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.     

The effect of a bolus injection of unfractionated or low molecular weight heparin during aortobifemoral bypass grafting

Eighteen patients undergoing aortobifemoral graft surgery for severe aortoiliac atherosclerotic disease received a bolus injection of 10,000 anti-Xa units of either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) into the distal aorta as prophylaxis against thromboembolic complications related to clamping. Heparin activity was measured by factor Xa inhibition and by prolongation of the APTT. In both groups there was a delay before peak levels of heparin were observed. In the LMWH group, this amounted to 30 min. In the UFH group, APTT was prolonged by 46 s, 7 min after injection but only by 5 s at the end of the operation. In contrast, in the LMWH group, the prolongation in APTT 7 min after injection was less (34 s) but more sustained since a 12.5 s prolongation was still present at the end of the operation. During surgery, heparin activity exceeded 0.7 U/ml in the LMWH group, compared to significantly lower levels in the UFH group (less than or equal to 0.20 U/ml). By the end of the operation no heparin activity was detectable in the UFH group. Protein C antigen decreased after heparin injection and this fall was more pronounced in the UFH group. The level of C1q (a subcomponent of the first component of the complement system) was decreased in the UFH group (P less than 0.04), whereas in the LMWH group C1q levels increased. Platelet aggregation with collagen was inhibited to a significantly greater degree in the LMWH group than the UFH group (54% compared with 23%) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Heparins and blood polymorphonuclear stimulation in haemodialysis: an expansion of the biocompatibility concept.

BACKGROUND: At the concentrations used in haemodialysis and in a dose-dependent way, unfractionated heparin (UFH) and, to a lesser degree, a low-molecular-weight heparin (LMWH) stimulate polymorphonuclear cells (PMN) in vitro, and could act in synergy with the stimulatory effect of dialysis membranes in vivo.To examine this hypothesis, we studied the effects of different heparin types and regimens on blood PMNs during haemodialysis sessions. METHODS: Ten haemodialysed patients were studied during regular dialysis sessions on a cellulose triacetate membrane (CT 110 G; 1.10 m(2); Baxter), with four different random heparin protocols: one high-UFH regimen (HHR) at 90 IU/kg body-weight (b.w.) and one low-UFH regimen (LHR) at 50 IU/kg b.w., and with a LMWH (nadroparin calcium) at 85 (HHR) or 45 (LHR) IU/kg b.w. Blood granulocytes, platelet counts, and plasma granulocyte degranulation products (elastase, lactoferrin) were measured serially during 4 h dialysis sessions. RESULTS: After 10 min, the reduction in PMNs with UFH was 29.5% for HHR (P<0.01) and 28.5% for LHR (P<0.01), and only 16.8 and 18.6% with LMWH (NS), significantly higher for HHR with UFH than with LMWH (P<0.01). At 60 min, the elastase increase with HHR was greater, 61% with UFH (P<0.01) and 37.8% with LMWH (P<0.01), significantly higher than LHR for UFH (P<0.05) or LMWH (P<0.05). The overall decrease in platelets (with LMWH P<0.01) and the overall increase in lactoferrin (P<0.001) were not different between heparinization procedures. CONCLUSION: Under a conventional heparin regimen, the PMN variation during the course of the dialysis session suggests a more biocompatible effect of LMWH over UFH. In addition, the variation of elastase favours the lower dose, whatever the type of heparin. Heparin type and dose should therefore be considered in studies addressing biocompatibility in haemodialysis: a low dose of LMWH may be viewed as a better biocompatible treatment with regard to leukocyte stimulation.     

A single bolus of a low molecular weight heparin to patients on haemodialysis depletes lipoprotein lipase stores and retards triglyceride clearing.

