1 Department of Internal Medicine and 2 Research Institute for Internal Medicine, National Hospital, Oslo, Norway
Correspondence and offprint requests to: Dr Solbjørg Sagedal, Med.avd B., Rikshospitalet, 0027 Oslo, Norway.
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Abstract |
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Methods. We performed an open, prospective study on the effect of decreasing doses of dalteparin in 12 haemodialysis patients during a total of 84 sessions (44.5 h). The normally applied dose of dalteparin in each patient was reduced by 25% for each session down to 50% of initial dose if no clotting was observed. Clinical clotting (grade 14) was evaluated by visual inspection after blood draining of the air trap every hour and by inspection of the dialyser after each session and compared to corresponding values for anti-FXa activity and dialysis time. Blood flow and ultrafiltration rate were kept within narrow limits throughout the study.
Results. No episodes of grade 4 clotting occurred, and no session was interrupted. Eighteen episodes of grade 3 clinical clotting (11%) were observed in patients without warfarin treatment, none with an anti-FXa activity >0.43 IU/ml. Oral warfarin treatment reduced the clinical clotting, and only one grade 3 episode was observed in patients on warfarin therapy. Anti-FXa activity and haemodialysis time were the only factors independently correlated to clotting in a logistic regression model.
Conclusion. An anti-FXa activity above 0.4 IU/ml after 4 h of dialysis inhibits significant clotting during haemodialysis. A bolus dose of dalteparin of 70 IU/kg usually seems appropriate, but may be reduced in patients on warfarin treatment. Dialysis time is an independent risk factor for clinical clotting.
Keywords: anti-FXa; anticoagulation; clotting; dalteparin; haemodialysis; single dose
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Introduction |
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We designed this study to assess the relationship between anticoagulant effect of dalteparin and clinical clotting and further to assess the dosage of dalteparin necessary to obtain adequate anticoagulation during HD. Other potential factors that might affect clinical clotting were also evaluated, such as the use of oral anticoagulants and dialysis time. These factors were subjected to multivariate analysis. Extracorporeal blood flow and ultrafiltration rate were kept within narrow limits throughout the study, and Hb and Hct remained unchanged.
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Subjects and methods |
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Six of the patients were treated with oral warfarin, two because of implanted heart valves (international normalized ratio, INR=3.3), one because of atrial fibrillation (INR=2.3), two because of a previously malfunctioning jugular cathether (INR=1.6), and one because of previous pulmonary embolism and a positive lupus anticoagulant (INR=2.3). The haemoglobin value was stable, and the dose of erythropoietin and iron supplement were kept unchanged the last 2 weeks prior to the study. Patients receiving acetylsalicylic acid treatment were excluded from the study. Other exclusion criteria were clinical signs of infection and disseminated malignant disease. None of the patients had bleeding disorders. The protocol was approved by the Regional Ethics Committee and informed consent was obtained from all the patients according to the Helsinki declaration.
Dialysis procedure
Dalteparin was given as a single bolus dose into the arterial line at start of dialysis. The mean applied dalteparin dose at the start of the study was 60.9±19.3 IU/kg in the patient group receiving warfarin and 69.5±11.5 IU/kg in those without oral anticoagulation. The dialysis sessions were 4 h three times per week in seven patients and 4.5 or 5 h three times per week in five patients. The dialyser used was F6 HPS, Fresenius, Germany, (polysulphone hollow-fibre filter) for at least 1 week before and during the study. Bicarbonate dialysate was used in all patients. During 12 weeks prior to the study (run-in period) the dialyser and the bubble trap were checked at the end of each dialysis session to ensure that there was no clot formation and the dalteparin dose was kept unchanged. The blood flow rate varied between 230 and 300 ml/min, but was kept close to constant within each patient. Blood flow was recorded by the regular dialysis machine flowmeter in the dialysis machine. The dialysate flow was kept constant at 500 ml/min.
