Comparison of low-molecular-weight heparin (enoxaparin sodium) and standard unfractionated heparin for haemodialysis anticoagulation.

BACKGROUND: Low-molecular-weight heparin (LMWH) has been suggested as providing safe, efficient, convenient and possibly more cost-effective anticoagulation for haemodialysis (HD) than unfractionated heparin, with fewer side-effects and possible benefits on uraemic dyslipidaemia. METHODS: In this prospective, randomized, cross-over study we compared the safety, clinical efficacy and cost effectiveness of Clexane (enoxaparin sodium; Rh?ne-Poulenc Rorer) with unfractionated heparin in 36 chronic HD patients. They were randomly assigned to either Clexane (1 mg/kg body weight, equivalent to 100 IU) or standard heparin, and followed prospectively for 12 weeks (36 dialyses) before crossing over to the alternate therapy for a further 12 weeks. Heparin anticoagulation was monitored using activated coagulation times. RESULTS: Dialysis with Clexane resulted in less frequent minor fibrin/clot formation in the dialyser and lines than with heparin (P<0.001), but was accompanied by increased frequency of minor haemorrhage between dialyses (P<0.001). Clexane dose reduction (to a mean of 0.69 mg/kg) eliminated excess minor haemorrhage without increasing clotting frequencies. Mean vascular compression times were similar in both groups. Over 24 weeks, no changes in standard serum lipid profiles were observed. CONCLUSIONS: This study suggests that a single-dose protocol of Clexane is an effective and very convenient alternative to sodium heparin, but currently direct costs are about 16% more. We recommend an initial dose of 0.70 mg/kg.     

A single dose of dalteparin effectively prevents clotting during haemodialysis.

BACKGROUND: A single bolus dose of LMW heparin at the start of haemodialysis effectively prevents clot formation in the dialyser and bubble trap. However, there are few studies on the appropriate dosage of LMW heparins in haemodialysis. Therefore we examined the relationship between the anticoagulant effect of dalteparin and clinical clotting during haemodialysis. METHODS: We performed an open, prospective study on the effect of decreasing doses of dalteparin in 12 haemodialysis patients during a total of 84 sessions (4-4.5 h). The normally applied dose of dalteparin in each patient was reduced by 25% for each session down to 50% of initial dose if no clotting was observed. Clinical clotting (grade 1-4) was evaluated by visual inspection after blood draining of the air trap every hour and by inspection of the dialyser after each session and compared to corresponding values for anti-FXa activity and dialysis time. Blood flow and ultrafiltration rate were kept within narrow limits throughout the study. RESULTS: No episodes of grade 4 clotting occurred, and no session was interrupted. Eighteen episodes of grade 3 clinical clotting (11%) were observed in patients without warfarin treatment, none with an anti-FXa activity >0.43 IU/ml. Oral warfarin treatment reduced the clinical clotting, and only one grade 3 episode was observed in patients on warfarin therapy. Anti-FXa activity and haemodialysis time were the only factors independently correlated to clotting in a logistic regression model. CONCLUSION: An anti-FXa activity above 0.4 IU/ml after 4 h of dialysis inhibits significant clotting during haemodialysis. A bolus dose of dalteparin of 70 IU/kg usually seems appropriate, but may be reduced in patients on warfarin treatment. Dialysis time is an independent risk factor for clinical clotting.     

Haemodialysis with Low MW Heparin: Dosage Requirements for the Elimination of Extracorporeal Fibrin Formation

We have performed a dose ranging study of a low MW heparin,Kabi 2165, during haemodialysis in humans (n=16) and comparedit to a dose of unfractionated commercial heparin that has alreadybeen shown to inhibit fibrin formation. Low MW heparin administeredas 5000 or 10000 anti-factor Xa units, s.c., half an hour priorto the initiation of dialysis was unable to prevent fibrin formationin the dialyser circuit. A single bolus injection of 5000 anti-factorXa units of low MW heparin given i.v. inhibited fibrin formation,as determined by FPA generation, for up to 4 h and permitteddialysis for 6 h. Such a bolus injection may be useful for shortfrequent dialyses. Infusion of low MW heparin in the same dosage regimen as unfractionatedheparin, 5000 anti-factor Xa units bolus plus 1500 anti-factorXa units/h, resulted in a progressive rise in heparin, causedby its longer half-life of elimination from the circulation,and almost completely suppressed both FPA generation and fibrinclot formation for 6 h dialysis. From these studies (a) we calculate that infusion of this lowMW heparin at a dose of approximately 4000 anti-factor Xa unitsbolus plus 750 anti-factor Xa units/h should be a useful regimenthat will be effective in suppressing fibrin formation duringprolonged dialysis, and (b) the plasma anti-factor Xa levelof low MW heparin may reflect its ability to inhibit fibrinformation, although exactly comparable anti-factor Xa levelsof unfractionated commercial heparin and low MW heparins maynot have identical inhibitory effects.     