BACKGROUND: Low molecular weight heparins (LMWH) are increasingly used during haemodialysis (HD) to prevent clotting in the extracorporeal devices. It has been suggested that LMWH release endothelial-bound lipoprotein lipase (LPL) less efficiently than unfractionated heparin (UFH) does and thereby cause less disturbance of lipid metabolism. Evidence from in vitro studies and from animal experiments indicate, however, that both types of heparin preparations have the same ability to release endothelial LPL, but LMWH are less effective in preventing uptake and degradation of LPL in the liver. Model studies in humans indicate that LMWH cause as much depletion of LPL stores and impaired lipolysis of triglyceride (TG)-rich lipoproteins as UFH does. METHODS: Two anticoagulant regimes based on present clinical practice were compared in nine HD patients. UFH was administered as a primed infusion, whereas the LMWH (dalteparin) was given only as a single bolus pre-dialysis. Blood was sampled regularly for LPL activity and TG. RESULTS: LPL activity in blood was significantly lower during the dialysis with dalteparin. To explore the remaining activity at the endothelium, a bolus of UFH was given after 3 h of dialysis. The bolus brought out about the same amount of LPL, regardless of whether UFH or dalteparin had been used during dialysis. The increase in TG was significantly higher during dialysis with dalteparin. CONCLUSIONS: This study indicates that a single bolus of dalteparin pre-dialysis interferes with the LPL system as much as, or more than an infusion of UFH does.     

Enoxaparin but not unfractionated heparin causes a dose-dependent increase in plasma TGF-beta 1 during haemodialysis: a cross-over study.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is a multi-functional cytokine that presents as a mediator of the heparin's pleiotropic action. In this cross-over study, we compared the effects of enoxaparin and unfractionated heparin (UFH) used as anticoagulants during haemodialysis (HD) on plasma TGF-beta1 levels and some platelet activation markers: platelet-derived growth factor-AB (PDGF-AB), beta-thromboglobulin (beta-TG) and platelet factor-4 (PF-4). METHODS: Plasma immunoreactive markers (in 22 chronically HD patients) were quantified at the start, at 10 and 180 min of HD session. Enoxaparin was administered as a single dose of 0.67 +/- 0.14 mg/kg at the onset of HD, while UFH was given as a bolus of 1500 (500-3500) IU followed by an infusion of 2750 (1500-6500) IU. The time of evaluation for each heparin was 3 months. RESULTS: Pre-dialysis, TGF-beta1 levels tended to be lower in patients anticoagulated with enoxaparin compared with UFH [6.9 (3.3-21.9) ng/ml vs 8.4 (3.8-30.2) ng/ml, respectively; P = 0.05]. Overdialysis, TGF-beta1 levels showed a significant 44.8% increase to 10.0 (2.9-28.0) ng/ml after 10 min (P = 0.002) and to 9.32 (5.3-23.7) ng/ml after 180 min (P = 0.016) of enoxaparin-anticoagulated HD and remained stable during UFH administration [9.4 (3.9-25.3) ng/ml after 10 min, 8.1 (4.1-21.9) ng/ml after 180 min; P = 0.385]. The 35% increase in plasma TGF-beta1 after 180 min of HD positively correlated with the enoxaparin dose/kg (r = 0.553, P = 0.008) and, interestingly, negatively with the baseline level of the cytokine (r = -0.544, P = 0.009). Despite a positive correlation between TGF-beta1 and PDGF-AB during HD, there were no associations between TGF-beta1 and beta-TG or PF-4 regardless of the type of anticoagulation. CONCLUSION: Enoxaparin, compared with UFH, induces a rapid overdialytic but not sustained increase in plasma TGF-beta1 levels. The effect is closely dose-dependent and may reflect systemic activation of this multi-potential cytokine.     

