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NDT Advance Access originally published online on December 2, 2005
Nephrology Dialysis Transplantation 2006 21(4):1013-1018; doi:10.1093/ndt/gfi293
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Anticoagulant-free Genius® haemodialysis using low molecular weight heparin-coated circuits

Rolf Dario Frank1, Ute Müller2, Regina Lanzmich1, Christian Groeger3 and Jürgen Floege1

1 Department of Nephrology and Clinical Immunology, University Hospital Aachen, 2 BMP Laboratory for Medical Material Testing, Aachen and 3 Artificial Organ Technologies, Bad Oeynhausen, Germany

Correspondence and offprint requests to: Rolf Dario Frank, MD, Department of Nephrology, University Hospital Aachen, 52057 Aachen, Germany. Email: dario.frank{at}ukaachen.de



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Regional citrate anticoagulation or saline flushes are often used in haemodialysis patients at high risk of bleeding. In an alternative approach we evaluated the effects of covalent circuit coating with low molecular weight heparin (LMWH) for intermittent haemodialysis.

Methods. In vitro, we compared the thrombogenicity of an uncoated polyvinylchloride (PVC) tubing set with LMWH-coated tubing (AOThel®) and a reference tubing with end-point attached heparin coating (Carmeda® Bioactive surface) under dynamic blood contact. In vivo, five chronic haemodialysis patients were studied using the Genius® dialysis system and F60S® filters. Each patient underwent three dialysis sessions separated by a standard haemodialysis each: (1) standard dialysis (uncoated circuit and regular dalteparin dosage), (2) dialysis with LMWH-coated circuit and regular dalteparin dosage and (3) dialysis with a completely LMWH-coated circuit without anticoagulant use.

Results. In vitro, both coated tubings showed significantly reduced thrombin–antithrombin (TAT) complex levels compared with PVC. The reference coating (Carmeda®) released substantial antifactor Xa (antiXa) activity into the plasma. The LMWH coating (AOThel®) released low antiXa activity only during the initial rinsing. In vivo, all dialysis sessions were well tolerated and completed without major clotting. Antithrombin levels and platelet counts were similar in all groups. P-selectin and D-dimer levels increased similarly in all groups. TAT levels were comparable in all groups during the first 3 h and significantly increased in the anticoagulant-free group after the fourth hour.

Conclusions. LMWH surface coating reduces thrombogenicity in vitro without releasing significant amounts of heparin from the surface. In vivo, anticoagulant-free haemodialysis using a completely LMWH-coated circuit is feasible and safe in stable chronic dialysis patients with normal coagulation.

Keywords: haemodialysis; low molecular weight heparin; surface coating



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
In haemodialysis patients with active bleeding or at high risk of bleeding the use of systemic anticoagulation can cause serious problems [1,2]. To avoid a systemic anticoagulant effect, regional citrate anticoagulation is often used in such patients [3]. However, a major drawback of this approach is the risk of metabolic complications, such as hypocalcaemia, alkalosis and hypernatraemia requiring frequent monitoring. Patients with liver insufficiency are especially at risk for metabolic complications [4]. Another alternative to systemic heparinization is the saline flush method, often referred to as heparin- or anticoagulant-free dialysis, whereby a continuous infusion of saline (300 ml/min) or saline boluses (50–250 ml every 15–30 min) are run through the extracorporeal system [5–7]. Disadvantages of these methods include its unreliability, the increased work load of the dialysis staff and the increased volume load which has to be removed by ultrafiltration. A third method, namely regional heparinization using protamin as a heparin antidote in the venous line, is no longer recommended due to a lack of a clear-cut clinical advantage and, in particular, the risk of rebound effects with bleeding complications caused by different half lives of heparin and protamin [2,8].

A different approach to achieve an anticoagulant-free haemodialysis is to increase the biocompatibility of the extracorporeal circuit by specific surface modifications, thereby reducing the thrombogenicity. The covalent coupling of heparin to biomaterial surfaces was developed over 20 years ago [9]. Several in vitro and in vivo studies have documented the beneficial effects of such a surface coating during cardiopulmonary bypass, including a reduced need for heparin and a significant amelioration of the bypass-induced systemic inflammatory response [10–18].

In this study we tested for the first time in routine haemodialysis treatments a novel biocompatible surface modification, consisting of a complete covalent coating of the extracorporeal circuit, i.e. needles, tubings and high-flux dialyser, with a low molecular weight heparin (LMWH) (AOThel® coating).



