© 1997 American Heart Association, Inc.
Articles |
Role of Hemostatic Risk Factors for Restenosis in Peripheral Arterial Occlusive Disease After Transluminal Angioplasty
From the Division of Angiology, Department of Internal Medicine and Haemostasis Laboratory (D.A.T., G.A.M.), Department of Central Laboratory, University Hospital Basel, Switzerland.
Correspondence to Prof K. Jäger, Head, Division of Angiology, Petersgraben 4, University Hospital, CH-4031 Basel, Switzerland.
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Abstract |
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Abstract In a prospective study, the role of various hemostatic factors known to be associated with thrombotic risk was investigated in 71 patients with peripheral arterial occlusive disease (PAOD, stages II through IV, Fontaine; aged 68±13 years). Laboratory investigations were done before; 1, 24, and 48 hours after; and 3 and 6 months after percutaneous transluminal angioplasty (PTA). Thirty of 71 (42.3%) patients developed restenosis (>50% reduction of the lumen diameter) at the site of PTA within 6 months, verified by color-coded duplex sonography. Significantly increased levels of thrombin–antithrombin III complexes (P<.01), prothrombin fragments 1+2 (P<.01), and D-dimers (P<.01) were found 1 hour, as well as 24 to 48 hours, after PTA. Fibrinogen (P<.01) and von Willebrand factor (P<.01) were significantly higher 48 hours after PTA. Restenotic patients as a whole had higher plasma fibrinogen (3.46±1.12 versus 2.95±0.62 g/L, P<.01) and C-reactive protein (25.4±46.7 versus 7.9±6.9 mg/L, P<.05) at baseline, as well as higher fibrinogen (P<.05) and prothrombin fragments 1+2 (P<.01) during months 3 to 6 after PTA. There was a nonsignificant tendency for higher values of von Willebrand factor (206±98% versus 184±100%, P=.2) at baseline in patients with restenosis, whereas tissue plasminogen activator, plasminogen activator inhibitor, coagulation screening tests, blood cell counts, and serum lipids showed no significant difference between the two groups. The relative risk for developing restenosis within 6 months while having high fibrinogen (>2.8 g/L) or C-reactive protein at baseline was 2.80 (95% CI: 1.30–6.02, P<.01) and 1.96 (95% CI: 1.07–3.58, P<.05), respectively. Patients with critical limb ischemia (stage III/IV, Fontaine) had significantly higher fibrinogen and von Willebrand factor at repeated points of time, as well as significantly higher C-reactive protein and lower creatinine clearance at entry. In the logistic regression risk factor analysis, baseline plasma fibrinogen, C-reactive protein concentration, and the severity of the arterial disease were significantly predictive of restenosis. Our results indicate that high procoagulant factors and persistent thrombin generation of the hemostatic system might promote restenosis, particularly in patients with extended atherosclerosis. This finding suggests that new treatment strategies should be taken under consideration for patients with PAOD and PTA.
Key Words: peripheral arterial occlusive disease (PAOD) • percutaneous transluminal angioplasty (PTA) • restenosis • hemostasis
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Introduction |
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Percutaneous transluminal angioplasty is an established treatment of PAOD. Despite a primary success rate greater than 90%, the long-term benefit continues to be compromised by the recurrence of stenotic lesions. Restenosis affects 30% to 50% of treated patients within 3 to 6 months.1–3
No appropriate medication consistently prevents restenosis.4 Although not fully understood, a major reason for restenosis is the formation of a neointima secondary to vascular injury.5–7 In addition to growth factors and inflammatory reactions, there is increasing evidence of the role of hemostatic factors involved in the pathogenesis of PAOD. Plasma fibrinogen and cross-linked fibrin degradation products were elevated in claudicants and associated with the severity of peripheral atherosclerosis.8–13 Furthermore, increased levels of TATs, prothrombin fragments 1+2, and DD have been found in peripheral arterial disease,14–17 indicating enhanced thrombin generation and fibrinolysis. vWF and tPA antigen, both markers of endothelial stimulation, have been found increased in peripheral and coronary vascular disease.18–20 In coronary heart disease, higher PAI levels, tPA antigen, and CRP were correlated with either the presence of stenosis or an increased incidence of myocardial infarction.21–23 In other studies, low fibrinolytic activity has been implicated for restenosis.24,25 However, the relationship of hemostatic functions and restenosis in patients with PAOD undergoing PTA has not been extensively studied. The purposes of this prospective study, therefore, were (1) to determine whether hemostatic variables are related to restenosis after PTA and (2) to assess whether these variables could identify patients at risk.
