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Keywords:

  • anti-Xa;
  • anti-IIa;
  • D-dimers;
  • hip surgery;
  • thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Studies in experimental animal models and in patients receiving low molecular weight heparin (LMWH) to prevent thromboembolic events after surgery have not demonstrated a clear relationship between anti-Xa and anti-IIa activities in plasma and either bleeding or prevention of thrombosis. The relationship between these clinical outcomes and ex vivo anti-Xa and anti-IIa activities, activated partial thromboplastin time (APTT) and D-dimers were evaluated in 440 patients undergoing total hip replacement and given prophylaxis once daily with a LMWH (tinzaparin or enoxaparin) in a multicentre double-blind randomized study. 221 patients received 4500 anti-Xa IU of tinzaparin; 219 patients received 40 mg (4000 anti-Xa IU) of enoxaparin. Both regimens were administered subcutaneously once daily. Blood samples for anti-IIa, anti-Xa, D-dimers levels and APTT were taken at baseline, on day 1, day 5 and on the day of discharge (days 8–14) and clinical assessments were performed daily until day 14. All patients had bilateral venography between days 8 and 14. All coagulation tests were performed in central laboratories. A significant correlation was observed between anti-IIa activity and anti-Xa activity and the dose of each LMWH injected. The anti-Xa activity was significantly higher with enoxaparin and the anti-IIa activity was significantly higher with tinzaparin. No clear relationship between these two activities and the clinical outcomes was observed. This was also true with regards to APTT. Before and after surgery, D-dimers were significantly higher in patients with deep vein thrombosis (DVT) than in those without DVT but had no predictive value. Interestingly, a significant post-operative increase of D-dimers persisted in both groups of patients during the whole observation period, possibly suggesting that a longer duration of prophylactic treatment may be appropriate.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are recognized complications following surgical procedures, with the greatest risk occurring after hip surgery (Clagett et al, 1995). Several regimens, low-dose or adjusted-dose unfractionated heparin (Collins et al, 1988; Leyvraz et al, 1983), oral warfarin, intravenous dextran, as well as mechanical methods (Francis et al, 1992; Rothermel et al, 1973), have been used in order to provide a safe and effective prophylaxis against these thromboembolic complications. The thromboprophylactic potential of low molecular weight heparin (LMWH) preparations has been examined in controlled clinical studies for patients undergoing surgery and they have been shown to significantly reduce the incidence of DVT. Nevertheless, this enhanced effectiveness was not achieved at the expense of decreased safety (Leizorovicz et al, 1992; Nurmohamed et al, 1992).

Tinzaparin and enoxaparin are LMWH with an average molecular weight of about 4500 Daltons (Haether et al, 1994; Kakkar et al, 1995). They have a greater bioavailability and a longer half-life than unfractionated heparin (UFH), permitting administration once daily by subcutaneous injection for both prophylaxis (Hull et al, 1992) and treatment of DVT (Leizorovicz et al, 1992; Hull et al, 1993). Tinzaparin and enoxaparin have different anti-Xa/anti-IIa ratios. The anti-Xa/anti-IIa ratio ranges from 1.5 to 1.8 for tinzaparin and is around 3.2 for enoxaparin (Matthiasson et al, 1993; Leizorovicz et al, 1991; Frydman et al, 1988).

Anti-Xa activity measurement has been the most widely used method for assessing LMWHs activity and to establish a therapeutic range for a particular LMWH. Even if anti-Xa and anti-IIa activities have been well correlated with the dose of subcutaneous (s.c.) injection of LMWH (Hirsh et al, 1987; Frydman et al, 1988; Bara et al, 1987, 1990), experimental studies in animals have not demonstrated a strong correlation between antithrombotic activity and ex vivo anti-Xa plasma levels (Holmer et al, 1982; Buchanan et al, 1985; Carter et al, 1982; Ockelford et al, 1982a; Fernandez et al, 1986). In contrast, some studies have found a significant statistical relationship between anti-Xa plasma levels and both thrombotic and haemorrhagic outcomes with different LMWHs (Levine et al, 1989; Koller et al, 1986). We could not confirm these results in general surgery (Bara et al, 1992). Evaluation of the relationship between plasma anti-IIa activity and haemorrhagic events, which may predict the efficacy and safety of the thromboprophylaxis with LMWH in orthopaedic surgery, has not previously been investigated. Low levels of D-dimers have been shown to have a good negative predictive value for the diagnosis of thromboembolic disorders (Bounameaux et al, 1994; Rochemaure et al, 1995). Evaluation of the relationship between initial high plasma levels of D-dimers and thrombotic events could help in the management of thromboprophylaxis in surgery.

