Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Abstract |
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Methods. Twenty-two haemodialysis patients (15 males and seven females) treated with unfractionated heparin were recruited. Sonoclot parameters, including activated clotting time (ACT), clot rate (CR), time to peak (TP) and peak amplitude (PA), were examined before and after haemodialysis, coupled with conventional coagulable variables, platelet count and fibrinogen level. Some indices were determined and verified to control heparin dose. Thrombotic and haemorrhagic complications were observed for 3 months. Sonoclot analysis was subsequently performed before initiation, 1 h later, 2.5 or 3 h later (before cessation of heparin infusion), and at the end of haemodialysis.
Results. Both CR and PA were positively correlated with platelet count and fibrinogen level. Sonoclot parameters except for PA were significantly correlated with heparin dose. Heparin dose was reduced without causing complications in 12 patients with ACT
40 s and/or CR after haemodialysis (CRpost) <20 U/min. Thrombotic complications occurred in five patients who had CRpost >30 U/min. ACT and TP increased during heparin treatment. ACT was reversed but TP did not change after cessation of heparin. CR significantly decreased after initiation of heparin and was reversed, although not completely, after cessation of heparin. PA showed no significant changes during haemodialysis.
Conclusions. Sonoclot analysis can monitor accurate coagulable states and determine an appropriate heparin dose during haemodialysis.
Keywords: coagulation; haemodialysis; heparin; Sonoclot analysis
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Introduction |
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Sonoclot analysis provides a rapid and complete evaluation of the overall haemostatic system, including the performance of the coagulation cascade and fibrinplatelet interaction [2,3]. In fact, Sonoclot analysis has been shown to be of clinical value in the evaluation of the haemostatic process during hepatic transplantation, cardiac surgery and other operations [46]. The aim of the present study is to investigate whether a new bedside Sonoclot analysis is useful for determining appropriate anticoagulation regimens during haemodialysis treatment.
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Subjects and methods |
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Protocol 1
Blood samples were drawn from an afferent cannula (arterialized blood) proximal to the addition of heparin and the dialyser membrane before initiation of heparin treatment and at completion of haemodialysis treatment. APTT (s), PT (%) and fibrinogen level (mg/dl) were measured using commercially available kits. Platelet count (counts/microlitre) was determined by automated cell counting in the course of performing routine full blood counts.
Whole blood coagulation was assessed using a Sonoclot Analyzer® (Sienco Inc., CO, USA) within 2 min of obtaining the blood sample. Immediately before analysis, a new plastic probe was inserted into the head, and the chart recorder was adjusted to the zero position. A pre-warmed (37°C) plastic cuvette containing powdered glass beads (as a contact activator) was placed into the instrument, and 0.4 ml of whole blood was pipetted into the cup. After ensuring proper mixing of the sample for 10 s, the probe was gently lowered into each sample by closing the head of the instrument, and a few drops of mineral oil (Sonoil®; Scienco Inc., CO, USA) were spread over the blood surface to prevent blood evaporation. The viscoelastic properties of clot formation were determined by impedance on a vibrating probe. An idealized Sonoclot graph is shown in Figure 1. The instrument automatically measures and displays whole blood ACT (s) and clot rate [CR (U/min)] of coagulation. Other parameters, time to peak [TP (min)] and peak amplitude [PA (U)], were determined manually from the recorder tracings.
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Protocol 2
Based on the results of protocol 1, two indices were determined to try the reduction of heparin dose in patients expected to have an excess of heparin dose. The indices were ACT
40 s, defined as the mean of
ACT+SEM (standard error of the mean), and CR after haemodialysis (CRpost) <20 U/min, defined as the mean of CRpostSEM. For 3 months the indices were verified by the absence of the following criteria: coagulation of the dialyser during haemodialysis, retention of blood in the dialyser at the end of dialysis after rinsing with saline, and prolonged bleeding after haemodialysis.
Protocol 3
After the appropriate heparin dose had been determined for each patient based on the results of protocol 2, blood samples were drawn before initiation of haemodialysis and heparin treatment (time point A), at 1 h after the start of haemodialysis (B), at 2.5 or 3 h after the start of haemodialysis (C, when heparin infusion was not stopped), and at the end of haemodialysis treatment (D, at 30 min after cessation of heparin infusion). Sonoclot analysis was performed in all blood samples, and changes in Sonoclot parameters, including ACT, CR, TP and PA, were determined during haemodialysis treatment.
Statistical analysis
Numeric variables were expressed as means±SD (standard deviation) for the characteristics of patients and as means±SEM for the parameters of Sonoclot analysis. The difference between two dependent variables was analysed using the paired Student's t-test. Spearman's rank correlation test was used for analysis of correlations between two variables. Group statistical comparison was assessed by simple analysis of variance. A P value of <0.05 was considered statistically significant.
