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330 Part IV / Practical Issues and Future Applications
in a total of 178 abciximab-treated patients in the setting of PCI (42,43). Both of these
studies demonstrated substantial interpatient variability in response to a standard, weight-
adjusted infusion of abciximab. Although neither study was designed to evaluate clinical
outcomes, the Cleveland Clinic study did find a significant association between the level
of platelet inhibition and the occurrence of a peri-PCI MI (42).
Based on these results, the first prospective study designed to correlate the level of plate-
let inhibition achieved with a GPIIb/IIIa antagonist and clinical outcomes was carried
out. The GOLD study serially evaluated platelet function inhibition in 500 patients at 13
centers undergoing a PCI with the use of a GPIIb/IIIa inhibitor (20). Platelet inhibition
was measured at 10 min, 1 h, 8 h, and 24 h following the initiation of therapy using the
Ultegra-RPFA. MACE (a composite of death, MI, and urgent target vessel revascular-
ization) were prospectively monitored, and their incidence was correlated with the mea-
sured level of platelet inhibition at all time points. As noted earlier, one-fourth of all patients
did not achieve ≥95% inhibition 10 min following the bolus, and these patients experi-
enced a significantly higher incidence of MACE (14.4% vs 6.4%, p = 0.006) (Fig. 5). Also,
patients whose platelet function was <70% inhibited at 8 h after the start of therapy had
a MACE rate of 25% vs 8.1% (p = 0.009) compared with those ≥70% inhibited.
The observed association between the level of platelet inhibition as determined by the
Ultegra-RPFA and clinical outcomes suggests clinical utility of this device; however, fur-
ther studies are necessary to confirm that titrating GPIIb/IIIa therapy based on measured
levels of platelet inhibition will decrease adverse events.
P
LATELET FUNCTION ANALYZER (PFA-100)
The PFA-100 (Dade Behring, Miami, FL) is an automated platelet function analyzer
that evaluates primary hemostasis in whole blood flowing through high shear conditions.
Fig. 5. Incidence of major adverse cardiac events (MACE) in 469 patients undergoing a percutaneous
coronary intervention in relation to the level of platelet function inhibition as determined by the Ultegra
—Rapid Platelet Function Assay at 10 min following the GPIIb/IIIa inhibitor bolus in the GOLD (AU-
Assessing Ultegra) study (20). MI, myocardial infarction; TVR, target vessel revascularization.
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 331
It is used to screen for von Willebrand’s disease and other congenital platelet disorders.
It has also been evaluated as a method for monitoring response to aspirin and GPIIb/IIIa
antagonists (44,45).
The disposable test cartridge consists of a sample reservoir, capillary, and biochemi-
cally active membrane with a central 150-µm aperture (Fig. 6). The membrane is coated
with collagen plus either ADP (50 µg) or epinephrine (10 µg). This instrument provides
a constant vacuum that apirates citrated whole blood through the capillary tube, where
it contacts the membrane. Aspiration through the capillary tube creates high shear stress,
which activates the platelets that then adhere and aggregate at the membrane aperture
until it occludes, causing cessation of blood flow. The time to cessation of flow is reported
as the closure time (CT). The normal range for the CT in a series of 225 patients prior to
undergoing PCI was defined as a range of 60–130 s (45). The maximal closure time has
been set at 300 s, which represents nonclosure of the aperture after 300 s.
The PFA-100 offers several advantages over laboratory-based methods of measuring
platelet function. The testing technique is easy to learn, uses whole blood, and does not
require a skilled technician to operate the analyzer. Also, blood is collected into standard
Vacutainer tubes and can then be kept at room temperature for up to 4 h before testing.
Finally, test results are available in approx 10 min.
The largest study to evaluate the PFA-100 for monitoring GPIIb/IIIa therapy involved
225 patients treated with abciximab in the setting of a PCI, with the results in only 27
patients having been reported to date (45). The CT was compared with turbidimetric aggre-
gometry and receptor occupancy by flow cytometry at 10 min, 4 h, 12 h, and 24 h after the
abciximab bolus. The CT was 300 s (maximal) in 96% of patients at 10 min, 100% at 4 h,
and 88% at 12 h. At 24 h, 72% of patients had a normal CT (≤130 s). Because virtually
all patients achieved maximal CT with abciximab, it was not possible to correlate PFA-
100 results with those of the accepted laboratory standards. These results suggest that the
Fig. 6. Schematic of the cartridge of the platelet function analyzer (PFA)-100. The membrane is coated
with collagen plus either ADP (50 µg) or epinephrine (10 µg). This instrument provides a constant
vacuum that aspirates citrated whole blood through the capillary tube, creating high shear stress, which
activates the platelets that then adhere and aggregate at the membrane aperture until it occludes, caus-
ing cessation of blood flow.