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Methods |
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Patients
Eighty-one patients with PAOD (stages II through IV, Fontaine) undergoing PTA were initially enrolled between January and December 1994. A written informed consent was obtained from every patient. Those with malignant disease or proven vasculitis were excluded. Ten patients were excluded from the study. In 7, PTA was primarily not successful (four reocclusions within 48 hours after recanalization, one bypass surgery, two residual calcified plaques), and 3 patients died before the 3-month vascular evaluation because of coronary heart disease. Thus, data from 71 patients (21 females, 50 males) with predominantly femoropopliteal PAOD were entered into the analysis (53 stenoses, 18 occlusions). None of the patients had any vascular reconstruction within the last 6 months. Demographic data of the patient sample are summarized in Table 1
. During the later
course of the study (months 3 to 6), 4 patients died of
coronary heart disease, and 3 patients underwent a second PTA.
At the time of the intervention, 59 patients received
acetylsalicylic acid, 100 mg/d, and 12 patients had
oral anticoagulants, which had been stopped at least 3 days before PTA.
It may be speculated that anticoagulant pretreatment may interfere with
study outcome variables; however, as baseline PT and APTT values
were not different in these patients, this hypothesis was considered
unlikely and results are not reported.
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Follow-up
All patients underwent a full physical examination and duplex
sonography of the affected leg before, 48 hours after, and 3 and 6
months after PTA. The main study end point was the incidence of
restenotic lesions within 6 months at the site of PTA.
Restenosis was noninvasively diagnosed with color-coded duplex
sonography (ATL Ultramark 9; ATL Inc,) and defined as >50% diameter
reduction of the lumen according to the Jäger/Strandness
classification,26,27 characterized by an increase
in peak systolic velocity of more than 100%, the loss of the
reverse flow component, and a marked spectral broadening of the
Doppler signal. The duplex sonographer was blinded toward all
clinical and laboratory results.
PTA Procedure
PTA was performed according to the technique of Grüntzig
and Hopff.28 During each catheter intervention,
5000 IU unfractionated heparin was given intra-arterially
as thrombosis prophylaxis. Four patients were additionally treated with
local fibrinolysis (urokinase, range from 150.000 to
300.000 U) because of a thrombosis of the affected artery. After PTA,
acetylsalicylic acid, 100 mg/d, was given as
standard treatment. In patients with appropriate indication (n=12), OAC
was continued as before (INR 2.0 to 3.0).
Laboratory Tests
Venous blood samples were drawn before PTA (between 8:00 and
10:00 AM), as well as 1, 24, and 48 hours and 3 and 6
months thereafter. Laboratory investigations included (1) hemostatic
variables such as PT, APTT, fibrinogen, thrombin time, and factor
V, all measured according to standard methods.29
Other hemostatic variables were vWF antigen (Laurell
immunoelectrophoresis), tPA antigen (kit Coaliza, Chromogenix), PAI
activity (kit Coatest PAI, Chromogenix,), TAT (kit Enzygnost TAT micro,
Behringwerke), F1+2 (kit Enzygnost
F1+2 micro, Behringwerke), and DD (Tina-quant
ELISA, Boehringer Mannheim); (2) blood cell counts; and (3)
biochemical variables such as triglycerides; total,
LDL, HDL, and VLDL cholesterol; and CRP. Not all
variables were determined at repeated points of time. tPA, PAI,
blood cell counts, coagulation screening tests (PT, APTT, factor V),
serum lipids, CRP, and the calculated creatinine clearance
using the method of Cockcroft and Gault30 were
assessed only before PTA.
