Individualizationof Nadroparin Doses in Haemodialysed Patients

Letter to the Editor

Individualizationof nadroparin doses in haemodialysed patients

Dear Editor,

Patients on haemodialysis (HD) are prone to two opposing hemostatic processes: a bleeding tendency and a hypercoagulable state.

Anticoagulation with low molecular weight heparins (LMWH) during HD is targeted to prevent the activation of coagulation in the extracorporeal circuit (1).As there is no defined the lowest dose of LMWH in patients who undergo HD in terms of preventing bleeding complications and clotting (vascular access/extracorporeal circuit), we decided to determine the lowest, individually optimised, single bolus dose of nadroparin calcium (Fraxiparine®, Glaxo Welcome Production, Notre Dame de Bondeville, France) for effective and safe HD.The actual starting bolus dose of nadroparin (HD1 nadroparin), which was used in our Center for a minimum of two months according to the manufacturer´s recommendation, was decreased twice by 25%: after the initial 4 weeks (HD2 nadroparin), and again after an additional 4 weeks (HD3 nadroparin). The maintenance period was 4 weeks (HD4 nadroparin) during which time this dose was adjusted due to clotting of the extracorporeal circuit.

We investigated four dialysis sessions: HD1 (the beggining of the study), HD2 (after 4 weeks), HD3 (after 8 weeks), and HD4 (the end of the study). The levels of factor anti-Xa, activated partial thromboplastin time (aPTT), thrombin-antithrombin complex (TAT) and D-dimers were determined as: HD-0, at the beginning of the HD session; HD-2, after 2 hours and HD-4, after 4 hours of investigated HD sessions. The clottings of the extracorporeal circuit and vascular access compression time were noted at the end of the HD sessions by the two authors. The efficacy was assessed by scoring the dialysers and arterial/venous chambers separately (from 0-no clot formation to 4-coagulation of the whole system). The safety was assessed by noting all bleeding episodes: major (required hospitalization/transfusion, bleeding into critical organ or space, cause of death) or minor (vascular access site, epistaxis, subconjunctival bleeding)(2).

Forty patients (18 females and 22 males, aged 64.93±12.34 years) on intermittent HD for 61,63±53,97months, were included in a 12-weeks long study. Thirty eight patients completed the study, two were transplanted, and none died.

The dose of nadroparin at the end of the study was increased from the HD3 nadroparin in 1 patient only, and was the same in 7 patients due to clotting in the extracorporeal circuit during the last 4 weeks of the trial. Therefore, the HD3 nadroparin was slightly higher than the HD4 nadroparin (Table 1).No accumulation effect of the nadroparin was observed during the study period (anti-Xa at the beginning of HD sessions). We found that a nadroprin dose decreased by 36.38% is safe and effective for HD patients in terms of bleeding/clotting episodes.

We did not notice any massive clotting of the extracorporeal circuit which would have resulted in the premature ending of the HD session or replacement of the dialyzer/blood lines. There was only one major and seven minor bleeding episodes. One major bleeding (gastrointestinal, which required blood transfusions) was found during the last 4 weeks of the study in a diabetic female patient with a nadroparin dose of 55.33 IU/kg/HD. No influence by decreasing the nadroparin dose on Kt/V was observed (Table 1).

As HD patients are exposed to LMWH for years, non-haemorrhagic effects (osteoporosis, the reduction of elevated blood pressure with lesser intra- and interdialytic hypotensive episodes, effect on brain microvascular circulation and decreasing of vascular dementia and Alzheimer's disease) (3,4),require newtrials with individualized doses of LMWH.

REFERENCES

1. The EBGP Expert Group on Haemodialysis (Part 1). Section V: Chronic intermittent haemodialysis and prevention of clotting in the extracorporal system. Nephrol Dial Transplant 2002; 17 (7): 63-71.
2. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular heparins for hemodialysis in patients with end-stage renal failure: A meta-analysis of randomized trials. J Am Soc Nephrol 2004; 15: 3192-3206.
3. Moretti R, Torre P, Antonello RM, Manganaro D, Vilotti C, Pizzolato G. Risk factors for vascular dementia:Hypotension as a key point. Vasc Health Risk Manag 2008; 4 (2): 395-402.
4. Zhu H, Yu J,Kindy MS. Inhibition of amyloidosis using low molecular weight heparins. Mol Med 2001; 7: 517-22.

Milenka Sain¹, Dragan Ljutic¹, Vedran Kovacic¹, Josipa Radic¹ and Ivo Jelicic¹

Department of Nephrology and Dialysis, UniversityHospitalCenterSplit, Split, Croatia¹

Corresponding author: Milenka Sain, Department of Nephrology and Dialysis, University Hospital Center Split, Soltanska 1, 21000 Split, Croatia. Tel. +385 21 557 203; fax. +385 21 464 554, E-mail address:

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TABLE

TABLE 1. Laboratory and clinical parameters by study period (Friedman test, significant correlations are marked).

Mean±SD, arithmetic mean±standard deviation; p, significancy; *p<0,05; HD1, HD at the beginning of the study; HD2, HD after 4 weeks, HD3, HD after 8 weeks; HD4, HD after 12 weeks;HD-0, values at the beginning of the HD session; HD-2, values after 2 hours of HD session; HD-4, values at the end of HD session; compression A (s), compression time at arteiral access site in seconds at the end of HD; compression V (s), compression time at venous access site in seconds at the end of HD; aPTT, activated partial thromboplastin time (25-35 sec.); anti-Xa, anti-Xa activity; TAT complex, thrombin antithrombin III complex (threshold of 5 µg/L); D-dimers(threshold of 200 mg/L).

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