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332 Part IV / Practical Issues and Future Applications
PFA-100 may be too sensitive to detect clinically relevant, high levels of platelet inhibi-
tion but that it can rapidly determine when platelet function has returned to normal follow-
ing treatment.
C
ONE AND PLATELET ANALYZER
The cone and platelet analyzer (CPA) tests platelet activation in whole blood under
flow conditions by monitoring shear-induced platelet deposition onto a surface designed
to mimic an extracellular matrix (46). A 200-µL sample of citrated blood is placed in poly-
styrene wells and circulated at high shear rate (1875 s-1) for 2 min with a rotating Teflon
cone. Wells are then washed, stained, and analyzed with an inverted light microscope that
is connected to an image analysis system. Results are expressed as the percentage of well
surface covered by platelets (47). Determination of both congenital and acquired platelet
disorders are determined based on the principle that platelet deposition on polystyrene
under flow is dependent on platelet activation and on the presence of fibrinogen, von
Willebrand factor, and their receptors. Advantages of this test are that it uses high shear
stress to simulate arterial physiology. The test also uses whole blood and does not require
a baseline reading.
A recent trial evaluated the CPA, turbidometric aggregometry, and RPFA vs flow
cytometry in 10 healthy volunteers (47). The CPA detection of platelet inhibition corre-
lated significantly better with the percentage receptor occupancy by flow cytometry than
did turbidimetric aggregometry (p = 0.0007), but these measurements were primarily at
midlevels of platelet inhibition. Compared with RPFA, CPA was a better predictor of free
GPIIb/IIIa receptors when the RPFA data were expressed as absolute values (p = 0.0015)
but not when RPFA was expressed as a percentage of baseline inhibition. This report also
evaluated platelet function in 16 patients who underwent PCI and received abciximab.
Platelet function was assessed by the CPA and turbidimetric aggregometry at baseline,
5 min, 4 h, and 1, 3, 7, and 30 d. By turbidometric aggregometry, platelet function remained
suppressed for only 1 d after abciximab therapy, whereas CPA-assessed platelet function
did not return to normal until between 7 and 30 d. The CPA may therefore have greater
sensitivity to detect lower levels of platelet inhibition, but, like the PFA-100, may be too
sensitive to monitor the high levels of inhibition required during short-term parenteral GPIIb/
IIIa antagonist therapy. Of note, clopidogrel and aspirin therapy in three volunteers did not
significantly change CPA values in this study.
T
HROMBOELASTOGRAPHY
Thromboelastography (TEG) provides a graphic representation of several aspects of
clot formation. Although TEG was used in the past primarily as a means of determining
hemostatic derangements in the setting of liver transplant and cardiac surgery, several
recent small studies have evaluated its utility in monitoring GPIIb/IIIa therapy (48).
TEG is performed on 0.35 mL of whole blood that is placed in a heated cup. A pin is
suspended in the cup from a torsion wire that is transduced to a monitor. The cup oscil-
lates 4º 45' in either direction every 4.5 s. Initially, prior to clotting, the motion of the cup
does not affect the suspended pin. When the blood in the cup begins to clot, the motion
of the cup is transmitted to the pin, and a tracing is generated. Several parameters of the trac-
ing are routinely measured including the reaction time, which is the latency time between
blood being placed in the cup and the start of clotting, and the maximal amplitude, which
is the greatest vertical amplitude of the TEG tracing (48).
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 333
A linear dose-dependent reduction in clot strength in response to the in vitro addition
of abciximab has been reported using a modified TEG (49). The investigators modified
the test by using thrombin as an agonist and found that this allowed the test to be com-
pleted in 15 min rather than 1 h. Another modified version of TEG utilizing tissue factor
found a differential efficacy among different GPIIb/IIIa antagonists despite equivalent
antiaggregatory potency (50).