Haemodialysis without anticoagulant: haemostasis parameters, fibrinogen kinetic, and dialysis efficiency

Background. Haemodialysis without anticoagulant is an alternative to systemic anticoagulation of patients at high risk of bleeding. However, reports have suggested that heparin-free haemodialysis might results in blood defibrination, and fibrin deposition in dialytic membrane with possible reduction in dialyser efficiency. Methods. Haemostasis parameters, fibrin-fibrinogen kinetic assessed by ¹²⁵-fibrinogen (¹²⁵I-F) turnover and ¹²⁵I-fibrinogen deposition within the dialyser membranes, and dialytic efficiency were studied in 10 stable chronic uraemic patients. Each patient was dialysed on two consecutive 4-h dialyses, once with each of two dialysis strategies: haemodialysis without anticoagulant and conventional haemodialysis using heparin as anticoagulant. Results. No significant changes were seen in mean platelet count, plasma fibrinogen, prothrombin time, and antithrombin II during haemodialysis without anticoagulation, and these parameters were not different from those in patients who underwent conventional haemodialysis. Compared with the predialysis values, a shortening of the mean aPTT from an initial mean value was noted (P <0.05) in haemodialysis without anticoagulation at 60, 120 and 240 min. Fibrin-fibrinogen degradation products remained unchanged during conventional haemodialysis, but were increased after the 30th minute of haemodialysis without anticoagulation (P <0.05), although all values were in normal range. The biological half-life of ¹²⁵I-F in uraemic patients before the haemodialysis was 5.02±0.43 days (control). There was a significant fall in ¹²⁵I-F half-life during haemodialysis without anticoagulation (2.56±0.58 days; P <0.01) but not during conventional haemodialysis (4.77 ±0.97, NS). After use each dialyser was dismantled and ¹²⁵I-F deposition within the membranes (M#5, M#12 and M#19) was measured. During haemodialysis without anticoagulation mean fibrin deposition in M#5 (28.74±10.50x10³ counts), M#12 (26.42±9.06x10³ counts), and M#19 (21.97±8.33x10³ counts) was greater (P <0.001) than that during conventional haemodialysis (1.70±0.92x10³, 1.33±0.65x10³, and 1.59±1.03x10³ counts respectively). However, this greater deposition of fibrin on membranes during haemodialysis without anticoagulation did not change dialyser efficiency as assessed (haemodialysis without anticoagulation vs conventional haemodialysis) by change in serum urea (- 53.96 ± 3.38% vs -51.96 ± 5.20%, NS), serum creatinine (-48.65 ± 5.99% vs -49.59 ± 6.65%, NS), serum potassium (-30.06 ± 4.46% vs -27.64 ± 2.81%, NS), serum bicarbonate (+3.20 ± 3.99% vs 2.15 ± 2.01%, NS) and haematocrit (+3.20 ± 3.99% vs 2.15 ± 2.01%, NS) The mean Kt/V was similar for conventional haemodialysis (0.870 ± 0.107). Conclusion. In conclusion, although conventional haemostasis parameters remained unchanged during haemodialysis without anticoagulation, some degree of activation coagulation system occurs, haemodialysis without anticoagulation was associated with greater decline in ¹²⁵I-F half-life and greater fibrin deposition on dialyser membranes, but with no change in dialyser efficiency.     