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
In vitro experiments
In vitro experiments with dynamic blood contact were performed using a modified Chandler loop model [19]. We compared uncoated polyvinylchloride (PVC) tubing (inner diameter: 0.25 inch; Raumedic ECC bloodline, Rehau, Rehau, Germany) with the LMWH-coated tubing (AOT, Bad Oeynhausen, Germany) and a reference tubing coated with end-point attached unfractionated heparin [Carmeda® Bioactive surface; Medtronic, Kerkrade, the Netherlands]. The tubes were cut into pieces of 60 cm length (filling volume: 17 ml). A silicone connector was used to form a closed loop. The loops were placed in the Chandler unit and rotated at a constant rate (20 r.p.m.) at 37°C. Prior to the experiments the tubes were rinsed three times with 15 ml isotonic saline and then three times with 5 ml aliquots of citrate-anticoagulated pooled plasma from five healthy blood donors (15 min each). In some experiments the plasma used for rinsing was collected for detection of antifactor Xa (antiXa) activity in order to evaluate the leaching of the surface coatings. After draining the plasma, the tubing loops were filled with 15 ml freshly drawn, heparinized human whole blood and rotated vertically for 30 min. Thereafter, the blood content of the loops was aliquotized in microtubes containing citrate or EDTA as anticoagulant, processed and stored until analysis as described below.

Patients
Five stable chronic haemodialysis patients from the university hospital dialysis unit were recruited for the study. All patients had undergone intermittent haemodialysis with dalteparin anticoagulation three times a week for >1 year. Patient characteristics are shown in Table 1. Exclusion criteria included haemoglobin level <100 g/l, central venous catheters, acute infectious or autoimmune diseases, known malignancy, haemorrhagic or thrombotic coagulation disorders, myocardial infarction during the preceding 3 months, need for long-term anticoagulation, surgery or blood transfusion during the last 2 weeks, known heparin-induced thrombocytopenia and abnormal findings in the laboratory screening. Prior to inclusion in the study, all patients were evaluated by physical examination and laboratory tests (full blood count, liver enzymes, total protein, serum protein electrophoresis, C-reactive protein, prothrombin time, activated partial thromboplastin time, antithrombin activity and fibrinogen).


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  		Table 1. Patient characteristics

 
The study was approved by the ethics committee of the University Hospital Aachen and written informed consent was obtained from all patients.

Haemodialysis modalities
Haemodialysis was performed using the Genius® therapy system (Fresenius Medical Care, Bad Homburg, Germany) [20]. The Genius® system is based on the single-pass batch principle and consists of a 75 l glass tank completely filled with dialysate. During the treatment fresh dialysate is taken from the top of the tank and is returned to the bottom after passing the dialyser. Fresh and used dialysate are separated by a sharp interface and do not mix. The extracorporeal circuit does not contain drip chambers and is, thus, devoid of contacts between blood and air. The dialyser used in this study was F60S® (Fresenius Medical Care) containing a 1.4 m2 high-flux polysulphone membrane.

Dialysate fluids were bicarbonate-buffered. The extracorporeal systems were rinsed and primed with 1000 ml isotonic saline without any anticoagulant. Blood flow was kept at 250 ml/min. The duration of the haemodialysis sessions was 4.5 h in all patients. Individual ultrafiltration volume was determined according to the individual weight gain between the haemodialysis sessions. After completion of the haemodialysis session and reinfusion of the blood, the extracorporeal circuit was disconnected from the patient and rinsed with 500 ml saline. Tubings, venous flow chambers and dialysers were inspected for signs of coagulation.

Anticoagulation
Systemic anticoagulation was performed with the LMWH dalteparin (Fragmin®; Pharmacia, Erlangen, Germany) given as an initial bolus injection followed by a continuous infusion into the arterial tubing line. The individual dalteparin dosage requirement had been established empirically during several preceding dialysis sessions. The recommended dosage of a 30 U/kg bolus and a 10 U/kg/h infusion was adapted in order to achieve an antiXa level of 0.4 antiXa units/ml after 4 h of dialysis treatment. The dalteparin dosages finally used were a 22±1 U/kg bolus and a 7±0.4 U/kg/h continuous infusion (means±SEM).

During the study, each patient underwent three different dialysis sessions separated by a standard (‘wash-out’) dialysis. For the standard dialysis, the patient was treated with a conventional, uncoated circuit and the regular dalteparin dosage (‘standard’). For the second dialysis, a modified, LMWH-coated circuit was used, again with regular dalteparin dosage (‘coated/dalteparin’). Finally, a LMWH-coated circuit was taken without any anticoagulant use during priming or treatment (‘coated/no dalteparin’).

