Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of dalteparin anticoagulation during haemodialysis

Rolf Dario Frank, Vincent M. Brandenburg, Regina Lanzmich and Jürgen Floege

Department of Nephrology and Clinical Immunology, University Hospital Aachen, Germany

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



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Low molecular weight heparins (LMWH) like dalteparin are increasingly used for anticoagulation during haemodialysis (HD). The available laboratory tests for monitoring LMWH anticoagulation are time-consuming and expensive, and the suitability of the conventional activated clotting time (ACT) is controversial. A simple and cheap bedside test would be useful.

Methods. We studied the factor Xa-activated whole blood clotting time (Xa-ACT) in vitro and in vivo in nine patients undergoing chronic HD with i.v. dalteparin bolus anticoagulation and compared it with the conventional ACT. Plasma anti-factor Xa (antiXa) activity was determined with a chromogenic assay. Thrombin–antithrombin complexes were measured to detect coagulation activation.

Results. Xa-ACT and ACT were prolonged with rising dalteparin concentration. In vitro, both clotting times were strongly correlated with the antiXa levels (r = 0.94 and 0.89, respectively). Nevertheless, compared with the ACT, the Xa-ACT was considerably more sensitive to the LMWH in vitro (healthy blood: Xa-ACT 90 s/U vs ACT 26 s/U; uraemic blood: Xa-ACT 96 s/U vs ACT 31 s/U) as well as in vivo (Xa-ACT 81 s/U vs ACT 22 s/U) and reflected different intensities of anticoagulation. An initial dalteparin bolus of 80±11 U/kg body weight was able to prevent coagulation activation for up to 4 h of HD.

Conclusion. For monitoring LMWH anticoagulation the Xa-ACT was superior to the conventional ACT in vitro as well as in vivo during HD. The Xa-ACT can be useful as a LMWH bedside test. The ACT was not sensitive enough to serve as a LMWH monitoring tool.

Keywords: activated clotting time; haemodialysis; low molecular weight heparin; monitoring



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
During haemodialysis (HD) or haemofiltration anticoagulation is required to prevent coagulation activation and clot formation in the extracorporeal circuit. The majority of the HD patients are still treated with unfractionated heparin (UFH). For point-of-care monitoring of UFH the activated whole blood clotting time (ACT) is commonly used as bedside test [13].

Recently, low molecular weight heparins (LMWH) like dalteparin have been increasingly used for anticoagulation during HD and were shown to be safe and convenient anticoagulants. In long-term use, LMWH offer several advantages compared with UFH including beneficial effects on serum lipids, factor VIII and bone density, less impact on platelet function [46], lower incidence of HIT type II [7] and fewer bleeding complications [8]. Furthermore, the prolonged half-life of LMWH allows simplified dosing with application as a single initial bolus [9,10]. For patients prone to bleeding complications, a continuous infusion is recommended to avoid high peak plasma levels. LMWH dosage recommendations are primarily based on the body weight, but since dosage requirements vary considerably between individuals and also may change due to co-morbidity, bleeding risk or dialysis modalities [11,12], the LMWH dosage has to be adapted individually and to the current clinical conditions in order to avoid over- or under-treatment.

In contrast to UFH, the antithrombotic effect of LMWHs is mediated mainly by inhibition of activated factor X, whereas the anti-factor IIa activity is less important. Since LMWHs only slightly prolong standard coagulation assays (aPTT, thrombin time), anticoagulation with LMWHs is almost exclusively monitored by a chromogenic substrate assay measuring the anti-factor Xa (antiXa) activity. This method requires a specialized coagulation laboratory and is therefore not generally available. Furthermore, the assay is expensive and time-consuming.

A simple and rapid bedside test, which reliably reflects the extent of LMWH anticoagulation, would be helpful for initial dose titration, dose adjustments and checking the delivered drug amount. The usefulness of the conventional ACT for LMWH monitoring is still under debate and available data are conflicting [1317].

In 1998, Mori et al. reported a modification of the ACT, called Xa-ACT, using bovine factor Xa as an activating agent instead of siliceous earth, which might serve as a bedside test for LMWH monitoring [18]. As the authors did not report antiXa levels and used a continuous infusion regimen achieving constant antiXa levels, the available data do not allow us to draw firm conclusions regarding the suitability of this test.

