Different effects of enoxaparin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study

Nephrology Dialysis Transplantation, Jul 2003

Background. Heparin inhibits prothrombotic tissue factor (TF) and releases its inhibitor, tissue factor pathway inhibitor (TFPI), from the endothelium, but repeated administration of heparin depletes vascular stores of TFPI. We studied the anticoagulant effects of unfractionated heparin (UFH) vs low‐molecular‐weight enoxaparin—used for thrice‐weekly maintenance haemodialysis (HD)—on plasma levels of total TF and TFPI and on those of an activated coagulation marker prothrombin fragment 1+2 (PF 1+2). Methods. Twenty‐five patients dialysed using a single injection of enoxaparin (at a mean dose of 0.68 mg/kg) were randomly assigned to either receive UFH administered as a mean bolus of 42.1 IU/kg and continuous infusion of 57.8 IU/kg (n=12) or to be maintained on enoxaparin (n=13), and were followed prospectively for 12 weeks. Plasma immunoreactive TF, TFPI and PF 1+2 were measured at the start and after 10 and 180 min of HD, and compared with values in 15 healthy controls. Results. Pre‐dialysis TF, TFPI and PF 1+2 were higher than normal (all P<0.0001). TF and PF 1+2 did not change, while TFPI levels, compared with baseline, increased at each interval in enoxaparin‐anticoagulated HD patients (all P<0.0001). TFPI increments correlated inversely with pre‐dialysis TFPI (both P<0.0007). In patients switched to UFH, TF levels remained unchanged compared with pre‐randomization values, TFPI increased at each interval of HD sessions (all P<0.035) and PF 1+2 increased pre‐dialysis (P=0.015). The over‐dialysis effects of UFH resembled those of enoxaparin. In contrast, baseline TFPI and its 10‐min rise correlated inversely with the UFH loading dose (both P<0.040). Pre‐dialysis PF 1+2 was inversely associated with TFPI increments (both P<0.034), and directly with pre‐dialysis TFPI (P=0.018) and the UFH loading dose (P=0.045). Conclusions. Depletion of heparin‐releasable stores of TFPI is an untoward effect of repeated anticoagulation during maintenance HD therapy. The traditional UFH regimen is more prothrombotic than single enoxaparin injections, with high loading doses of UFH being involved in TFPI exhaustion and subsequent hypercoagulability.

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Different effects of enoxaparin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study

Beata Naumnik 0 1 Jacek Borawski 0 1 Michal Mysliwiec 0 1 0 of Nephrology and Internal Medicine, Medical Academy , 14 Zurawia St, PL 15-540, Bialystok, Poland 1 Department of Nephrology and Internal Medicine, Medical Academy , Bialystok, Poland Background. Heparin inhibits prothrombotic tissue factor (TF) and releases its inhibitor, tissue factor pathway inhibitor (TFPI), from the endothelium, but repeated administration of heparin depletes vascular stores of TFPI. We studied the anticoagulant effects of unfractionated heparin (UFH) vs low-molecularweight enoxaparinused for thrice-weekly maintenance haemodialysis (HD)on plasma levels of total TF and TFPI and on those of an activated coagulation marker prothrombin fragment 1q2 (PF 1q2). Methods. Twenty-five patients dialysed using a single injection of enoxaparin (at a mean dose of 0.68 mgukg) were randomly assigned to either receive UFH administered as a mean bolus of 42.1 IUukg and continuous infusion of 57.8 IUukg (ns12) or to be maintained on enoxaparin (ns13), and were followed prospectively for 12 weeks. Plasma immunoreactive TF, TFPI and PF 1q2 were measured at the start and after 10 and 180 min of HD, and compared with values in 15 healthy controls. Results. Pre-dialysis TF, TFPI and PF 1q2 were higher than normal (all P-0.0001). TF and PF 1q2 did not change, while TFPI levels, compared with baseline, increased at each interval in enoxaparinanticoagulated HD patients (all P-0.0001). TFPI increments correlated inversely with pre-dialysis TFPI (both P-0.0007). In patients switched to UFH, TF levels remained unchanged compared with prerandomization values, TFPI increased at each interval of HD sessions (all P-0.035) and PF 1q2 increased pre-dialysis (Ps0.015). The over-dialysis effects of UFH resembled those of enoxaparin. In contrast, baseline TFPI and its 10-min rise correlated inversely with the UFH loading dose (both P-0.040). Pre-dialysis PF 1q2 was inversely associated with TFPI increments (both P-0.034), and directly with pre-dialysis TFPI (Ps0.018) and the UFH loading dose (Ps0.045). Introduction Unfractionated heparin (UFH) and low-molecularweight heparins (LMWHs) inhibit blood coagulation by potentiating the inhibitory action of antithrombin against its target proteases such as thrombin and factor Xa. Moreover, they bind to vascular endothelial cells and mobilize tissue factor pathway inhibitor (TFPI) into circulating blood [13]. TFPI is a potent inhibitor of the extrinsic coagulation pathway that is triggered by tissue factor (TF), neutralizing both factor Xa and the activated factor VIIauTF complex [3]. The TFPImediated action of heparin is important and contributes more than one-third to its total anticoagulant effect [3]. Recently, both UFH [2,4] and LMWH [2] have been found to prevent also the rise in plasma TF in patients with acute coronary syndromes. This novel anticoagulant effect results from the down-regulation of TF activity and gene expression in endothelial cells [5] and monocytes [6]. Thus, the anticoagulant action of both UFH and LMWHs is complex and exerted via at least four different mechanisms, including inhibition of thrombin, factor Xa and TF, and up-regulation of TFPI (Figure 1). The main difference between the heparins is that LMWHs are more specific against factor Xa [3]. Moreover repeated intravenous (i.v.) infusions of UFH cause a depletion of endothelial TFPI stores and reduce the anti-thrombotic potential of vascular lining [710]. This may explain the superior efficacy of prolonged therapy with subcutaneous (s.c.) Fig. 1. Some anticoagulant effects of heparin. LMWH over the use of i.v. UFH in a wide variety of patients with thrombotic complications [7]. Traditionally UFH, and increasingly LMWHs [11,12], are used as anticoagulants in intermittent haemodialysis (HD). To date, studies of circulating TFPI in this clinical situation have shown increased levels of the inhibitor both during [1315] and after HD sessions with UFH [1618], but no change of TFPI with non-heparin anticoagulants [13]. TFPI levels have also been reported to be higher in HD sessions using UFH compared with those using LMWH [16,17]. All of these findings suggest that heparin is an important stimulus for the release of TFPI also during HD, and that the type of heparin used may affect haemostasis also via the TFPI-related mechanism. Regarding plasma TF, investigations employing UFH for HD anticoagulation have yielded contradictory results [15,17], and no change in TF has been found during enoxaparin-anticoagulated HD [18]. So far, there have been no prospective controlled studies of the effects of UFH vs LMWH on circulating TF and TFPI in relation to the actual activation of the coagulation system during HD and thereafter. The issue is clinically important, because repeated and prolonged exposure to different heparins may further disturb haemostasis in chronic HD patients. In this study, we followed over-dialysis plasma levels of total TFPI and TF in relation to an activated coagulation marker, prothrombin fragment 1q2 (PF 1q2), in HD patients initially anticoagulated with LMWH enoxaparin, and then randomly assigned to receive either UFH or LMWH enoxaparin. Our aim was to determine how the type of heparin used during HD affected circulating TF and TFPI, and whether it had any impact on blood coagulation. Patients and methods Patients Twenty-five patients (10 women) of a mean age of 59.3" 13.3 years who had been undergoing intermittent HD for a median period of 40.4 (2.0162) months were enrolled in the study. They were selected from the group of patients who had been receiving enoxaparin (Clexane, Bellon Rho ne-Poulenc Rorer, Montrouge, France) as an anticoagulant during their HD sessions for at least 2 months prior to the study. The enrolment criteria excluded patients with diabetes, malignancy, HIV, severe liver disease, those receiving immunosuppressive, contraceptive, lipid-lowering, anti-platelet and non-steroidal anti-inflammatory drugs, and those who had had any inflammatory or infectious diseases during the preceding month. The causes of end-stage renal failure in our cohort were chronic glomerulonephritis (ns8), interstitial nephritis (ns6), polycystic kidney disease (ns3), hypertensive nephropathy (ns1), amyloidosis (ns1), acute renal failure (ns1), and unknown causes (ns5). Sixteen participants had cardiovascular disease, 11 were seropositive for one or both viral hepatitis C and B markers, eight were current smokers, 21 were being treated with