Regional anticoagulation with citrate in hemodialysis in patients with a high risk for hemorrhage

During haemodialysis in the patient at high risk for bleeding, heparin cannot be safely used to prevent clotting in the dialysis assembly. Among numerous procedures proposed to reduce the risk for bleeding, Pinnick et al. (N Engl J Med, 308: 258, 1983) proposed the use of citrate as the sole anticoagulant. Citrate toxicity and efficiency were studied during 44 haemodialyses carried out in thirteen patients with a high risk for bleeding or with active bleeding. Three patients had hepatic failure. Two types of citrate solution were used, the trisodium form of citrate (102 mmol.l-1 citrate) or the monosodium form (306 mmol.l-1 citrate). The solutions were infused with a calibrated, pressure insensitive pump, before the dialysis unit at a flow rate of 600 ml.h-1 and 200 ml.h-1 respectively. Sufficient citrate was infused to maintain a clotting time of the blood line and dialyser of more than 18 min. Standard 10% calcium chloride was infused at a constant rate of 7 mg.min-1 into the blood being returned to the patient. The patients were dialysed for 4 h for each haemodialysis with a single-pass system. The dialyses were uncomplicated; no active bleeding was noted. The patient's clotting time was significantly reduced during haemodialysis (18.1 +/- 8.9 min to 14.5 +/- 6.3 min; p less than 0.001). Two-hundred and twenty serum citrate levels were measured. Only nine were above the toxic value of 2 mmol.l-1. No clinical evidence of a decrease in ionized calcium was found: there was no change in the corrected QT intervals and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of high-efficiency and standard haemodialysis providing equal urea clearances by partial and total dialysate quantification

Background. Short-duration high-efficiency haemodialysis has been utilized increasingly in recent years to deliver adequate blood urea clearances per dialysis session. However, high-efficiency and standard-duration haemodialysis schedules, which achieve equal patient urea clearances, may not represent equivalent dialytic therapy due to solute differences in intercompartmental dysequilibrium during dialysis and differences in dialysis mechanics. Methods. To circumvent the effects of intercompartmental dysequilibrium and postdialysis rebound solute clearances were measured by direct dialysis quantification (total and partial dialysate collections) rather than blood clearances. High-efficiency haemodialysis (dialyser blood flow rate=400 ml/min; dialysis time=170.67 min) was compared with standard haemodialysis (dialyser blood flow rate=200 ml/min; dialysis time=240 min) performed in random order in six anuric patients using Fresenius F8 dialysers and the same haemodialysis machine. Such haemodialysis schedules were prescribed to provide equivalent urea clearances. Results. Patient plasma water urea clearances measured by direct quantification were equivalent, whereas high efficiency haemodialysis achieved significantly lower phosphate clearances (P=0.01), less net bicarbonate absorption (P=0.01), and {beta}2microglobulin removal (P<0.001) than standard haemodialysis. Estimated total dialysate effluent volumes with partial dialysate collection and total dialysate collection correlated closely (r=0.95) and there were no differences between patient urea, creatinine and phosphate clearances measured by partial and total dialysate quantification. Conclusions. The data indicate that even if high-efficiency and standard haemodialysis provide equal whole-body urea clearances, delivered dialysis therapy is not equivalent. The partial dialysate collection method is as accurate as the cumbersome total dialysate collection approach and may be applied to assess delivered dose by minor modification of current haemodialysis machines.     

Citrate anticoagulation does not correct cuprophane bioincompatibility as evaluated by the expression of leukocyte surface molecules

Background: Citrate, used for the anticoagulation of the extracorporeal dialysis circuit, reduces ionized calcium by chelation and has been claimed to attenuate dialyser membrane bioincompatibility. Dialysis with complement-activating cuprophane membranes is associated with leukopenia which has been related to an increase in adhesion molecule expression on the surface of circulating leukocytes. Methods: The effect of citrate anticoagulation on the expression of CD11b, CD11c and CD45 on the surface of granulocytes and CD14 on monocytes during haemodialysis with cuprophane membranes, was evaluated by flow cytometric analysis. A comparison of standard heparin vs citrate was performed in 14 chronic haemodialysis patients. During citrate anticoagulation a calcium-free dialysate was used and citrate was infused to obtain a concentration of 4.3 mmol/l blood. The unchallenged 'baseline state' expression of the surface molecule and the increase after ex vivo stimulation with phorbol 12-myristate 13-acetate (delta-PMA) or formyl-methionyl-leucyl-phenylalanine (delta-fMLP) was studied. Results: With heparin, as well as with citrate, a sharp fall in granulocyte and monocyte count was observed after 15 min of dialysis, followed by a recovery at the end of the session. The expression of CD11b, CD11c ad CD45 on granulocytes increased markedly during cuprophane dialysis with a peak at 15 min; there were no differences in response between heparin and citrate anticoagulation. Delta-PMA and delta-fMLP for CD45, CD11c and CD14 showed a decrease during cuprophane dialysis vs t0; again there were no differences between heparin and citrate. Conclusion: We conclude that the use of citrate was not associated with reduced leukocyte activation as measured by the expression of surface molecules during cuprophane dialysis and that no effect on dialysis leukocytopenia could be registered.     