Therefore, we evaluated the Xa-ACT, adapted to the Trimed ACTester®, in vitro and in patients undergoing chronic HD with dalteparin bolus anticoagulation and compared it with the conventional ACT.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Nine stable patients (three males, six females, mean age±SD, 61±15 years, range 34–80 years, mean body dry weight±SD, 64.8±15.2 kg, range 43–98 kg) from the University Hospital dialysis unit were included. All patients had end-stage renal failure and were undergoing uneventful intermittent HD (five patients) or haemodiafiltration (HDF) (four patients) with dalteparin anticoagulation three times a week for >6 months. The coagulation studies were done during a midweek session after a short dialysis-free interval. As vascular access, arteriovenous native forearm fistulae (seven patients) or fistulae with PTFE interponates (two patients) were used.

Before participation, 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).

Exclusion criteria were acute infectious or autoimmune diseases, known malignancy, haemorrhagic or thrombotic coagulation disorders, need for long-term anticoagulation, surgery or blood transfusion during the last 2 weeks and abnormal findings in one or more parameters of the laboratory screening.

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

Dialysis procedure
HD was performed in two patients using the Genius® therapy system (Fresenius Medical Care, Bad Homburg, Germany) and in three patients with the MTS 4008 E (Fresenius). For HDF (four patients) the AK 100 Ultra from Gambro (Hechingen, Germany) was employed. The following dialyser resp. haemofilter types were used: F7 HPS (low-flux polysulfone, Fresenius Medical Care, four patients), Polyflux 14 S (high-flux polyamide membrane, Gambro, Hechingen, Germany, three patients), Tricea 190 G (cellulose triacetate, Baxter, Illinois, USA, one patient) and Arylane H9 (Polyarylethersulfone, Hospal, one patient). Dialyzate resp. substitution fluids were bicarbonate-buffered. The extracorporeal systems were primed with isotonic saline without anticoagulant. Blood flow was kept between 200 and 300 ml/min (mean±SD, 252±37 ml/min). The duration of the HD or HDF treatment sessions was 4–5 h (mean±SD, 4.4±0.4 h).

Anticoagulation
The patients were anticoagulated with the LMWH dalteparin (Fragmin®, Pharmacia, Erlangen, Germany) given as a single bolus injection into the arterial tubing line prior to HD or HDF. The individual dalteparin dosage requirement had been established empirically during several preceding dialysis sessions based on the antiXa levels after 4 h and clinical judgement of the extracorporeal circuit at the end of treatment (no clotting in air traps, clean dialyser/haemofilter). The dalteparin dosage varied considerably between the patients (range 40–96 U/kg).

Blood sampling
For the in vitro studies, venous blood was taken from healthy laboratory staff members (aged 22–41 years) or from the dialysis patients. After discarding the first 5 ml, blood was carefully collected from a cubital vein or from the forearm fistula in sterile single-use syringes (B. Braun, Melsungen, Germany) pre-filled with 1/10 Vol dalteparin solution (final calculated dalteparin concentration 0–1.0 antiXa U/ml blood).

For the in vivo studies, blood samples were taken immediately before the start of HD treatment and 1, 2, 3 and 4 h thereafter. The first sample (time point 0 h) was drawn from the arterial dialysis needle after clean puncture of the fistula and before application of the anticoagulant. To avoid artificial coagulation activation 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 without delay.

For the bedside measurement of the whole blood clotting times, native blood was used. To obtain citrated platelet-poor plasma for the other coagulation assays, blood samples were immediately transferred into micro tubes (Sarstedt, Nümbrecht, Germany) containing 1/10 Vol 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 and stored in small aliquots at –70°C until analysis.

Whole blood clotting times
The whole blood clotting times were carried out as bedside measurements by one experienced laboratory assistant using the ACTester® equipment (Trimed, Huntington Beach, CA, USA). The standard activated clotting time (ACT) was determined according to the manufacturers instructions. Immediately after blood sampling, 500 µl native whole blood was carefully injected in an ACTest blood collection tube (72 x 14, Quest Medical Inc., Allen, TX, USA) containing powdered siliceous earth as activating agent. The tube was inverted three times to allow complete mixing of blood and activator and placed in the ACTester. The clotting time was automatically measured. To determine the normal range, the standard ACT was measured in 16 healthy volunteers (age range 24–41 years).

