Significance of platelet activation in vascular access survival of haemodialysis patients
Yao-Cheng Chuang1,,
Jin-Bor Chen1,
Lin-Cheng Yang3 and
Ching-Yuan Kuo2
1 Division of Nephrology,
2 Division of Hematology, Department of Internal Medicine and
3 Second Department of Anesthesiology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
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Abstract
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Background. Vascular access failure is the most common cause of morbidity and hospitalization in haemodialysis (HD) patients. Although there are reports that anti-platelet agents can prevent vascular access thrombosis, the relationship between platelet activation and vascular access failure is not clear. The aim of this study was to investigate the role of platelet activation in recurrent vascular access failure.
Methods. The studied subjects were divided into three groups: group I included 23 HD patients with recurrent vascular access failure (native arteriovenous fistula <2 year survival or synthetic arteriovenous graft <1 year survival), group II included 15 HD patients with longer vascular access survival (>5 year survival) and group III included 10 healthy volunteers as controls. The expression of platelet activation markers (CD62P and fibrinogen receptor) and the numbers of platelet-derived microparticles were measured and compared between groups.
Results. CD62P-positive platelets were significantly higher in group I than in both group II (7.3±3.7 vs 3.5±1.3%; P<0.0005) and group III (2.9±0.9%; P<0.00005). Fibrinogen receptor-positive (PAC-1-positive) platelets were also significantly higher in group I than in group II (2.2±2.1 vs 0.9±0.7%; P<0.01) and group III (0.8±0.6%; P<0.01).
Conclusions. A higher level of circulating activated platelets is associated with shorter survival of vascular access in HD patients. The higher level of circulating activated platelets may be a predictor of recurrent vascular access failure. The potential advantageous effects of anti-platelet therapy on this patient population warrant further investigation.
Keywords: CD62P; haemodialysis; PAC-1; platelet activation; platelet-derived microparticles; vascular access survival
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Introduction
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Vascular access complications are the greatest cause of morbidity and hospitalization in haemodialysis (HD) patients [1,2]. The most frequent complication of vascular access is dysfunction or failure due to thrombosis or stenosis [1], either in a native arteriovenous (AV) fistula or a synthetic AV graft. Although it has been reported that anti-platelet agents can prevent vascular access thrombosis [3], the relationship between platelet activation and vascular access failure is not clear.
Platelets are necessary for haemostasis and play an important role in thrombus formation. During platelet activation, platelet agonists, such as ADP or thromboxane A2, induce a variety of cellular responses, including shape change, activation of surface receptors for fibrinogen and other adhesive proteins, secretion of substances from intracellular granules and induction of procoagulant activity. Methods for detecting platelet activation include measuring substances released by activated platelets as well as surface changes of activated platelets. In the past, the most reliable markers of platelet activation in vivo were substances released from activated platelets that could be measured in plasma or urine, such as platelet factor 4, ß-thromboglobulin, thromboxane B2 and serotonin [4,5]. Although these markers have been useful in research settings, they are not clinically valuable because of technical limitations of the assays. When platelets are activated, several changes occur on their surface that can be detected with specific monoclonal antibodies. One of these changes is the fusion of
-granule membranes with the platelet plasma membrane during platelet secretion. This process can be detected with the anti-CD62P monoclonal antibody, which is specific for
-granule membrane glycoprotein, GMP-140 (also named P-selectin, PADGEM or CD62P) [6]. Another change is the conversion of the platelet glycoprotein (GP) IIb/IIIa complex (also named CD41/CD61) into a functional receptor for fibrinogen, a process that is required for normal platelet aggregation. This process can be detected with PAC-1, a monoclonal antibody that, like fibrinogen, binds to GPIIb/IIIa only after functional receptor exposure [7]. In previous reports, increased levels of circulating activated platelets were found in several diseases, including cerebral infarction [8], coronary artery disease [9], diabetes mellitus [10], peripheral vascular disease [11] and chronic renal failure or HD patients [12,13]. Therefore, it has been postulated that increased levels of activated platelets can predict the risk of thromboembolism [14].
The vesicles derived from the platelet plasma membrane, known as platelet-derived microparticles (PMP), can be detected when platelets are activated by collagen or in the blood of patients with intravascular platelet lysis [15]. In healthy humans, circulating activated platelet levels and levels of PMP are low and PMP increases occur during conditions of platelet activation, such as diabetes mellitus, uraemia, cerebral infarction, coronary artery disease, cardiopulmonary bypass, high shear stress, immune thrombocytopenic purpura, heparin-induced thrombocytopenia and paroxysmal nocturnal haemoglobinuria.