Activation of hepatocyte growth factor/activin A/follistatin system during hemodialysis: role of heparin

BACKGROUND: Hepatocyte growth factor (HGF), activin A, and follistatin compose an organotrophic system that may be modulated by heparin. We prospectively studied the effects of unfractionated heparin (UFH) versus low-molecular-weight heparin (LMWH) enoxaparin-anticoagulated hemodialysis on plasma levels of the cytokines. METHODS: The factors were measured by immunoassays in 25 chronic hemodialysis patients at the start and at 10 and 180 minutes of the hemodialysis procedure anticoagulated with bolus enoxaparin. Then, the patients were randomized to either receive a bolus and infusion of UFH or to continue LMWH, and were reexamined after 12 weeks. RESULTS: Predialysis HGF and follistatin were increased (both P < 0.0001), while activin A was normal in hemodialysis patients. Baseline HGF directly correlated with activin A in hemodialysis subjects (P=0.004). In healthy controls, it was positively associated with follistatin (P=0.001). Both HGF and activin A were markedly increased at each interval of enoxaparin-anticoagulated hemodialysis, and follistatin was increased at 10 minutes (all P < 0.0001). The early increments in HGF and follistatin directly depended on the dose of enoxaparin (both P < 0.030). Remarkably, the rise in activin A was inversely associated with the predialysis level of the cytokine (P < 0.0001). The actions of UFH resembled those of LMWH, although the releasing effects on the growth factors were not dose-dependent. The switch from LMWH to UFH resulted in a significant increase in over-dialysis HGF, a fall in follistatin, and no change in activin A. CONCLUSION: HGF/activin A/follistatin system is activated and disturbed in chronic hemodialysis patients, including depletion of tissue stores of activin A. Type and dose of heparin used during hemodialysis procedures profoundly influence this pleiotropic system, and may thus modulate vital body functions and course of critical diseases.     

Low molecular weight heparin (CY-216) versus unfractionated heparin in chronic hemodialysis.

In 14 patients undergoing chronic hemodialysis, we investigated the safety and efficacy of the low molecular fragment (CY-216) in comparison to unfractionated heparin (UFH) in the prevention of clotting in the extracorporeal circuit (ECC). In this study, 168 hemodialysis sessions were undertaken with UFH in 2 bolus doses (5,437 +/- 1,477 SD IU) and 231 with CY-216 in a single bolus dose [initial dose 150 anti-Xa U Institut Choay (IC)/kg]. There were no clots in the bubble trap in any UFH sessions, and 14.8% had coagulated fibers in the dialyzer. Clotting in the bubble trap was observed in 2 CY-216 sessions (0.8%) and coagulated fibers in 22.6% of the sessions. At the end of the study, the mean dose of CY-216 was 250 anti-Xa UIC/kg but a dose of 350 anti-Xa UIC/kg was needed in the 2 patients treated by recombinant human erythropoietin. Anti-Xa levels at the end of the runs were higher (0.47 +/- 0.1 U/ml) in the CY-216 group than in the UFH group (0.28 +/- 0.1 U/ml). There was a correlation between anti-Xa levels and efficacy in the CY-216 group. An anti-Xa activity above 0.4 U/ml was needed in order to minimize thrombus formation. Antithrombin III-protease complexes (ATM) and D dimer fibrin derivatives (D dimer) were used as thrombotic markers but they were of little value for the detection of fibrin formation in the ECC. Our findings suggest that CY-216 administered as a single bolus dose seems to be of similar effectiveness to UFH.     

Heparin-Induced Hyperkalemia in Chronic Hemodialysis Patients: Comparison of Low Molecular Weight and Unfractionated Heparin