P
LATELET COUNT RATIO S (PLATELETWORKS)
The principle behind the platelet count ratio is that the number of free platelets mea-
sured in whole blood is decreased in relation to the number of platelet aggregates that form
after an agonist is added (Fig. 7). The Plateletworks (Helena Laboratories, Beaumont, TX)
is a point-of-care version of this concept that automatically determines the platelet count
ratio between a sample of whole blood in which an agonist such as ADP is added and the
same sample in which aggregation is prevented by the addition of a calcium chelating agent
(51). The platelet count ratio has been found to correlate well with platelet aggregation
measured by turbidometric aggregometry (52), but typically identifies a lower level of inhi-
bition than that determined by turbidimetric aggregometry. This has led some investiga-
tors to speculate that whereas turbidimetric aggregometry provides information regarding
the inhibition of platelet macroaggregate formation, the platelet count ratio actually mea-
sures the inhibition of microaggregation, which might have important implications in terms
of the therapeutic effectiveness of GPIIb/IIIa antagonists (27).
Platelet count ratios have an advantage in that the ability to perform platelet counts exists
at virtually every hospital, and since samples are fixed following initial preparation, anal-
ysis time can be delayed up to 4 h. However, unless the automated Plateletworks device is
used, platelet count ratios can only be determined in the laboratory setting with the require-
ment for sample manipulation.
Fig. 7. Single platelet count ratios are determined by measuring the number of platelets before and after
the addition of a specific agonist and then determining the ratio.
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334 Part IV / Practical Issues and Future Applications
CLOT SIGNATURE ANALYZER
The Clot Signature Analyzer (CSA; Xylum, Scarsdale, NY) is an automated device
designed to mimic vascular injury and provide a measure of both platelet and coagulation
function. Nonanticoagulated blood is perfused through two channels. In one channel blood
flows through tubing with pressure continuously monitored. The tubing is then pierced
by a 0.15-mm needle, causing an immediate drop in pressure. This change in blood flow
pattern also leads to a marked increase in shear rate, which initiates platelet activation and
aggregation at the punch site. As a platelet aggregate forms at the site, blood flow at the
punch site stops, and the measured pressure in the tubing rebounds. As the flow of blood
in the tubing continues, the simultaneous activation of the coagulation cascade promotes
fibrin generation and the buildup of a fibrin clot that leads to a decrease in flow and pres-
sure. At the same time, in the second channel, blood is perfused at high shear over a colla-
gen fiber. As platelets adhere and aggregate onto this thrombogenic surface, this tubing
also occludes, resulting in a decrease in pressure. The changes in pressure in the two chan-
nels are monitored and displayed in real time as graphical “signatures” of platelet and
coagulation function (53).
The advantages of the CSA are that it is an automated benchtop analyzer and is the only
one that does not require the use of anticoagulated blood samples. Also, it has the potential
to monitor the effects of both anticoagulant and antiplatelet therapies. Although it can mea-
sure the effects of GPIIb/IIIa antagonists, one study involving 36 patients undergoing a
PCI with a GPIIb/IIIa antagonist found that CSA results did not correlate with those of
turbidimetric aggregometry (54). Also, in many patients only the assay’s maximal values
were obtained, suggesting that, like the PFA-100 and CPA, the CSA may be overly sensi-
tive to high levels of platelet inhibition.
Special Considerations in Platelet Monitoring
MULTIPLE ANTITHROMBOTIC AGENTS
Patients treated with a GPIIb/IIIa antagonist will almost always also receive at least one
and typically several antithrombotic agents including aspirin, clopidogrel, unfractionated
heparin, low-molecular-weight heparin, fibrinolytics, or direct thrombin inhibitors. Just
monitoring platelet inhibition alone is complicated by the frequent, concomitant use of
these antiplatelet agents. An ideal test for monitoring platelet inhibition for the preven-
tion of thrombotic and bleeding events would ideally take into account all antiplatelet ther-
apies a patient is receiving, but such a test does not currently exist.
Although aspirin, clopidogrel, and the GPIIb/IIIa antagonists are all categorized under
the umbrella of antiplatelet agents, their very different mechanisms of action have made
it difficult to develop a clinically useful test that can distinguish the effects of all three
agents. Whereas aspirin and thienopyridines inhibit platelet activation, virtually every
test of their antiplatelet effects measures the inhibition of platelet aggregation. The GPIIb/
IIIa antagonists so profoundly inhibit platelet aggregation that their effects greatly over-
whelm any measured effect on aggregation that aspirin or a thienopyridine might have.