The relationship between the incidence of post-operative thrombosis and haemorrhagic events and plasma concentrations of anti-Xa, anti-IIa, D-dimers and APTT was evaluated in a controlled multicentre double-blind randomized study in patients undergoing total hip replacement who were given prophylaxis once daily with a LMWH (tinzaparin or enoxaparin).

MATERIAL AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

The trial was a multicentre randomized, double-blind, parallel group study. The protocol was accepted by the Ethics Committee of La Rochelle (France).

Patient population

During an 8-month period 499 patients were enrolled by 43 orthopaedic surgery departments located in France and 440 patients were evaluated.

Patients included were scheduled for elective hip replacement. Patients of both sexes were recruited and had to be 40 years of age. Patients allergic to iodine or heparin, patients with bleeding disorders, thrombocytopenia, macroscopic haematuria, active gastric or duodenal ulcer and previous gastroduodenal bleeding, were excluded. Treatment with any anticoagulant or antiplatelet agent within the 8 d prior to surgery was an exclusion criterion. All patients weighed between 50 and 95 kg, and gave their signed informed consent before inclusion.

Patients were randomized to receive either one injection of 4500 IU anti-Xa tinzaparin subcutaneously, or one injection 4000 IU anti-Xa (40 mg) of enoxaparin subcutaneously. The first injection was given 12 h before surgery and then injections were given every 24 h for at least 15 d. The anti-Xa/anti-IIa ratio of tinzaparin is 1.7 and that of enoxaparin is 3.2. It was therefore calculated that each dose contained 2650 anti-IIa IU of tinzaparin and 1250 anti-IIa IU of enoxaparin.

The primary efficacy criterion was the incidence of deep vein thrombosis (DVT) assessed by bilateral venography performed on days 8–14 (in patients with no clinical evidence of DVT) or performed before day 10 in patients with clinical signs of DVT or pulmonary embolism.

Clinical outcome

All patients had a clinical examination daily from day 1 to days 8–14 in order to detect DVT, pulmonary embolism or any bleeding event. In case of suspicion of DVT or pulmonary embolism, a bilateral venography (possibly preceded by an echodoppler) or a pulmonary angiography (possibly preceded by a pulmonary scintigraphy) was performed. All patients had bilateral venography on days 8–14. Venographies were examined by three radiologists unaware of the treatment received.

Haemorrhages were defined as major or minor. A major haemorrhage was a clinically overt bleeding associated with a fall in haemoglobin level of 2.0 g/dl or more or leading to a transfusion of 2 or more units of red blood cells, or any retroperitoneal, intracranial or pericardial haemorrhage warranting surgical treatment and/or definitive treatment discontinuation. A minor haemorrhage was a bleed which did not meet criteria for major haemorrhage.

Haemorrhage was evaluated on the day of surgery (baseline) and during hospitalization, by determining peri- and post-operative blood loss by weighing swabs and suction bottles. Post-operative wound haematoma drainage and injection haematoma at the injection site were also taken into consideration.

Laboratory tests

Blood samples were taken 24 h before surgery, on days 1 or 2, days 5 or 6, and on the day of discharge (days 8–14) in CTAD (citrate, theophylline, adenosine, dipyridamole) evacuated tubes. Blood samples were collected 3–4 h after injection in a subgroup of patients and 10–14 h after injection in another subgroup. Plasma from these samples was stored below −20°C and then transferred to a central laboratory for determination of anti-Xa activity, anti-IIa activity and APTT. Anti-Xa activity was measured using an amidolytic assay with CBS 3139 as a substrate and bovine factor Xa (Stachrom from Stago, Asnières, France) with automatic reading of results at 405 nm (SBA 300 Gilford from CIBA CORNING, Cergy-Pontoise). Determination of anti-IIa activity used an amidolytic assay with S2238 as a substrate (Chromogenix Mölndal Sweden) and human thrombin (Fibrindex, Ortho Diagnostic Systems, Aubervilliers, France) with automatic reading of results at 405 nm (SBA 300). Measurement of APTT (PTTA) was measured by using a reagent from Stago and D-dimers by an ELISA Method (Elisa kit from Stago).