The aim of this study was to investigate the relationship between platelet activation and vascular access survival in HD patients. The extent of platelet activation was quantified as the percentage of CD62P-positive and PAC-1-positive platelets and as the number of PMP per 10 000 platelets. Also evaluated and compared were other comorbid conditions possibly associated with the survival of vascular access.
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Subjects and methods
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Patients and controls
In accord with Zibari et al. [16], we defined shorter survival of vascular access as access survival <2 years in native AV fistulas and <1 year in synthetic AV grafts. Patients receiving maintenance HD at our hospital were recruited into the recurrent vascular access failure group if they fitted the above criteria and had at least two revisions of vascular access. A longer survival was defined as access survival >5 years with only one vascular access creation. Thirty-eight patients with end-stage renal disease were studied and of these 23 were recruited into the recurrent vascular access failure group (group I) (age: 60.5±13.3 years, range 3687 years). The aetiology of uraemia in this group included diabetic nephropathy (n=7), hypertensive nephrosclerosis (n=5), chronic glomerulonephritis (n=7), obstructive nephropathy (n=1) and unknown causes (n=3). Among the 15 patients recruited into the longer vascular access survival group (group II) (age: 39.6±13.4 years, range 2166 years), the aetiology of uraemia included diabetic nephropathy (n=1), hypertensive nephrosclerosis (n=4), chronic glomerulonephritis (n=8) and unknown causes (n=2). All of the patients received bicarbonate-based HD three times per week. Only two surgeons were involved in access creation. Vascular accesses were created at an earlier date in group II (
5 years ago) and the majority of access surgeries were performed by the same surgeon (group I: 64.2%; group II: 66.7%). Sixty-eight native AV fistulas were created in group I and 15 in group II and the majority were again created by the same surgeon (group I: 58.8%; group II: 66.7%).Ten healthy volunteers, recruited into group III from our hospital staff (age: 33.1±2.8 years, range 2939 years), were used as controls. None of the subjects had ever taken anti-platelet agents before testing.
Blood collection
In order to minimize artificial platelet activation, patients and healthy volunteers rested for at least 30 min prior to blood collection. Blood was collected from the arterial end of the vascular access using a 16G AV fistula needle (1.65x25 mm) in HD patients before HD and from the antecubital fossa using a 21G needle (PrecisionGuide®) and Vacutainer® system with luer adaptor in healthy volunteers. All blood sampling was performed in the morning in the fasting state. In the first blood sample (6 ml), blood was collected into a sterile Vacutainer® containing SST® gel and clot activator to determine standard biochemical parameters (albumin, blood urea nitrogen, creatinine, cholesterol, triglyceride and lipoprotein levels) as well as anticardiolipin antibodies. The second blood sample (2 ml) was collected into a sterile Vacutainer® containing 0.054 ml EDTA (K3) to determine complete blood count. The third blood sample (4.5 ml) was collected into a sterile Vacutainer® containing 0.5 ml 3.8% sodium citrate to determine platelet activation markers.
Flow cytometry analysis of activated platelets and microparticles
Activated platelets and PMP were detected using modified methods from a previous report [17]. Within 10 min of blood collection, platelet-rich plasma (PRP) was prepared by centrifugation at 200 g for 10 min at room temperature. Ten microlitres of PRP was added to the bottom of appropriately labelled Falcon® polystyrene test tubes containing 100 µl phosphate-buffered saline (PBS) and incubated with 20 µl PE-labelled anti-CD61 monoclonal antibody in the dark at room temperature. After 15 min, 20 µl fluorescein isothiocyanate (FITC)-labelled anti-CD62P monoclonal antibody or FITC-labelled anti-platelet GPIIb/IIIa (epitope of fibrinogen receptor) monoclonal antibody (PAC-1) was added and incubation was performed again in the dark for another 15 min. Following this, 2 ml PBS was added to each tube and the tubes were centrifuged at 1400 g for 5 min. Finally, the supernatant was aspirated and 1 ml 1.0% paraformaldehyde was added to each tube before flow cytometric analysis. All samples used for platelet activation marker studies were analysed within 90 min of blood collection. The samples were analysed on a Becton-Dickinson FACScan equipped with 15 mW air-cooled argon laser and 10 000 gated events positive for CD61 per sample were analysed with Cell Quest software (Becton-Dickinson). To differentiate between platelets and PMP, a cut-off value was set by comparing forwards light scatter with that of fluorescently labelled reference beads of 2.0 µm diameter. PMP was calculated as number/104 platelets. The gates positive for CD62P and PAC-1 were obtained by comparing unstained (using mouse IgG as control) and stained samples with only anti-CD61 monoclonal antibodies. The ability of these antibodies to detect markedly activated platelets was verified in positive-control experiments using 20 µl thrombin as an agonist (data not shown).
