(Circulation. 1995;92:31-38.)
© 1995 American Heart Association, Inc.
Articles |
Fibrinogen After Coronary Angioplasty as a Risk Factor for Restenosis
From the Department of Cardiology (G.M., G.D., Y.G., D.T.) and the Laboratory of Hemostasis (A.A.), Centre Hospitalier Universitaire Pitié-Salpétrière, and the Laboratory of Biophysics, Hôpital F. Widal (E.V.), Paris, France.
Correspondence to Gilles Montalescot, MD, PhD, Department of Cardiology, Centre Hospitalier Universitaire Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75013, Paris, France.
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Abstract |
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Background Fibrinogen is a risk factor for cardiovascular disease and is related to the severity of coronary atherosclerosis. Its role in restenosis after coronary angioplasty remains unknown. Although platelets and thrombosis contribute to the pathogenesis of restenosis, few clinical data are available concerning the relations between restenosis and proteins of the coagulation and fibrinolytic systems.
Methods and Results In 107 consecutive patients undergoing coronary angioplasty, we measured plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor–1 (PAI-1), von Willebrand factor, and fibrinogen before and immediately after angioplasty and at a 6-month follow-up. The individual changes of intraluminal diameter were measured by quantitative coronary angiography, and patients were classified according to four definitions of restenosis: (1) a final stenosis >50%, (2) a loss of minimal luminal diameter during the follow-up period greater than the measurement variability in our laboratory (>0.52 mm), (3) a loss of at least 50% of the gain in luminal diameter achieved by angioplasty, and (4) the combination of definitions 1 and 2. The relations between coagulation variables and each definition of restenosis were assessed univariately; then with the clinical variables included, the relations were analyzed multivariately. Angiographic follow-up was obtained in 92% of patients with a primary success of angioplasty. Global restenosis rates were 38%, 43%, 48%, and 30% for definitions 1 through 4, respectively. Plasma levels of t-PA antigen and PAI-1 antigen were not associated with any of the four definitions of restenosis. Multivariate analysis demonstrated that von Willebrand factor measured immediately after angioplasty predicted restenosis according to definitions 2 and 3. Fibrinogen measured within 6 months of follow-up was significantly increased in all restenosis groups of the four definitions. Patients with a fibrinogen concentration >3.5 g/L at follow-up had higher restenosis rates than patients with a concentration <3.5 g/L: 55% versus 22% (P=.001), 68% versus 31% (P=.002), 63% versus 37% (P=.01), and 74% versus 26% (P=.002) for definitions 1 through 4, respectively. The loss index was lower (P=.003) and the net gain higher (P=.03) in patients with a fibrinogen level <3.5 g/L. There was a significant correlation between fibrinogen level and angiographic loss index (r=.41; P<.0001). Multivariate analysis confirmed that the fibrinogen level predicted restenosis with all definitions.
Conclusions An independent relation exists between von Willebrand factor measured immediately after angioplasty and restenosis defined by the degree of intraluminal renarrowing. An elevated fibrinogen level during follow-up is a strong biochemical predictor of restenosis. Therefore, fibrinogen should be considered at least as an independent marker of restenosis and perhaps as a common risk factor for both spontaneous coronary atherosclerosis and postangioplasty restenosis, which is an accelerated form of atherosclerosis.
