Anticoagulation in haemodialysis
Email: jchanard{at}chu-reims.frSir,
We read with interest the recent article of R.D. Frank [1] dealing with the search of an anticoagulant-free extracorporeal circuit in haemodialysis using an original technique of low molecular weight heparin coating the various materials of the extracorporeal circuit.
The haemodialysis sessions were performed using the Genius® system (a modern version of the historical 75 l tank Rhodial® system, the first haemodialysis machine able to control ultrafiltration thus allowing high-flux membranes to be used). One of the most provocative innovations of the construction of the extracorporeal circuit tested in Dr Frank's study is the absence of a bubble trap chamber at the venous line. Indeed, this design avoids the thrombogenic contact between blood and air, but with an increased risk of causing an air embolism. In addition, this does not overcome the rheological changes that occur in the dialysis circuit during a session, which lead to turbulences and clotting.
A major achievement for performing heparin-free dialysis could be the use of a non-thrombogenic material. In this scope, Frank et al. [1] propose the binding of dalteparin to all biomaterial surfaces of the circuit using a process called AOThel®, the rationale of which is not indicated in their article. This process was tested in vitro in an experimental model, testing the quality of the coating on the tubing using the AOThel® on one hand to results obtained with the Carmeda® process, a proven method of grafting heparin onto PVC used to manufacture product for cardiopulmonary bypass surgery [2] on the other. In contrast to the Carmeda® process, evidence was not given for the grafting of heparin onto the metallic surface of needles, nor onto the surface of the polysulfone dialysers which were used in the present study. Thus, we are not convinced that the proposed model demonstrates the assumption that ‘a complete covalent coating of the extracorporeal circuit, i.e. needles, tubings and high-flux dialyser’ has been obtained. To reach such an objective, for example, the basic polyacrylonitrile AN69 membrane has been modified by layering Polyethyleneimine (PEI) onto the surface resulting in a new membrane, the AN69 ST membrane [3]. Consequently, carboxylic and sulfonic groups of heparin cross-link with the amine groups of PEI and produce stable heparin binding without altering the anticoagulant properties of the heparin [4].
We consider that in the present study, additional data are needed to demonstrate a lowered thrombogenic effect due to heparin coating the surface of a polysulfone membrane. In vitro studies are presented, but are restricted to heparin-coated blood tubing sets. The investigators do not mention if heparin has been grafted onto polysulfone membrane, nor do they show in vivo results supporting such grafting. If the membrane is coated with heparin, the amount of heparin that leaches from the surface is not mentioned. One wonders whether the AOThel® coating process is as efficient onto polysulfone, as it seems to be on PVC. A similar fibrin generation, as measured by D-dimer levels and similar platelet activation, as measured by P-selectin levels, were documented in the three tested protocols: standard dialysis, dialysis using coated circuits and dialysis with ‘coated circuits’ without dalteparin. The significant difference concerning the lesser TAT complex generation in patients treated with heparin-coated tubing as compared with those with standard tubing, could be the result of a decrease in thrombogenicity due to the efficient heparin coating of the tubes only. However, one cannot exclude that the sustained low thombogenicity reflects some heparin binding onto the membrane.
The number of haemodialysed patients at high risk of bleeding is increasing; therefore, their uraemic condition, age, risk of cardiac arrhythmias, risk of atheromatous plaque rupture and cholesterol crystal embolism disease must be taken into account when prescribing an anticoagulant regimen. So far, in the difficult balance between risk of patient bleeding and risk of clotting of the circuit, a safe solution has not been proposed. European guidelines for the prevention of clotting in the haemodialysis circuit in patient with elevated bleeding risk have recommended strategies that combine absence of anticoagulant with regular saline flushes or regional citrate anticoagulation, while avoiding regional heparinization (Protamin) due to a rebound effect. The recent study of Sagedal et al. [5] has clearly demonstrated that the use of flushing, by itself, is not protective and, moreover, increases the risk of clotting. Since trisodium citrate haemodialysis remains cumbersome and time consuming, research in the development of non-thrombogenic dialysis material is welcome. Past attempts at grafting heparin onto a cellulose membrane proved to be unsuitable for regular haemodialysis. More recently, a dose-ranging study of systemic heparin administration vs clotting in the extracorporeal circuit after priming the AN69 ST haemodialyser with heparinized saline has stressed the mandatory clinical evaluation of any anticoagulation protocol [6]. Using standard doses of heparin—doses that have been empirically defined in patients chronically haemodialysed—the risk of clotting seems presently around one per thousand sessions or less. In other words, good statistics are now required in order to claim that a material is ‘less thrombogenic’ and can be used to reduce or avoid heparin during a session without increasing the risk of clotting.
Conflict of interest statement. None declared.
Centre Hospitalier et Universitaire
service de Néphrologie et
Transplantation rénale 45
rue Cognacq-Jay
51100 Reims
France
References
- Frank RD, Müller U, Lanzmich R, Groeger C, Floege J. (2006) anticoagulant-free Genius® Haemodialysis using mow molecular weight heparin-coated circuits. Nephrol Dial Transplant 21:1013–1018.
[Abstract/Free Full Text] - Wendel HP and Ziemer G. (1999) Coating techniques to improve the hemocompatibility of artificial devices used for extracorporeal circulation. Eur J Cardiothorac Surg 16:342–450.
[Abstract/Free Full Text] - Valette P, Thomas M, Déjardin P. (1999) Adsorption of low molecular weight proteins to hemodialysis membranes: experimental results and stimulations. Biomaterials 20:1621–1634.[CrossRef][Web of Science][Medline]
- Moachon N, Boullanger C, Fraud S, Vial E, Thomas M. (2002) Influence of the charge of low molecular weight proteins on their efficacy of filtration on dialysis membranes with different intrinsic properties. Biomaterials 23:651–658.[CrossRef][Web of Science][Medline]
- Sagedal S, Hartman A, Osnes K, et al. (2006) Intermittent saline flushes during haemodialysis do not alleviate coagulation and clot formation in stable patients receiving reduced doses of dalteparin. Nephrol Dial Transplant 21:444–449.
[Abstract/Free Full Text] - Lavaud S, Canivet E, Wuillai A, et al. (2003) Optimal anticoagulation strategy in haemodialysis with heparin-coated polyacrylonitrile membrane. Nephrol Dial Transplant 18:2097–2104.
[Abstract/Free Full Text]
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