The small number of studies that have attempted to measure the additive effects of a thieno-
pyridine and a GPIIb/IIIa antagonist have typically only been able to show an effect of the
thienopyridine after treatment with the GPIIb/IIIa antagonists has stopped and its effects
diminished (55–58).
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 335
ANTICOAGULATION OF SAMPLES
Almost every test of platelet function requires the use of anticoagulated blood. Out of
habit and convenience, blood samples for platelet testing in the past most often used citrate,
an agent that prevents in vitro clotting by reducing ionized calcium levels, as the anticoag-
ulant. Recently, the importance of physiologic concentrations of calcium for the proper
function of the GPIIb/IIIa receptor and its influence on measured levels of platelet inhibi-
tion achieved with the various GPIIb/IIIa antagonists has been recognized (13). Although
the influence of calcium chelators on artificially inflating the measured level of inhibition
are best described for eptifibatide, recent work suggests that the other small molecule, tiro-
fiban, may also be substantially affected, with abciximab to a much lesser extent (27,59).
V
ARIABLE METHODS OF DETERMINING PLATELET FUNCTION
An 80% level of inhibition is frequently quoted as the goal for therapy with a GPIIb/IIIa
antagonist, frequently without stating 80% of what. Although original dosing goals of these
agents were targeted for 80% blockade of platelet GPIIb/IIIa receptors, which roughly
provided 80% inhibition of 20 µM ADP-induced platelet aggregation as measured by tur-
bidimetric aggregometry, these results cannot be translated into a goal level of inhibition
as determined by other methods of measuring platelet function. That is, 80% inhibition
of 20 µM ADP-induced turbidimetric aggregometry is not even equivalent to 80% inhibi-
tion of platelet function as determined by using another agonist or another concentration
of ADP in turbidimetric aggregometry, much less as determined by a point-of-care device
or flow cytometry. Therefore, the appropriate level of inhibition needed to optimize out-
comes must be determined for each device. Ideally, this would be determined through explor-
atory clinical trials correlating outcomes with measured levels of platelet function.
Conclusions
Virtually all available data for the GPIIb/IIIa antagonists confirm that the degree of
inhibition of the platelet GPIIb/IIIa integrin and platelet aggregation is critical to their clin-
ical effectiveness. Similarly, all studies that have evaluated the level of inhibition achieved
with these agents have found substantial interpatient variability. These facts support a com-
pelling theoretical benefit to the monitoring of all patients treated with a GPIIb/IIIa antag-
onist, coupled with dose adjustment, to optimize their safety and efficacy. In the past,
real-time monitoring was not possible owing to the technical constraints of platelet func-
tion testing. Today, however, there exist several point-of-care devices that allow for the
rapid determination of the effects of a GPIIb/IIIa antagonist at the bedside. At least one of
these devices has already been shown to provide clinically relevant results in a large, pro-
spective series. Nevertheless, before platelet monitoring can be routinely recommended
for all patients, further studies are needed to prove that dose adjustment is more than just
a theoretical benefit. Once the extra effort and expense of platelet monitoring can be justi-
fied through the confirmation of improved outcomes, it will probably become a standard
component of GPIIb/IIIa antagonist therapy.
INTERACTION OF GPIIb/IIIa
ANTAGONISTS WITH OTHER ANTIPLATELET AGENTS
When a patient is treated with a GPIIb/IIIa antagonist, an additional antiplatelet agent
is almost always utilized—in most cases at least aspirin. With recent studies confirming a
more widespread and long-term benefit of the ADP receptor antagonist clopidogrel, it is
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336 Part IV / Practical Issues and Future Applications
likely that an increasing number of patients who are candidates for treatment with a GPIIb/
IIIa antagonist may now be receiving dual antiplatelet therapy with clopidogrel and aspirin.
Because the GPIIb/IIIa antagonists inhibit platelet aggregation caused by all agonists,
including thromboxane A
2
and ADP, it might be suspected that any additional antiplatelet
effects of aspirin and clopidogrel may be superfluous. This assumption is reinforced by
the fact that most routine measures of antiplatelet effects involve some measure of inhi-
bition of in vitro platelet aggregation—a much greater function of GPIIb/IIIa inhibition
rather than thromboxane A
2
and ADP inhibition. However, by inhibiting platelet activa-
tion rather than aggregation, clopidogrel and aspirin may provide additional important
antiplatelet and possibly antiinflammatory effects.