Key Words: stenosis • angioplasty • fibrinolysis • von Willebrand factor • plasminogen activators
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Introduction |
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Restenosis remains the main problem associated with percutaneous transluminal coronary angioplasty (PTCA), and its pathogenesis is only partially understood. Abnormalities reflecting a prothrombotic state or an altered fibrinolytic state have been associated with coronary events and/or atherosclerosis, but few data are available on their relations to coronary restenosis.1 2 3 4
The level of tissue-type plasminogen activator (t-PA) synthesis by endothelial cells determines the fibrinolytic state, but plasminogen activator inhibitor–1 (PAI-1), by binding to circulating t-PA, inhibits fibrinolysis and protects clots from rapid lysis. High levels of the fast-acting PAI-1 have been reported in patients with coronary atherosclerosis and in patients presenting acute coronary syndromes.4 5 6 7 A few studies have reported conflicting results concerning PAI-1 levels measured before and after angioplasty8 9 10 ; only one of these three studies measured PAI-1 antigen, which is more reliable than PAI-1 activity, and found no difference in preangioplasty levels between patients developing or not developing restenosis.10
Among proteins involved in the procoagulant process, von Willebrand factor mediates platelet adhesion to exposed subendothelium, thereby promoting the role of platelets at sites of vascular injury. Raised plasma levels of von Willebrand factor have been reported in patients with acute myocardial infarction, and high levels reflect a large extent of necrosis and/or a lack of recanalization after thrombolysis.6 11 12 13 Levels of von Willebrand factor could increase in patients presenting acute closure after angioplasty,14 but the relations of von Willebrand factor to the incidence of restenosis have not been studied. However, the hypothesis of a role of this factor in the process of restenosis is supported by experimental data that show less thrombus formation in models of vascular injury and less proliferative atheromatous lesions in animals lacking von Willebrand factor.15 16 17 18 An important aspect of the role of von Willebrand factor in the platelet–vessel wall interaction after vascular injury is the concomitant release of mitogens, leading to smooth muscle cell proliferation.18 19
Elevated fibrinogen levels constitute a strong independent risk factor for myocardial infarction, as shown by several epidemiological studies.2 20 21 22 Furthermore, smaller studies have demonstrated the association between fibrinogen levels and the extent of coronary atherosclerosis angiographically evaluated.4 23 24 We questioned whether fibrinogen may be related to restenosis, which has been considered an accelerated form of atherosclerosis. Fibrinogen may act by many mechanisms because it is an important factor of platelet aggregation, causes the release of vasoconstrictor mediators and growth factors, increases blood viscosity, and contributes to fibrin deposits.
This prospective study examined the relations between these factors of the hemostatic function and fibrinolytic system and the occurrence of restenosis after PTCA. We considered restenosis both as a continuous variable with a normal distribution and as a binary variable with four classic definitions of restenosis. We analyzed three sets of samples in each patient: before angioplasty (basal state, to detect individual factors predisposing to restenosis), immediately after angioplasty (to search for early risk factors of restenosis related to the procedure), and at the time of follow-up angiogram (to detect risk factors during the healing phase not directly related to the procedure). The relation of each variable to each definition of restenosis was assessed directly by univariate analysis and multivariately after adjustment for other associated risk factors.
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Methods |
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Study Patients
For this prospective study, we enrolled 107 consecutive patients referred to our department. To be included, patients had to have coronary heart disease requiring a first angioplasty of one or several coronary arteries. Myocardial infarction during the acute phase was an exclusion criterion, but PTCA for recent unstable angina was permissible. Patients gave their informed consent and accepted the angiographic follow-up in our center. All patients continued their antianginal medications during PTCA and the follow-up period. Aspirin (250 mg/d) was prescribed before angioplasty until the follow-up angiography. Conventional treatment was given during PTCA, including isosorbide dinitrate (2 mg) and heparin (10 000 U). Additional heparin was given, depending on the duration of the procedure. Baseline and control angiographies were always obtained after nitroglycerin administration.
We excluded 6 patients from the final analysis because of emergency bypass (n=1; 0.9%), major dissection with or without myocardial infarction (n=3; 2.8%), or death during the follow-up period (n=2; 1.8%). In 4 other patients (3.7%), PTCA was considered successful by visual assessment but not by quantitative coronary angiography (residual stenosis exceeded 50% of the vessel diameter), and these patients were excluded. We excluded 8 more patients (7.4%) because they were not reevaluated angiographically after 6 months—2 for geographical reasons, 1 for medical reasons, and 5 for personal reasons. We obtained medical information for 6 of these 8 patients who were free of any major coronary event. The rate of angiographic follow-up was 92% in surviving patients with a primary success of PTCA. The study population was restricted to 89 subjects who underwent successful PTCA with a subsequent control angiography at 6 months or earlier if restenosis was suspected on clinical and/or ECG grounds.
