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(Circulation. 2001;103:2328.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
Effects of Abciximab on the Architecture of Platelet-Rich Clots in Patients With Acute Myocardial Infarction Undergoing Primary Coronary Intervention
Presented in part at the 49th Congress of the American College of Cardiology, Atlanta, Ga, March 7–10, 1999, and published in abstract form (J Am Coll Cardiol. 1999;33:1220).
From the Department of Cardiology (J.P.C., G.M., R.C., G.D., D.T.) and the Hematology Laboratory (C.L.), Pitié-Salpêtrière Hospital, Paris; Unité Propre de Service 937 (Z.M., J.S., C.S.), Centre National de Recherche Scientifique, Paul Brousse Hospital, Villejuif; Eli Lilly Company (P.P.), Saint-Cloud; and Clinique Beauregard (P.B.), Marseille, France.
Correspondence to G. Montalescot, MD, PhD, Department of Cardiology, Centre Hospitalier Universitaire Pitié-Salpêtrière, 47 boulevard de l’Hôpital, 75013 Paris, France. E-mail gilles.montalescot{at}psl.ap-hop-paris.fr
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Abstract |
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Background—Abciximab plus aspirin improves the TIMI 3 flow rate of the infarct-related artery in patients treated with either percutaneous coronary intervention or thrombolysis. The present study investigated whether the reperfusion efficacy of abciximab relates to modifications of clot architecture in patients admitted for acute myocardial infarction (AMI).
Methods and Results—A total of 23 AMI patients in the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long term follow-up (ADMIRAL) trial received, in a double-blind fashion, either abciximab (n=13) or placebo (n=10) before primary stenting. Viscoelastic (G' in dyne/cm2) and morphological (mean platelet aggregate surface area [SAG] in µm2) indexes of ex vivo platelet-rich clots (PRC) were assessed in a double-blind fashion before and after the bolus administration of abciximab or placebo. G' and SAG reflect the mechanical and morphological impact of activated platelets on the PRC fibrin network, respectively. Abciximab administration reduced G' by 63% (P=0.0001) and SAG by 65% (P=0.0007), and no effect was seen in the placebo group. These abciximab-related changes increased fibrin exposure as a consequence of the platelet-aggregate surface reduction and may have improved endogenous fibrinolysis. These effects were identified in all patients, independent of previous heparin administration.
Conclusions—Abciximab dramatically reduces platelet aggregate size and increases the fibrin accessibility of ex vivo PRC in AMI patients. These modifications could participate in the better coronary artery patency observed with abciximab.
Key Words: myocardial infarction • fibrin • platelets • abciximab • thrombosis
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Introduction |
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The reperfusion efficacy of abciximab in the setting of acute myocardial infarction (AMI) was initially described by Gold et al,1 and it was confirmed recently in large trials, with full reperfusion achieved in 17% to 32% of patients.2 3 4 The French study, Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long term follow-up (ADMIRAL), assessed the superiority of abciximab over placebo in AMI patients treated with primary percutaneous coronary intervention and stenting. The aim of the present work, a substudy of the ADMIRAL trial, was to investigate whether abciximab could modify the physical properties of ex vivo platelet-rich clots (PRC) in 23 patients admitted to the same center for AMI who were eligible for primary percutaneous coronary intervention. We previously reported that the PRC architecture in healthy volunteers was modified by the addition of abciximab in vitro, which led to a faster fibrinolysis rate.5
In the present study, physical properties of PRC were assessed ex vivo by measuring the viscoelastic (G' in dyne/cm2) and morphological (platelet aggregate surface area [SAG] in µm2) properties of native, fully hydrated PRC from AMI patients randomized to receive, in a double-blind fashion, abciximab or placebo. G' and SAG reflect the mechanical and morphological impact of activated platelets on the clot fibrin network, respectively. The lower the values of G' and SAG, the more sensitive the fibrin network is to endogenous or therapeutic fibrinolysis. We hypothesized that modifications of clot physical properties in AMI patients could be induced by abciximab and participate in the complex mechanisms of reperfusion.