Abstract: Aldosterone suppression and subsequent hyperkalemia are well described reversible side effects of prolonged treatment with heparin. This study was designed to examine whether the discontinuous use of heparin three times a week to prevent thrombosis formation during hemodialysis sessions could also induce hypoaldosteronism and might contribute to increased predialysis kalemia in hemodialysis patients. Two different heparinization regimens were prospectively compared in a crossover study of 11 chronic hemodialysis patients. During 2 consecutive weeks, the patients were dialyzed each week with either their usual doses of unfractionated heparin (UH) (6,160 IU ± 1,350 IU) or low molecular weight heparin (LMWH) (15 anti-Xa activity [aXa] U/kg + 5 aXa U/kg/h). In all but 2 patients, the predialysis level of plasma K⁺ was higher with UH than with LMWH, and the mean value was higher (5.66 ± 0.83 versus 5.15 ± 0.68 mM, p = 0.01) while no differences in the predialysis plasma concentrations of creatinine, phosphate, urea, and bicarbonate were observed, excluding the potential role of differences in diet and dialysis efficacy in explaining the higher plasma K⁺ concentration with UH. The mean plasma aldosterone to plasma renin activity (pRA) ratio was higher with LMWH than with UH (149.54 ± 123.1 versus 111.91 ± 86.22 pg/ng/h, p < 0.05). Individual plasma aldosterone values were found to be correlated to pRAs both during the UH period and the LMWH period, and the slope of the positive linear relation between plasma aldosterone and pRA was lower during the UH treatment period (63 versus 105 pg/ng/h). Finally, a negative linear correlation was found between the differences in individual predialysis plasma K⁺ observed during the 2 protocols and the differences in the corresponding plasma aldosterone levels, suggesting a link between the higher kalemia and the lower aldosterone responsiveness to angiotensin with unfractionated heparin. Although it cannot be concluded whether or not LMWH inhibits aldosterone synthesis, should LMWH decrease aldosterone production, this side effect is 33% less marked than that of UH so that the predialysis plasma K⁺ levels are 10% lower. This property makes LMWH use preferable to that of UH in patients with elevated predialysis kalemia.     

Low molecular weight heparin in hemodialysis patients with a bleeding tendency

Efficacy and safety of a low-molecular-weight heparin (LMWH) were studied in 33 stable maintenance hemodialysis patients who had a bleeding tendency on unfractionated heparin. The optimal dose of LMWH for each patient was titrated before the study; the mean total LMWH dosage was 1,152 +/- 574 IU. No major bleeding or clot formation was noted in a total of 2,470 hemodialysis sessions during 6 months of LMWH administration. The mean value of plasma anti-factor Xa (anti-Xa) activity increased from 0.05 +/- 0.03 IU/ml before dialysis to 0.34 +/- 0.28 IU/ml after 2 h of dialysis and returned to 0.15 +/- 0.09 IU/ml after 4 h of dialysis; the mean activated partial thromboplastin time was 26.1 +/- 4.4 s before dialysis, 30.7 +/- 9.5 s (an 18% increase) after 2 h of dialysis, and 26.2 +/- 4.4 s after 4 h of dialysis. No significant change in serum antithrombin levels was noted throughout the whole study period. We conclude that a low dosage of LMWH is safe and effective in hemodialysis patients who have a risk of bleeding with unfractionated heparin. Serum anti-Xa activity is better than activated partial thromboplastin time and antithrombin in assessing the optimal dose of LMWH. A plasma anti-Xa activity of 0.37 IU/ml after 2 h of hemodialysis may represent an optimal dosage of LMWH for most patients.     

Different effects of enoxaparin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study.