Quantitative Coronary Angiography
All cineangiograms were
analyzed with a computer-assisted
technique (Sigma Cardio, Traitement Synthèse Image) as previously
reported,25 and measurements were made with no knowledge
of the clinical or biological status. Briefly, the image on the first
angiogram before angioplasty was chosen to show the most severe
incidence, at end diastole, with care taken to display the long axis of
the vessel without significant overlapping and foreshortening. Then
identical views were selected on all angiograms of the same patient.
Each cine frame was digitized by a high-resolution video camera, and
the image was magnified. The region of interest centered on the
stenosis was drawn, and vessel contours were automatically determined
on the basis of the arterial centerline. The operator placed
cross-sectional lines at stenosis and reference locations, and the
computer automatically calculated artery diameters along these lines.
The computer measured the absolute values of the stenosis and reference
diameters using the known catheter diameter as a scaling device.
Because the algorithm was not able to measure total occlusions, a value
of 0 mm for the minimal lumen diameter (100% stenosis) was given. A
single angiographer trained in quantitative coronary angiography
performed the analyses, and his variability was assessed during the
study. This intraobserver variability was determined on 35 randomly
selected films among coronary angiograms performed before PTCA,
immediately after PTCA, and at a 6-month follow-up. Repeated
measurements on these 35 films were obtained at a 3-month interval
without preselection of images. The variability in measurements of
coronary angiograms was expressed by the SD of the difference between
paired measurements. This variability (0.28 mm for the minimal lumen
diameter, 0.32 mm for the reference coronary diameter, and 9.9% for
the percent diameter stenosis) is similar to previous evaluations under
the same conditions.26
Definitions of Restenosis
Coronary angioplasty was considered
successful when the residual
diameter stenosis was <50% without major complication. Of our 89
patients, 16 underwent multivessel angioplasty during the same
procedure. The risk of restenosis of the second or third dilated lesion
is not independent of the outcome of the first dilated stenosis; thus,
we analyzed only the outcome of the most severe lesion on the initial
angiogram for these 16 patients.27 Discrepancies exist
among the numerous definitions used to identify patients with or
without restenosis, mainly because they do not consider the same
criteria for assessing the evolutionary process of restenosis. To
examine the relations between the hemostatic function and restenosis,
we considered four classic definitions of restenosis. First, restenosis
was defined as a final stenosis >50%, which is the most common
definition based on the concept of a critical stenosis with limited
coronary flow reserve.28 The second definition considered
the degree of intimal hyperplasia assessed by the absolute loss of
intraluminal diameter. Restenosis was present when the decrease in
minimal luminal diameter between the results immediately after PTCA and
the follow-up angiogram exceeded the measurement variability in our
laboratory. This definition was proposed by Reiber and
colleagues,29 who reached a cutoff point of 0.72 mm that
was used in later studies on coronary restenosis. We recalculated the
measurement variability in our own laboratory, knowing that this
variability corresponds to 2 SD of the difference between duplicate
measurements of the stenotic diameter on two different angiograms.
Thirty patients underwent a diagnostic angiogram with a 6F or 7F
catheter and a control angiogram several days later, immediately before
angioplasty, with an 8F catheter. The mean interval between both
angiographies was 7.6±6.4 days. The measurement variability, including
that caused by the type of catheter, for the minimal luminal diameter
allowed us to determine our second definition of restenosis. The
difference between the two measurements of the stenotic diameter was
0.05±0.26 mm. A change >2 SD (ie, a loss >0.52 mm) was regarded
as a
significant difference at the site of stenosis. The third definition
was a loss of at least 50% of the gain in luminal diameter achieved by
PTCA and was proposed by the National Heart, Lung, and Blood Institute
as the so-called NHLBI IV definition.30 Three measures
were required to determine restenosis by definition 3, but only one was
necessary for the first definition and two for the second definition.
Our fourth definition required the presence of both definitions 1 and 2
and was considered only in cases with both an important renarrowing
process and a significant stenosis at follow-up. In contrast to the
categorical approach of restenosis, which is the most useful to
physicians, restenosis can be regarded as a continuous variable with a
normal distribution. Thus, the acute gain was defined as the increase
in minimal luminal diameter immediately after PTCA; late loss was
defined as the subsequent decrease in minimal luminal diameter of the
same segment by the time of the follow-up angiogram. The net gain was
the difference between the acute gain and late loss. The loss index was
the ratio of late loss to acute gain.