Study design
To examine the relationship between anticoagulant effect of dalteparin and intradialytic clinical clotting the dalteparin dose was gradually tapered in subsequent dialysis sessions. A total of 84 HD sessions were studied in 12 patients over a period of 3 weeks in eight patients and 1 week in four patients. The regularly applied dose of dalteparin was given in the first session and then reduced by 25% for each session down to 50% if no clotting was observed. Clinical clotting was evaluated by visual inspection after blood draining of the air trap every hour (1, no clotting in the trap; 2, fibrinous ring; 3, clot formation and 4, coagulated system) and by visual inspection of the dialyser at the end of each session (1, clean filter; 2, a few blood stripes (affecting less than 5% of the fibres seen at the surface of the dialyser); 3, many blood stripes (affecting more than 5% of the fibres) and 4, coagulated filter). If clinical signs of clotting grade 3 or 4 were observed, the dalteparin dose was increased by one step (25% of the initial dose). Clinical clotting was compared to simultaneously measured anti-FXa activity, Hb, Hct, platelet count, blood flow, and ultrafiltration rate.
Blood sampling
Blood specimens were taken from the arterial line after lowering the blood flow to 100 ml/min for 1 min. Hb, Hct, platelets, white cell count, INR, and urea were measured at the start and at the end of the dialysis sessions.
Anti-FXa activity was measured after 1, 3 and 4 h in each of the 84 dialysis sessions. Blood for anti-FXa was collected into tubes containing citrate and cooled in an ice-water mix before centrifuging at 4°C at 2500 g for 30 min.
Laboratory methods
Anti-FXa activity was measured with a chromogenic assay (Coatest®, Chromogenix AB, Mölndal, Sweden).
Statistics
In order to estimate the effect of actual dialysis time and anti-FXa activity on the odds of getting coagulation (defined as clotting grade 2 and 3), a logistic regression model of repeated measurements was adopted (there were several measurements per patient). Since no clotting was found after 1 h only data from 3 and 4 h after the start of dialysis were included in this analysis. SAS version 6.12 (SAS Institute, Cary, NC) was used for the calculations. The relationship between clinical clotting and anti-FXa activity was assessed by one-way analysis of variance by use of one-exponential decay relationship with a computer-based statistical software program, Graph Pad Prism, CA, US. In order to evaluate the relationship between anti-FXa activity and dalteparin dose (IU/kg), a linear regression model was performed (Statistical Software, SPSS). A P value of <0.05 was considered statistically significant. All statistical tests were two-sided. The results are expressed as mean values ±SD if not otherwise stated.
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Results |
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Blood flow and ultrafiltration rate were kept within narrow limits throughout the study to avoid possible influence of these factors on clinical clotting. Hb, Hct, and platelet count remained unchanged in each patient throughout the study. Blood cell parameters are shown in Table 1. The factors correlated to clinical clotting in the bubble trap were anti-FXa activity, warfarin treatment, and time on haemodialysis. The relationship between clotting in the bubble trap and anti-FXa activity followed one-exponential decay relationship with a highly significant correlation (R=0.67, P<0.0001) in patients not receiving oral anticoagulants (Figure 1A
). Warfarin therapy displaced the curve to the left (R=0.32, P=0.0003), Figure 1B
. The same relationship was found for clotting in the dialyser in the patients who did not receive warfarin (R=0.30, P=0.026, data not shown). There were too few clotting episodes to study dialyser clotting in the warfarin-treated patients. Both time and anti-FXa activity were independently correlated to clotting (grade 2 or 3) in a logistic regression model of repeated measurements performed 3 and 4 h after start of dialysis (P<0.001), see Table 2
. The odds ratio for clotting is 3.2 (95% CI, 1.825.70) after 4 h of dialysis as compared with 3 h (with a constant anti-FXa activity), and the odds ratio is 0.69 (95% CI, 0.560.84) by an increase in anti-FXa by 0.1 IU/ml at a given time of dialysis.
