improvement in major bleeding rates such that
they were no different from that of placebo (22–24).
Fig. 3. Correlation between plasma steady-state lamifiban concentrations in PARAGON-B (Platelet
IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization
Network) and the incidence of death, myocardial infarction (MI), and severe recurrent ischemia in 1272
patients (18). A trend toward greater benefit with increasing plasma levels in the overall PARAGON-
B population is seen. In the subgroup of troponin-positive patients those with low plasma levels derived
no benefit compared with patients randomized to placebo, whereas patients with target levels or greater
of inhibition experienced a >50% relative decrease in ischemic events.
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326 Part IV / Practical Issues and Future Applications
Only a very limited number of clinical studies have attempted to correlate some mea-
sure of platelet inhibition and bleeding risk. An early report of bleeding times in two pilot
trials investigating the forerunner of abciximab found no correlation between measured
template bleeding times and the risk of hemorrhagic events (25). A more recent study,
which evaluated bleeding complications among the 500 patients enrolled in the GOLD
trial, also found no correlation between the level of platelet inhibition, as measured by the
point-of-care Ultegra-RPFA, and major bleeding complications (26). Importantly, the
investigators were able to show a significant correlation between major bleeding and increas-
ing procedural activated clotting time (ACT), suggesting that there was adequate power
to demonstrate a similar relationship between the level of platelet inhibition and bleeding
if one existed.
Presently, no clear threshold level of platelet inhibition with parenteral GPIIb/IIIa antag-
onists has been established that is associated with an increased risk of major bleeding. How-
ever, the ability to ensure a return to normal function in case emergent surgery is required
in GPIIb/IIIa antagonist-treated patients, may be an essential role of platelet monitoring.
METHODS OF MONITORING OF PLATELET INHIBITION
Laboratory-Based Assays
TURBIDIMETRIC AGGREGOMETRY
Historically, the most widely used laboratory assay for determining platelet function
and response to antiplatelet therapies has been turbidimetric aggregometry. In fact, the
current dosing of all available GPIIb/IIIa antagonists was primarily based on turbidimetric
aggregation results (7–9). With this technique, platelet-rich plasma (PRP) is stirred while
the optical density of the suspension is continuously monitored. An agonist, typically ADP,
collagen, epinephrine, or thrombin receptor-activating peptide (TRAP), is then added,
causing activation of the platelets in suspension. The degree of platelet activation is depen-
dent on the agonist used and its concentration, as well as platelet-dependent properties.
Platelet activation initiates the formation of aggregates, which leads to a decrease in the
total number of particles in solution and therefore a decrease in optical density of the PRP.
Agents that inhibit platelet activation (such as aspirin and clopidogrel) and platelet aggre-
gation (such as the GPIIb/IIIa antagonists) prevent or diminish this decrease in optical
density based, at least in part, on the level of platelet inhibition.
There are a number of limitations to the use of turbidimetric aggregometry that prohibit
its routine use for monitoring GPIIb/IIIa antagonist therapy. First, it is a specialized test
that requires extensive sample preparation, expensive testing equipment, frequent quality
control, and a certain level of operator expertise, all of which make it available only in
specialized laboratories in a limited number of hospitals. Besides these practical limita-
tions, certain physiologic limitations also exist. Preparation of PRP creates changes in the
milieu and density of platelets, negating the influence of other blood components in throm-
bus formation. Also, since PRP turbidimetric aggregometry is insensitive to platelet mic-
roaggregates, failing to detect aggregates with fewer than approx 100 platelets, clinically
important platelet function may remain unmonitored (27,28). Despite these significant
limitations, turbidimetric aggregometry remains the gold standard by which other devices
are most frequently compared.
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 327
ELECTRICAL IMPEDANCE AGGREGOMETRY
Electrical impedance aggregometry is one of the first whole-blood assays developed
with the hope of overcoming many of the limitations of turbidimetric aggregometry (29).
This technique measures aggregation as an increase in the electrical impedance across
two precious metal wires resulting from the accumulation of platelets in response to an
agonist. Unlike turbidimetric aggregometry, no cell separation is required, and the sample
only needs to be diluted 1:1 with saline followed by a 5-min incubation time prior to the
initiation of the assay. Other advantages include a relatively rapid result and a reduced
need for lab technician training.