The factor Xa-ACT was measured essentially as described by Mori et al. [18] for the Hemochron device, adapted to the Trimed ACTester. The siliceous earth was completely removed from the test tubes and replaced by 50 µl of a solution containing bovine factor Xa. For the preparation of this solution, the content of one vial of bovine factor Xa (10 IU/vial, F 2027, Sigma Aldrich, Deisenhofen, Germany) was dissolved in 1 ml of sterile isotonic saline. One part of this stock solution was diluted with nine parts isotonic saline giving a factor Xa activity of 1 U/ml. To avoid loss of factor activity, the prepared test tubes and the stock solution were stored for a maximum of 4 weeks in aliquots at –20°C until use. 450 µl of whole blood were injected in the test tube, inverted three times and placed in the ACTester. A final factor Xa activity of 0.1 U/ml as originally proposed by Mori et al. was used.

Other 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 purposes (Chromogenix).

To detect coagulation activation during HD, the thrombin–antithrombin (TAT) complexes were determined with the Enzygost TAT micro® sandwich ELISA (Dade Behring, Marburg, Germany).

Statistical analysis
The statistical calculations were performed using the software package SPSS 10.0 for Windows (SPSS Inc., Chicago, IL, USA). All data are expressed as mean±standard deviation (SD). Bivariate correlation was analysed by calculating the Pearson correlation coefficient. A linear regression analysis was performed. Violations of the standard assumptions of the linear regression analysis (autocorrelation and heteroscedasticity) could not be found. The Student's t – l test for paired or unpaired samples, 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
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In vitro studies
Using dalteparin-spiked whole blood from five healthy volunteers we compared the effect of increasing amounts of antiXa activity on Xa-ACT and conventional ACT. As shown in Figure 1, both coagulation times showed an increasing prolongation with rising antiXa content of the blood and displayed a strong correlation with the plasma antiXa levels (Pearson correlation coefficients r = 0.94 and 0.89, respectively). However, the Xa-ACT revealed a distinctly steeper slope of the correlation curve than the ACT (a = 89.84 vs 25.83 s/U) indicating a higher sensitivity for LMWH than the conventional ACT. According to our in vitro data the Xa-ACT is able to distinguish between antiXa levels relevant for dialysis patients (0.5–1.0 IU/ml). An antiXa plasma level of 0.6 IU/ml was associated with an Xa-ACT increase from 118±9 (baseline) to 166±9 s (141±5% of baseline). At 1.0 U/ml the Xa-ACT reached 221±16 s (189±22% of baseline), whereas the conventional ACT only increased from 91±8 to 118±11 s (130±12% of baseline). Even a very high antiXa level (2.0 IU/ml) only lead to a moderate prolongation of the conventional ACT (146±11 s, 161±16% of baseline), while in contrast, the Xa-ACT reached 302±27 s (257±28% of baseline).



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Fig. 1. In vitro correlation of Xa-ACT (diamond) and conventional ACT (square) with the plasma antiXa level in dalteparin-spiked blood from healthy volunteers (n = 5). The equations of the correlation curves are given in the diagram.

 
The Xa-ACT coefficient of variation (CV) was determined by repeated measurement of blood samples spiked with two different dalteparin amounts (0.1 and 0.25 antiXa U/ml whole blood, n = 5 each) corresponding to clinically relevant antiXa plasma levels during HD. The CV was found to be 3±0.7 and 2±1%, respectively, indicating an excellent reproducibility of the test.

We also performed an in vitro study with dalteparin-spiked blood from five dialysis patients. The correlation curves generated with uraemic blood (regression equations Xa-ACT y = 99.5x + 127.41; r = 0.948; ACT y = 30.86x + 103.61; r = 0.747) were similar to the curves obtained with healthy blood indicating that the chronic renal insufficiency itself did not affect the correlation between antiXa levels and the whole blood clotting times.

In vivo studies
The spontaneous Xa-ACT in our dialysis patients was 139±6 s (range 132–150 s, n = 9). The baseline Xa-ACT in the patient group was additionally measured on three consecutive HD sessions before application of the dalteparin bolus. The coefficient of variation was 7±3% indicating a good reproducibility from day to day.

Next, we studied the in vivo performance of Xa-ACT and ACT during HD with single bolus dalteparin anticoagulation. Figure 2 displays the overall correlation between Xa-ACT respective to conventional ACT and antiXa levels during dialysis. The Xa-ACT correlated well with the antiXa plasma levels in vivo (r = 0.697), however, to a lesser extent than in vitro (r = 0.94; see Figure 1). ACT and antiXa level were only weakly correlated (r = 0.522). The calculated change of clotting time per unit change of dalteparin level in vivo was 81 s/U for the Xa-ACT and 22 s/U for the ACT.