Anticardiolipin antibodies
IgG-anticardiolipin antibodies were measured by indirect non-competitive enzyme immunoassay using microtitre plates coated with cardiolipin antigen (Varelisa Cardiolipin Antibodies EIA kit; Pharmacia & Upjohn). The assay was calibrated against recognized standards. Results were expressed as GPL-U/ml, with one GPL unit corresponding to the binding activity of 1 µg/ml cardiolipin IgG antibody that was purified from standard serum by affinity chromatography. Patients with titres >12 GPL-U/ml were considered to have elevated IgG-anticardiolipin antibodies.
Statistical analysis
Laboratory data are presented as means±SD. Student's t-tests were used to compare differences between groups. Linear regression analysis was used to detect any relationship between groups (Pearson correlation). A P-value of <0.05 was considered significant.
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Results
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Clinical characteristics and laboratory data
The clinical characteristics and laboratory data of the subjects are shown in Tables 1
and 2
. There were no significant differences between the recurrent vascular access failure group (group I) and the longer vascular access survival group (group II) with respect to sex and percentage of patients with hypertension and diabetes. However, age and the frequency of access creations were significantly higher in group I than in group II. In contrast, the period of HD, the length of vascular access survival and percentage of patients using synthetic dialyser membranes (polysulphone or polymethacrymethyl acid) were significantly higher in group II than in group I. There were no differences between groups I and II with respect to Kt/V, blood urea nitrogen (BUN), creatinine, cholesterol (CHOL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), haematocrit and platelets. However, albumin was significantly lower in group I than in group II, whereas triglyceride (TG) and very low-density lipoprotein (VLDL) were significantly higher in group I than in group II.
Platelet expression of CD62P, PAC-1 and PMP
Figure 1
shows the expression of platelet activation markers and PMP in patients and healthy volunteers (group III). CD62P-positive platelets were significantly higher in group I than in group II (7.3±3.7 vs 3.5±1.3%; P<0.0005) and in group III (2.9±0.9%; P<0.00005) (Figure 1
A). Fibrinogen receptor-positive (PAC-1-positive) platelets were also significantly higher in group I than in group II (2.2±2.1 vs 0.9±0.7%; P<0.01) and in group III (0.8±0.6%; P<0.01) (Figure 1
B). Groups II and III were not different with respect to CD62P-positive platelets and PAC-1 positive platelets. In addition, there were no differences between the three groups in PMP levels (group I: 1161±416.3/per 104 platelets; group II: 1398±431.3/per 104 platelets; group III: 1320±229.8/per 104 platelets) (Figure 1
C).

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Fig. 1. Comparison of platelet activation markers in patients and healthy volunteers (A) CD62P-positive, (B) PAC-1-positive platelets and (C) PMP. Data are shown as means±SD. aP<0.0005 vs group II, bP<0.00005 vs group III, cP=NS vs group II, dP<0.01 vs groups II and III, eP=NS vs groups I and II.
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Age-matched subgroup analysis was also performed in HD patients after excluding subjects above age 60 and below age 40 (Table 3
). CD62P-positive platelets were still significantly higher in group I than in group II (8.0±4.6 vs 3.1±1.0%; P<0.05), but PAC-1-positive platelets were no longer different between the two groups (2.4±2.3 vs 1.1±0.5%; P=0.097).
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Table 3. Comparison of platelet activation markers and age in group I and group II after excluding ages above 60 and below 40 years
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Because of a marked sex ratio discrepancy between groups I and II, differences in platelet activation markers were also compared in male and female subgroups. In the male subgroup, values were still higher in group I than in group II for CD62P-positive platelets (9.5±4.0 vs 3.6±1.5%; P<0.05) and for PAC-1-positive platelets (3.1±2.1 vs 1.1±0.8%; P<0.05) (Table 4
). In the female group, CD62P-positive platelets were still significantly higher in group I than in group II (6.5±3.4 vs 3.4±1.3%; P<0.05), but PAC-1-positive platelets were similar between the two groups (1.9±2.0 vs 0.6±0.5%; P=0.109) (Table 5
). The average age of recurrent vascular access failure patients remained significantly higher in both the male and female subgroups.
Figure 2
shows the distribution of percentage of CD62P-positive platelets and PAC-1-positive platelets in the three groups. More than 50% (12 in 23) of patients in group I had >7% CD62P-positive platelets. The majority of studied subjects (29 in 48) had <2% PAC-1-positive platelets.