Statistics
Results are given as mean±SD. Comparison was done by the paired
nonparametric Wilcoxon test if Kruskal-Wallis
analysis indicated a significant difference between multiple
groups. Two-group comparisons were done with the Mann-Whitney
U test. Comparison of parameters measured over
various points of time was also confirmed with an analysis of
variance for repeated measurements. A probability level of .05 or less
was considered significant. For the evaluation of qualitative
variables, contingency tables were compared with
2 test. RRs were calculated from two-by-two
contingency tables. A stepwise logistic regression analysis was
used to examine the relationship between hemostatic factors and
restenosis. All computations were performed with the SPSS 6.1.2
software package (SPSS Inc).
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Results |
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All dilatations (n=71) were primarily successful according to angiography (<50% residual diameter reduction) and duplex sonography measurements 48 hours after PTA. Thirty of 71 patients (42.3%) developed restenosis at the site of PTA within 6 months, verified by duplex sonography. Significantly increased levels of TAT (P<.01), F1+2 (P<.01), and DD (P<.01) were found 1 hour, as well as 24 or 48 hours, after PTA in all patients. Fibrinogen (P<.01) and vWF (P<.01) were significantly increased 48 hours after PTA in comparison to baseline. These differences declined at 3 months, but fibrinogen (P<.05) remained higher than baseline at 6 months (Table 2
). The fact that some
patients were treated with oral anticoagulants post-PTA did not
influence the results of the hemostatic parameters under
study, as shown by a statistical comparison of the results of OAC-
(n=12) and non-OAC (n=59)–treated patients (results not reported in
detail). However, OAC-treated patients developed restenosis
with a nonsignificantly higher incidence of 50% (6 of 12).
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In patients developing a restenosis after PTA, fibrinogen was
significantly higher before and 1 hour (P<.01), 24 hours
(P<.05), 48 hours, and 3 months (P<.01) after,
respectively, as shown in Figs 1 and 2. This statement holds true for OAC and
non-OAC patients. After 6 months, however, fibrinogen was significantly
increased in non-OAC patients only (3.68±1.12 versus 3.17±0.59 g/L at
baseline, P<.05). TAT and DD showed a variable pattern
without significant differences between the groups.
F1+2 (Fig 3) was
significantly increased in the group with restenosis at 3
months (P<.05, all patients; P<.01, non-OAC
patients), as well as at 6 months (P<.01), all patients and
non-OAC patients, respectively).
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In Table 3, some variables measured
before PTA are listed in relation to the outcome. Fibrinogen
(P<.01) and CRP (P<.05) were statistically
higher, and creatinine clearance (P<.01) was
lower in the restenosis group. Other variables, including
vWF, TAT, F1+2, and DD were higher but not
statistically different in patients with restenosis.
Coagulation screening tests (PT, APTT, factor V) and blood cell counts
did not show any differences between the two groups. Analyzing the
distribution in each variable at baseline in relation to the
frequency of restenosis, we found that the group with high
fibrinogen levels (>2.8 g/L) had a significantly higher
restenosis rate (RR=2.80, 95% CI: 1.30 to 6.02,
P<.01 2). The same could be
observed for CRP (RR=1.96, CI: 1.07 to 3.58, P<.05
2). This observation was obvious but not
significant for vWF (RR=1.24, CI: 0.72 to 2.14, P=.47
2). To allow for the interpretation of the
clinical value of a restenosis predictor through increased
fibrinogen levels, sensitivities and specificities of fibrinogen cutoff
points varying between 2.7 g/L and 3.4 g/L were calculated (Fig 4).
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Twelve of 17 patients (70.6%) in stage III/IV (critical limb
ischemia) and 18 of 54 patients (33.3%) in stage II
(intermittent claudication) developed restenosis
(P<.01 2). Since patients with
critical limb ischemia are expected to present more
extensive vascular lesions, all variables measured at entry were
analyzed in relation to the severity of PAOD, independent of
the outcome. Fibrinogen, vWF, and CRP were significantly higher, and
creatinine clearance (P<.01),
cholesterol (P<.05), and LDL
cholesterol (P<.01) lower in stage III/IV
patients (Tables 4 and 5). Evaluating the data without OAC
patients, TAT and DD were significantly higher 1 hour after PTA in the
group with critical limb ischemia (P<.01 and
P<.05, respectively).