The major disadvantage for this assay in measuring response to GPIIb/IIIa antagonists
is the dilution step, which may limit its utility in monitoring the low-molecular-weight
agents like tirofiban and eptifibatide with high dissociation constants. Other limitations
to its usefulness in routine clinical practice are the need to prepare and pipet reagents and
the requirement for frequent, meticulous care of the electrodes. The test is also less reliable
at lower hemoglobin concentrations.
Electrical impedance aggregometry has been compared with turbidimetric aggregom-
etry in one study involving 14 patients undergoing a PCI with the use of a standard bolus
and infusion of abciximab (30). The investigators found a close correlation between the
level of GPIIb/IIIa receptor blockade and platelet inhibition as determined by electrical
impedance and turbidimetric aggregometry.
F
LOW CYTOMETRY
All other methods of monitoring platelet function discussed in this chapter involve some
measurement of actual platelet function in an artificially induced thrombotic environ-
ment. In contrast, flow cytometry allows for the direct measurement of the actual in vivo
status of the platelet by detecting the expression or configuration of any platelet surface
antigen (31). Whole blood flow cytometry allows for the minimization of artifactual plate-
let activation.
Flow cyotometric analysis begins with the dilution of anticoagulated whole blood in
order to minimize platelet aggregate formation (32). The “test” monoclonal antibody
(recognizing the antigen to be measured) labeled with a fluorophore is then added at near
saturating concentrations. Then the “platelet identifier” monoclonal antibody is added at
similar concentrations. An agonist such as TRAP, ADP, collagen, or others can then be
added if desired prior to sample stabilization with fixation by paraformaldehyde. Samples
are then analyzed by flow cytometry. After the platelets are identified by their character-
istic light scatter and by platelet identifier labeling, binding of the test monoclonal anti-
body is determined by analyzing 5000–10,000 individual platelets.
Flow cytometric methods have been used extensively in the research setting for monitor-
ing GPIIb/IIIa antagonists. Drug receptor occupancy can be measured either directly or
indirectly. Examples of direct methods include competitive binding assays and measurement
of binding of an antibody directed against the GPIIb/IIIa antagonist being measured (33,34).
A recent investigation utilizing two monoclonal antibodies (MAbs), LYP18 (MAb1)
and 4F8 (MAb2), demonstrated the utility of flow cytometry in identifying the difference
in binding characteristics of different GPIIb/IIIa antagonists (35). MAb1 binds to the intact
GPIIb/IIIa receptor complex, whereas MAb2 binds to a different epitope on the β3 sub-
unit of the GPIIb/IIIa receptor. Abciximab was found to reduce the binding of MAb1 to
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328 Part IV / Practical Issues and Future Applications
platelets, probably by occupying the MAb1 binding site on the GPIIb/IIIa receptor but
did not alter MAb2 binding. In contrast, the small-molecule GPIIb/IIIa receptor antago-
nists eptifibatide and xemilofiban did not alter MAb1 binding but displaced MAb2.
The primary limitation of flow cytometry involves the technical sophistication of the
technique. The equipment is very specialized and relatively expansive. Also, substantial
training and expertise are required to run and interpret results. At present, use of these
assays is limited to research purposes.
Point-of-Care Assays
BLEEDING TIME
The bleeding time was initially described in 1901 and first suggested to be a measure
of platelet function in 1910 (36,37). The test simply involves a superficial incision, typi-
cally with an automated device that creates an incision of controlled dimensions, with
serial blotting of the site until bleeding stops and the time is recorded. The most common
method is that described by Ivy and coworkers (38), who utilized a blood pressure cuff
to the arm to maintain a standard venous pressure and established the site of the super-
ficial incision to the volar aspect of the forearm. The test is labor-intensive and subject
to considerable inter- and intraobserver variability.
Although bleeding time has been used for decades for diagnosing platelet-related bleed-
ing disorders, recent reviews have concluded that there is no evidence supporting its use
for predicting bleeding or response to antiplatelet therapy (39). As noted above, the one
study that specifically evaluated bleeding time in the setting of GPIIb/IIIa antagonist ther-
apy found no correlation with bleeding complications (25).