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Fig. 2. In vivo correlation of (A) conventional ACT and (B) Xa-ACT with the plasma antiXa level during 4 h of HD treatment. The Pearson correlation coefficient r was 0.522 for ACT and 0.697 for Xa-ACT.

 
Table 1 displays the time courses of Xa-ACT, conventional ACT, corresponding antiXa levels and TAT levels (mean±SD) in vivo up to 4 h after the dalteparin bolus.


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Table 1. Time courses of Xa-ACT, ACT, antiXa and TAT levels during HD

 
In six patients, receiving a single dalteparin bolus of 80±11 U/kg (range 64–96), the antiXa level after 1 h was 0.94±0.18 IU/ml. The Xa-ACT increased to 170±19% of baseline after 1 h and 160±14% after 2 h. The corresponding conventional ACT values were only 120±10% after 1 h and 115±5% after 2 h. Even 4 h after the bolus injection the Xa-ACT was still significantly elevated (131±17% of baseline). In contrast, the conventional ACT had returned to the baseline level at 3 h (104±8%), although the antiXa level was still in the therapeutic range. In these patients the dalteparin bolus prevented significant TAT complex generation throughout the dialysis session.

In the remaining three patients, who received a distinctly lower dalteparin bolus (40–44 U/kg), we observed a different Xa-ACT respective to ACT time course. The maximum antiXa level 1 h after the bolus was only 0.64±0.11 IU/ml. Correspondingly, the Xa-ACT remained below 200 s after 1 h (125±4% of baseline), but was statistically significantly different from baseline (P = 0.037). The Xa-ACT was back to the baseline levels after 3 h (102±2%) and even fell below the individual baseline values after 4 h (93±7%). In contrast, the conventional ACT did not significantly increase and was only 108±10% of the baseline after 1 h. Similar to the Xa-ACT, the ACT then reached values lower than the baseline. Subsequently, we detected a strong increase of the TAT levels indicating insufficient anticoagulation.

Nevertheless, all HD sessions could be completed without clotting of air traps, tubings or dialysers. Bleeding complications were not observed.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present study we evaluated the suitability of the Xa-ACT as a novel tool for the bedside monitoring of LMWH during HD and compared it with the conventional ACT. Our data show that the Xa-ACT is useful for dalteparin monitoring and superior to the conventional ACT.

The Xa-ACT fulfils the criteria of a bedside test, as it is a simple and cheap assay giving a reliable result within minutes. If necessary, the test can be repeated as often as needed during a dialysis session, which is not possible with a chromogenic assay.

This modified ACT was described for the first time in 1998 [18], but the published data did not allow drawing final conclusions about the suitability of the method. We therefore decided to study the Xa-ACT during HD with single bolus dalteparin anticoagulation, which has become the standard regimen for LMWH anticoagulated dialysis treatment. Our data substantially extend previous findings.

We could demonstrate that the Xa-ACT correlated well—in vitro as well as in vivo—with the plasma antiXa activity. The observed correlation coefficient of r = 0.697 in vivo is comparable with values published for the conventional ACT (r 0.6–0.75) used for the monitoring of UFH in the lower dose range [1921]. Additionally, the correlation curves obtained for the Xa-ACT showed reasonable slopes, which is another important criterion that has to be taken into account for the judgement of a laboratory method.

The Xa-ACT closely followed the considerably changing antiXa levels. In three patients remarkably high TAT complex levels were detected at the end of the dialysis session indicating insufficient anticoagulation. These patients were distinct from the other six patients in terms of the dalteparin dose received and the peak antiXa levels. This was reflected by the Xa-ACT showing that the Xa-ACT is able to detect insufficiently anticoagulated patients. The in vitro data suggest, that the Xa-ACT also has the ability to detect patients with over-anticoagulation. An antiXa level of 2.0 IU/ml was associated with a Xa-ACT of >300 s indicating that exceeding clinically relevant antiXa levels is reflected by the Xa-ACT excluding a so-called ‘ceiling effect’.