Anti-Xa and anti-IIa activities were determined in one central laboratory and APTT and D-dimers plasma levels were measured in another central laboratory.

Statistical analysis

Mean levels ±SEM of anti-Xa, anti-IIa and D-dimers, as APTT, were compared between patients who presented with clinical outcomes and those who did not, using the Student's t-test. The alpha risk value was 0.05 and beta risk value 0.20. A P value of 0.05 was taken as cut-off for significance. Means and SEM are presented in this article. Computations were made with the SAS® package.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Clinical results

The clinical results have been reported elsewhere (Planes et al, 1999). In summary, tinzaparin appears to be as effective and safe as enoxaparin in the prophylaxis of deep vein thrombosis (DVT) after total hip replacement. The rate of DVT was similar in both groups of patients, 21.7% and 20.1% respectively. Bleeds were slightly more frequent in the enoxaparin group, but the difference was not significant.

Biological results

Biological baseline characteristics (anti-Xa activity, anti-IIa activity, APTT and D-dimers) were similar for the two groups (Table I). The mean plasma anti-Xa activities were significantly higher in the enoxaparin group (P < 0.001) either at peak time or 10–14 h after injection and either on days 1–2, days 5–6, and on days 8–14 (Table II and Fig 1). The mean plasma anti-IIa activities were significantly higher in the tinzaparin group (P < 0.001) at peak time but not 12 h after injection, either on days 1–2, days 5–6, and on days 8–14 (Table III and Fig 2).

Table 1. Table I. Biological baseline characteristics.Thumbnail image of
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    *  Analysis of variance (F test).

  • Table 2. Table II. Mean plasma anti-Xa activity.Thumbnail image of
  • a

    *  Analysis of variance (F test).

  • image

    Figure 1. . Anti-Xa activity after subcutaneous injection of enoxaparin at peak level (3–4 h) (♦) and 10–14 h after s.c. injection (⋄) or tinzaparin at peak level (3–4 h) (●) and 10–14 h after s.c. injection (○), measured before surgery, day 1, day 2 after surgery, and at the end of the treatment.

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    Table 3. Table III. Mean plasma anti-IIa activity.Thumbnail image of
  • a

    *  Analysis of variance (F test).

  • image

    Figure 2. . Anti-IIa activities after subcutaneous injection of enoxaparin at peak level (3–4 h) (♦) and 10–14 h after s.c. injection (⋄) or of tinzaparin at peak level (3–4 h) (●) and 10–14 h after s.c. injection (○), measured before surgery, day 1, day 2 after surgery, and at the end of the treatment.

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    At peak time and at each assessment, APTT mean values were significantly longer with tinzaparin than with enoxaparin. However, 12 h after injection, the results were similar (Table IV and Fig 2). The increase in APTT (compared to the baseline mean values) were significantly different on days 1–2, days 5–6 and days 10–14 (peak time) but were similar in the blood samples collected 10 to 14 h after injection (Table IV, Fig 3). Interestingly, the APTT was longer on days 1–2 than on days 5–6 (Table IV). The prolongation was significantly greater in tinzaparin than in enoxaparin group (P = 0.021). The difference was no longer significant on days 5–6 and days 10–14.

    Table 4. Table IV. APTT mean values ± SEM.Thumbnail image of
  • a

    *  Analysis of variance (F test).

  • image

    Figure 3. . APTT after subcutaneous injection of enoxaparin at peak level (3–4 h) (♦) and 10–14 h after s.c. injection (⋄) or of tinzaparin at peak level (3–4 h) (●) and 10–14 h after s.c. injection (○), measured before surgery, day 1, day 2 after surgery, and at the end of the treatment.