Hemostasis Measurements
Blood was sampled three times in each
patient: before
angioplasty, immediately after angioplasty, and at follow-up before
control coronary angiography. Arterial blood (9 vol) was collected into
siliconized evacuated tubes (Vacutainer; Becton-Dickinson) containing
0.129 mol/L trisodium citrate (1 vol). Patients had fasted for at least
12 hours, and sampling was performed after a 10-minute rest period. To
measure t-PA and PAI-1, the first tube was centrifuged at 4°C and
3000g for 20 minutes. Aliquots of plasma were transferred
immediately into plastic tubes and stored at -80°C until assayed.
The t-PA and PAI-1 antigens were measured by commercial kits using
enzyme-linked immunosorbent assay (ELISA) from the Stago laboratory
(Asserachrom tPA, Asserachrom PAI-1, Stago).
To evaluate fibrinogen and von Willebrand factor levels, platelet-poor plasma was obtained by centrifugation of a second test tube at 3000g for 20 minutes at 10°C. Plasma was divided into aliquots and stored at -80°C. Fibrinogen was measured by the thrombin time method (Thrombin Reagent, Baxter, Dade Division) with a KC10 Coagulometer, as described by Clauss.31 The assay to measure von Willebrand factor levels was performed with a commercial kit using ELISA (Asserachrom von Willebrand factor, Stago).
Statistical Analysis
Results are expressed as mean±SD.
Simple linear regression was
used to test the association between continuous variables like loss
index and fibrinogen values. Potential associations between coagulation
or clinical parameters and restenosis were first tested by univariate
procedures with Student's t or 
2
tests. To estimate the potential predictive values of coagulation
parameters independently of clinical parameters, all variables were
analyzed in a multivariate procedure with stepwise logistic regression
(Biomedical Data Processing Package, University of California, Los
Angeles).32 To avoid overestimation of the number of
predictive variables, we used conservative criteria to select
predictive variables: (1) limits to enter or remove variables in the
regression equation must have a 5% probability value; (2) the ratio
between the corresponding regression coefficient and its standard error
must be >233 ; and (3) results were verified by use of two
different numerical procedures, an asymptotic covariance estimate and
the maximum-likelihood method.
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Results |
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Clinical and Angiographic Characteristics
There were no differences in age, sex, medical history, and left ventricular function between patients of the restenosis and no-restenosis groups (Table 1
). The distribution of
cardiovascular risk factors was comparable between both groups of the
four categorical definitions of restenosis (Table 1). None of
the
baseline clinical variables predicted restenosis after multivariate
analysis.
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At enrollment, the mean percentage of stenosis in patients
included in
the study was 69±12%. The dilated artery was the left anterior
descending artery in 55%, the circumflex artery in 22%, and the right
coronary artery in 23% of patients. The mean residual stenosis was
29±11%, with a mean immediate gain obtained by angioplasty of
0.97±0.44 mm. The mean late loss was 0.44±0.62 mm. Individual
values
of late loss correlated with acute gain, so the larger late loss may be
the result of greater stimulation of intimal hyperplasia by exposure of
deeper wall components (Fig 1). The net gain (acute
gain-late loss) was 0.53±0.57 mm. When late loss was adjusted for
its
relation to acute gain by calculation of the loss index (late
loss/acute gain), we observed that this variable was normally
distributed, with an average value of 0.43±0.65 mm. The restenosis
rates at the end of follow-up were 38% for definition 1 (>50%
stenosis), 43% for definition 2 (loss >0.52 mm), 48% for definition
3 (loss >gain/2), and 30% for definition 4 (definitions 1 and 2
combined). Among patients who had at least one definition of
restenosis, only half of them met the criteria for all four
definitions.
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PAI-1, t-PA, von Willebrand Factor, and Restenosis
Univariate
analysis found that PAI-1 was slightly increased in
patients with restenosis immediately after PTCA according to definition
2 (P=.13) and at follow-up for definitions 1
(P=.20), 2 (P=.08), and 4
(P=.09).