Coated dialysis circuits
The extracorporeal systems, including needles and dialyser modules, were completely covalently coated with a LMWH (AOThel® coating) and supplied in sterile packs from AOT (Artificial Organ Technologies, Bad Oeynhausen, Germany).

Blood sampling
For the in vitro studies, venous blood was taken from healthy laboratory staff members (aged 22–41 years). After discarding the first 5 ml, blood was carefully collected from a cubital vein in sterile single-use syringes (20 ml; B. Braun, Melsungen, Germany) prefilled with 1/10 volume unfractionated heparin solution (final calculated heparin concentration: 1.0 IU/ml blood) and carefully transferred into the tubing loops.

For the in vivo study, blood samples were obtained immediately before the start of haemodialysis treatment (baseline) and 1, 2, 3 and 4 h thereafter. The baseline sample was drawn from the arterial dialysis needle after clean puncture of the fistula before the start of circulation and injection of the anticoagulant. To avoid activation of coagulation due to the puncture trauma, the first 5 ml of blood were discarded. During extracorporeal circulation, blood was collected from the arterial line of the circuit through 20 G steel needles (Terumo, Leuven, Belgium) into sterile syringes and processed (see below) without delay.

To obtain citrated platelet-poor plasma for the coagulation assays, blood samples were immediately transferred into tubes (microtubes or Monovette® tubes; Sarstedt, Nümbrecht, Germany) containing 1/10 volume 0.106 M trisodium citrate and kept in ice water (4°C) until further processing. After centrifugation (2000 g, 10 min, room temperature) the plasma supernatant was carefully pipetted off and stored in small aliquots (Eppendorf tubes) at –70°C until analysis.

Blood samples for blood counts were collected in EDTA-containing tubes and analysed in an automatic cell counter (ABX Counter Micros 60 OT; ABX Diagnostics, Montpellier, France).

Coagulation assays
The antiXa levels were measured in citrated platelet-poor plasma using a chromogenic substrate assay (Coatest® LMW Heparin/Heparin; Chromogenix, Mölndal, Sweden). Commercially available control plasmas with known antiXa activity (0.3 and 0.7 antiXa U/ml) were used for quality control (Chromogenix). Antithrombin activity was determined using the chromogenic assay Coatest® Antithrombin (Chromogenix).

To detect coagulation activation during haemodialysis, the thrombin–antithrombin (TAT) complexes were quantified using the Enzygnost TAT micro® sandwich enzyme-linked immunosorbent assay (ELISA) (Dade Behring, Marburg, Germany). For the measurement of D-dimers, the cleaving product of cross-linked fibrin, we employed the Asserachrom® D-Dimer ELISA (Roche Diagnostics, Mannheim, Germany).

The circulating (‘soluble’) P-selectin (sP-selectin immunoassay; R&D Systems, Wiesbaden, Germany) was used as a plasma marker for platelet activation during haemodialysis.

Statistical analysis
The statistical calculations were performed using the software package SPSS 12.0 for Windows® (SPSS Inc., Chicago, IL, USA). All data are expressed as means±SEM. The Student's t-test for paired or unpaired samples, analysis of variance (ANOVA) for repeated measurements and univariate ANOVA were employed, where appropriate. For multiple comparisons the alpha correction according to Bonferroni was used. Statistical significance was assumed if the two-tailed P-value was <0.05.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
In vitro studies
In a dynamic in vitro Chandler model the prothrombotic properties of a standard medical grade PVC tubing were compared with the LMWH-coated tubing (AOThel®) and the Carmeda® tubing, used as a reference product. As shown in Figure 1A, both coated tubings showed ~75% reduction of TAT complex generation, indicating markedly lower thrombogenicity as compared with the standard tubing (P = 0.001).


Figure 1
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  		Fig. 1. In vitro Chandler model experiments. (A) Comparison of TAT complex generation in human heparinized whole blood after contact with an uncoated control tubing and two different heparin-coated tubings. TAT values are expressed as ratio compared to the control. *Statistically significant differences compared with uncoated tubing. Means±SEM of four experiments. (B) AntiXa activity after sequential incubation with citrated plasma; control tubing (hatched), heparin-coated (Carmeda® Bioactive surface (CBAS); black) and LMWH-coated (AOThel®; white) tubing. Means±SD of three experiments.

 
The stability of the coating was studied by measuring antiXa activity in citrated plasma after incubation with the coated tubings. Figure 1B shows that a considerable amount of antiXa activity could be detected in the plasma after contact with the unfractionated heparin coating (Carmeda®). In contrast, the LMWH coating (AOThel®) appeared to release less heparin with a low antiXa activity only in the first rinsing plasma.