Optimal anticoagulation strategy in haemodialysis with heparin-coated polyacrylonitrile membrane.

BACKGROUND: Binding of polycationic unfractionated heparin onto the modified AN69 polyacrylonitrile membrane, whose surface electronegativity has been neutralized by layering polyethyleneimine (AN69ST), produces stable coating. We investigated whether the heparin-coated membrane was suitable for regular haemodialysis with low heparin doses. METHODS: Sheep were instrumented for extracorporeal circulation perfusing a dialyser equipped with either the AN69ST or the original AN69 membrane. Dialysis sessions were performed after priming the dialyser with heparinized saline. The session was conducted without systemic administration of heparin. In chronic haemodialysis patients, the AN69ST membrane was tested for safety, clotting and thrombin generation according to protocols of 4-h haemodialysis sessions with tapered heparin doses. The goal was to define optimal heparin requirements with the heparin-coated membrane in the setting of continuous or intermittent administration of heparin. Both unfractionated and low molecular weight heparin (LMWH) (enoxaparin) were tested. RESULTS: In sheep, systemic heparin-free haemodialysis was conducted for 6 h without clotting using the heparin-coated dialyser. In the same conditions, massive clotting was observed within 90 min of dialysis with the native AN69 membrane. In man, through kinetic measurements of activated partial thromboplastin time (APTT), heparin anti-Xa concentration and thrombin-anti-thrombin complexes levels (TAT), significant dialyser clotting was avoided when APTT and anti-Xa concentration at 180 min of dialysis, were maintained at >40 s and >0.2 IU/ml, respectively. With the AN69ST heparin-coated membrane, thrombin generation was reduced then suppressed, as compared with the original AN69, primed in the same conditions. Safety of haemodialysis conducted with the AN69ST heparin-coated membrane and low doses of unfractionated heparin (50% reduction of the reference dose) was validated by a survey of 2590 sessions in 32 patients. Doses of LMWH were also safely reduced by 50%. In addition, haemodialysis without systemic administration of heparin was possible with minor risk of clotting. CONCLUSION: During the rinsing phase, the ionic interactions between the new AN69ST polyacrylonitrile membrane and unfractionated heparin induce stable heparin coating. This allows a significant reduction of systemic anticoagulant requirements without increasing the risk of clotting, both in the experimental setting and in the chronic haemodialysis patients. Further studies are required to assess this advantage in patients with acute renal failure and at risk of bleeding and to reduce the metabolic consequences of long-term treatment with heparin.     

Synthetic,organic compound vepoloxamer (P-188) potentiates tissue plasminogen activator

Objective

Poloxamer-188 is a synthetic, organic compound that acts by binding hydrophobic pockets on damaged lipid bilayers in the circulation. P-188 reduces blood viscosity and confers anti-inflammatory and cytoprotective effects. Vepoloxamer (Mast Therapeutics, San Diego, Calif) is a purified version of this compound that has limited side effects. The aim of this study was to investigate drug interactions between vepoloxamer and heparin and tissue plasminogen activator (tPA).

Citrate versus heparin anticoagulation in chronic haernodialysis patients

Anticoagulation with citrate at a rate of 0.68 mM/min in combinationwith a calcium and magnesium-free dialysate and i.v. supplementationof calcium and magnesium at rates of 0.18 mM/min and 0.08 mM/minrespectively, was compared with lowdose heparin. The heparindose was a loading dose of 2500 IU and a sustaining infusionof 750–1250 IU/h; or a loading dose of 1250 IU and a sustaininginfusion of 500–750 IU–h until I h before the endof the dialysis if the patlent was taking concomitantly coumarinanticoagulation for a Goretex shunt. Six chronic haemodialysispatients changed from heparin to citrate anticoagulation becausethey reported bleeding between dialyses. Heparin, after 2 hdialysis, induced a significant 10% prolongation of each patient'swholeblood activated clotting tlme (WBACT) as compared to thepredialysis value: while the WBACT at the dialyser outlet wasless than 3% prolonged as compared to the patient's WBACT. However,after 2 h cltratc the patient's WBACT was not prolonged butthe WBACT at the dialyser outlet was 20–100°A longer,indicating a better anticoagulation of the extracorporeal systemwithout systemic effects. With heparin the shunt pressure time(SPT). i.e. the time needed to stop bleeding from the puncturesites of the Goretex shunts. was 12 of 28 tlrnes 20 niln ormore Citrate reduced these episodes by 75%. Thus citrate should be considered for chronic haemodialysispatients who are at risk of bleeding because of the concomitantuse of anticoagulants. Other patients who could benefit fromcltrate are those with premorbid vascular abnormalities suchas intestinal arterlovenous malforniations. diabetic retinopathymalignant hypertension or adult polycystic kidney disease. Claimsthat cltrate gave improved biocompatibility. 1.e. less leukopeniaor thrombocytopenia. were not confirmed. lndications that citratecaused better dialysis efficiency were found. but should beconfirmed In a greater number of patients.     

