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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2010  |  Volume : 21  |  Issue : 1  |  Page : 43-49
Profile of low molecular weight tinzaparin sodium for anticoagulation during hemodialysis


Prince Salman Center for Kidney Disease, Riyadh, Saudi Arabia

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Date of Web Publication8-Jan-2010
 

   Abstract 

Low-molecular-weight heparin (LMWH) has been suggested as providing safe, effi­cient, convenient, and possibly more cost-effective anticoagulation for hemodialysis (HD) than un­fractionated heparin (UFH) with a single bolus dose at the start of hemodialysis effectively pre­vents clot formation in the dialyzer and bubble trap with fewer side-effects and possible benefits on uremic dyslipidemia. In this study, we compared the safety, clinical efficacy, and cost effectiveness of Tinzaparin sodium (Innohep) with unfractionated heparin (UFH) in 23 chronic HD patients; their extracorporeal anticoagulant protocol-consisted of UFH was switched to Tinzaparin for a period of 6 months. Clinical clotting (grade 1-4) was evaluated by visual inspection after blood draining of the air trap every hour and the dialyzer after each session. Anticoagulation with Tinzaparin sodium re­sulted in less frequent dialyzer and air-trap clotting compared to UFH (P= 001 and 0.04 respec­tively). Over 24 weeks, we observed no alteration in the serum lipid profile of the patients. There was a statistically significant improvement in the dialysis single pool Kt/V after 6 months of Tinza­parin use (1.40 ± 0.28 for Tinzaparin versus 1.23 ± 0.28 for heparin) without any modification in the hemodialysis prescription. The total cost for 24 weeks use of Tinzaparin sodium was 23% more expensive compared to that for UFH. We conclude that a single bolus of Tinzaparin sodium injec­tion at the start of the dialysis session was more effective and convenient in our patients than UFH, but at a higher total cost. Furthermore, at least on the short term, there was no observed benefit on the lipid profile.

How to cite this article:
Al-Saran KA, Sabry A, Taha M, Ghafour MA, Al Fawzan F. Profile of low molecular weight tinzaparin sodium for anticoagulation during hemodialysis. Saudi J Kidney Dis Transpl 2010;21:43-9

How to cite this URL:
Al-Saran KA, Sabry A, Taha M, Ghafour MA, Al Fawzan F. Profile of low molecular weight tinzaparin sodium for anticoagulation during hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Oct 30];21:43-9. Available from: https://www.sjkdt.org/text.asp?2010/21/1/43/58706

   Introduction Top


Hemodialysis (HD) requires anticoagulation to avoid clotting of dialyzers and extracorporeal has consisted of an i.v. bolus dose of unfractio­nated heparin (UFH) followed either by i.v. con­tinous infusion or a repeated bolus dose during dialysis. However, Low Molecular Weight He­parin (LMWH) is reported to have several potential advantages over UFH. [1] The risk of bleeding is lower than with UFH, since LMWH interacts less with platelets and walls of vessels; [2] the risk of heparin-induced thrombocytopenia is also smaller. [3] In addition, the administration of LMWH is practical, and its effect on the blood lipids may be more favorable. [4] LMWH has a longer half life than UFH, [5] so it can be admi­nistered as a single bolus injection at the start of the dialysis session. LMWH is as effective as UFH in preventing thrombosis in animal models and may has less bleeding risk than UFH. How­ever, these findings have not been confirmed in clinical studies. [6]

LMWH does not stimulate plasma lipase to the same extent as UFH [7] ; however, its effect on ure­mic dyslipidemia is controversial, [8] with some [9],[10],[11],[12] but not all studies [13] reporting a beneficial effect.

Although there are several studies that com­pared a variety of LMWH with UFH in hemo­dialysis patients, experience with Tinzaparin so­dium is limited.

We aim in this study to compare the clinical efficacy, safety, and cost effectiveness of Tinza­parin sodium with UFH in our chronic hemo­dialysis patients.


   Patients and Methods Top


Patients

We studied 23 adult patients (17 male, 6 fe­male) on chronic hemodialysis in Prince Salman Center for Kidney Diseases, Riyadh, Saudi Ara­bia. Their age, original renal disease, disease duration, hemodialysis duration, comorbid con­ditions and current medications are given in [Table 1]. The patients received hemodialysis thrice weekly for 3-4 hours per session at blood flow rates of 250-350 mL/min using polysulphone hollow-fiber filter (F7 HPS, Fresenius, Germany). The vascular acesses included native arteriove­nous fistulas, artificial grafts or permanent ca­theters. The study patients were started on chro­nic hemodialysis for at least 6 months before enrollment to the study.

