Heparin-free renal replacement therapy for chronic hemodialyzed patients at high risk for bleeding: a comparison of on-line predilution hemodiafiltration with conventional hemodialysis : Free-heparin maintenance dialysis

The coagulation system has gained much interest again as new anticoagulatory substances have been introduced into clinical practice. Especially patients with renal failure are likely candidates for such a therapy as they often experience significant comorbidity including cardiovascular diseases that require anticoagulation. Patients with renal failure on new anticoagulants have experienced excessive bleeding which can be related to a changed pharmacokinetic profile of the compounds. However, the coagulation system itself, even without any interference with coagulation modifying drugs, is already profoundly changed during renal failure. Coagulation disorders with either episodes of severe bleeding or thrombosis represent an important cause for the morbidity and mortality of such patients. The underlying reasons for these coagulation disorders involve the changed interaction of different components of the coagulation system such as the coagulation cascade, the platelets and the vessel wall in the metabolic conditions of renal failure. Recent work provides evidence that new factors such as microparticles (MPs) can influence the coagulation system in patients with renal insufficiency through their potent procoagulatory effects. Interestingly, MPs may also contain microRNAs thus inhibiting the function of platelets, resulting in bleeding episodes. This review comprises the findings on the complex pathophysiology of coagulation disorders including new factors such as MPs and microRNAs in patients with renal insufficiency.

Few studies have examined risk factors for hemorrhage in hemodialysis patients. The contribution of warfarin and antiplatelet agent exposure to the incidence of first major bleeding episodes in hemodialysis patients was determined. Retrospective chart review was performed in eligible hemodialysis patients. Incidence rates were determined as the number of first major bleeding events divided by the total exposure time on each treatment combination. Time-dependent covariates and Cox proportional hazard models were used to determine the hazard rate of having a first major bleeding event. A total of 1028 person-years of exposure were observed from 255 patients with a median follow-up time of 3.6 yr. The incidence rate of major bleeding episodes was 2.5% per person-year. The incidence of major bleeding episodes was 3.1% per person-year of warfarin exposure, 4.4% per person-year of aspirin exposure, and 6.3% per person-year of exposure to the combination of warfarin and aspirin. Compared with patients who were not prescribed warfarin or aspirin, the multivariable hazard ratio for time to first major bleeding event was 3.59 for warfarin, 5.24 for aspirin, and 6.19 for the combination of aspirin and warfarin. The risk for major bleeding episodes in hemodialysis patients increases significantly while on aspirin and/or warfarin, although warfarin alone did not reach statistical significance. Future studies should evaluate the efficacy of these agents in the secondary prevention of cardiovascular events in this high-risk population.

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.