Pharmacokinetics of pantoprazole in patients with end-stage renal failure

Background: Pantoprazole is a selective inhibitor of the gastric H⁺/K⁺-ATPase with a low potential to interact with the cytochrome P450 enzyme system. Since pantoprazole is metabolized in the liver to metabolites which are mainly cleared by the renal route, it was the aim of this study to investigate its pharmacokinetics in patients with end-stage renal failure undergoing regular haemodialysis. Methods: Eight patients with end-stage renal failure (creatinine clearance <5 ml/min, age 45-65 years) on regular haemodialysis (duration of haemodialysis 4-5 h, cuprophan-dialyser Hemoflow E3, surface 1.3 m²) were given single i.v. doses of 40 mg pantoprazole one day before haemodialysis (A) and on a haemodialysis day immediately before the start of the haemodialysis (B). Concentrations of pantoprazole and metabolite M2 were determined in plasma and urine over 24 h and in timed samples of the dialysis fluid by HPLC. The protein binding was determined using equilibrium dialysis. Results: The pharmacokinetic characteristics of pantoprazole AUC, t½, CL and Vd area (geometric means) were 2.4 mgxh/l, 0.63 h, 0.227 l/h/kg and 0.206 l/kg on day A (without dialysis) and 2.3 mgxh/l, 0.8 h 0.237 l/h/kg and 0.273 l/kg on day B (with dialysis), respectively. The protein binding was 96%. Pantoprazole was found in small amounts in the dialysis fluid (max. 2.1% of the dose) but not in the urine. Pantoprazole was well tolerated. In particular, there were no clinically relevant changes in blood count, electrolytes or liver enzymes. Conclusions: Haemodialysis has no influence on the pharmacokinetic characteristics of pantoprazole. Thus, pantoprazole is not dialysed to any relevant degree, and therefore no dose-adjustment is required for patients with endstage renal failure undergoing regular haemodialysis treatment.     

Preventing hemorrhage in high-risk hemodialysis: regional versus low-dose heparin

Hemodialysis in patients with increased risk for hemorrhage can be accomplished with either a regional or a low, total dose of heparin. In a prospective study of 69 series of dialyses performed on an alternating schedule of heparinization for each patient, bleeding complications during and immediately following dialysis occurred in 23 of 122 dialyses (19%) with regional heparin compared to 13 of 133 dialyses (10%) with low-dose heparin (P less than 0.05). The incidence of hemorrhage correlated with the estimated degree of bleeding risk both at expected and at occult bleeding sites, and was the same or higher with regional heparin in all categories. Hemorrhage was not correlated with preexisting coagulation abnormalities, concurrent anticoagulant drugs, level of azotemia, or ability to successfully limit systemic heparinization during dialysis. The incidence of partial clotting of the dialyzer was 3 to 5% with both heparin protocols. We conclude that regional heparinization has no clinical or practical advantage over low-total-dose heparin in preventing bleeding associated with hemodialysis.     

The use of PEG-Hirudin in chronic hemodialysis monitored by the Ecarin Clotting Time: influence on clotting of the extracorporeal system and hemostatic parameters

