© 1999 American Heart Association, Inc.
Original Contributions |
Effect of Thrombolytic Therapy on Platelet Expression and Plasma Concentration of PECAM-1 (CD31) in Patients With Acute Myocardial Infarction
From the Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, Md.
Correspondence to Victor L. Serebruany, MD, PhD, Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 W Belvedere Ave, Schapiro Research Building R202, Baltimore, MD 21215. E-mail Heartdrug{at}aol.com
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Abstract |
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Abstract—Animal studies have shown that the administration of antibodies against platelet/endothelial cell adhesion molecule-1 (PECAM-1) before reperfusion can reduce infarct size. The purpose of the present study was to define the effects of thrombolytic therapy in acute myocardial infarction (AMI) patients on the platelet expression and plasma concentrations of PECAM-1 at prespecified time points after attempted reperfusion. The plasma concentration and platelet expression of PECAM-1 were determined in 23 AMI patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 22 healthy controls. At baseline, PECAM-1 was expressed significantly more on the platelet surface in the AMI patients than in controls (P=0.027) while soluble PECAM-1 plasma levels were almost identical between groups. There were no significant diurnal variations in both plasma and platelet PECAM-1 levels in controls. A significant decrease in platelet PECAM-1 expression was observed 3 hours after thrombolysis (P=0.03) compared with baseline, followed by a significant increase (P=0.004) in fluorescence intensity later at 24 hours after thrombolysis. Conversely, a significant increase in soluble PECAM-1 was observed 3 hours after thrombolysis (P=0.02), followed by a significant decrease later at 24 hours after attempted reperfusion (P=0.03). The expression of platelet-bound PECAM-1 is increased in AMI patients. Discordantly directed changes in soluble and platelet PECAM-1 after the first 24 hours after thrombolytic therapy may represent redistribution of the whole PECAM-1 pool. Further investigation of the possible role of PECAM-1 and the relationship between its soluble and platelet fractions in AMI are warranted.
Key Words: PECAM-1 • acute myocardial infarction • thrombolysis • humans
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Introduction |
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Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), a 130-kDa integral membrane glycoprotein (GP) and a member of the immunoglobulin gene superfamily, is found on the surface of platelets and leukocytes and at intercellular junctions of endothelial cells.1 2 PECAM-1 is directly involved in the formation of the vascular bed, affects the upregulation of integrin function on leukocytes, and has been implicated as a trigger that regulates leukocyte trafficking through the vessel wall.3 4 5 As an
-granule constituent, PECAM-1 is a distinct, well-defined component
of the platelet plasma membrane, with an intracellular distribution
identical to that of GP IIb/IIIa.6 Native, resting human
platelets express 
8000 molecules per platelet, whereas
thrombin-stimulated platelets exhibit nearly 2-fold
expression.7 A soluble form of PECAM-1, which is 5 to 10 kDa smaller than platelet-associated PECAM-1, contains a cytoplasmic tail and is encoded by an alternatively spliced mRNA from which the exon containing the transmembrane domain has been removed.8 Despite the proposed importance of PECAM-1, little is known about its biosynthesis, processing, and turnover on the cell surface.
Limited evidence from in vitro9 and animal10 studies show that monoclonal antibodies against PECAM-1 block leukocyte migration and neutrophil accumulation and reduce acute inflammation. Recognizing the role of leukocytes in the pathogenesis of acute coronary thrombosis and the modulation of injury after reperfusion, it is reasonable to expect that anti–PECAM-1 antibodies may diminish infarct size. Indeed, the administration of monoclonal antibodies against PECAM-1 resulted in a significant reduction in infarct size, presumably via blockade of neutrophil accumulation in the myocardium in both rats11 and cats.12 These studies suggest that PECAM-1 may be an attractive target for a novel, adjunctive therapeutic approach in the treatment of acute myocardial infarction (AMI).
However, the role of PECAM-1 in acute coronary syndromes has been suggested but never explored. No data are available on platelet PECAM-1 expression and plasma levels in AMI patients; similarly, the effects of thrombolytic therapy are unknown. Moreover, possible diurnal variations in platelet and plasma PECAM-1 levels in healthy controls have not been elucidated. Simultaneous determination of both platelet and soluble forms could lead to the discovery of helpful correlations between PECAM-1 and arterial patency, the success of thrombolysis, infarct size, reocclusion, or reinfarction.
Thus, the purpose of the present study was to define the immediate, early, and delayed effects of thrombolytic therapy in AMI patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial on the platelet expression and plasma concentrations of PECAM-1 at prespecified time points after attempted reperfusion and to compare these results with a cohort of healthy controls matched over the same time period at the same time of day.