BACKGROUND: Heparin inhibits prothrombotic tissue factor (TF) and releases its inhibitor, tissue factor pathway inhibitor (TFPI), from the endothelium, but repeated administration of heparin depletes vascular stores of TFPI. We studied the anticoagulant effects of unfractionated heparin (UFH) vs low-molecular-weight enoxaparin-used for thrice-weekly maintenance haemodialysis (HD)-on plasma levels of total TF and TFPI and on those of an activated coagulation marker prothrombin fragment 1+2 (PF 1+2). METHODS: Twenty-five patients dialysed using a single injection of enoxaparin (at a mean dose of 0.68 mg/kg) were randomly assigned to either receive UFH administered as a mean bolus of 42.1 IU/kg and continuous infusion of 57.8 IU/kg (n=12) or to be maintained on enoxaparin (n=13), and were followed prospectively for 12 weeks. Plasma immunoreactive TF, TFPI and PF 1+2 were measured at the start and after 10 and 180 min of HD, and compared with values in 15 healthy controls. RESULTS: Pre-dialysis TF, TFPI and PF 1+2 were higher than normal (all P<0.0001). TF and PF 1+2 did not change, while TFPI levels, compared with baseline, increased at each interval in enoxaparin-anticoagulated HD patients (all P<0.0001). TFPI increments correlated inversely with pre-dialysis TFPI (both P<0.0007). In patients switched to UFH, TF levels remained unchanged compared with pre-randomization values, TFPI increased at each interval of HD sessions (all P<0.035) and PF 1+2 increased pre-dialysis (P=0.015). The over-dialysis effects of UFH resembled those of enoxaparin. In contrast, baseline TFPI and its 10-min rise correlated inversely with the UFH loading dose (both P<0.040). Pre-dialysis PF 1+2 was inversely associated with TFPI increments (both P<0.034), and directly with pre-dialysis TFPI (P=0.018) and the UFH loading dose (P=0.045). CONCLUSIONS: Depletion of heparin-releasable stores of TFPI is an untoward effect of repeated anticoagulation during maintenance HD therapy. The traditional UFH regimen is more prothrombotic than single enoxaparin injections, with high loading doses of UFH being involved in TFPI exhaustion and subsequent hypercoagulability.     

Optimal regimen of low-dose heparin prophylaxis in gastrointestinal surgery.

Four low-dose heparin regimens were compared with respect to the postoperative frequency of deep venous thrombosis (DVT) diagnosed with the 125I-fibrinogen method and other thrombosis variables as well as to peroperative and postoperative bleeding. The study comprised 204 patients undergoing gastrointestinal surgery who received 5,000 IU of either calcium heparin or sodium heparin (Vitrum AB) subcutaneously 2 hours before the operation and either every 8 or every 12th hours afterwards for 6--8 days. DVT was diagnosed in 17 and 16% of the patients who received calcium heparin every 8th or 12th hour respectively and in 11 and 10% respectively of those given sodium heparin every 8th or 12th hour. The differences in the incidence of DVT between the four groups were not statistically significant. An 8-hourly regimen was not accompanied by more bleeding incidents than a 12-hourly regimen. Sodium heparin was associated with a significantly increased number of patients who required blood transfusion and had more bruising at the injection site. It is concluded that the safest, most practical and still effective of the four investigated low-dose heparin regimens is calcium heparin 5,000 IU/ml administered 2 hours before the operation and every 12 hours afterwards for the first postoperative week.     

Standard heparin versus low-molecular-weight heparin. A medium-term comparison in hemodialysis

BACKGROUND: To compare standard heparin (SH) and low molecular weight heparin (LMWH) in terms of anticoagulation, platelet activation and lipid metabolism, we selected 54 patients who had been on 4-hour hemodialysis three times weekly for at least 12 months, without bleeding disorders or dyslipidemic diseases. 28 were on hemodialysis with Polysulfone low-flux, 26 were on hemodiafiltration with Polysulfone high-flux. All patients underwent EPO. METHODS: During the first 18 months, we administered SH 1,500 IU on starting dialysis and 1,500 +/- 500 IU in continuous intradialytic infusion per session. In the following 18 months, we administered LMWH 64.6 IU/kg on starting dialysis in a single arterious bolus. We assessed aPTT, anti-factor Xa activity, TAT and FPA, beta-TG and PF4. Blood samples were taken monthly at times 0, 30, 60, 180 and 240 min, as well as 1, 4 and 20 h after dialysis end. Predialysis cholesterol, HDL, LDL, triglycerides and lipoprotein(a) were checked monthly. RESULTS: During both LMWH and SH sessions no clotting or major bleeding complications were observed. APTT with LMWH was lower than that found with SH (p < 0.001); aFXa using LMWH was higher than when using SH (p < 0.001); TAT and FPA were lower in LMWH sessions (p < 0.01) than in SH sessions. We also detected lower beta-TG (p < 0.05) and PF4 levels (p < 0.05) using LMWH than using SH. As regards lipids, we only observed a significant decrease in triglycerides after 18 months of LMWH treatment. CONCLUSIONS: Routine use of LMWH during hemodialysis affords a safe and effective alternative to SH, and causes reduced platelet activation.     