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    Basal D-dimers mean values were 1019 ng/ml in patients treated with tinzaparin and 1009 ng/ml in patients treated by enoxaparin and increased to 3233 ng/ml and 3394 ng/ml respectively on days 8–14 but were not significantly different (Table V and Fig 4).

    Table 5. Table V. D-dimers (ng/ml) in patients with and without DVT. Plasma levels at days −1 (basal value), 1, 5, and 11–14.Thumbnail image of
  • a

    No difference was observed between the two groups enoxaparin and tinzaparin (results not shown).

  • image

    Figure 4. . Distribution of basal D-dimers in (a) patients with DVT (▪) as compared to patients without DVT (□) at day 1 or day 2 after surgery, (b) patients with DVT (▪) as compared to patients without DVT (□) at day 1 or day 2 after surgery, (c) patients with DVT (▪) as compared to patients without DVT (□) at day 5 or day 6 after surgery, and (d) patients with DVT (▪) as compared to patients without DVT (□) at the end of the treatment. Distribution of D-dimers (ng/ml): 1, <1000; 2, [1000–2000]; 3, [2000–3000]; 4, [3000–4000]; 5, [4000–5000]; 6, [5000–6000]; 7, >6000.

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    In the evaluable patient population, these four parameters were analysed according to the occurrence of thromboembolic (DVT) or haemorrhagic events.

    No relationship could be found between anti-Xa, anti-IIa or APTT, at peak time or 10–14 h after injection, and the occurrence of DVT (Table V and Table VI). There was also no relationship between these parameters and the haemorrhagic events. However, the number of haemorrhagic events was too low to allow an appropriate evaluation.

    Table 6. Table VI. Anti-Xa activity (IU/ml) ± SEM/occurrence of DVT.Thumbnail image of
  • a

    *  Wilcoxon rank sum test.

  • In contrast, the mean plasma level of D-dimers before and after surgery in patients with DVT was significantly higher than that in patients without thrombosis (Table V). The distribution of plasma levels of D-dimers in patients with and without DVT correlates with these results, but shows the overlap of both populations (Fig 4). Interestingly, the post-operative increase of D-dimers persisted during the whole period of observation in both groups of patients with and without DVT.

    DISCUSSION

    1. Top of page
    2. Abstract
    3. MATERIAL AND METHODS
    4. RESULTS
    5. DISCUSSION
    6. Acknowledgements
    7. References

    In thromboprophylaxis with LMWH most studies have shown that the efficacy and safety are similar or better than with UFH. This efficacy has been confirmed in two meta-analyses (Leizorovicz et al, 1992; Nurmohamed et al, 1992), and showed an additional, practical benefit, as LMWH are given as a single daily subcutaneous injection. However, the question concerning the recommended dosage of LMWH still remains to be discussed and must be considered for each LMWH separately.

    Indeed LMWHs are neither similar in terms of their molecular weight distribution, nor in terms of their anti-Xa/anti-IIa activities. For tinzaparin this ratio is <2 and for enoxaparin it is around 3.3.

    The new international standard (IU) which allows the comparison of the different LMWHs is expressed in terms of anti-Xa activity. However, when looking at the scale of values for all LMWHs it is possible that this is not the most pertinent method for comparison (Matthiasson et al, 1993; Leizorovicz et al, 1993).

    Experimental studies in animals (Carter et al, 1982; Ockelford et al, 1982b; Fernandez et al, 1986; Bara et al, 1989) and four clinical studies (Koller et al, 1986; Bara et al, 1992; Bounameaux et al, 1994; Leyvraz et al, 1991; The Danish Enovaparin Study Group, 1991) have not demonstrated a significant relationship between prevention of thromboembolic events and ex vivo anti-Xa plasma levels. One of the studies concerned tinzaparin in the prevention of thromboembolic events in general surgery (Bara et al, 1992), and concluded that it was unnecessary to adjust the dosage of tinzaparin either to body-weight or to daily laboratory results.