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Methods |
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This study was approved by the Institutional Review Boards of St Agnes Hospital and Union Memorial Hospital (Baltimore, Md). Informed, written consent was obtained from all participants of the study.
Controls
Ten nonsmoking, nondiabetic subjects (aged 21 to 43 years; 6
men, 4 women) without a history of bleeding disorders, hypertension,
and cardiovascular disease and who did not use
pharmacological agents for at least 2 weeks before the study were
enrolled. All subjects underwent blood sampling after at least 30
minutes of rest and 2 or more hours of fasting. From 12 additional
volunteers, blood was drawn 6 times every 4 hours over a 24-hour period
to determine any possible diurnal influence and was sampled from an
antecubital vein as in the experimental group.
Patients
Twenty-three consecutive patients admitted to the emergency
departments of St Agnes Hospital or Union Memorial Hospital between
July and December 1996 with a diagnosis of AMI were included. All
patients were enrolled in the randomized trial of reteplase (n=13)
versus accelerated alteplase (n=10) for treatment of AMI (GUSTO-III
trial).13 The inclusion criteria have been previously
reported.13 In summary, patients of any age who
presented within 6 hours of symptom onset with >30 minutes of
continuous symptoms of AMI and who, on a 12-lead ECG, had demonstrated
at least a 1-mm ST-segment elevation in 2 or more limb leads, at least
a 2-mm ST-segment elevation in 2 or more contiguous precordial
leads, or bundle branch block were included in this trial. Patients
were excluded if they had a history of bleeding diathesis, stroke,
major surgery, or significant trauma in the previous 6 weeks and a
blood pressure reading >200/110 mm Hg. Patients randomized to
reteplase therapy received 2 intravenous 10-MU boluses
given 30 minutes apart. Those randomized to alteplase received an
accelerated dosing regimen: a 15-mg bolus, then 0.75 mg/kg over 30
minutes, and 0.50 mg/kg over 1 hour. During baseline sampling, every
patient received 325 mg aspirin and at least 5000 U
intravenous heparin. After administration of the
thrombolytic therapy, all patients received a
continuous infusion of heparin for the first 24 hours as recommended in
the GUSTO-III protocol. Blood samples for ELISA and for
flow-cytometric studies were taken at prespecified intervals: in the
emergency department immediately before administration of the
thrombolytic therapy; in the coronary care unit
at 3, 6, and 12 hours; and finally at 24 hours thereafter. To avoid
possible observer bias, blood samples were coded and blinded. Sampling
procedures, ELISA, and flow-cytometric studies were performed by
individuals unaware of the protocol.
Time Course and Exclusion of Blood Samples
The schedules for blood drawing, sample preparation, and
processing were critical issues of the study design and were monitored
by an independent observer. The actual timing of blood collection for
the baseline sample was 9.5±1.4 minutes before the start of
thrombolytic therapy, 174.6±21.8 minutes for the
3-hour sample, 371.1±24.2 minutes for the 6-hour sample, 709.4±17.8
minutes for the 12-hour sample, and 1402.9±18.8 minutes for the
24-hour sample. Samples were processed within 1 hour after blood
drawing. Four patients did not complete the protocol at various time
points. The reasons for early termination were patient transfer for
emergency coronary angioplasty (3) and inability to obtain a
blood sample (1). Twenty-three baseline samples,
22 samples collected at 3 hours, 20 samples collected at 6 hours, 20
samples collected at 12 hours, and 19 samples collected at 24 hours
were included in the study analysis.
Soluble PECAM-1
Platelet-poor plasma was obtained by
centrifugation of whole blood at 4°C in a
Labofuge at 3000g for 10 minutes. Samples were stored at
-80°C before final determinations. An ELISA for PECAM-1 (Bender
MedSystems) was used according to standard techniques. Each
sample was measured in triplicate, and the overall intra-assay
coefficient of variation was 2.1±0.3%.
Platelet-Bound PECAM-1
Flow-cytometry procedures have been previously described
in detail.14 15 In brief, venous blood (8 mL) was
collected in a plastic tube containing 2 mL acid-citrate-dextrose (ACD)
and mixed well. The blood-ACD mixture was centrifuged at 1000
rpm for 10 minutes at room temperature. The upper 2/3 of the
platelet-rich plasma (PRP) was then collected and adjusted to pH
6.5 by adding ACD. The PRP was then centrifuged at 3000 rpm for
10 minutes. The supernatant was removed and the platelet pellet
gently resuspended in 4 mL of the washing buffer (10 mmol/L
Tris-HCl, 0.15 mol/L NaCl, and 20 mmol/L EDTA, pH 7.4).