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Fig. 2. Distribution of the percentage of (A) CD62P-positive platelets and (B) PAC-1-positive platelets in all studied subjects.
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The correlation between the percentage of CD62P-positive platelets and PAC-1-positive platelets in all studied subjects and the correlation between age with either the percentage of CD62P-positive platelets or PAC-1-positive platelets in HD patients are shown in Figure 3
. There was a significant correlation between the percentage of CD62P-positive platelets and PAC-1-positive platelets in all studied subjects (r=0.628, P<0.000005) (Figure 3
A). After excluding healthy control subjects (because of their uniformly young age), age was neither correlated with the percentage of CD62P-positive platelets (r=0.208, P=0.209) (Figure 3
B) nor the percentage of PAC-1-positive platelets (r=0.313, P=0.056) (Figure 3
C).

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Fig. 3. Correlation between (A) the percentage of CD62P-positive platelets and PAC-1-positive platelets in all studied subjects and correlation between age and the percentage of CD62P-positive platelets (B) or PAC-1-positive platelets (C) in haemodialysis patients.
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Table 6
shows comparisons of platelet activation markers and lipid profile between groups I and II after excluding diabetic patients. The levels of CD62P-positive and PAC-1-positive platelets and the levels of TG and VLDL remained significantly higher in group I than in group II. Table 7
shows the same comparison between diabetic and non-diabetic patients in group I. There were no significant differences with respect to platelet activation markers or lipid profile. Although there was a trend for higher levels of CD62P-positive platelets in diabetic patients (8.5±3.2 vs 6.8±3.9%), this was not significant (P=0.3).
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Table 6. Comparison of platelet activation markers and lipid profile in groups I and II after excluding diabetic patients
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Table 7. Comparison of platelet activation markers and lipid profile between diabetic and non-diabetic patients having recurrent vascular access failure
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Anticardiolipin antibody
None of the studied subjects had titres of anticardiolipin antibody that exceeded 12 GPL-U/ml (range: <1.011.3 GPL-U/ml), indicating that all subjects, including uraemic patients and healthy volunteers, had negative anticardiolipin antibody tests. Although this is in contrast to a previous study [18], our findings indicate that anticardiolipin antibodies do not play a role in recurrent vascular access failure in HD patients.
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Discussion
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Many comorbid conditions have been associated with shorter survival of vascular access, including older age, black ethnicity, synthetic AV graft, small vein size, diabetes mellitus, erythropoietin therapy, increased haematocrit, reduction of fistula flow, hypoalbuminaemia [19], increased lipoprotein(a) [20] and the presence of anti-phospholipid antibody [18]. Although it is possible to avoid synthetic AV graft implantation and to reduce fistula flow, thereby avoiding complications of dialysis needle placement, excessive post-dialysis needle site compression and hypotension, parameters such as patient age, race, small vein size or the presence of diabetes mellitus and anticardiolipin antibody are impossible to alter. Anti-platelet agents are providing an interesting treatment in HD patients. Although several studies have concluded that anti-platelet agents prevent vascular access thrombosis [3], they have not gained widespread clinical use primarily because of a lack of large clinical trials showing their usefulness in recurrent vascular access failure. Another problem is side effects. For example, aspirin is the most frequently used anti-platelet agent, but many patients cannot tolerate gastrointestinal (GI) upset following its use since uraemic patients are susceptible to GI bleeding. In the present study, we demonstrated a relationship between increased platelet activation and recurrent vascular access failure. CD62P-positive platelets and PAC-1-positive platelets were significantly higher in recurrent vascular failure patients than in the other two patient groups. In addition, the percentage of CD62P-positive platelets and PAC-1-positive platelets were not different in healthy volunteers and the longer vascular access survival patients. These results suggest that excessive platelet activation itself may cause recurrent vascular access failure or it could be a coexisting phenomenon. In addition, other contributory factors that cause frequent access failure lead to greater platelet activation in recurrent vascular access failure patients than in other patients. Thus, in patients with recurrent vascular access failure, at least in those with higher circulating activated platelets, treatment with anti-platelet agents may be worthwhile.