AIM: The aim of our study was to investigate the use of polyethylene glycol (PEG)-Hirudin (PEG-H) as an anticoagulant in hemodialysis including drug monitoring with the Ecarin Clotting Time (ECT) in whole blood and to compare this regimen with standard anticoagulant unfractionated heparin (UFH) for influence on hemostatic parameters and clot frequency of the extracorporeal system. PATIENTS AND METHODS: The application of PEG-H as an anticoagulant in patients on chronic HD was studied in 20 patients (12 males, 8 females) from a single center in an exploratory, open-label, controlled, single-blind, dose-finding study. The patients were divided in 2 groups with 10 patients each (Group I and II); both received 3 dialyses with UFH, thereafter Group I received 5 dialyses with PEG-H and Group II 10 dialyses with PEG-H. Starting dose of PEG-H in the first dialysis was a bolus of 0.08 mg/kg bwt, the mean dose of the following HD was 0.041 mg/kg bwt (range 0.026 0.065 mg/kg bwt). PEG-H was applied as an intravenous bolus-dose followed by a 0.9% saline as a placebo-infusion. HD was performed regularly 3 times a week. All dialysis treatments were performed exclusively with a hollow fiber dialyzer type. Fibrinogen, antithrombin III, prothrombin fragments, thrombin-antithrombin and soluble fibrin were measured with commercial tests. ECT was determined in a mechanical coagulometer. A semiquantitative score was given for the presence of clots in the extracorporeal system after each dialysis. RESULTS: PEG-H was effectively used as an anticoagulant in 150 chronic dialysis treatments using ECT as a simple monitoring method. The optimal whole blood concentration for PEG-H is 600-1000 ng/ml. Clotting in the whole extracorporeal system was decreased by 45% (p = 0.059) with PEG-H anticoagulated HD in comparison to UFH. Fibrinogen, prothrombin fragments (F1+2-fragments) and thrombin-antithrombin-complex showed no significant change in comparison with UFH, antithrombin III (AT III) increased to normal concentrations. Highly sensitive coagulation markers such as a soluble fibrin showed a significant decrease (p < 0.001) before and after HD with PEG-H compared with UFH. CONCLUSION: PEG-H can be used effectively as an alternative anticoagulant in patients on chronic HD using ECT as a simple drug monitoring method. The lower frequency of clots in the extracorporeal system, the stronger and more efficient inhibition of coagulation during HD as indicated by soluble fibrin, may have a positive influence on the disturbed blood coagulation of these patients.     

A low-molecular-weight heparin (Kabi 2165, 'Fragmin') in repeated use for haemodialysis: prevention of clotting and prolongation of the venous compression time in comparison with commercial unfractionated heparin

We have compared a low-molecular-weight heparin (LMWH), Kabi 2165, with commercial unfractionated heparin (UFH) in 21 patients undergoing haemodialysis (1 month with each heparin). The UFH dose regimen comprised a UFH-saline prime of the extracorporeal circuit, an initial bolus of 5000 international units (IU) and an infusion of 1500 IU/h. The LMWH dose regimen comprised a LMWH-saline prime, a bolus of 3000-4000 anti-factor Xa units (aXa U) and an infusion of 750 aXa U/h. Plasma concentrations of the LMWH were slightly less than those of UFH for the first hour of dialysis (0.87 aXa U/ml vs 0.99 IU/ml) but were very similar by the end of the infusion (0.96 vs 1.00) and slightly greater at the end of dialysis, an hour later (0.85 vs 0.69). All haemodialysis sessions were completed uneventfully, with infrequent wispy clot deposits in the drip chamber. The mean frequency of clot deposition was slightly higher with the LMWH (0.20 vs 0.15). Fibrin generation was almost fully suppressed: plasma concentrations of fibrinopeptide A were slightly greater during dialysis with the LMWH (3.31-3.98 vs 2.29-2.75 pmol/ml) but were almost identical by the end of dialysis (5.62 vs 5.49 pmol/ml). The mean 'venous' compression time at the end of dialysis was significantly shorter with the LMWH than with UFH (8.45 min vs 11.12 min). We conclude that the LMWH is effective and safe in repeated use for haemodialysis. It prevents fibrin generation and clot formation to a similar degree as UFH. The shorter venous compression time of the LMWH may reflect a reduced haemorrhagic risk.     

Sonoclot coagulation analysis: new bedside monitoring for determination of the appropriate heparin dose during haemodialysis.