Platelets were washed 4 times in the washing buffer and an
additional 4 times in Tris-buffered saline (10 mmol/L Tris and
0.15 mol/L NaCl, pH 7.4). One portion of washed platelets was
incubated with 5 µL FITC-conjugated antibodies in the dark at 4°C
for 30 minutes, and 1 part remained unstained and served as a negative
control. Surface antigen expression was determined with monoclonal
murine anti-human antibodies to CD31 (PECAM-1; PharMingen, San Diego,
Calif). After incubation, the cells were washed 3 times with
Tris-buffered saline and resuspended in 0.25 mL of 1%
paraformaldehyde. Samples were stored at 4°C and
analyzed on a Becton-Dickinson FACScan flow cytometer with a
laser output of 15 mW, an excitation wavelength of 488 nm, and emission
detection at 530±30 nm. The instrument was calibrated daily with
fluorescence beads (CaliBRITE; Becton-Dickinson) and measured
FITC-conjugated fluorescence intensity. All
parameters were obtained by logarithmic amplification to
the fourth decimal place. The data were collected and stored in
list mode and then analyzed with CELLQuest (version 1.2.2)
software.
Statistical Analyses
A post hoc t test comparison using the Bonferroni
correction was performed to identify specific differences in soluble
PECAM-1 and platelet receptor expression between AMI patients and
controls and between different time points within the control and AMI
groups. A Mann-Whitney U test was used to analyze
nonparametric data. Normally distributed data are expressed
as mean±SD, and P<0.05 was considered significant.
Differences between individual flow-cytometric histograms were assessed
using the Smirnov-Kolmogorov test incorporated in the CELLQuest
software.
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Results |
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The clinical characteristics of the AMI patients are shown in Table 1
. Table 2 and Figure 1 summarize the data on the soluble and
platelet-bound PECAM-1 levels in AMI patients before and after
thrombolytic therapy and in healthy controls.
Individual data on the diurnal variations in healthy volunteers are
plotted for soluble (Figure 2A) and
platelet-bound (Figure 2B) PECAM-1. There were no meaningful
differences in diurnal variations in healthy volunteers. However,
platelet-bound PECAM-1 was slightly higher during the night and
early morning hours.
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Plasma PECAM-1
At baseline, the data were almost identical between controls and
the AMI group. A significant increase of plasma PECAM-1 was observed 3
hours after thrombolysis (P=0.02) and was
followed by a significant decrease later at 24 hours
(P=0.03).
Platelet-Bound PECAM-1
At baseline, before any reperfusion strategies were applied,
PECAM-1 was expressed significantly more on the platelet surface of
the AMI patients compared with controls (P=0.027). A
significant decrease of platelet PECAM-1 expression was observed 3
hours after thrombolysis (P=0.03) when
compared with baseline, followed by a significant increase
(P=0.004) in fluorescence intensity later at 24
hours after thrombolysis.
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Discussion |
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The data from the present study describe the time course of soluble and platelet-bound PECAM-1 levels after thrombolytic therapy in patients with AMI. A negative correlation was observed for soluble and platelet-bound PECAM-1 at 3 and 24 hours after thrombolysis. That is, while plasma PECAM-1 increased early after thrombolysis, platelet expression of PECAM-1 diminished at the same time point. Conversely, later after thrombolytic administration, soluble PECAM-1 levels dropped below baseline while platelet expression increased significantly (Figure 1
). The present
data suggest that plasma levels and platelet expression of PECAM-1
are inversely related to each other during the course of
thrombolysis for AMI. Future basic studies are
necessary to determine the normal distribution of the human PECAM-1
pool and the factors affecting this adhesion molecule. This study also demonstrates that the expression and plasma levels of PECAM-1 in the AMI population are heterogeneous. We have observed similar heterogeneity with other platelet-surface receptors, including P-selectin and GP IIb/IIIa. Contrary to expectations, we did not observe marked PECAM-1 activation at baseline in the AMI population when compared with controls. Certain individuals exhibited a 2-fold increase in PECAM-1; however, more than a half of AMI patients have a platelet expression of PECAM-1 that is within the normal range or lower. Furthermore, the soluble PECAM-1 level was identical between the AMI group and healthy controls.