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In Table 6 the influence of classical
risk factors on hemostatic variables is shown. Patients with
diabetes mellitus had higher vWF levels (P<.01) at entry
than those without. Elevated t PA (P<.01) and PAI
(P<.01) were found in both arterial
hypertension and hypercholesterolemia, the
latter also having higher fibrinogen (P<.01).
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In the risk factor analysis with a stepwise logistic regression model for all numerical variables, fibrinogen (P<.01) and CRP (P<.01), measured before PTA, were found to be highly predictive of restenosis at 6 months. Fibrinogen at 48 hours (P<.01) and at 6 months (P<.05), as well as F1+2 at 6 months (P<.01), were also found to be significantly associated with restenosis. When the clinical risk factors diabetes mellitus, smoking, hypertension, hypercholesterolemia, and the severity of PAOD were taken together as categorical variables, only the last was predictive of restenosis (RR=2.26, 95% CI: 1.06 to 4.85, P<.01). Analyzing all numerical and categorical variables together, the severity of arterial disease (P<.01) remained predictive for restenosis.
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Discussion |
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Endothelial denudation, stretching, or intima fissures caused by angioplasty of an atherosclerotic plaque, as well as activation of platelets and inflammatory cells, are thought to induce a complex variety of processes that finally lead to neointimal growth and/or arterial remodeling. However, recent findings suggest that lumen renarrowing after angioplasty is more complex. Measurement of vascular smooth muscle cell proliferation in human restenotic coronary atherectomy tissue has shown that proliferation is less common, at least in the chronic situation, than previously assumed.7 Furthermore, a chronic vasoconstrictor component may contribute to restenosis.31,32 In addition, persistent endothelial dysfunction postinjury may further contribute to a thrombogenic environment prone to vasospasm and activation of hemostatic mechanisms.33 Previous epidemiological studies have demonstrated increased blood viscosity, intravascular fibrin deposition, and activation of blood coagulation in patients with intermittent claudication.12,19,34 Although some hemostatic factors have been shown as indicators for increased coronary risk,23 the relationship to restenosis after angioplasty in PAOD has not been extensively investigated.
Our study demonstrated that angioplasty caused a persistent activation
of thrombin generation markers and DDs during the 48 hours
after PTA. This indicates first that not only was thrombin
production stimulated by the vessel injury but also thrombin
activity, with subsequent fibrinolysis, as was
demonstrated by increased fibrin degradation products
(DDs). Conventional antithrombotic treatment of these
patients with unfractionated heparin during PTA and antiplatelet
therapy thereafter were not able to protect them from activation of
hemostatic mechanisms. An increase of fibrinogen and vWF was generally
noted at 24 hours, which became significant at 48 hours after PTA,
probably due to stimulation of their synthesis. The increase in
fibrinogen could be explained as an acute-phase
reaction35 or stimulation of its synthesis in the
liver due to the increase of fibrin degradation products. vWF was
elevated with a delay of 48 hours after PTA, indicating increased
synthesis by endothelial cells. Patients with
restenosis as a whole at baseline revealed higher plasma
fibrinogen compared with those without. In patients with a plasma
fibrinogen >2.8 g/L, the RR to develop restenosis was
increased to 2.8. However, baseline plasma fibrinogen concentrations
could not be directly related to individual patients who went on to
develop restenosis because of an overlap of fibrinogen levels
between the two patient groups (Fig 1
).