BACKGROUND: Thrombotic and haemorrhagic complications affect cardiovascular morbidity and mortality in haemodialysis patients. We investigated whether a new bedside Sonoclot analysis is useful for determining an appropriate heparin dose during haemodialysis. METHODS: Twenty-two haemodialysis patients (15 males and seven females) treated with unfractionated heparin were recruited. Sonoclot parameters, including activated clotting time (ACT), clot rate (CR), time to peak (TP) and peak amplitude (PA), were examined before and after haemodialysis, coupled with conventional coagulable variables, platelet count and fibrinogen level. Some indices were determined and verified to control heparin dose. Thrombotic and haemorrhagic complications were observed for 3 months. Sonoclot analysis was subsequently performed before initiation, 1 h later, 2.5 or 3 h later (before cessation of heparin infusion), and at the end of haemodialysis. RESULTS: Both CR and PA were positively correlated with platelet count and fibrinogen level. Sonoclot parameters except for PA were significantly correlated with heparin dose. Heparin dose was reduced without causing complications in 12 patients with DeltaACT >/=40 s and/or CR after haemodialysis (CRpost) <20 U/min. Thrombotic complications occurred in five patients who had CRpost >30 U/min. ACT and TP increased during heparin treatment. ACT was reversed but TP did not change after cessation of heparin. CR significantly decreased after initiation of heparin and was reversed, although not completely, after cessation of heparin. PA showed no significant changes during haemodialysis. CONCLUSIONS: Sonoclot analysis can monitor accurate coagulable states and determine an appropriate heparin dose during haemodialysis.     

Plasma hypercoagulability in haemodialysis patient: impact of dialysis and anticoagulation

Background: Thrombotic complications are common in patients with endstage renal disease and contribute substantially to the morbidity and mortality in this population. The aim of the present study was to: I) determine the prevalence and the extent of hypercoagulability in patients undergoing dialysis treatment by measuring parameters that directly reflect thrombin concentrations, ii) assess changes in coagulation status during haemodialysis (HD); iii) quantify the relative impact of heparin, dialysis and their combined effects on coagulation status and iv) detect factors that modify coagulation haemostasis in dialysis patients. Method: A total of 39 patients (HD: n=29, CAPD: n=10) was analysed for procoagulatory and fibrinolytic activity determined by measurements of partial thromboplastin time, prothrombin fragments F1+2, thrombin-antithrombin complexes and D-dimer concentrations. HD patients were investigated prior to and during dialysis. A subgroup of patients was infused heparin alone without dialysis or was dialysed without heparin administration. Furthermore, subgroup and correlation analyses were performed for the type of dialysis (HD vs CAPD), dialyzer and shunt, Kt/V, underlying disease and treatment with recombinant erythropoietin (rhEPO). Results: Baseline levels of all parameters-procoagulatory and fibrinolytic- were substantially elevated in all patients, but to a higher degree among those on CAPD. Moreover, haemodialysis treatment increased procoagulatory markers even further, suggesting stimulated coagulation and/or insufficient anticoagulation during dialysis. However, after 3 h of dialysis thrombin concentrations, determined by quantification of prothrombin fragments, were inversely correlated with Kt/V. Selective heparin infusion diminished procoagulatory activity only slightly and incompletely, whereas HD without heparin resulted in excess thrombin accumulation. Finally, subgroup analyses revealed more pronounced thrombin formation among patients treated with polysulfon dialyzers, whereas erythropoietin dosage was positively related with lower procoagulatory activity. Conclusion: A majority of patients on dialysis are in a hypercoagulable state, which is further aggravated by the haemodialysis procedure itself and may not be sufficiently controlled with current anticoagulation regimens. Intensified heparin treatment and the use of rhEPO are likely to improve coagulation haemostasis, whereas the type of dialyzer should be considered as a relevant procoagulatory factor.     

Effects of argatroban as an anticoagulant for haemodialysis in patients with antithrombin III deficiency.

BACKGROUND: In congenital or acquired antithrombin III-deficient patients undergoing haemodialysis, coagulation or residual blood in the blood circuit and dialyser is commonly observed under anticoagulation with heparin. Argatroban, a synthetic thrombin antagonist, directly inhibits thrombin activity in a manner that is different from that of heparin, thereby displaying an anticoagulating effect without the activation of antithrombin III. For this reason, the anticoagulating effect of argatroban in haemodialysis patients with antithrombin III deficiency was investigated. METHODS: A retrospective nationwide survey was conducted among patients with congenital or acquired antithrombin III deficiency who had undergone haemodialysis with argatroban as an anticoagulant from April 1996 to April 2000. Inclusion criteria were patients with antithrombin III activity <70% of normal, and patients in whom blood coagulation or residual blood in the extracorporeal circuit could not be prevented by the use of heparin during haemodialysis. RESULTS: Of 80 patients who underwent haemodialysis with argatroban, 59 met the inclusion criteria. Compared with the data before the administration of argatroban, significant improvements of residual blood in the dialyser and arterial and venous drip chambers were observed at the last administration of argatroban. A significant rise in antithrombin III activity was also observed. Among 80 safety analysis cases, no adverse events were reported in 66 patients (82.5%). As severe adverse events, one showed bleeding tendency and one had prolongation of prothrombin time. CONCLUSION: Argatroban was an effective and safe anticoagulant for haemodialysis in patients with congenital or acquired antithrombin III deficiency.     