We excluded from the study patients with known bleeding disorders, anemia with hemo­globin levels less than 10 g/dL, recent trauma, surgery, infectious disease or hemorrhagic dis­order (< 1 month) in addition to those receiving oral or other forms of anticoagulant therapy (e.g. warfarin, aspirin), or drugs that could affect he­parin activity (e.g. tetracyclines, digitalis, and antihis-tamines).

Subjects continued their regular medications including lipid-lowering therapy and their diets were maintained throughout the trial. Body mass index (BMI) and serum albumin levels remained stable during the study. Human re­combinant erythropoietin dose was administered where necessary to maintain target hemoglobin of 11-12 g/dL.

The patients were subjected to the following stages each lasted for 6 months duration:

First stage

The extracorporeal circuits were anticoagula­ted with UFH (sodium heparin 5000 IU/mL) administered as a bolus dose (50 IU/kg body weight) intravenously into the pre-dialyzer arte­rial line of the extracorporeal blood circuit, fo­llowed by a maintenance dose of 1000 IU hepa­rin per hour. Infusion was discontinued 1 hour prior to cessation of HD. Activated coagulation times were monitored and maintained around 200 s early in the HD session and 150 s later in the session, and UFH dose was adjusted accor­dingly.

Second stage

During this stage, the UFH was switched to Tinzaparin sodium (anti-Xa). The starting dose was 40-50% of the total UFH previously used according to manufacturer's instructions. The dose was modified in case of clotting or blee­ding in steps of 500 IU until a satisfactory dose was obtained, and it was administered 3-4 min before dialysis as a bolus dose injected into the pre-dialyzer arterial line.

During each stage clinical clotting was eva­luated by visual inspection after blood draining of the air trap every hour (1, no clotting in the trap; 2, fibrinous ring; 3, clot formation and 4, coagulated system) and by visual inspection of the dialyzer at the end of each session (1, clean filter; 2, a few blood stripes (affecting less than 5% of the fibers seen at the surface of the dialy­zer); 3, many blood stripes (affecting more than 5% of the fibers) and 4, coagulated filter).

Blood specimens were obtained from the ar­terial line after lowering the blood flow to 100 mL/min for 1 min. Laboratory investigations for each patient included fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDL), Low-density lipoprotein cholesterol (LDL) and triglyceride concentrations (TG), which were measured on a high-throughput auto-analyser (Dimension X band) using reagents supplied by Dade Behring (Germany). Complete blood count, Kt/V was also measured before and after each stage of the anticoagulant protocols. The proto­col was approved by the local ethical committee.


   Statistical Analysis Top


All analysis was performed using the Statis­tical Package for Social Science (SPSS, Chicago) version 10.0 for windows. Variables are dis­played as mean ± standard deviation (SD) un­less otherwise stated. Chi-squared test was used to compare the prevalence of non-parametric variables, while differences between variables were analyzed by paired Student's t test or Mann­Whitney test as deemed appropriate. A P of < 0.05 was considered statistically significant.


   Results Top


A total of 3312 HD sessions were studied in 23 patients over a period of 12 months. No changes in standard serum lipids (Total choles­terol, LDL, TG and HD lipoprotein), hemo­globin, WBCs count, and platelet count after changing from UFH to Tinzaparin sodium. However, there was statistically significant im­provement in dialysis efficiency-evidenced by improved single pool Kt/V 6 months after switching to Tinzaparin (1.40 ± 0.28 for Tinzaparin versus 1.23 ± 0.28 for heparin, P= 0.008) with­out any change in the hemodialysis prescription [Table 2].

No clotting was observed in the air trap cham­ber in 10 and 14 patients, moderate clotting was observed in 12 and 8 patients, and mild clotting in 1 and zero patients during UFH and Tinzapa­rin stages respectively, (P= 0.04). No episodes of grade 4 (coagulated system) were observed in either treatment protocol [Table 3].

No clotting was observed in the dialyzers in 15 and 21 patients, moderate clotting in 1 and 2 patients, and mild clotting in 7 and no patients during UFH and Tinzaparin stages respectively (P= 0.001). No episode of grade 4 (coagulated filter) was observed in either treatment protocol [Table 4].

Tinzaparin use was accompanied by minor he­morrhage between dialyses in 3 patients after the first and second dialysis sessions of con­version from UFH, which was easily managed with dose reduction. The dose of Tinzaparin/ session (mean ± Sd) remained relatively cons­tant with minor modification over the trial pe­riod [Figure 1].

The mean cost for the use of Tinzaparin/pa­tient/6 months (67.57 ± 25.42 USD) was signi­ficantly higher compared to that for UFH (51.23 ± 23.91 UDS), P= 0.001 [Table 5].