Haemodialysis study
Coagulation parameters of the patients prior to inclusion into the study were normal (INR <1.0, APTT 33±1 s, fibrinogen 3.8±0.3 g/l, platelets 261±47 G/l). All dialysis sessions were well tolerated and completed after 4.5 h without complications. There was no early termination of dialysis due to filter or circuit clotting. The ultrafiltration volumes of the three study dialysis treatments were similar (standard 2440±500 ml, coated/dalteparin 2780±470 ml and coated/no dalteparin 2460±980 ml; P = NS). The haematocrit values increased slightly from 0.33±0.004 at baseline to 0.36±0.006 (mean: +9%) after 4 h and were similar in the three groups.

With the bolus/injection dosage regimen of dalteparin during haemodialysis the antiXa levels achieved were around the target level of 0.4 IU/ml and remained constant during the dialysis session. They did not differ between standard dialysis and coated/dalteparin dialysis. During the coated/no dalteparin dialysis treatments the antiXa activity levels were below the detection limit of the assay (<0.01 U/ml) (Figure 2A).


Figure 2
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  		Fig. 2. Time courses in vivo of (A) antiXa activity, (B) soluble P-selectin, (C) D-dimers and (D) TAT complexes during standard dialysis (hatched bars), dialysis with coated circuits and systemic dalteparin (black bars) and dialysis with coated circuits without dalteparin (white bars). *,#Statistically significant differences (P<0.05). Means±SEM of five patients each.

 
The baseline antithrombin levels were normal in all patients without significant differences between the groups (standard 102±5%, coated/dalteparin 96±3% and coated/no dalteparin 112±10%; P = NS). During the dialysis sessions, antithrombin levels did not change significantly and were similar in the three groups (after 4 h: standard 105±3%, coated/dalteparin 106±7% and coated/no dalteparin 116±8%; P = NS).

Platelet counts increased by an average of 9% during dialysis, probably due to haemoconcentration (baseline: standard 256±55, coated/dalteparin 255±40 and coated/no dalteparin 263±43 G/l; after 4 h: standard 278±51, coated/dalteparin 275±41 and coated/no dalteparin 288±47 G/l; P<0.05 vs baseline in all groups, differences between groups NS).

The time course of circulating P-selectin as a plasma marker for platelet activation is depicted in Figure 2B. We observed a moderate increase over the treatment time, which was statistically significant compared to baseline (mean change after 4 h: +33%). However, there was no difference between the three groups at any time-point.

Figure 2C depicts the time course of D-dimers during haemodialysis. All three treatments induced a strong increase of the D-dimer levels without significant differences between the groups.

The time course of TAT complexes is shown in Figure 2D. In the standard and the coated/dalteparin group, TAT levels did not significantly change during the treatment time. In the anticoagulant-free group (coated/no dalteparin) we observed significantly elevated TAT levels compared with the baseline value and with the coated/dalteparin group after 4 h of circulation. After 3 h, the standard and the anticoagulant-free group still had comparable TAT levels. The lowest TAT levels were observed in the group with coated circuits and regular dalteparin dosage.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In the present study we applied for the first time a complete covalent surface coating of the extracorporeal circuit to routine haemodialysis and showed that using this technique it is feasible and safe to perform anticoagulant-free haemodialysis treatments. We studied stable end-stage renal disease patients with normal blood coagulation and platelet counts and were able to complete all dialysis sessions after 4.5 h without major clotting or other complications.

The attractiveness of an approach using a surface modification with improved thrombogenicity is the simplicity of application. The systems are ready to use and, ideally, do not necessitate any other intervention during the treatment session. If the surface coating is stable, systemic adverse events are not to be expected. In patients with suspected or proven heparin-induced thrombocytopenia, type II heparin-coated dialysis systems must not be used.

Covalent coupling of heparins attempts to mimic features of the thromboresistant properties of the vascular endothelium, which is covered by proteoglycans [21]. To preserve the anticoagulatory activity of the immobilized heparin it is essential that the high-affinity antithrombin-binding sites of the heparin molecule are unaffected by the chemical grafting process [22]. Such surface coating is then able to bind antithrombin from the blood stream and inhibit primarily activated factor X and thrombin [22,23]. In vitro studies show that the TAT complexes formed are mainly retained at the surface, without blocking the active sites, and are only partially released into the circulation [23]. Other effects that are associated with the increased biocompatibility of heparin-coated surfaces are a reduced adsorption of fibrinogen, reduced platelet adhesion and activation, diminished complement activation and leukocyte-platelet aggregate formation [24,25]. Our in vitro experiments confirm the improved haemocompatibility of the heparin-coated surfaces. Coagulation activation was reduced, as estimated by a 75% reduction of the TAT levels. Additionally, the stability of the coating could be demonstrated by incubation with citrated human plasma, which has been used for the detection of loosely attached heparin [9]. Only the first rinsing plasma of the AOThel® coated tubing contained small amounts of antiXa activity.