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Results |
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Protocol 2
The reduction in heparin dose was safely performed in 12 patients with ACT
40 s and/or CRpost <20 U/min. During the 3-month follow-up period there was no coagulation of the dialyser, retention of blood in the dialyser, or prolonged bleeding after haemodialysis for any of these 12 patients. On the other hand, coagulation of the dialyser or retention of blood in the dialyser after haemodialysis treatment occurred during the observation period in five of the 22 patients. CRpost in all of these five patients was >30 U/min. Heparin dose was subsequently increased in these patients, and CRpost was adjusted appropriately to within a range of 2030 U/min.
ACT and CRpost in the remaining five patients were <40 s and 2030 U/min, respectively, and no thrombotic or haemorrhagic complications were observed during the follow-up period.
Protocol 3
The time course of each Sonoclot variable in appropriate heparin dose is shown in Figure 2. ACT gradually increased during heparin treatment (time points A to C) and rapidly decreased after cessation of heparin treatment (time points C to D). There was no significant difference between the values of ACT at time points A and D. CR significantly decreased after initiation of heparin treatment and was promptly reversed, but not completely, after cessation of heparin treatment. There was a significant difference between the values of CR at time points A and D. TP significantly increased after initiation of heparin treatment but did not significantly change after cessation of heparin treatment. PA showed no significant changes during haemodialysis and heparin treatment.
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Discussion |
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The Sonoclot signature gives a more comprehensive overview of the clotting cascade as a process. The possible advantages of Sonoclot analysis are as follows: (i) only a small specimen volume is needed; (ii) real-time curves are created, providing a permanent record; (iii) the coagulation process can be observed; (iv) the test is simple, compact and easy to start, and the test runs by itself and requires little servicing; (v) results are obtained within 30 min; and (vi) the cost is only several US dollars for each analysis. Thromboelastography is also a well known reliable method for assessing coagulability [9]. It has been reported that thromboelastography is useful for monitoring heparin dose during haemodialysis [10]. However, Sonoclot analysis is superior to thromboelastography in terms of not only sensitivity [11], but also practical cost and availability [3]. In addition, no special solid platform for shock absorption is necessary for Sonoclot analysis. Sonoclot analysis provides a fast and easy-to-perform bedside test for monitoring heparin dose during haemodialysis treatment.
ACT and CR seemed to be useful for determining heparin dose during haemodialysis because they changed following the initiation and cessation of heparin. Therefore, we determined and estimated the criteria, such as ACT
40 s and/or CRpost <20 U/min, for reducing heparin dose. The reduction of heparin dose was safely performed in 12 (54.5%) of the 22 patients based on these criteria. These criteria seem to be useful for reducing heparin dose in patients expected to have an excess of heparin dose. The index of CRpost >30 U/min also seems to be useful for predicting the probability of thrombotic complications occurring in the future. After the appropriate heparin dose had been determined, there was a significant difference between the values of CR, but not between the values of ACT, at time points A and D. CRpost is considered to be more useful and sensitive to control heparin dose in detail than
ACT. That is, adjusting CRpost to within a range of 2030 U/min enables us to determine appropriate heparin dose during haemodialysis.
Moreover, CR and PA were considered to be reliable indices of coagulation because they were correlated with platelet count and fibrinogen level. Since CR changed following the initiation and cessation of heparin but PA did not, these parameters seemed to be different indices of coagulation; it has been reported previously that CR means fibrin polymer formation and PA shows potential coagulability [3]. PA was significantly elevated in diabetic patients (known as a hypercoagulable state [12]) compared with that in non-diabetics, and patients with PA of >100 U had past histories of thromboembolism. PA is not suitable for heparin monitoring, but it is useful for estimating hypercoagulability.
The value of antiplatelet drugs such as low-dose aspirin for prevention of myocardial infarction and stroke has been demonstrated, and this has resulted in an increasing number of patients receiving antiplatelet therapy. Seven (32%) of the 22 patients in this study received antiplatelet therapy. No significant differences in any of the Sonoclot variables were found between patients who received antiplatelet therapy and those who did not. It was previously reported that Sonoclot analysis did not enable the effects of aspirin in normal volunteers to be determined [13]. Sonoclot analysis may be insensitive to the effect of antiplatelet treatment on platelet function, but not that on platelet count.
Several limitations of this study must be considered. First, our study is limited in terms of the number of patients examined, and it is important to confirm the findings with larger studies. Secondly, since the follow-up period in this study was only 3 months, we could not assess thrombotic complications other than coagulation of the dialyser. Therefore it is necessary to investigate other thrombotic complications in a long-term follow-up study. Thirdly, in the present study, heparin was first infused by a bolus and then infused at a constant rate until 30 min before completion of haemodialysis treatment. An appropriate range of CRpost may be different in other prescriptions of heparin treatment. However, CR seems to be useful because of its sensitivity to changes in heparin treatment.
In conclusion, heparin therapy in patients can be monitored during haemodialysis treatment by bedside Sonoclot analysis. CR at completion of haemodialysis treatment is particularly useful for monitoring heparin dose, and an appropriate CRpost for determining heparin dose during haemodialysis is within the range of 2030 U/min.
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Acknowledgments |
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Notes |
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References |
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