If the purpose of bedside monitoring of anticoagulation in the clinical practice is defined as the ability to rapidly and reliably stratify the patients as adequately anticoagulated, inadequately too much or too little anticoagulated, thereby preventing bleeding or thrombotic complications, the above described findings suggest that the Xa-ACT is sufficiently accurate and sensitive for the clinical use as LMWH bedside test in dialysis patients. According to the presented data, we would recommend a target Xa-ACT >200 s 1 and 2 h after the LMWH bolus and of >160 s after 4 h in order to suppress coagulation activation. To avoid over-anticoagulation the maximum Xa-ACT should be kept clearly below 300 s. A larger number of patients should be studied to confirm this regimen using Xa-ACT as the primary parameter for dosage adjustments.

There is an ongoing controversy about the role of the conventional ACT in LMWH monitoring. Based on in vitro studies suggesting a good correlation between ACT and antiXa concentration, the ACT has been applied to LMWH monitoring [13]. Schulz et al. [14] reported positive experiences with the ACT in dalteparin treated dialysis patients and recommended it for monitoring. In a very recent publication, Marmur et al. [17] presented in vitro and clinical in vivo data also supporting the use of the ACT for monitoring dalteparin anticoagulation. In patients undergoing percutaneous coronary interventions they observed a significant increase of the ACT 5 minutes after i.v. administration of 80 U dalteparin/kg body weight from baseline 123±11 to 192±24 s. However, the transferability of their findings to the HD setting is limited: first they achieved this ACT prolongation with an antiXa level (1.9±0.8 IU/ml), which is almost 2-fold higher than the levels typical during HD. Secondly, the authors did not investigate time points later than 60 min and included patients treated with the glycoprotein IIb/IIIa antagonist abciximab, which has been shown to substantially prolong the ACT [22].

Our data suggest, that the ACT is not a sensitive parameter for LMWH monitoring during HD, although our in vitro data showed a strong correlation between antiXa levels and ACT (r = 0.89). However, the low gradient of the correlation curve indicates a poor sensitivity of the ACT compared with the Xa-ACT. Furthermore, although we observed significant ACT changes during the dialysis treatment, the extent of the ACT increase at clinically relevant antiXa levels was comparably small (maximum 20±10% of baseline, corresponding to antiXa 0.94±0.16 IU/ml), which—in our opinion—precludes a reliable monitoring. Our findings are in accordance with a recently published study [15], investigating the conventional ACT during continuous dalteparin infusion. Despite constantly elevated antiXa levels (0.5–0.6 IU/ml) the authors observed a significant increase of the ACT only 10 min after the initial bolus.

In contrast to the chromogenic antiXa activity assay, the Xa-ACT is a functional test, which can be affected by coagulation activation in vivo leading to thrombin generation and platelet activation. At a given antiXa level this pre-activation of the blood sample leads to a relatively too short Xa-ACT, thus underestimating the antiXa activity in the blood sample. For the use as a clinical monitoring parameter this should be considered to be an advantage over the chromogenic test, since this feature can be used to detect insufficiently anticoagulated patients by serial measurements as evidenced by our data.

This study focused on the LMWH dalteparin, but other LMWH (e.g. enoxaparin and tinzaparin) are also used for HD. Considering that the LMWH significantly differ regarding molecular weight distribution and pharmacodynamic data [23], the performance of the Xa-ACT could be affected.

Our observations confirm that the dalteparin bolus regimen is safe and effective to prevent coagulation during routine dialysis. A dalteparin bolus of 80±11 U/kg (range 64–96) prevented a significant TAT generation. This is in accordance with the dalteparin dosages used in previously published studies [912].

One possible drawback of the Xa-ACT is the need to prepare tubes containing a diluted factor Xa solution and the fact that the factor Xa solution should be stored at temperatures around –20°C to prevent loss of activity. The necessary equipment may not be readily available in every dialysis unit, but this should not a priori invalidate an otherwise useful laboratory method.

In conclusion, our data show that the Xa-ACT is superior to the conventional ACT for the bedside monitoring of LMWH anticoagulation during HD treatment, suggesting that the Xa-ACT can serve as a LMWH monitoring parameter for the clinical practice. This should be proven in a larger clinical study with Xa-ACT as the primary monitoring tool. The conventional ACT was much less sensitive to LMWH than the Xa-ACT and did not prove suitable for LMWH monitoring.



   Acknowledgments
 
This study was supported by a grant from Pharmacia & Upjohn, Erlangen, Germany. We are indebted to the staff of the university hospital dialysis unit and the coagulation laboratory of the Department of Nephrology.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 6. 8.03
Accepted in revised form: 9. 2.04