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      Where and When To Inject Low Molecular Weight Heparin in Hemodiafiltration? A Cross Over Randomised Trial

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          Abstract

          Background and Objective

          Low molecular weight heparins (LMWHs) are small enough to pass large pore dialysis membranes. Removal of LMWH if injected before the start of the session is possible during high-flux dialysis and hemodiafiltration. The aim of this study was to determine the optimal mode (place and time) of tinzaparin administration during postdilution hemodiafiltration.

          Study Design, Setting, Patients

          In 13 chronic hemodiafiltration patients, 3 approaches of injection were compared in a randomised cross over trial: i) before the start of the session at the inlet blood line filled with rinsing solution (IN 0), ii) 5 min after the start at the inlet line filled with blood (IN 5) and iii) before the start of the session at the outlet blood line (OUT 0). Anti-Xa activity, thrombin generation, visual clotting score and reduction ratios of urea and beta2microglobulin were measured.

          Results

          Anti-Xa activity was lower with IN 0 compared with IN5 and OUT 0, and also more thrombin generation was observed with IN 0. No differences were observed in visual clotting scores and no clinically relevant differences were observed in solute reduction ratio. An anti-Xa of 0.3 IU/mL was discriminative for thrombin generation. Anti-Xa levels below 0.3 IU/mL at the end of the session were associated with worse clotting scores and lower reduction ratio of urea and beta2microglobulin.

          Conclusions

          Injection of tinzaparin at the inlet line before the start of postdilution hemodiafiltration is associated with loss of anticoagulant activity and can therefore not be recommended. Additionally, we found that an anti-Xa above 0.3 IU/mL at the end of the session is associated with less clotting and higher dialysis adequacy.

          Trial Registration

          Clinicaltrials.gov NCT00756145

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          Most cited references29

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          Calibrated automated thrombin generation measurement in clotting plasma.

          Calibrated automated thrombography displays the concentration of thrombin in clotting plasma with or without platelets (platelet-rich plasma/platelet-poor plasma, PRP/PPP) in up to 48 samples by monitoring the splitting of a fluorogenic substrate and comparing it to a constant known thrombin activity in a parallel, non-clotting sample. Thus, the non-linearity of the reaction rate with thrombin concentration is compensated for, and adding an excess of substrate can be avoided. Standard conditions were established at which acceptable experimental variation accompanies sensitivity to pathological changes. The coefficients of variation of the surface under the curve (endogenous thrombin potential) are: within experiment approximately 3%; intra-individual: <5% in PPP, <8% in PRP; interindividual 15% in PPP and 19% in PRP. In PPP, calibrated automated thrombography shows all clotting factor deficiencies (except factor XIII) and the effect of all anticoagulants [AVK, heparin(-likes), direct inhibitors]. In PRP, it is diminished in von Willebrand's disease, but it also shows the effect of platelet inhibitors (e.g. aspirin and abciximab). Addition of activated protein C (APC) or thrombomodulin inhibits thrombin generation and reflects disorders of the APC system (congenital and acquired resistance, deficiencies and lupus antibodies) independent of concomitant inhibition of the procoagulant pathway as for example by anticoagulants. Copyright 2003 S. Karger AG, Basel
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            Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials.

            Low molecular weight heparins (LWMH) are the preferred initial treatment for many thromboembolic disorders but are renally excreted and relatively contraindicated in patients with renal failure because of concerns of increased bleeding risks. The purpose of this study was to evaluate the safety and efficacy of LMWH compared with unfractionated heparin (UFH) for preventing thrombosis of the extracorporeal dialysis circuit. Studies were identified with the use of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and FirstSearch; reference lists were reviewed; and pharmaceutical companies were contacted. Randomized, controlled trials that compared an LMWH with another anticoagulant during hemodialysis in patients with ESRD and reported at least one of bleeding, extracorporeal circuit thrombosis, or anti-Xa levels were chosen. Two reviewers independently extracted data on methodologic quality, study design, clinical outcomes, and anti-Xa levels. Seventeen trials were included in this systematic review, 11 of which were included in the meta-analysis. It was found that LMWH did not significantly affect the number of bleeding events (relative risk, 0.96; 95% confidence interval [CI], 0.27 to 3.43), bleeding assessed by vascular access compression time (weighted mean difference, -0.87; 95% CI, -2.75 to 1.02), or extracorporeal circuit thrombosis (relative risk, 1.15; 95% CI, 0.70 to 1.91) as compared with UFH. LMWH seem to be as safe as UFH in terms of bleeding complications and as effective as UFH in preventing extracorporeal circuit thrombosis. However, inferences from these trials assessing anticoagulation for patients who undergo hemodialysis will continue to be weak until larger, more rigorous randomized trials are conducted.
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              What are the anticoagulation options for intermittent hemodialysis?

              Prevention of clotting in the extracorporeal circuit was one of the major hurdles that had to be overcome to enable the expansion of routine outpatient hemodialysis to free-standing satellite centers and the home. Unfractionated heparin, the anticoagulant of choice for many years, is now being replaced by low-molecular-weight heparins (LMWHs) in an expanding number of countries. This trend is attributable to the ease and convenience of the administration of LMWHs coupled with their reliability and predictability of dosing. However, the choice of which LMWH to use depends on the duration and frequency of the dialysis sessions. For patients who are allergic to heparin or have heparin-induced thrombocytopenia, alternative anticoagulants--the direct thrombin inhibitors and heparinoids--are now available. These agents either have short half-lives (and therefore need to be delivered by infusions), or prolonged half-lives, which allows simple bolus administration, but increases the risk of drug accumulation, overdosage and hemorrhage. In patients at risk of bleeding, regional anticoagulants enable anticoagulation to be limited to the extracorporeal circuit. Prostanoids and nafamostat mesilate are expensive regional anticoagulants, and citrate infusions add complexity to the procedure. A citrate-based dialyzate has now been introduced that might enable heparin-free dialysis or reduce systemic anticoagulant requirements.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 June 2015
                2015
                : 10
                : 6
                : e0128634
                Affiliations
                [1 ]Department of Nephrology, Ghent University Hospital, Ghent, Belgium
                [2 ]Coagulation Laboratory, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium
                Medical University of Graz, AUSTRIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AD. Performed the experiments: AD RP. Analyzed the data: AD RP KD SE GG RV. Wrote the paper: AD RP KD SE GG RV.

                Article
                PONE-D-14-57421
                10.1371/journal.pone.0128634
                4468116
                26076014
                335646d6-0f7b-4602-921c-5c11a3a76211
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 2 February 2015
                : 27 April 2015
                Page count
                Figures: 4, Tables: 3, Pages: 13
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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