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Figure 2 shows a highly significant linear relationship between the anti-FXa activity after 4 h of dialysis and dalteparin dose (IU/kg). The data comprises repeated measurements in 12 patients following normal and reduced doses of dalteparin, assuming independence. For anti-FXa levels under the detection limit (0.1 IU/ml) the value was calculated assuming first order decline. The regression analysis shows that the anti-FXa level increases 0.10 IU/ml per 10 IU/kg increase in dalteparin dose (confidence interval 0.080.12). The three very low values in Figure 2
comprise three different patients treated with warfarin. Although the data are scattered, the biological activity of anti-FXa activity during haemodialysis from a given dose of dalteparin can be roughly estimated from this plot. A dose of at least 50 IU/kg of dalteparin is indicated to obtain an anti-FXa activity of more than 0.4 IU/ml after 4 h of dialysis. The dose needed to obtain the same anticoagulant effect after 5 h of dialysis is indicated by the broken line. The estimated anti-FXa values after 5 h are calculated from the the formula C=C0 e-kt, assuming first-order decline.
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Discussion |
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The individual effects of dialysis time and anticoagulant effect may be difficult to assess since an increase in dialysis time is accompanied by reduced anticoagulant effect from a single initial dalteparin dose. Nevertheless, using a logistic regression model of repeated measurements we revealed that dialysis time is an independent risk factor for clinical clotting during haemodialysis. This finding may not be surprising but has not been positively demonstrated by previous studies.
The aim of this study was to relate dalteparin dosage to clinical clotting. Traditionally the dose is arbitrarily chosen according to clinical experience. We found a highly significant linear relationship between anti-FXa level after 4 h of dialysis and dalteparin dose (Figure 2). An estimate of the dose needed to avoid significant clinical clotting can be made from this plot. Because of the great biologically interindividual variance in the anti-FXa activity (dalteparin) elimination half-life, up to 50% may be added to the estimated dose to ensure a level of at least 0.4 IU/ml at the end of a 4 h dialysis session. With an added safety margin of 50% to the calculated dose, the recommendation will be about 5000 IU dalteparin for a 4 h session in a patient weighing 70 kg. Alternatively, the actual anti-FXa activity level may be measured after 4 h and the dose adjusted if necessary.
A standard polysulphone dialyser (Fresenius F6) was used in all sessions in this study. Since dalteparin is removed by dialysis the clearance of small molecules of the dialyser may be of importance. High-clearance filters may remove dalteparin at a higher rate and result in a more rapid decrease in anticoagulant effect over time. Also variation in `biocompatibility' between different dialysers may modify the anticoagulant effect. However, such mechanisms could not be elucidated in our study. The elimination half-life of dalteparin averaged 2.2±0.9 h during haemodialysis. Interestingly, this is in agreement with the half-life of dalteparin given i.v. to healthy people without renal failure [12].
It is well known that oral anticoagulant treatment may prevent thrombosis in central venous catheters, including dialysis catheters [14,15]. Obviously, oral anticoagulant treatment may also reduce clinical clotting episodes during haemodialysis, but to our knowledge such an effect has not previously been examined in dialysis patients. In the present study treatment with oral warfarin had a major impact on the degree of clinical clotting episodes. The mean INR for the six patients receiving warfarin was 2.2, indicating that a moderate anticoagulation protects against clotting during haemodialysis. Actually, the patients treated with warfarin were in need of a very low dose of dalteparin. In general, anti-FXa activity at the lowest detection level at the end of dialysis was sufficient to avoid severe clotting in these patients. This may have clinical relevance since many of the dialysis patients are treated with warfarin for cardiovascular comorbidity [16,17].
Extracorporal blood flow and ultrafiltration rate may also be factors influencing clinical coagulation. In the present study these factors were kept within narrow limits, and Hb, Hct, and platelet count remained virtually unchanged throughout the study. Therefore any correlation between these factors and clinical clotting cannot be assessed by the present study.
In conclusion, we found that a single dose of dalteparin effectively inhibits significant clotting for at least 4 h during haemodialysis. Clinical clotting is correlated to anticoagulant effect and is avoided with an anti-FXa activity above 0.4 IU/ml at the end of a 4 h dialysis session. This is normally obtained with an initial bolus dose of dalteparin of about 70 IU/kg. Our data also show that the dose of dalteparin may be reduced with simultaneous oral warfarin treatment, and that time of dialysis is an independent variable for clinical clotting.
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Acknowledgments |
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References |
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