U
LTEGRA-RAPID PLATELET FUNCTION ASSAY (RPFA)
The Ultegra-RPFA (Accumetrics, San Diego, CA), unlike all other methods of mea-
suring platelet function, was specifically designed to be utilized in patients treated with
GPIIb/IIIa antagonists. It is an automated, whole-blood, point-of-care assay that allows
platelet inhibition to be measured rapidly by patient care providers at the bedside.
The basis of the Ultegra-RPFA assay is that fibrinogen-coated polystyrene microparti-
cles will agglutinate in whole blood in direct proportion to the number of unblocked plate-
let GPIIb/IIIa receptors. Pharmacologic blockade of GPIIb/IIIa receptors prevents this
interaction and therefore diminishes agglutination in proportion to the degree of receptor
blockade achieved. Because the speed of bead agglutination is more rapid and reproduc-
ible if platelets are activated, a modified thrombin receptor-activating peptide, iso-TRAP
[(iso-S)FLLRN] is incorporated into the assay (40). Blood samples are obtained in either
a standard citrate blood tube, or PPACK (Phe-Pro-Arg chloromethyl ketone) can be uti-
lized for the anticoagulant instead of citrate. The tube is inserted into a disposable plastic
cartridge, and 160 µL of the blood is automatically drawn into two sample channels con-
taining lyophilized iso-TRAP and fibrinogen-coated beads. The reagents are reconstituted
so that the final concentration of iso-TRAP is 4 µmol/L, a concentration selected to corre-
late best with the results obtained with turbidimetric aggregometry using 20 µM ADP as
the agonist. The sample is then mixed for 70 s by the movement of a microprocessor-driven
steel ball. The light absorbance of the sample is measured 16 times/s by an automated
detector. As the platelets interact with the fibrinogen-coated beads, resulting in agglutina-
tion, there is a progressive increase in light transmission (Fig. 4). The rate of agglutination
is quantified as the slope of the change of absorbance over a fixed time interval and reported
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 329
as millivolts per 10 s (mV/10 s). This numerical value is reported as platelet aggregation
units (PAU). An individual patient’s baseline PAU is retained in memory, and all addi-
tional specimens are reported as a raw PAU as well as a percentage of the baseline PAU.
Initial evaluations of the automated RPFA found an excellent correlation between the
assay and both turbidimetric platelet aggregometry with PRP and radiolabeled receptor
binding assays (40). Neither heparin nor aspirin use influenced the results of the assay.
To evaluate real-world clinical utility, precision, and reliability of the Ultegra-RPFA, a
study involving 192 patients at four centers undergoing PCI with the use of the GPIIb/IIIa
inhibitor abciximab was carried out. All patients had platelet function monitored at three
time points: (1) baseline, (2) within 1 h of abciximab bolus administration, and (3) at 24 h
after the abciximab bolus. Abciximab was administered in the standard bolus and 12 h intra-
venous infusion. Platelet function was determined at each time point using the Ultegra-
RPFA, conventional turbidimetric aggregometry, and [
125
I]abciximab receptor binding
assay. Of the 125 evaluable patients in whom all three methods could be compared, the level
of inhibition determined by the Ultegra correlated well with both standard aggregometry
(r = 0.87) and the receptor binding assay (r = 0.89) (41). This level of correlation was sim-
ilar to that observed in comparisons between the accepted gold standards for determining
platelet inhibition—turbidimetric aggregometry and the receptor binding assay (r = 0.87).
A number of clinical studies have been carried out using the Ultegra-RPFA. Two early
studies performed at The Lindner Center for Research and Education, Cincinnati, Ohio,
and at the Cleveland Clinic serially determined platelet function inhibition using the RPFA
Fig. 4. Diagram representing how platelet function is determined with the rapid platelet function assay.
The mixing chamber contains thrombin receptor-activating peptide (TRAP) and the fibrinogen-coated
beads. Whole blood is added, and the platelets become activated by the TRAP. The activated GPIIb/
IIIa receptors on the platelets bind via the fibrinogen on the beads and cause agglutination of the beads.
Light transmittance through the chamber is measured and increases as the agglutinated beads fall out
of solution. With blockade of the GPIIb/IIIa receptors, agglutination is much slower, and light trans-
mittance changes much less over time.
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