Multivariate analysis found no significant relation between PAI-1
levels and restenosis, regardless of the definition and the sampling
period. Levels of tPA increased after PTCA in patients with restenosis
only for definition 2 (P=.13), but the levels of tPA were
significantly higher at follow-up in the restenosis groups according to
definitions 2 (P=.03), 3 (P=.03), and 4
(P=.04). After multivariate analysis, these differences
were no longer valid (Table 2).
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Patients with restenosis
had higher levels of von Willebrand factor
before angioplasty, especially those with definitions 2
(P=.06) and 3 (P=.14). Levels of von
Willebrand
factor increased after angioplasty for definitions 2
(P=.02), 3 (P=.05), and 4
(P=.15).
Multivariate analysis confirmed that von Willebrand factor measured
immediately after PTCA was a significant independent predictor of
restenosis defined as a loss >0.52 mm (definition 2) or a loss
>gain/2 (definition 3) (Table 2
). This difference in von
Willebrand
factor levels between both groups of patients did not persist at 6
months.
Fibrinogen and Restenosis
Fibrinogen levels were similar in
patients with or without
restenosis when measured before or immediately after angioplasty. In
contrast, mean levels were significantly higher in all restenosis
groups of the four categorical definitions when patients came for
follow-up evaluation (Table 2). Patients with a fibrinogen
concentration exceeding 3.5 g/L (median value) at follow-up evaluation
had higher restenosis rates than patients with a fibrinogen
concentration below 3.5 g/L: 55% versus 22% (stenosis >50%,
P=.001), 68% versus 31% (loss >0.52 mm,
P=.002), 63% versus 37% (loss >gain/2,
P=.01),
and 74% versus 26% (stenosis >50% in addition to loss >0.52 mm,
P=.002). Cumulative distribution curves before, immediately
after, and 6 months after angioplasty show the difference at follow-up
evaluation between the two groups of patients (Fig 2).
The mean acute gain obtained by angioplasty was similar in the two
groups defined by the cutoff point of 3.5 g/L, but patients with high
fibrinogen values had an increased late loss (0.64±0.62 mm,
n=44,
versus 0.24±0.57 mm, n=45; P=.002) and an
increased loss
index (0.64±0.63, n=44, versus 0.23±0.62, n=45;
P=.003)
compared with patients with lower fibrinogen concentrations. The net
gain was better in the low-fibrinogen group compared with the
high-fibrinogen group (0.66±0.58 mm, n=45, versus
0.40±0.55 mm, n=44;
P=.03). The rate of progression of endoluminal thickening
estimated by the late loss was significantly higher in the upper
tertile (P=.001) and in the upper quartile
(P=.005) of fibrinogen values. The relation between
fibrinogen and the degree of healing was also demonstrated by the
significant correlation between fibrinogen concentrations and late loss
values. Because the strongest known determinant of late loss is acute
gain (Fig 1), we considered the relation between fibrinogen and
loss
index (late loss adjusted to acute gain) and found a significant
correlation between these two independent variables (Fig 3).
Moreover, multivariate analysis confirmed that
fibrinogen measured after angioplasty was a strong determinant of
restenosis with all selected binary definitions. This factor was
predictive of restenosis independently of all the other coagulation
parameters and clinical variables. When individual changes in
fibrinogen values over the follow-up period were considered instead of
the absolute values at follow-up, there was also a significant relation
between change in fibrinogen values and definitions 1, 2, and 4 after
univariate and multivariate analyses. However, the absolute value
appeared to be a stronger predictor than the change in fibrinogen.
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Discussion |
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It is acknowledged that platelet deposition and thrombosis are mechanisms contributing to coronary restenosis.16 17 18 However, hemostatic factors and fibrinolytic state are rarely considered in clinical trials on restenosis. In the present study, plasma levels of PAI-1 and t-PA antigens are not associated with restenosis, refuting a preeminent role of the individual fibrinolytic potential at any step of the restenosis process. von Willebrand factor, a major protein involved in platelet adhesion to injured vessel wall, is significantly increased immediately after PTCA in patients who develop restenosis in the following months. This is particularly true with the definitions of restenosis that consider the degree of intraluminal hyperplasia (and not the final degree of stenosis), and multivariate analysis confirms the independent relation between the post-PTCA von Willebrand factor plasma level and the angiographic diagnosis of restenosis (definitions 2 and 3). The most important finding of this study is the strong association between high levels of fibrinogen as measured before the follow-up angiogram and all definitions of restenosis. Higher restenosis rates are present in patients with a fibrinogen level >3.5 g/L, and fibrinogen correlates to loss index, which is a continuous variable depicting restenosis. Multiple logistic analysis, including the associated atherogenic risk factors that may be related to both fibrinogen and restenosis, indicates the independent importance of fibrinogen level as a risk factor of restenosis.