erythropoietin, and 24 with anti-hypertensive drugs. All of the patients were dialysed three times a week for 4.0 h (4.05.0) per session using the double-needle technique, native arteriovenous fistulae, bicarbonate-buffered dialysate, low-flux modified cellulose dialysers, and machines with ultrafiltration controllers. Before each HD session, the extracorporeal circuit was rinsed with 1000 ml of isotonic saline containing 2.0 IUuml of unfractionated sodium heparin (Heparin, Biochemie, Kundl, Austria). Then, at the beginning of HD, enoxaparin was injected as a single bolus of 40 (2060) mg into the predialyser arterial line. The effective dose of enoxaparin was 0.68"0.20 mgukg dry weight (1 mgs100 IU of anti-factor Xa activity), this having been established on the basis of clinical guidelines: no visible fibrin clots in the arterial and venous bubble traps during HD, no clotted filters after HD, and no bleeding from the fistula puncture sites after compression [11,12]. Fifteen age- and sex-matched healthy non-smoking individuals served as controls for the determination of plasma levels of TF, TFPI and PF 1q2. Study design Plasma levels of TF, TFPI and PF 1q2 were measured at the start of and after 10 and 180 min of HD in 25 patients anticoagulated with enoxaparin. The subjects were next randomly assigned either to continue enoxaparin (ns13) or to receive UFH (ns12) during HD. The study was designed to keep the heparin doses, other HD prescriptions and pharmacological regimens constant throughout the followup. The approval of our institutional ethics board was obtained, and all patients and controls gave their informed consent in conformity with the Helsinki declaration. UFH was administered as a loading dose of 2500 (1500 3500) IU (42.1"9.2 IUukg) into the arterial line just prior to the start of HD, followed by a continuous infusion of 3750 (25004000) IU (57.8"12.4 IUukg) via a syringe pump. The infusion was started at the same time as the loading dose, continued during HD and stopped 1 h before its scheduled completion. The dosage of UFH had been individually titrated, based on the whole-blood activated partial thromboplastin time (WBAPTT) and established during the first three sessions. The goal was to attain an approximately 2-fold prolongation of WBAPTT at both 30 and 120 min after the start of HD compared with baseline. Twenty-three patients were re-examined after a 3-month interval. In 12 patients who had been switched to UFH, the over-dialysis TF, TFPI and PF 1q2 levels were compared to those obtained when they were on enoxaparin. Eleven of the 13 subjects maintained on HD treatment with enoxaparin completed the study. Two patients died out of hospital during the follow-up. Methods Fasting blood was drawn into Monovette vacutainers (Sarstedt, N umbrecht, Germany) containing 0.129 M trisodium citrate (1 vol. anticoagulant and 9 vol. whole blood) by free flow from the arterial outlet of the fistula before heparinization and start of a midweek morning HD, and again after 10 and 180 min of HD. Intra-dialysis blood samples were taken after lowering the blood flow to 100 mlumin for 1 min. In healthy controls, fasting blood samples were obtained without stasis from the antecubital vein punctured with a 19-gauge needle. Cell-free plasma was prepared by centrifugation at 3000 g for 20 min at room temperature, aliquoted and stored in plastic tubes at 408C until further processing. Plasma antigens of TF and TFPI were measured using commercial two-antibody sandwich assay kits (Imubind, American Diagnostica Inc., Greenwich, CT, USA). The monoclonal antibodies used in the TF assay recognize both free and factor VIIa-complexed TF particles. The TFPI assay detects both intact and truncated forms of the inhibitor as well as its complexes with TFuVIIa. Plasma PF 1q2 was determined by an immunoassay (Enzygnost F 1q2 micro) purchased from Dade Behring (Marburg, Germany). The assay indirectly quantifies the amount of thrombin formed during conversion of prothrombin. The detection limits of the TF, TFPI and PF 1q2 assays are 10 pguml, 0.36 nguml and 0.04 nmolul, respectively. The measurements were performed in duplicate on a 400 SFC photometer (SLTLabinstruments, Gr odinguSalzburg, Austria), calibrated using the supplied reference samples and standards. For calculations of the results, a computer and curve-fitting software were used. Their intra- and inter-assay coefficients of variations were -10%. The values obtained after 180 