The thrombin generation markers TAT and F1+2 did not differ significantly in the acute phase during and after PTA between patients with and without restenosis. However, F1+2 remained higher 3 to 6 months after PTA in the group with restenosis, indicating a persistent activation of thrombin generation. The fact that TAT did not show the same pattern might be explained by the intermittent character of its activation. TAT, having a very short half-life of 5 to 7 minutes,36 disappears quickly after activation and generation of thrombin, whereas F1+2, with a half-life of approximately 2 hours remains longer in the circulation, facilitating the detection of higher plasma levels. Thrombin and its receptor are central to triggering platelet aggregation, coagulation, and the release of various growth factors. Persistent thrombin generation might activate endothelial cells locally or stimulate mitogenesis of smooth muscle cells, as it has been demonstrated in human atherosclerotic arteries37 and cell cultures.38,39 In addition, thrombin is a potent vasoconstrictor that could maintain vasospasm at the site of injury. There is also evidence that the intimal vascular smooth muscle cells after injury show an increase in expression of endothelin and thrombin receptors.40,41
Increased plasma PAI and tPA antigen have been previously reported as risk factors for developing coronary events.19,22 We observed no evidence of an independent effect of PAI activity or levels of tPA antigen on restenosis in PAOD. It is, however, possible that local concentrations of tissue-associated fibrinolytic activity may be increased in different layers of the atherosclerotic vessel wall, as demonstrated in the human postmortem aorta.42
In the present study, CRP was significantly associated with restenosis. The mechanism that relates CRP to atherosclerosis and restenosis is unclear. Increased plasma concentrations of CRP have been detected in coronary heart disease and predicted poor outcomes in patients with angina pectoris or myocardial infarction.22,43 Moreover, among apparently healthy men, baseline level of inflammation as assessed by CRP predicted the risk of a first myocardial infarction and ischemic stroke.44 It is possible that CRP may be associated with the recruitment of mononuclear cells at sites of inflammation45 or with the expression of tissue factor by monocytes.46 In this regard, the finding of both higher fibrinogen and CRP with increased risk of restenosis suggests that fibrinogen may become elevated, at least in part, as a consequence of inflammatory processes. This possibility would be in agreement with the result that pronounced and likely ongoing atherosclerotic disease, as found in critical limb ischemia patients, did correlate with both high baseline fibrinogen levels and the restenosis rate. It remains to be determined whether an increased plasma fibrinogen is causally related to restenosis development or whether it should be seen as an epiphenomenon, occurring in concert with an active atherosclerotic process.47–50 However, independent of the causal relationship, fibrinogen levels can be seen as a marker for the potential occurrence of restenosis.
Elevated plasma concentrations of vWF were found in patients with critical limb ischemia compared with patients with less pronounced peripheral arterial occlusive disease. vWF is synthesized by megakaryocytes and endothelial cells and may favor a procoagulant activity by prompting platelet aggregation and adhesion to the subendothelium.17,18 In addition, thrombin may promote the release of vWF into the blood.51
Smoking and arterial hypertension were not associated with higher vWF, fibrinogen, or thrombin generation markers. Patients with diabetes mellitus, however, had higher vWF at baseline but not higher restenosis rates 6 months after PTA. The same could be observed for tPA and PAI in arterial hypertension or hypercholesterolemia, suggesting an impaired fibrinolytic potential under these conditions. In the risk factor analysis, the classical risk factors were not predictive for restenosis, with the exception of the severity of arterial disease. This is probably due to the small number of patients studied. Finally, a crucial point is the definition of the restenosis end point. In animal models, restenosis is defined histologically, whereas in the clinical situation, the lumen diameter is estimated by angiography. However, angiography may not be sensitive enough to detect changes in lumen area and wall thickness.52 Furthermore, functional parameters such as pulsatile flow dynamics should be taken into account to understand the process of wall remodeling after injury. In our study, we used B-mode imaging and consecutive hemodynamic changes such as the velocity increase at the site of stenosis with color-coded duplex sonography. This technique is well established in the diagnosis of peripheral arterial disease, with a reported sensitivity of 92% and a specificity of 98% in detecting >50% diameter-reducing stenosis in the superficial femoral artery.53
In conclusion, our data indicate that (1) restenosis defined as >50% diameter reduction is rather common after angioplasty in PAOD, (2) high baseline values of fibrinogen and CRP are associated with a high RR and may be predictive of restenosis, (3) a persistent activation of thrombin generation markers (F1+2) is evident after PTA, despite administration of heparin or antiplatelet agents, (4) the more extended the atherosclerotic lesions were, the higher the restenosis rate and signs of endothelial disturbance. This finding may have implications for future drug interventions.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was financially supported by a Swiss National Science Foundation grant (No. 32 to 36294.92). We thank Francine Wolf for her excellent technical assistance.
Received September 16, 1996; accepted June 10, 1997.
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