Effects of unfractionated heparin and low-molecular-weight heparin on colonic anastomoses in the presence of experimental peritonitis

BACKGROUND: We aimed at investigating the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on the healing process of colonic anastomoses in the presence of peritonitis which is known to adversely affect the healing process. STUDY DESIGN: Three groups of Wistar albino rats (n = 15 in each group) with experimental fecal peritonitis were studied. A 1-cm colonic segment was resected, and an end-to-end anastomosis was performed. The control group (group 1) was given no treatment; group 2 animals received 50 IU/kg s.c. UFH twice a day, and group 3 rats received LMWH at a dose of 1.5 mg/kg daily for 7 days postoperatively. Relaparotomy was done on day 7 in the surviving rats. The rats were sacrificed by resection of the colonic segment. The anastomosis bursting pressures were measured and the tissue samples from anastomosis lines were histopathologically examined. RESULTS: The bursting pressures were significantly higher in UFH and LMWH groups as compared with the controls (p = 0.021 and p < 0.001, respectively), while there was no statistically significant difference between UFH and LMWH groups. Positive bacterial culture results were more common in controls (90%) than in the other two groups (p = 0.029 and p = 0.002, respectively). Also the polymorphonuclear leukocyte counts were higher (p = 0.005) and the fibrin formation more common (p = 0.007) in the controls. On the other hand, the number of fibroblasts was higher (p = 0.002) and collagen formation and revascularization more frequent (p = 0.001 and p = 0.001, respectively) in the UFH and LMWH groups. CONCLUSION: UFH and LMWH may have positive effects on the healing process of colonic anastomoses in the presence of peritonitis.     

Safety and efficacy of single bolus anticoagulation with enoxaparin for chronic hemodialysis. Results of an open-label post-certification study

BACKGROUND: Low-molecular-weight heparin (LMWH) is supposed to be advantageous compared to unfractionated heparin for chronic hemodialysis (HD) with respect to lipid and bone metabolism, polymorphonuclear cell stimulation, induction of antibody-mediated thrombocytopenia, and aldosterone suppression. Due to longer biological half-life, LMWH offers the possibility of single bolus administration. METHODS: To assess safety and efficacy of single bolus anticoagulation with enoxaparin for chronic HD, 781 stable HD patients from 79 German dialysis centers (mean age 62 years; 31% ESRD due to diabetes mellitus) were monitored by clinical and laboratory parameters for 32 weeks. Additionally, in a single dialysis center, 22 chronic HD patients were investigated by molecular markers of coagulation during chronic HD under conditions of single bolus or continuous anticoagulation regimens. Anti-Xa activity and the thrombin- antithrombin-III complex (TAT) were determined before the enoxaparin bolus, after 15 min, 2 h, and at the end of HD in venous and arterial blood lines. RESULTS: Chronic HD was performed in 24,117 HD treatments with enoxaparin at a median dose of 70.1 IU/kg (5,000 IU median total dose) for single bolus anticoagulation. In 83.0% of HD treatments, enoxaparin was given as single bolus. In 98.3% of patients no adverse event was reported. No drug-related severe adverse event occurred. Significant clotting problems were observed in only 0.3% of HD treatments with single bolus anticoagulation. As assessed in 257 HD treatments, essentially identical anti-Xa levels were detected at the end of HD with single bolus (50 IU/kg) or continuous (mean total dose 43 IU/kg) anticoagulation regimens. Bolus anticoagulation resulted in higher TAT generation at the end of HD. However, this was not associated with increased macroscopic clot formation. CONCLUSION: Single bolus anticoagulation with enoxaparin was safe and effective for chronic HD. For a duration of 4 h HD, a median dose of 70 IU/kg can be recommended for regular use, which is in accordance with the manufacturer's instructions for use of enoxaparin recommending a range of 50-100 IU/kg.     