min of HD were corrected for haemoconcentration according to plasma protein levels. WBAPTT was measured using an automated coagulation system and reagents supplied by bioMerieux (Marcy-lEtoile, France). Statistics The results were expressed as mean"1 SD or median (range) depending on their normal or skewed distribution provided by ShapiroWilks W test. For intra- and inter-group comparisons, non-parametric Friedmans one-way analysis of variance (ANOVA), MannWhitneys U, Wilcoxons and chi-squared test were used when appropriate. Bivariate correlations were assessed using Spearmans regression analysis. Every P was two-tailed, and P-0.05 was considered significant. Computations were performed using Statistica 6.0 (StatSoft, Tulsa, OK, USA). TF, TFPI and PF 1q2 during LMWH haemodialysis Plasma TF levels were stable during enoxaparinanticoagulated HD (x2 ANOVAs2.48, Ps0.289). They were 340 (1001144) pguml at the start, 380 (2281192) pguml after 10 min and 366 (155 1106) pguml after 180 min. In contrast, TFPI levels showed a marked over-dialysis change (x2s50.0, P-0.0001). They increased by 155"73% (P-0.0001) from 141 (85.0304) nguml at baseline to 371" 20.2 nguml after 10 min. After 180 min, TFPI levels were 249 (126371) nguml and lower than those at 10 min (P-0.0001) but still elevated by 73"60% compared with baseline values (P-0.0001). PF 1q2 concentrations were 1.69"0.20 nmolul at the start, 1.68"0.21 nmolul after 10 min and 1.73"0.24 nmolul after 180 min, and unchanged (x2s3.86, Ps0.145). All the variables studied were higher in HD patients than in healthy controls (TF 137"88.4 pguml; TFPI 97.2"32.9 nguml; PF 1q2 1.14"0.41 nmolul, all P-0.0001). The percentage increases in TFPI after both 10 min (rs 0.972, P-0.0001, Figure 2A) and 180 min of HD (rs 0.640, Ps0.0006) correlated inversely with the pre-dialysis levels of the inhibitor. Neither the TFPI increments nor its pre-dialysis concentrations depended on the dose of enoxaparin (all P)0.300). Pre-dialysis PF 1q2 was not associated with baseline TFPI and TF levels, TFPI increments or dose of enoxaparin (all P)0.137). In healthy subjects, there were no relations between plasma F 1q2 concentrations and those of TF or TFPI (both P)0.178). Effects of a change from LMWH to UFH As shown in Table 1, over-dialysis TF levels did not significantly change in the 12 patients changed to UFH compared with their pre-randomization values. Respective TFPI concentrations were increased at each interval (Figure 3A), while those of PF 1q2 were higher pre-dialysis (Figure 3B). The change of predialysis TFPI did not correlate with that in PF 1q2 (Ps0.914). All TF, TFPI and PF 1q2 levels in UFHanticoagulated HD patients were higher than in healthy controls (all P-0.0001). In the 11 patients who completed the LMWH arm of the study, TF, TFPI and PF 1q2 were unchanged compared with their pre-randomization levels (Table 1). The LMWH and UFH groups did not differ with regard to baseline levels of the variables studied (Table 1), age, gender or prevalence of co-morbid conditions (data not shown). There were no bleeding, thrombotic or infectious complications during follow-up. Pre-dialysis haematocrit, platelet count, plasma fibrinogen, serum C-reactive protein, plasma lipids, ultrafiltration and blood flow rates, over-dialysis blood pressure and dry body weight did not change in either group (data not shown). No patient required adjustment of the treatment. TF, TFPI and PF 1q2 during UFH haemodialysis Plasma TF and PF 1q2 levels were stable (x2s1.17, Ps0.558 and x2s5.50, Ps0.064, respectively), while those of TFPI were markedly altered (x2s22.2, Ps0.0002) also during UFH-anticoagulated HD (Table 1). TFPI increased by 133"40% (P-0.0001) after 10 min and by 85"62% (P-0.0001) after 180 min. The percentages of the TFPI increments did not differ from those induced previously by enoxaparin in the 11 respective subjects (both P)0.530). As for LMWH, the TFPI increases after both 10 min (rs 0.937, P-0.0001, Figure 2B) and 180 min of HD (rs 0.839, P-0.0001) correlated inversely with pre-dialysis TFPI. In contrast to TF (pguml) TFPI (nguml) PF 1q2 (nmolul) TF (pguml) TFPI (nguml) PF 1q2 (nmolul) Before randomization Enoxaparin (ns12) Enoxaparin (ns11) 378 (1681144) 150 (120304) 1.66"0.16 404 (2281192) 373"20.0 1.63"0.24 372 (1551106) 245"64.7 1.69"0.19 After 12 weeks Unfractionated heparin (ns12) 376 (248624) 192"76.8a 1.88"0.22d 366 (276832) 175"48.7 1.64"0.23 Enoxaparin (ns11) 398 (300612) 400"18.1b 