Surprisingly, there are few clinical data regarding the interaction of the currently avail-
able antiplatelet agents, even though current guidelines recommend therapy with aspirin,
clopidogrel, and a GPIIb/IIIa antagonist in a large proportion of patients with acute coro-
nary syndromes (60). Although randomized trials are currently under way that will help
define any potential additive benefits and risks of starting a GPIIb/IIIa antagonist in patients
already receiving aspirin and clopidogrel, some observational and nonrandomized data
are currently available that provide some evidence of benefit.
GPIIb/IIIa Antagonists and Aspirin
Essentially every clinical trial of the parenteral GPIIb/IIIa antagonists has required con-
comitant aspirin therapy. There has been one randomized trial in acute coronary syndrome
patients that compared aspirin alone with aspirin plus a low dose of the oral GPIIb/IIIa
antagonist sibrafiban and a high dose of sibrafiban alone (61). The addition of aspirin to
sibrafiban was associated with a nonsignificant trend toward a decrease in the combined
primary endpoint of death, MI, or severe refractory ischemia (aspirin plus low-dose sibrafi-
ban 9.2% vs high-dose sibrafiban alone 10.5%). There was also a nonsignificant trend
toward increased major bleeding with aspirin plus sibrafiban (5.7%) vs sibrafiban alone
(4.6%). However, the many unanswered questions regarding oral agents as well as the dif-
ferent doses of sibrafiban studied make any conclusions regarding the role of aspirin with
a GPIIb/IIIa antagonist problematic.
GPIIb/IIIa Antagonists and Thienopyridines
Today, virtually all patients receiving a coronary stent receive a limited course of a thie-
nopyridine, typically clopidogrel, along with aspirin. If the thienopyridine is started after
the procedure, there is minimal interaction with any GPIIb/IIIa antagonist utilized owing
to the relatively slow (hours for clopidogrel, days for ticlopidine) onset of action of these
agents. However, a significant proportion of patients is now being pretreated with a thieno-
pyridine prior to percutaneous coronary intervention because of reports in several studies,
none randomized comparisons, of a benefit in decreasing thrombotic complications (62–
64). Whether a GPIIb/IIIa antagonist offers additional benefit (or risk) in this patient pop-
ulation is unknown. The results of the EPISTENT analysis suggested that pretreatment was
no longer beneficial in reducing adverse events at 30 d when the IIb/IIIa inhibitor abciximab
was used, but the duration of pretreatment with the slower onset ticlopidine was unknown
and probably short (62) (Fig. 8). On the other hand, the results of the TARGET trial sug-
gested that event rates were lower among patients pretreated with clopidogrel even when
all patients received a GPIIb/IIIa antagonist (64) (Fig. 9). However, both the EPISTENT
and TARGET trials were not designed to answer the question about the benefit of pretreat-
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Chapter 15 / Platelet Monitoring and GPIIb/IIIa Interactions 337
ment with a thienopyridine among patients receiving a IIb/IIIa inhibitor, and therefore
the optimal use of a GPIIb/IIIa antagonist when a patient has already received clopidogrel,
or of clopidogrel in a patient already receiving a GPIIb/IIIa antagonist, remains unclear.
Conclusions
Despite current recommendations for greater widespread utilization, the risks and
benefits of triple antiplatelet therapy with aspirin, clopidogrel, and a GPIIb/IIIa antagonist
remain unknown. The results of future trials will better identify the actual benefit of these
regimens and clarify any safety issues.
Fig. 8. Incidence of the 30-d composite endpoint in patients in the EPISTENT trial randomized to
receive a stent with or without abciximab, who also did or did not receive pretreatment with ticlo-
pidine based on the decision of the treating physician. MI, myocardial infarction.
Fig. 9. Incidence of the 30-d composite endpoint in patients in the TARGET trial randomized to the
GPIIb/IIIa antagonists abciximab or tirofiban and whether or not they were pretreated with clopido-
grel as recommended in the study protocol. MI, myocardial infarction; PCI, percutaneous coronary
intervention; TVR, target vessel revascularization.
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338 Part IV / Practical Issues and Future Applications
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