Quantitative coronary angiography is more reliable than visual evaluation in assessment of the percentage of stenosis.34 This led us to exclude 4 patients with unsuccessful PTCA after computer analysis depicted >50% residual stenosis. Usual binary definitions consider restenosis either as a hemodynamically obstructive stenosis (eg, definition 1, stenosis >50%) or as an absolute luminal renarrowing exceeding a cutoff point corresponding to measurement variability (eg, definition 2, loss >0.52 mm) or a percentage of the immediate gain (eg, definition 3, loss >gain/2). In our study, the most definite cases of restenosis, with both an important amount of late loss and a tight final stenosis, are identified by definition 4. Restenosis rates in the present study, calculated with a 92% angiographic follow-up rate, are similar to what has been reported with the same definitions in prior studies.35 36 37 The precise relations between a procoagulant protein or an antiproliferative drug and intimal hyperplasia are best analyzed by definitions based on the concept of late loss (definitions 2 and 3) or by calculation of the loss index (late loss adjusted to its strong determinant, acute gain).
Vascular injury produced by angioplasty initiates platelet adhesion through the glycoprotein Ib receptor followed by platelet recruitment with expression of the IIb-IIIa receptor and leads to mural thrombus formation. von Willebrand factor is a multivalent, multimeric plasma protein that has binding sites for platelet glycoprotein Ib and glycoprotein IIb-IIIa receptors. It is generally assumed that von Willebrand factor acts as a bridging molecule between platelets and the subendothelial components by binding to the glycoprotein Ib-IX-V complex and promotes platelet-platelet interaction by binding to the glycoprotein IIb-IIIa complex.38 Marked platelet accumulation and degranulation are already present 30 minutes after experimental angioplasty39 and are followed by an intense proliferation of smooth muscle cells that begins within 48 hours.40 Swine homozygous for von Willebrand's disease that lack von Willebrand factor are resistant to thrombosis and to the development of proliferative atheromatous lesions.40 Similar results were obtained with the use of monoclonal antibodies that blocked the binding of von Willebrand factor to platelets.15 Although experimental models provided clear evidence of the major role played by von Willebrand factor and platelets after severe vessel wall injury,15 16 17 38 40 clinical studies have not focused on von Willebrand factor after coronary angioplasty. In our study, von Willebrand factor immediately after PTCA was an independent predictive factor of restenosis defined by the amount of late loss, ie, the degree of intimal hyperplasia. Because von Willebrand factor is synthesized by endothelial cells, it may reflect a more severe endothelial injury caused by the balloon in patients who will have a more intense proliferation during follow-up. However, a preexisting endothelial dysfunction in patients with restenosis cannot be ruled out because these patients already had a nonsignificant trend to higher values of von Willebrand factor before angioplasty. Both explanations may be present, and this result requires further confirmation.
Prospective epidemiological studies clearly demonstrated that fibrinogen is an independent risk factor for coronary events and that its predictive value is similar to that of other major risk factors such as cholesterol and smoking.2 20 21 22 Moreover, angiographic studies reported the association between fibrinogen and the presence and severity of coronary stenoses, suggesting that fibrinogen is involved in the progression of spontaneous coronary atherosclerosis.4 23 24 Our study is the first demonstration of a link between fibrinogen and coronary restenosis, which has been described as an accelerated form of atherosclerosis after mechanical vascular injury.18 A fibrinogen level >3.5 g/L during follow-up was associated with a 1.7- to 2.8-fold increase in restenosis rates according to the four definitions used, and univariate comparisons found highly significant increases in mean plasma fibrinogen levels in the restenosis groups determined by the four definitions. Furthermore, the individual values of loss index, characterizing the degree of intraluminal thickening, correlated significantly with the plasma levels of fibrinogen, suggesting a quantitative relation between both parameters. Fibrinogen was proved to be related to other risk factors such as smoking, cholesterol, and overweight.2 20 Multivariate analysis demonstrates in this study that fibrinogen is an independent indicator of restenosis after adjustment for the other atherogenic factors.