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Methods |
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Selection of Patients and Study Design
All 23 patients were enrolled in the ADMIRAL trial at Pitié-Salpêtrière hospital with a diagnosis of AMI, as defined in the protocol (ischemic chest pain >30 minutes; onset of symptoms <12 hours; and ST elevation in
2 contiguous leads). All
patients received aspirin (500 mg IV), heparin, and, in a double-blind
fashion, a bolus (0.25 mg/kg) of either abciximab (n=13) or placebo
(n=10) before primary percutaneous coronary
intervention and stenting. A 12-hour continuous infusion (0.125 µg
· kg–1 ·
min–1) of abciximab (or placebo) was
immediately started.
Formation of PRC
Venous blood was drawn (1 volume of 0.13 mol/L
citrate for 9 volumes of blood) immediately before and 10 minutes after
the bolus administration. Both blood samples were obtained before the
first contrast media injection and before heparin administration,
except in 5 patients who received heparin (5000 IU) during
transportation to the catheterization laboratory. All
patients received aspirin before blood sampling. Platelet-rich
plasma was obtained as previously described to reach an average final
platelet count of 125 000
cells/µL.5 Adding 20
mmol/L CaCl2 and 0.125 IU/mL thrombin (Enzyme
Research Laboratories Inc) led to the formation of
PRC.
Analysis of the Physical Properties
of Ex Vivo PRC
As previously
described,5 physical
properties of PRC were assessed within 30 minutes of venous blood
collection. All measurements were done in a blinded fashion regarding
the treatment. Briefly, the rigidity index G'
(dyne/cm2) was measured; it reflects the
mechanical retraction of the fibrin network by
platelets.5 6
The PRC were labeled with fluorescein isothiocyanate
(Sigma) and processed with a laser confocal system to generate a 3D
reconstructed image of PRC architecture, which allowed the
determination of the average fibrin/platelet aggregate surface area
(SAG in
µm2).5 7
Statistical Measurements
Statistical analysis was performed with the
StatView software package (Version 5.0, Abacus Concepts, Inc).
Continuous variables were expressed as mean±SEM, and group
differences were determined by ANOVA with the Bonferroni correction. An
level of 0.05 was accepted as
significant.
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Results |
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Patient Characteristics
Ten patients were randomly assigned to placebo (80% men; mean age, 67±3 years), and 13 received abciximab (85% men; mean age, 61±3 years). Infarct location was anterior in 40% and 50% of placebo and abciximab patients, respectively. The mean delay between the onset of symptoms and study drug administration trended to be shorter in abciximab patients than in placebo patients (270±70 versus 170±30 minutes, P=0.16). The first angiogram was always performed after the initiation of treatment, and TIMI 3 flow at first contrast media injection was seen in 10% and 23% of placebo and abciximab patients, respectively (P=0.77).
Abciximab and placebo patients had similar levels of fibrinogen (2.9±0.9 versus 3.1±1.2 g/L, respectively, P=0.55) and similar platelet counts (253 200±21 300 versus 231 500±12 500 platelets/µL, respectively, P=0.19).
Effect of Abciximab on PRC Properties
Confocal micrographs of PRC showed a
heterogeneous structure with branching fibers alternating
with dense platelet-rich areas
(Figure 1A
). These aggregates were made of a high
concentration of fibrin fibers retracted by the platelet
contractile force
(Figure 1B).5
Boundaries of these aggregates were detected as shown in
Figures 1A and 1B. In platelet-poor areas, individual
fibers and branching fibers were easily visualized
(Figure 1B).
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A significant and positive correlation was found between G'
and SAG (r=0.6,
P<0.01), indicating that
patients with the largest aggregates displayed the stiffest clots as a
consequence of a greater retraction of the fibrin fibers by
activated platelets. There were no significant differences
for G' and SAG between placebo and abciximab patients before
administration of the bolus
(Figure 2). However, patients who received a bolus of heparin
before reaching the catheterization laboratory (n=5)
had a weaker PRC than patients who were free of heparin at the time of
blood sampling (G', 950±192 versus 2085±233
dyne/cm2 in patients with and without
heparin, respectively, P=0.01).