In the present study, we aimed to determine whether platelet activation is associated with recurrent vascular access failure. Age-matching is necessary because age-related increases in atherosclerosis may be associated with recurrent vascular access failure. In addition, it has been reported that platelet activation parameters, such as ß-thromboglobulin, increase with advancing age [21]. However, our study showed that neither the percentage of CD62P-positive platelets nor the percentage of PAC-1-positive platelets were correlated with age in HD patients. Age-matched subgroup analysis in HD patients also showed that CD62P-positive platelets were higher in recurrent vascular access failure patients, although PAC-1-positive platelets were similar between the two HD groups. These results suggest that older age and increased platelet activation are independent risk factors for recurrent vascular access failure. However, sex may be a confounding factor because of the marked difference in the male/female ratio between groups I and II. In addition, it is well known that AV fistula creation is more difficult in elder females and that the fistulas last for shorter time periods due to the smaller and more fragile arteries and veins in females. However, whereas in male HD patients, CD62P-positive and PAC-1-positive platelets remained significantly higher in recurrent vascular access failure patients, in females, CD62P-positive platelets but not PAC-1-positive platelets were still higher in recurrent vascular access failure patients. These findings indicate that increased platelet activation is associated with recurrent vascular access failure in male patients. The same may also be true for female patients, at least with respect to CD62P-positive platelets.
Hyperlipidaemia and especially hypercholesterolaemia and high LDL levels represent a risk factor for coronary artery disease and increased lipoprotein(a), a lipoprotein variant of LDL, has been associated with shorter survival of vascular access [20,22]. Mixed hyperlipidaemia is common in diabetic and non-diabetic uraemic patients. The present study showed that recurrent vascular access failure patients are prone to higher TG and VLDL levels than other patients and that this same group also had a higher percentage of patients with diabetes mellitus, although this was not significant. Although the effects of diabetes mellitus on the lipid profile and platelet activation markers are questionable, the recurrent vascular access failure group still had higher CD62P-positive platelets, PAC-1-positive platelets, VLDL and TG after excluding diabetic patients. Albumin is an index of nutritional status and it is widely accepted that a lower albumin level is associated with higher mortality and morbidity in HD patients. A greater risk of thrombosis of synthetic AV grafts was found in patients having serum albumin levels <3.0 g/dl in the Canadian Hemodialysis Morbidity Study [19,20]. Hypoalbuminaemia will cause reductions in oncotic pressure, leading to decreased intravascular volume, which might contribute to thrombosis [20]. The difference in albumin levels between recurrent vascular access failure patients and longer vascular access survival patients was small but significant in the present study.
The role of PMP in the pathogenesis of diabetes mellitus [17] and atherosclerosis has been intensively studied in the past 10 years. PMP may be involved in the normal haemostatic response to vascular injury because they are rich in membrane receptors for coagulation factor Va with VIIIa, they provide a catalytic surface for the prothrombinase reaction and tenase reaction [17,23,24] and they cause an increase in procoagulant activity through assembly and activation of the prothrombinase complex. PMP can also directly activate platelets and endothelial cells. Although uraemic patients have been reported to have higher PMP levels, we found no obvious differences in PMP levels in our three study groups. We therefore conclude that PMP does not play a role in recurrent vascular access failure.
In conclusion, the present study is the first to investigate the relationship between platelet activation and recurrent vascular access failure. The majority of patients with recurrent vascular access failure had higher circulating activated platelets, especially CD62P-positive platelets. After excluding diabetic patients, the percentage of CD62P-positive and PAC-1-positive platelets remained significantly higher in recurrent vascular access failure patients than in the other two groups. These findings suggest that increased plasma levels of CD62P-positive and PAC-1-positive platelets may result in hypercoagubility and cause frequent vascular access thrombosis in HD patients. In addition, VLDL and TG levels were significantly higher in recurrent vascular access failure patients, whether they were diabetic or not. There results suggest that hyperlipidaemia may also play a role in recurrent vascular access failure and the question of whether hyperlipidaemia treatment may help to prevent recurrent vascular access failure warrants further investigation. Although the pathogenesis of vascular access failure may not be the same as in coronary artery disease and cerebral infarction, it may prove worthwhile to treat patients with frequent vascular access thrombosis with anti-platelet agents. However, caution is advised for treatment of patients with a history of haemorrhagic disorders. In the future, it may be possible to compare the efficiency of different anti-platelet agents in recurrent vascular access failure patients both in terms of clinical results and in changes in circulating activated platelets, before and after therapy.
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Acknowledgments
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The authors thank Mr Fu-Chien Lin for technical assistance in the analysis of flow cytometry and Dr Chien-Te Lee for assistance in statistical analysis. This work was supported by a Chang-Gung Memorial Hospital Research Grant (CMRP983, 2000). Part of this work was presented in abstract form at the 33rd annual meeting of the American Society of Nephrology.
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Notes
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Correspondence and offprint requests to: Yao-Cheng Chuang, MD, Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, 123 Ta-Pei Road, Niaosung Hsiang, Kaohsiung Hsien, Taiwan 833, Republic of China. Email: mdchuang{at}giga.net.tw 
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Received for publication: 14. 6.02
Accepted in revised form: 7.11.02