1.66"0.25 383 (2761028) 390"28.0 1.61"0.25 371 (260600) 320"47.1c 1.68"0.36 352 (271684) 266"57.7 1.67"0.27 Differences by Wilcoxons signed-rank test between patients switched from enoxaparin to unfractionated heparin: aPs0.005, bPs0.008, cPs0.034, dPs0.015. Fig. 3. Over-dialysis plasma (A) TFPI and (B) PF 1q2 levels in 12 patients switched from enoxaparin to UFH anticoagulation. Abbreviations as in Figure 2. Asterisk indicates variables increased while on UFH. The increments are significant even after exclusion of the patient with baseline TFPI of 403 nguml. enoxaparin, the 10 min TFPI rise was significantly (rs 0.615, Ps0.033, Figure 2C), while that after 180 min marginally (rs 0.545, Ps0.067) inversely associated with the loading dose of UFH. The bolus (rs0.601, Ps0.039) but not the infusion (rs0.315, Ps0.318) dose of UFH correlated also with baseline TFPI. Pre-dialysis levels of PF 1q2 were inversely associated with both increments of TFPI at 10 min (rs 0.629, Ps0.028, Figure 2D) and 180 min (rs 0.615, Ps0.033), and directly with the loading dose of UFH (rs0.587, Ps0.045, Figure 2E) and pre-dialysis TFPI (rs0.664, Ps0.018). Discussion This prospective study shows that total plasma TFPI levels but not those of TF depend on the type of heparin used for repeated anticoagulation during maintenance HD. Although both LMWH enoxaparin and UFH cause a depletion of heparin-releasable stores of anticoagulant TFPI in this clinical situation, the untoward effect of UFH is more pronounced and dose-dependent, and accounts for a rebound activation of the coagulation system. Heparin, besides interfering with circulating haemostatic factors, causes a substantial increase in plasma TFPI levels [13]. The underlying mechanism and the vascular sites from which the molecule is released are not clear. Heparin has been found to displace TFPI from its endothelial membrane-bound complexes with glycosaminoglycans, i.e. heparan sulphate [3], as well as to mobilize TFPI from intracellular stores [19,20]. Recent comprehensive in vitro studies [19,20] have also shown that both UFH and LMWH augment TFPI synthesis by cultured endothelial cells and enhance their anti-thrombotic potential. However, circumstantial clinical evidence indicates that prolonged i.v. treatment with UFH depletes TFPI stores and results in the partial loss of its anticoagulant action [710]. This is a consequence of the endothelium-bound TFPI being more haemostatically active than the circulating lipid-bound form of the inhibitor [3]. In healthy subjects, the increase in plasma TFPI in response to a single traditional dose of i.v. UFH is more pronounced than that due to s.c. LMWH [710], which may be explained by their different bioavailability and pharmacokinetics. On the other hand, single equi-gravimetric i.v. doses of UFH and LMWH can induce comparable peak levels of circulating TFPI [1]. The causal role of heparin in the release of TFPI during HD was evidenced for the first time by Kario et al. [13]. They found a striking increase in plasma TFPI during HD procedures that used either LMWH or UFH, but no change of the inhibitor with nonheparin anticoagulants such as nafamostat mesilate or argatroban. The increase of TFPI levels during UFH-anticoagulated HD has been confirmed by others [1417]. Kario et al. [13] have also reported that the over-dialysis increase in TFPI is more marked with UFH than with LMWH. In the present report, we show that pre-dialysis plasma TFPI levels are higher than normal, and confirm that they further increase during both enoxaparin and UFH-anticoagulated HD. Our prospective study indicates that the TFPI increments after 10 and 180 min of HD are equal when the heparins are used in doses ensuring clinically adequate anticoagulation during the procedures. However, this does not exclude different behaviours of the inhibitor in between these time points. Moreover, our results demonstrate for the first time that the thrice-weekly administration of both enoxaparin and UFH results in depletion of heparin-releasable TFPI in patients on maintenance HD. This conclusion is based on the strong inverse associations between the post-heparin TFPI increments and the baseline levels of the inhibitor. A biologically similar phenomenon was previously reported by Hansen et al. [7], who found progressively lower increases in plasma TFPI during both repeated and continuous i.v. infusions of UFH in healthy subjects. This effect was accompanied by a significant loss