Local heparin is superior to systemic heparin in preventing arterial thrombosis

Thrombosis poses a significant problem in microvascular surgery, despite antithrombotic therapy. The purpose of the present study was to investigate whether a topical application of unfractionated heparin is equally efficient as a systemic bolus in avoiding thrombosis. A rat femoral artery model was used. Three different doses of systemic heparin (50, 100, and 200 U/kg) and one dose of locally administered heparin (100 U/ml) were evaluated and compared to a control group receiving isotonic saline. A thrombogenic injury, simulating poor microsurgical technique, was applied to the artery. The thrombus area was visualized by transillumination, and recorded for 60 min on video, for subsequent measurement. In addition, the level of activated partial thromboplastin time (APTT) and of anti-activated clotting factor X (aXa) was determined. Local heparin significantly reduced thrombus size as compared to isotonic saline and systemic heparin (50 and 100 U/kg). High-dose systemic heparin (200 U/kg) was equally potent, but local heparin had significantly less influence on the hemostatic parameters.     

Incidence of pancreas graft thrombosis using low-molecular-weight heparin

Abstract: Introduction: Simultaneous pancreas–kidney transplantation is the current treatment of choice for patients with type I diabetes and end stage renal disease. Vascular graft thrombosis (VGT) after pancreas transplantation is the main cause of early graft loss. Methods: A total of 188 consecutive pancreas transplantations were performed between January 2000 and December 2006. A retrospective study was carried out in order to compare incidence of VGT and relaparotomy‐for‐bleeding rate of once daily fixed dose low‐molecular‐weight‐heparin (LMWH) to dose‐adjusted intravenous unfractionated heparin (UFH). Results: Fifty‐eight patients receiving LMWH and 129 receiving UFH were identified. There were 7% (4/58) VGTs in the LMWH and 17% (22/129) in the UFH group (p = 0.047). The frequency of major bleeding requiring relaparatomy was not significantly different in the groups related to LMWH and UFH, respectively (6.9% vs. 7.8%). One yr patient and pancreas graft survival was 98.9/89.6% in the LMWH and 97.8/74.4% in the UFH group. Donor and recipient characteristics were similar. Conclusion: In our experience once daily fixed dose LMWH might not be inferior to dose‐adjusted intravenous heparin in preventing pancreas graft thrombosis.     

Anticoagulation with Low Molecular Weight Heparin (Fragmin) during Continuous Hemodialysis in the Intensive Care Unit

Abstract: A preparation of low molecular weight heparin (Fragmin) was administered to patients with multiorgan failure receiving continuous venovenous hemodialysis. Three patients received a high-dose regimen (35 IU/kg bolus followed by 13 IU/kg infusion), and 7 received a low-dose regimen (8 and 5 IU/kg, respectively) for 36 h. High-dose Fragmin was associated with minimal clotting in the extracorporeal circuit. Plasma fibrinopeptide A levels declined, and mean anti-Xa activity was in the range 0.47-0.79 IU/ml. The urea equilibration coefficient (UEC) (100% at initiation) remained above 90% throughout. All 3 patients had mild bleeding episodes, which led to discontinuation of Fragmin in 1. During all low-dose treatments, marked thrombus formation occurred in the extracorporeal circuit, and in 2, the circuit clotted within the study period. Fibrinopeptide A levels further increased in 4 patients, and mean anti-Xa activity was in the range 0.27-0.53 IU/ml. UEC declined appreciably in 3 treatments (including the 2 in which early circuit clotting occurred). One patient experienced a mild bleeding episode. The low-dose Fragmin regimen produced safer anticoagulation in patients at risk from bleeding and is suitable for prolonged renal support although the tendency to thrombosis may necessitate more frequent circuit changes.     

Pharmacokinetics of the low molecular weight heparin enoxaparin during 48 h after bolus administration as an anticoagulant in haemodialysis.