Our in vivo study focused on the extent of the coagulation activation during standard dialysis and anticoagulant-free dialysis. Starting from low baseline levels, the D-dimers were highly elevated as early as 2 h after start of dialysis and further increased over time. D-dimers are clinically used as a marker for hypercoagulation and thrombotic processes [26–28]. D-dimers are fibrin fragments, which are released when plasmin cleaves cross-linked fibrin. During the coagulation process, thrombin acts on soluble fibrinogen, generating fibrin monomers. These fibrin monomers polymerize and form a clot. In parallel with fibrinogen cleavage, thrombin also activates plasma factor XIII that cross-links the polymerized fibrin monomers. Some D-dimer assays use highly specific antibodies recognizing only cross-linked fibrin degradation products, whereas other assays also react with epitopes on non-cross-linked soluble fibrin or fibrinogen split products [29]. Besides rare clinical conditions, like fibrinolytic therapy or spontaneous hyperfibrinolysis, elevated D-dimer levels, as observed in our in vivo study, are evidence for hypercoagulation and thrombin generation.

Since the D-dimer levels increased similarly in all treatment groups, this suggests that the overall coagulation activation, fibrin deposition and fibrinolysis activation were similar during our standard dialysis and the anticoagulant-free dialysis with coated circuits. On the one hand, this implies that the antiXa levels achieved during systemic dalteparin application were not able to prevent fibrin generation. On the other hand, we can conclude from the successful dialysis sessions and the coagulation parameters that the LMWH coating was equivalent to the systemic anticoagulation with a constant antiXa level of ≥0.4 IU/ml.

Despite the progressively increasing D-dimers, TAT levels remained relatively low. During the haemodialysis sessions with systemic dalteparin anticoagulation, TAT levels only increased slightly, suggesting a sufficient suppression of coagulation activation, which is in contrast to the high D-dimers. The explanation underlying our observations is probably the fact that we measured both parameters in the arterial line of the circuit and the levels therefore reflect the systemic status, i.e. the result of generation and elimination. Elimination half-lives of TAT vs D-dimers in turn are thought to be strikingly different: minutes in the case of TAT vs hours in the case of D-dimers. Consequently, D-dimers appear to be a more sensitive parameter for the detection of blood coagulation processes induced by extracorporeal treatments than TAT.

In the anticoagulant-free group we observed a late TAT increase that became statistically significant after the fourth hour of dialysis. This could indicate TAT release from the coated surface after saturation. The late TAT increase could also mean that the surface was no longer able to suppress thrombin generation. Increasing amounts of thrombin would react with the surface-bound or the circulating antithrombin-generating TAT complexes.

To detect platelet activation we also measured soluble P-selectin in citrated plasma. P-selectin is constitutively present in the alpha granules of platelets. Upon stimulation of platelets and release of the alpha granule contents, P-selectin appears on the platelet surface and is then, at least in part, shed into the circulation [30]. The levels only moderately increased during the treatment sessions without differences between the groups, which indicates that the anticoagulant-free dialysis was not associated with a more pronounced platelet activation than the other treatments.

In conclusion, our study shows that the coated haemodialysis circuits can be safely used without any anticoagulation. It allowed the completion of regular haemodialysis sessions of 4.5 h in otherwise stable chronic dialysis patients without clotting of the circuit. Our data thereby serve as proof of concept and as the basis for follow-up studies in a larger number of patients at high risk of bleeding.



   Acknowledgments
 
We are indebted to the committed staff of the university hospital dialysis unit and the coagulation laboratory of the Department of Nephrology. We also thank Dr Christian Groeger, who developed the LMWH coating and made this study possible as the manager of AOT. He contributed to the conception of the study, but was not involved in data collection, analysis, statistics and writing of the manuscript. His current address is Asternweg 3, 33659 Bielefeld, Germany. The study was supported by a grant from Omnis Hospitalbedarf, Hamburg, Germany. The coated dialysis systems were provided free of charge by AOT, Bad Oeynhausen, Germany.

Conflict of interest statement. Other than C.G., the authors declare no conflict of interest.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 1. 9.05
Accepted in revised form: 7.11.05


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J. Chanard, S. Lavaud, and P. Rieu
Anticoagulation in haemodialysis.
Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3600 - 3601.
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