These findings are related to the anticoagulant effect of heparin,
which affects fibrin formation and leads to a looser conformation of
the fibrin network made of fewer and thicker fibers
(Figure 1C
).8
However, platelet aggregate size (SAG) remained similar in patients
with and without heparin (2478±418 versus 2754±283
µm2, respectively,
P=0.62).
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) and morphological (
) properties of PRC in patients with AMI receiving either placebo or abciximab before primary stenting and percutaneous coronary intervention. Unlike placebo, abciximab infusion significantly (*) lowered G' by 63% and SAG (S.ag) by 65%, indicating weaker PRC with smaller platelet aggregates.
Abciximab dramatically affected the physical properties of
PRC: G' decreased by 63% (from 1870±317
dyne/cm2 at baseline to 689±139
dyne/cm2 after abciximab) and SAG decreased
by 65% (from 2522±330 µm2 at baseline to
891±89 µm2 after abciximab), but placebo
had no significant effect on either G' or SAG
(Figures 1D, 1E, 1F, and 2). The correlation between G' and
SAG remained significant after administration of the bolus
(r=0.59,
P=0.024). A similar magnitude
in the reduction of G' and SAG was measured in abciximab patients who
received heparin and those who did not (74±13% with heparin versus
64±5% without heparin,
P=0.99, for G'; 71±5% with
heparin versus 60±6% without heparin,
P=0.21, for
SAG).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Abciximab administration in vitro can disaggregate PRC formed with the blood of healthy volunteers, improving fibrinolysis as a consequence of a better fibrin exposure to lytic agents within areas of platelet aggregates.5 The present study further demonstrates that abciximab alters the physical properties of PRC in AMI patients, and this may be one of the mechanisms for the effect of abciximab in restoring TIMI 3 flow when it is given with aspirin.
The administration of heparin and aspirin is associated with a TIMI 3 flow rate <13%.9 10 Abciximab on top of aspirin and heparin can achieve TIMI grade 3 flow in 17% to 32% of patients,2 3 4 and the rapid effect of abciximab on reperfusion suggests a direct action on the thrombus structure.1 The major finding of this study is that abciximab in AMI patients dramatically affects the architecture of ex vivo PRC compared with placebo. These modifications primarily consist of an increase in fibrin exposure within platelet-rich areas. These abciximab-related changes have been shown to increase the rate of fibrinolysis in vitro, and they offer a mechanistic explanation regarding why reduced doses of fibrinolytic agents may be successful in restoring flow in epicardial infarct arteries when combined with abciximab.3 4 5 Although heparin has been shown to affect fibrin formation and to abolish platelet contractile forces,8 11 abciximab efficacy in modifying PRC was independent of the effect of heparin on fibrin properties.
The PRC of AMI patients are 2-fold stiffer than the PRC of healthy volunteers formed under the same conditions, but the reductions of G' and SAG reported here in abciximab-treated AMI patients are similar to those measured previously when abciximab (0.068 µmol/L) was added in vitro to platelet-rich plasma from healthy volunteers before the initiation of coagulation.5 Furthermore, pressure-driven permeation studies with a similar bolus of abciximab added to preformed PRC showed disaggregation of these PRC, resulting in a significant increase of fibrinolysis.5 Altogether, these data suggest that abciximab-related changes in PRC properties due to platelet disaggregation may improve endogenous fibrinolysis and coronary artery patency. However, in vivo thrombus formation is a complex phenomenon involving numerous intricate mechanisms that our experimental design cannot consider.
In conclusion, abciximab treatment in AMI patients limits platelet aggregate formation, promotes fibrin exposure in ex vivo PRC, and may account for the improved culprit artery patency when compared with placebo.
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Acknowledgments |
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This work was supported by a grant from Eli Lilly & Company, Saint-Cloud, France.
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Footnotes |
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Dr Pinton heads the Cardiovascular Therapeutic Unit of the French affiliate of Eli Lilly and Company.
Received December 14, 2000; revision received March 9, 2001; accepted March 15, 2001.
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