   Discussion Top


In our study, Tinzaparin was more effective than UFH over 1656 HD sessions evidenced by significantly less air trap and dialyzer clotting. This is in agreement with the observations of several investigators who have noticed similar beneficial effect of LMWH compared with UFH. [14],[15],[16],[17]

The annual cardiovascular disease mortality in end-stage renal disease (ESRD) patients on HD is 9.5%, which is 35 times higher than in the ge­neral population. [18] The characteristic perturba­tions in lipoprotein metabolism are considered as a cardiovascular risk factor in these pa­tients. [19] Common dyslipidemic changes include increased in triglycerides levels, very low den­sity lipoproteins (VLDL), intermediate density lipoproteins (IDL), remnant lipoproteins, and li­poprotein-(a) besides decreased high density li­poprotein (HDL) cholesterol. [20]

The primary cause for the accumulation of tri­glyceride-enriched lipoproteins in patients on HD is a defective catabolism of triglyceride-rich lipoproteins by lipoprotein lipase (LPL) and he­patic lipase (HL). LPL activity in post-heparin plasma of uremic patients was found to be lo­wer than in healthy individuals, [21] probably due to reduced enzyme synthesis by the parenchy­mal cell secondary to peripheral insulin resistance and hyperparathyroidism, which both down-re­gulate synthesis of LPL; [21] decreased LPL acti­vity may largely contribute to the generation of atherogenic dense LDL. [22]

Repeated administration of heparin for anti­coagulation during HD causes depletion of LPL and may exhaust lipolytic capacity. LMWH was reported to release LPL from the vessel wall to a lesser extent. [21] Accordingly, the lipolytic po­tential will increase gradually over months if patients are switched from UFH to LMWH [23] .

Preliminary studies on LMWH suggested be­neficial effects on the lipid metabolism in he­modialysis patients, but this has not been sup­ported by later larger studies, at least in the short term. [8],[13] In our study, we did not observe any significant improvement of any element of lipid profile 6 months after Tinzaparin therapy, which is in concordant with other studies. Kro­nenberg et al 1995 [13] failed to observe any bene­fit on lipids in 153 HD patients treated with three different LMWH preparations (dalterparin, sandoparin and enoxaparin) and a similar num­ber on UFH over at least 6 months, even after allowing for gender, age, and diabetes mellitus. In another study involving 36 patients using three LMWH preparations for 6 months, no effects on cholesterol or triglyceride concentra­tions were found. [12] A long-term study of Spaia et al 1994 [24] of 30 HD patients switched from UFH to enoxaparin found significantly lower HDL and higher triglyceride concentrations after 33 months of the LMWH treatment. Noticeably, the lipid parameters returned to baseline in the 10 patients switched back to UFH for 6 months.

Furthermore, the beneficial effect of LMWH was reported not to occur with all preparations of LMW heparin, since heparin preparations with a relatively large heparin molecules do not appear to have an LPL activity. [13] In our study, values of Kt/V urea were signi­ficantly better 6 months after the use of Tinza­parin compared to UFH; To our knowledge this finding was not reported previously and can be explained by less microthrombi formation in the dialyzer that allows better blood flow and solute clearance.

Previous pharmacokinetic studies suggested that HD patients receiving LMWH during dia­lysis are at risk of bleeding up to 10 hours after the injection. In our study, no severe hemo­rrhagic complications were observed with the use of either heparin preparation, however mo­derate hemorrhagic events occurred in 3 pa­tients early after switch to Tinzaparin therapy, which was easily managed with dose modifi­cation.

The total mean cost of Tinzaparin use as anti­coagulant during HD in our study was 23%higher than that of UFH, which is in agreement with what was reported previously. [3]

Finally, limitations of our study included a re­latively small study population, a short duration, and lack of a control group. Furthermore, it was not a specifically a dose-finding study. This study was performed with Tinzaparin and any genera­lization to other LMWH should be inferred with caution as the pharmacology of each LMWH is unique.

In conclusion, Tinzaparin should be considered as an effective, safe and may be a superior al­ternative to conventional heparin anticoagulation in hemodialysis patients. However, during the short-term Tinzaparin therapy, we did not ob­serve any affect on lipid profile in these patients. Currently, the direct cost in KSA is a little more than standard heparin by about 23%. However, with more widespread usage, the price of Tinzaparin is likely to decrease and the small extra cost will be counterbalanced by the con­venience of administration.