Restenoses occur within 6 months after PTCA. Most of the proliferation develops between the first and the third month, and restenosis rates reach a plateau after 6 months.35 41 The increase in fibrinogen levels in our patients with restenosis was detected at the follow-up evaluation (ie, at 6 months) or before when restenosis was strongly suspected. Although sampling was performed during the artery healing period, our sampling time might have been too late relative to the time course of restenosis, and fibrinogen values might be even higher if sampled 2 or 3 months after angioplasty. Schumacher et al42 measured similar values of fibrinogen late after angioplasty (4.1±1.3 g/L in the restenosis group versus 3.5±0.9 g/L in the group without restenosis, P=NS). Considering the nonsignificant difference after a simple comparison of means in their small group of patients, those authors concluded that fibrinogen was not a risk factor for restenosis. Our multiple sampling times demonstrate that fibrinogen, when measured a few months after the procedure during the chronic healing period, is an independent marker of restenosis and can predict it. In contrast, fibrinogen measured before angioplasty does not identify patients at risk for restenosis, and this may explain prior negative results observed when only one measurement was made before PTCA.10 Individual changes in fibrinogen level over the follow-up period predict restenosis as defined by three of the four definitions. Fibrinogen measured at the end of the procedure is not related to restenosis, suggesting that it is not necessary in the early platelet adhesion at the site of vascular injury. Similarly, in a different type of study, antibodies against fibrinogen added to afibrinogenemic blood to remove any trace of fibrinogen did not inhibit the initial platelet–vessel wall interaction.43 Fibrinogen could act in the restenosis process more chronically as in spontaneous atherosclerosis, but in both situations mechanisms by which fibrinogen contributes to atherogenesis remain hypothetical and may be related to fibrin formation, blood viscosity, inflammation, platelet aggregation, expression of an existing thrombophilia, and stimulation of smooth muscle cell proliferation.44 45
Medications for reducing fibrinogen selectively have not yet been developed. Controlling the action of fibrinogen may require treating associated risk factors that increase plasma fibrinogen; counteracting some effects of fibrinogen by prescribing aspirin or ticlopidine, which can also decrease fibrinogen levels; avoiding medications that increase fibrinogen; and prescribing fibrates when necessary, because fibrates can lower both cholesterol and fibrinogen. Experimental studies evaluated various monoclonal antibodies to platelet receptors that block the binding of adhesive proteins such as fibrinogen or von Willebrand factor to platelets. Administration of these antibodies allows a significant reduction of platelet deposition on subendothelium. The selective inhibition of von Willebrand factor binding to glycoprotein Ib receptor by recombinant fragments of von Willebrand factor represents another appropriate antiplatelet approach.38 These new antithrombotic therapies have highly selective and potent actions against platelets. Recent clinical reports of less abrupt closure and less clinical restenosis with the blockade of platelet glycoprotein IIb-IIIa integrin during high-risk angioplasty suggest that platelets are a key element of the restenosis process, which is not controlled by the use of aspirin alone.46 47
Our findings emphasize the role of platelets and thrombosis in the pathogenesis of restenosis. A role of von Willebrand factor is likely in the human renarrowing process early after angioplasty. When measured late after the procedure, fibrinogen appears to be a risk factor for restenosis. To date, biochemical variables have not been useful in identifying the recurrence of stenosis after angioplasty. Plasma levels of fibrinogen may help to predict restenosis during the follow-up period. Lowering plasma fibrinogen levels may be important after angioplasty, but the risk-lowering effect remains to be shown.
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Acknowledgments |
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This work was supported by a grant from La Fédération Française de Cardiologie, Paris. We are indebted to Marie H. Genevée, BS, for technical assistance in the laboratory of hemostasis and to Bénédicte Chanvallon, MD, for assisting in the data analysis.
Received August 31, 1994; revision received December 5, 1994; accepted December 18, 1994.
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