of the anticoagulant effect of UFH. Furthermore, once-daily s.c. injections of enoxaparin have also been shown to result in transiently increased TFPI levels, but not in a rebound activation of the coagulation system after discontinuation of the therapyas evidenced by stable plasma PF 1q2 or antithrombin levels [8,10]. These studies have shown that, compared with i.v. UFH, standard regimens using s.c. LMWHs do not exhaust the endothelial pool of heparin-releasable TFPIwhich could explain previous failures of UFH treatment [3]. So far, no studies have compared the effects of repeated i.v. infusions of LMWH vs those of UFH on TFPI-related haemostasis, the situations resembling intermittent HD therapy. In our prospective study over-dialysis plasma TFPI levels increased following the switch from enoxaparin to UFH. This effect of UFH may be due to TFPI being extensively mobilized from the endothelium over a longer period of time, the haemostatic consequence of which is enhanced blood coagulation between the procedures, as evidenced by the significant 13% increase in plasma PF 1q2 before the next UFH dialysis. Although neither the time point nor the magnitude of the maximal over-dialysis increase in TFPI were established by this study, we hypothesize that UFH administration evokes greater release of the inhibitor during HD than does enoxaparin. Moreover, regression analyses of our data suggest that the loss of the long-term anticoagulant effect of UFH directly depends on its high-dose administered at the initiation of HD. The UFH bolus was found to cause a dosedependent increase in circulating TFPI, but the association was, unexpectedly, inverse rather than direct. It points to the progressive depletion of heparin-releasable TFPI pool by repeated i.v. infusions of UFH during intermittent HD therapy. Moreover pre-dialysis levels of PF 1q2, a marker of intravascular thrombin, were associated directly with the loading dose of UFH, and inversely with the extent of TFPI release during HD. Regression analysis indicates that increasing the UFH bolus dose from 30 to 50 IUukg could result in doubled PF 1q2 levels. Based on these findings, we suggest that a high loading dose of UFH is a risk factor for thrombotic complications in intermittent HD patients due to severe exhaustion of endothelial pool of TFPI. This, however, requires confirmation. This study shows for the first time that enoxaparin ensures efficient anti-thrombotic protection not only during HD procedures but also in between dialysis sessionsas evidenced by stable PF 1q2 levels. The mean dose of enoxaparin used in our patients was 0.68 mgukg (range 0.301.08 mgukg), which was generally lower than the 1 mgukg recommended by the manufacturer. The dosage is almost identical to that established by Saltissi et al. [11] to be clinically adequate, safe and probably more cost-effective than UFH. In contrast, an LMWH, dalteparin, at a single dose of about 5000 IU, was found to provide clinically sufficient anticoagulation but not to prevent actual activation of haemostasis during HD [12]. In conclusion, depletion of heparin-releasable stores of anticoagulant TFPI is an untoward consequence of repeated blood anticoagulation in maintenance HD therapy. The effect becomes evidently prothrombotic when the traditional UFH regimen of bolus and infusion is used instead of a single injection of LMWH enoxaparin. High loading doses of UFH may be a risk factor for severe endothelial TFPI depletion, resulting in the activation of the coagulation system in chronic HD patients. Enoxaparin administered as a single bolus of 0.7 mgukg is haemostatically effective in this situation. Acknowledgements. This work was supported by grant No 6P05B 064 20 from the National Research Committee (Komitet Badan Naukowych), Poland; won one of the 2002 European Renal Association-European Dialysis and Transplant Association Congress Grants; and was presented in oral form during the XXXIX ERAEDTA Congress, Copenhagen, Denmark, July 1417, 2002. We are indebted to Dr Krystyna Pawlak for research assistance, and patients of our Dialysis Unit for their cooperation. The authors were not financially supported by the manufacturer of enoxaparin.


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Beata Naumnik, Jacek Borawski, Michał Myśliwiec. Different effects of enoxaparin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study, Nephrology Dialysis Transplantation, 2003, 1376-1382, DOI: 10.1093/ndt/gfg058