Platelets have established interactions with both
physiological and drug-induced
fibrinolysis.16 For example, platelet
-granules, in addition to containing PECAM-1, incorporate
plasminogen activator
inhibitor-116 and
2-antiplasmin.17 Release of these
proteins theoretically could result in reduced
thrombolysis. The resistance to arterial
opening after thrombolysis has been reported in animal
models of platelet-rich coronary thrombi.18
Studies supporting the "platelet hypothesis" have demonstrated
enhanced reperfusion with concomitant use of antibodies and other
antagonists to GP IIb/IIIa.19 20 In addition,
it has recently been demonstrated that systemically administered
antibodies against GP IIb/IIIa alone, presumably by facilitating
platelet disaggregation, can restore infarcted artery
reperfusion.21 Nevertheless, the relative contribution of
each of the individual platelet-surface receptors to
platelet-mediated vessel occlusion in the pathogenesis of AMI
remains undefined.
Flow cytometry has been found to be a sensitive, objective, and reproducible method for the detection and measurement of platelet receptors.14 15 A large number of cellular antigens have been demonstrated on platelets by flow cytometry, and their quantification is an objective and accurate method.22 Some of the platelet receptors (eg, GP IIb/IIIa, P-selectin) are relatively well described, and their role in acute coronary syndromes is under thorough investigation, whereas much less is known about other surface GPs, including PECAM-1.
The involvement of PECAM-1 in platelet adhesion and aggregation remains a matter of considerable controversy. Anti–PECAM-1 monoclonal antibodies did not inhibit platelet aggregation or platelet adherence to the extracellular matrix7 and had no effect on platelet aggregate formation after epinephrine-induced activation23 in humans. However, although no effects of PECAM-1 on platelet aggregation have been reported, an important role in aggregation-induced cell signaling has been observed.24 In contrast, PECAM-1 has been implicated in platelet aggregation25 and has been described as an important modulator of platelet function in mice.26 Our data on the diminished platelet expression of PECAM-1 followed by its increase later during thrombolysis is in agreement with the few available observations on the dynamic patterns of the platelet-27 and neutrophil-28 expressed PECAM-1 during cardiopulmonary bypass in humans.
Another meaningful issue is an obvious concern for a possible diurnal
variation of PECAM-1 in normal controls, which were described earlier
for the fibrinolytic system29 and platelet
serotonin transport30 but not for
platelet aggregability31 and membrane
2-adrenoceptor expression32 or
eicosanoid urinary excretion.33 Diurnal variations are
important because there is clear clinical evidence of circadian
patterns in myocardial ischemic episodes. In patients with
effort angina, the highest activity occurs between 6 AM and
noon. This maximum coincides with peaks in the diurnal variation in
frequency of AMI, stroke, and sudden death.34 35 Indeed,
we found no significant diurnal variations in both soluble and
platelet PECAM-1 values; however, slightly higher levels of
platelet-bound PECAM-1 expression during the night and early
morning hours are in full agreement with the above-mentioned
studies.
There are several limitations of the study. The sample size is small and therefore is compromised by low power. Statistical differences between and within groups in the soluble form and in surface platelet receptor expression could possibly be revealed in a larger sample of patients. It will be important in future studies to determine possible interactions between PECAM-1 and more-explored platelet antigens like GP IIb/IIIa and P-selectin and to develop specific anti–PECAM-1 strategies in patients with acute coronary syndromes. In addition to the observed differences in PECAM-1, clinical characteristics such as use of antecedent aspirin and the timing of thrombolytic agent delivery may influence the results.
In conclusion, PECAM-1 plasma concentrations are dynamic after thrombolytic therapy in AMI patients and exhibit an early rise followed by a slow decline. The mechanism of the above observation is unknown but may be related to myocardial reperfusion. An enticing speculation is that it is derived from the ischemic vascular bed after reperfusion. Platelet PECAM-1 is increased at baseline in the AMI population, declines early after reperfusion, and is followed by a second phase of enhanced expression. This phenomenon, observed with other platelet antigens, may indicate delayed platelet activation after thrombolysis.
The determination of the role of less-studied platelet and endothelial receptors in patients with AMI cannot be overstated. Given the predominance of PECAM-1 on the endothelium, its proposed importance in transendothelial migration of leukocytes, and the role of leukocytes and platelets in coronary thrombosis, further investigation of the relation between soluble and platelet PECAM-1 fractions in myocardial ischemia/reperfusion is warranted.
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Acknowledgments |
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This study was supported in part by Medtronic, Inc, and Boehringer Mannheim GmbH (to V.L.S. and P.A.G.). We are indebted to the staff of the emergency departments and critical care units of St Agnes and Union Memorial Hospitals.
Received November 4, 1997; accepted June 30, 1998.
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