    In contrast, a significant relationship between plasma anti-Xa activity and thrombosis has been observed in a few studies (Levine et al, 1989; Turpie et al, 1987; Samama et al, 1988) and a significant relationship between anti-Xa and haemorrhages in three studies has also been found (Levine et al, 1989; Koller et al, 1986; Bergqvist et al, 1986). As Levine et al (1989) found a significant correlation between anti-Xa activity measured just before injection, and thrombosis and bleeding, with 40 mg of enoxaparin administered once daily in the same surgical indication, it appeared pertinent to compare the effects of tinzaparin to that of enoxaparin in the prevention of thrombosis in patients undergoing hip surgery using a dose near to 4000 anti-Xa-IU.

    The contradictory results suggested that plasma anti-Xa activity should not be used as an indicator of antithrombotic activity and so other parameters would have to be found.

    In another study, no relationship was observed between APTT and haemorrhagic events (Koller et al, 1986). Other criteria for dose adjustment in the clinical setting could be anti-IIa activity and D-dimers plasma levels.

    Anti-Xa and anti-IIa activities and APTT

    Although the injected dose of enoxaparin expressed in anti-Xa IU (4000) was slightly lower than that of tinzaparin (4500), mean plasma anti-Xa IU peak levels were significantly higher in patients receiving enoxaparin. In contrast, the amount of anti-IIa IU given in the tinzaparin group was approximately twice that of enoxaparin and mean plasma anti-IIa peaks were significantly higher, but lower than expected, in patients receiving tinzaparin. Interestingly, the mean anti-IIa activity for both drugs 12 h after s.c. injection was comparable to that measured at the basal state before any heparin treatment. If anti-IIa was a good marker of the antithrombotic activity, it was strange that its duration was <12 h when patients received a single injection daily, at least in Europe. In contrast, a significant anti-Xa activity was persistent for both drugs 12 h after injection.

    Mean basal values of APTT were similar in both groups of treatment. APTT means values were significantly longer with tinzaparin than with enoxaparin at peak time but were similar at 12 h for each assessment. This difference could be related to the higher anti-IIa activity in patients treated with tinzaparin. When studying the lengthening of APTT, it was only significantly different between treatments at peak time on days 1 or 2. The shortening of APTT after days 1–2 could correspond to the classic post-operative hypercoagulable reaction.

    Anti-Xa, anti-IIa, APTT and occurrence of thromboembolism

    For the anti-Xa and anti-IIa activities, no statistical difference was detected between patients with DVT and those without DVT, for tinzaparin and enoxaparin, and at any time after injection (peak time or 12 h after) or on any day of sampling (Tables VI and VII).

    Table 7. Table VII. Anti-IIa activity (IU/ml) ± SEM/occurrence of DVT.Thumbnail image of
  • a

    *  Wilcoxon rank sum test.

  • Since the clinical results were similar, it may be hypothesized that both activities play a role in the antithrombotic activity of LMWHs.

    APTT showed the same behaviour, except in the tinzaparin group 12 h after injection on the last day of treatment: a difference was detected (P = 0.03) between APTT values of patients with DVT (35.87 s) and without (38.49 s) (not shown).

    The small number of haemorrhagic episodes (minor or major) did not permit a reliable analysis.

    Our findings are not consistent with those of Levine et al (1989) or other studies (Koller et al, 1986; Turpie et al, 1987; Bergqvist et al, 1986) showing a relationship between anti-Xa activity and clinical outcomes. Our findings are probably valid since bias was avoided, ensuring that virtually all eligible patients were included in this analysis, that the clinical outcomes were objectively diagnosed, and that all measurements were performed blindly in central laboratories. Moreover, as we found that the anti-Xa activity plasma mean levels were higher in the enoxaparin-treated patients (0.55 ± 0.015 IU/ml) than those given by Koller et al (1986) (0.48 IU/ml) and Levine et al (1989) (0.46 IU/ml) as associated with the highest risk of bleeding, our conclusion of no relationship becomes stronger. It confirms our previous findings in general surgery and it is closely akin to the results of Caen (1988).

    The ratio of the two activities (anti-Xa/anti-IIa) was also unrelated to clinical outcome in this study.