Continuous administration of intravenous iron during haemodialysis

A simple, safe and potentially cost effective method of giving intravenous iron to patients receiving regular haemodialysis therapy is described. The heparin and iron are mixed in normal saline and given as a continuous infusion via the syringe pump present on the modern dialysis machine. No pharmacological incompatibility was observed between iron polymaltose and Heparin Choay® or Heparin Roche®. No adverse reactions attributable to i.v. iron were observed in over 400 patients and more than 30 000 dialyses.      

Successful use of single-lumen, urokinase immobilized femoral catheters as a temporary access for haemodialysis

Method: Placement of a femoral vein catheter as temporary vascular access for haemodialysis was conducted and the indications, catheter patency rate, and incidence of catheter-related infections were examined. A urokinase immobilized femoral vein catheter (UIFC) is a soft polyurethane single-lumen catheter 2.7 mm in diameter and 22 cm in length which needs no heparin infusion (Japan Shawood Co., Ltd., Tokyo; Unitica Co., Ltd., Hyogo, Japan). A soft silicon rubber was attached to the tip of the catheter in order to avoid excessive bleeding during insertion. Aseptic adhesive wound dressing was employed at the exit-site which was cleansed with popidone-iodine and renewed at each dialysis session. Results: Eighty-one UIFCs were used for haemodialysis in 64 patients (acute renal failure: 11; vascular access trouble: 53; initiation of chronic dialysis: 17). The average age of the patients was 58±13 years, ranging from 26 to 80 years. The mean duration of catheter indwelling was 22.4±13.1 days. An adequate blood flow of 180-200 ml/min was obtained through UIFC and returned to another peripheral vein punctured at each dialysis session. Unexplained fever occurred in four cases while the UIFC was in place (4.9%) but culture of either blood or the catheter tip was negative for bacteria. The catheter was removed immediately and fever subsided in all cases. The overall catheter survival rate was 84% at 34 days calculated using the Kaplan-Meier method. Catheter insertion was easy to perform and no serious complications such as pulmonary embolism or septicaemia occurred. Conclusion: Our modified type of UIFC is very useful as a temporary access for haemodialysis with a very low incidence of catheter-related infections and no need for heparinization. Excellent catheter patency was maintained with the plug system and careful dressing techniques without unnecessary bleeding during catheter care. Key words: femoral vein catheterization; haemodialysis; temporary vascular access; catheter survival rate      

Risk factors of system clotting in heparin-free haemodialysis

Heparin-free haemodialysis must be considered for all dialysis patients with a risk of haemorrhage. This technique is associated with increased danger of system coagulation with a blood loss of up to 250 ml. In 84 patients with a risk of haemorrhage, 296 heparin-free haemodialyses were recorded prospectively. First signs of coagulation were found very much more frequently in the venous airtrap than in the dialyser (146 vs 42). System coagulation occurred in 13 of the 296 dialyses (4%) and was prevented by prophylactic switching of the system and dialyser in 140 dialyses (47%). The time of system coagulation was on average 1.8 hours (+/- 0.2) after the beginning of dialysis. The 13 patients with system coagulation had a reduced blood flow on dialysis (217 +/- 52 vs 240 +/- 36 ml/min). Their initially normal clotting time (12 +/- 5 vs 14 +/- 4 min) was more significantly shortened after 2 h (4 +/- 3 vs 8 +/- 3 min). The activities of antithrombin III (87 +/- 34% vs 88 +/- 39%) and protein C (66 +/- 45% vs 59 +/- 37%) do not differ from those of 47 other patients, even at the time of system coagulation, as measured in five patients (92 +/- 34% for antithrombin III, 51 +/- 29% for protein C). System coagulation and shortening of clotting time thus cannot be regarded as a consequence of absorption of these inhibitory factors of plasmatic coagulation. The danger of system coagulation in heparin-free haemodialysis could probably be further reduced by an improvement of the biocompatibility of systems (airtrap) and dialysers (less activation of thrombocytes).