BACKGROUND: The interest of low molecular weight heparins (LMWH) regarding bleeding risk is controversial in renal failure patients. In haemodialysis patients, there are very few data on the pharmacokinetics of LMWH after the end of the session. The aim of the study was to evaluate the duration of anticoagulation after bolus administration of the LMWH enoxaparin at the start of haemodialysis. METHODS: The pharmacokinetics of enoxaparin were studied during the 48 h following a single bolus injection at the start of the dialysis session in 30 chronic haemodialysis patients. Pharmacokinetics were determined using a population approach (Non Linear Mixed Effects Modelling). RESULTS: A single injection of enoxaparin at 60 U IU/kg (4000 +/- 455 IU) led to an anti-Xa activity higher than 1.2 IU/ml during the first 2 h of the session, and between 0.4 and 1.2 IU during the third and fourth hours. After the end of the session, anti-Xa activity remained higher than 0.4 IU/ml up to 10 h after injection, and higher than 0.1 IU/ml up to 24 h. The pharmacokinetic model showed that only weight improved the predicted vs observed anti-Xa activity plot. The model was used to simulate single and multiple dosing with decreased enoxaparin doses. Whatever the procedure, anti-Xa activity remained high (>0.22 +/- 0.99 UI/ml) up to 12 h after the start of the dialysis session. CONCLUSIONS: These results suggest that haemodialysis patients receiving the LMWH enoxaparin during dialysis are at risk of bleeding up to 10 h after the injection.     

Effect of intraperitoneal administration of low-molecular-weight heparin on plasma tissue factor pathway inhibitor levels in CAPD patients

We investigated the systemic effect of intraperitoneal low-molecular-weight heparin (LMWH) in continuous ambulatory peritoneal dialysis (CAPD) patients by measuring plasma total tissue factor pathway inhibitor (TFPI) levels, regarding the fact that the levels of plasma TFPI increases 2- to 4-fold after subcutaneous and intravenous administration of unfractioned heparin or LMWH. Eleven men and 6 women who had been on CAPD for 32 +/- 26 months and 15 healthy controls were included in the study. After administration of intraperitoneal enoksiparin in dialysate, plasma samples were obtained 4 h later. TFPI levels were significantly higher in CAPD patients (207.8 +/- 55 ng/ml) compared to the healthy subjects (72.5 +/- 29 ng/ml) (p < 0.0001). Both TFPI levels (225.9 +/- 47 vs. 207.8 +/- 55 ng/ml) (p < 0.54) and plasma factor Xa (anti-FXa assay) (0.097 +/- 0.14 vs. 0.093 +/- 0.16 U/ml) (p < 0.54) levels did not show any statistical difference before and after intraperitoneal administration of LMWH. By these findings we might suggest that intraperitoneal LMWH does not have any systemic effect.     

Lack of efficacy of low molecular weight heparin in a boy with congenital nephrotic syndrome

SUMMARY: The congenital nephrotic syndrome (CNS) is characterized by severe proteinuria, followed by hypoalbuminaemia and hypercoagulopathy. the boy was born in the 39th gestational week (1980 g bodyweight). In the first days of his life, he developed proteinuria and oedema, and on the 10th day, a thrombosis of the vena cava inferior was diagnosed. the boy was treated with unfractionated heparin, antithrombin concentrates and a low-dose of recombinant tissue plasminogen activator (rtPA). After 2 days, a complete resolution of the thrombus was observed. Treatment with unfractionated heparin and antithrombin III was continued. At the age of 3 months, low molecular weight heparin (LMWH) was started before the patient was discharged. Despite a high dose of LMWH, 250 IU/kg bodyweight, the anti-Xa-activity was always below 0.1 U/mL. Therefore, anticoagulation was achieved by the administration of vitamin K antagonist. Low molecular weight heparin is bound to albumin and antithrombin. Therefore, the renal loss of these proteins may result in low plasma levels of LMWH, and may not be effective in patients with CNS.