    This study was the first to evaluate the relationship between anti-IIa activity and clinical outcome. The lack of relationships observed in our study confirmed that anti-IIa activity, similarly to anti-Xa activity, may not be causal, since there are other potential mechanisms, such as inhibition of platelet function, inhibition of factor IXa, inhibition of thrombin generation, enhancement of fibrinolytic activity, etc., by which LMWH may influence haemostasis. Tissue factor pathway inhibitor (TFPI) could be one of these other causal markers (Abildgaard, 1993; Bara et al, 1993; Peterson et al, 1995). TFPI plasma levels were increased after repeated injections of LMWH and could contribute to its anticoagulant effects (The DVTENOX Study Group, 1993). To what extent this means that TFPI also contributes to the antithrombotic effect of LMWH is still unknown and further clinical studies will be required to determine this.

    APTT is the most widely used test for monitoring treatment with heparin (UFH). There was an unreliable relationship between APTT values and clinical events in the present study. These results are in agreement with those found by Koller et al (1986).

    Thromboprophylaxis with a fixed dose of about 4000 anti-Xa IU in all patients has been shown in this study to be effective and safe. Our findings are consistent with the prophylactic diagram (Leizorovicz et al, 1992; Nurmohamed et al, 1992; Kakkar et al, 1995) and conclusions previously reached (Bara et al 1992; Caen, 1988). The predictive value of the anti-Xa and anti-IIa activities for the occurrence of bleeding is, however, difficult to estimate, since the number of haemorrhagic events was too low to allow a reliable evaluation.

    D-dimers

    Baseline D-dimers mean values were similar in both groups but were relatively high: 1019 ng/ml in patients treated with tinzaparin and 1009 ng/ml in patients treated with enoxaparin. These values, higher than in a normal population, are probably due to the patient age, inflammatory process, and high numbers of disease increasing the D-dimers level (Rowbothman et al, 1992). For all patients included (enoxaparin and tinzaparin patients mixed), there was a statistical difference at baseline between the patients with DVT (mean value 1153.9 ng/ml) and the patients without DVT (mean value 952.5 ng/ml) (P = 0.005). During follow-up the D-dimers levels increased in both populations (with or without DVT), but this enhancement was proportionately more important in patients with DVT. This observation was original and interesting but had no clinical relevance. D-dimer levels distribution did not discriminate for the occurrence of DVT or not because of a significant overlap of both populations (with or without DVT) distribution (Fig 4).

    These findings confirm the high sensitivity of D-dimers plasma levels for thromboembolic disorders (Bounameaux et al, 1994; Rochemaure et al, 1995) as they were significantly higher in patients with DVT at each assessment. However, although we found a higher baseline level, it did not have a predictive value. In a previous study (The DVTENOX Study Group, 1993), it had already been shown that D-dimers were not related to the anti-Xa activities, either for enoxaparin or for UFH treatment.

    It is essential to note that the increase of the D-dimers persisted for at least 10–14 d after surgery. This observation suggests that a longer duration of prophylactic treatment may be more appropriate as suggested also by three recent clinical trials (Dahl et al, 1995; Lassen et al, 1996; Planes et al, 1996).

    In conclusion, anti-Xa, anti-IIa activities and APTT at 3 or 4 h or at 12 h after injection were not predictive of clinical events in patients receiving LMWH to prevent DVT after hip replacement.

    Thus, plasma levels of anti-Xa and anti-IIa activity may be markers for effects of LMWH on haemostasis which may or may not be causally related to the clinical outcomes. However, it may be hypothesized that both activities play a role in the antithrombotic activity of LMWH.

    Interestingly, before and after surgery, D-dimers were significantly higher in patients with DVT than in patients without DVT. However, they had no predictive value for a given patient. The increase of D-dimers persisted for at least 2 weeks after surgery. A longer duration of prophylactic treatment may be more appropriate.

    Acknowledgements

    1. Top of page
    2. Abstract
    3. MATERIAL AND METHODS
    4. RESULTS
    5. DISCUSSION
    6. Acknowledgements
    7. References

    We acknowledge A. Rakotomanga and Dr J. J. Heilmann from Leo Laboratory for their help in statistical analysis and Dr P. Pinton for his help during the preparation of the manuscript.

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    1. Top of page
    2. Abstract
    3. MATERIAL AND METHODS
    4. RESULTS
    5. DISCUSSION
    6. Acknowledgements
    7. References
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