 
   References Top

1.Ljungberg B, Jacobson SH, Lins IE, Pejler G. Effective anticoagulation by a low molecular weight heparin (Fragmin) in hemodialysis with a highly permeable polysulfone membrane. Clin Nephrol 1992;38:97-100.  Back to cited text no. 1      
2.Pham PT, Miller JM, Demetrion G, Lew SQ. Clotting by heparin of hemoaccess for hemo­dialysis in an end-stage renal disease patient. Am J Kidney Dis 1995;25:642-7.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Warkentin TE, Levine MN, Hirsh J, et al. Heparin­induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332(20):1330-5.  Back to cited text no. 3      
4.Schmitt Y, Schneider H. Low-molecular-weight heparin (LMWH): Influence on blood lipids in patients on chronic haemodialysis. Nephrol Dial Transplant 1993;8:438-42.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Bratt G, Tornebohm E, Lockner D, Bergstrom K. A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment. Thromb Haemost 1985;53: 208-11.  Back to cited text no. 5      
6.Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low­molecular-weight heparin Mechanisms of action, pharmacokinetics, dosing considerations, moni­toring, efficacy, and safety. Chest 1998;114: 489S-510S.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Nikolay J, Schulz E, Traut G, Nieth H, Biesel E, Zielke E. The post-effect of anticoagulation with low-molecular-weight heparin upon increased triglyceride and cholesterol concentrations in chronic hemodialysis patients. Nieren- Hoch­druckkr 1990;19:519-23.  Back to cited text no. 7      
8.Stenvinkel P. Low molecular weight heparin­does it favorably affect lipid levels? Nephrol Dial Transplant 1995;10:16-8.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Schrader J, Stibbe W, Armstrong VW, et al. Com­parison of low molecular weight heparin to standard heparin in hemodialysis/hemofiltration. Kidney Int 1988;33:890-6.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Deuber HJ, Schulz W. Reduced lipid concentra­tions during four years of dialysis with low mo­lecular weight heparin. Kidney Int 1991;40:496­-500.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Schmitt Y, Schneider H. Low-molecular-weight heparin (LMWH): Influence on blood lipids in patients on chronic haemodialysis. Nephrol Dial Transplant 1993;8:438-42.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Hombrouckx R, Devos JY, Larno L. Standard heparin (SM) versus 3 low-molecular-weight heparins (LMWH) in chronic dialysis. Nephrol Dial Transplant 1994;9:988 (Abstract).  Back to cited text no. 12      
13.Kronenberg F, Ko nig P, Lhotta K, Steinmetz A, Dieplinger H. Is Low molecular weight heparin does not necessarily reduce lipids and lipopro­teins in hemodialysis patients? Clin Nephrol 1995; 43:399-404.  Back to cited text no. 13      
14.Lohr JW, Schwab SJ. Minimizing hemorrhagic complications in dialysis patients. J Am Soc Nephrol 1991;2:961.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]  
15.Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79:1-17.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Saltissi D, Morgan C, Westhuyzen J, Healy H. Comparison of low-molecular-weight heparin (enoxaparin sodium) and standard unfractionated heparin for haemodialysis anticoagulation. Nephrol Dial Transplant 1999;14:2698-703.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.Siguenza F, Maduell F, Perella M, Lopez­Menchero R, Grau R, Pastor E. Low molecular weight heparin ('fragmin') in haemodialysis: Is laboratory monitoring worthwhile? Nephrol Dial Transplant 1995;10(11):2163-4.  Back to cited text no. 17      
18.Levey AS, Beto JA, Parfrey PS, et al. Contro­lling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis 1998;32:85-90.  Back to cited text no. 18      
19.Wanner C. Importance of hyperlipidaemia and therapy in renal patients. Nephrol Dial Transplant 2000;15[Suppl 5]:92-6.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]  
20.Oda H, Keane WF. Lipid abnormalities in end­stage renal disease. Nephrol Dial Transplant 1998; 13[Suppl 1]:45-9.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  
21.Arnadottir M. Pathogenesis of dyslipoproteinemia in renal insufficiency. The role of lipoprotein lipase and hepatic lipase. Scand J Clin Lab Invest 1997;57:1-11.  Back to cited text no. 21      
22.Campos H, Dreon DM, Krauss RM. Associations of hepatic and lipoprotein lipase activities with changes in dietary composition and low density lipoprotein subclasses. J Lipid Res 1995;36: 462-72.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]  
23.Arnadottir M, Kurkus J, Nilsson-Ehle P. Different types of heparin in hemodialysis: Long-term effects on post-heparin lipases. Scand J Clin Lab Invest 1994;54:515-21.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]  
24.Spaia S, Pangidis P, Kanetidis D, et al. Long­term effects of low molecular-weight heparin in hemodialyzed patients. Hellen Nephrol 1994;6: 426-30.  Back to cited text no. 24      

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Correspondence Address:
Khalid A Al-Saran
Prince Salman Center for Kidney Disease, Riyadh
Saudi Arabia
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PMID: 20061691

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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BMC Nephrology. 2010; 11(1)
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