Mean anti-Xa Levels Research Articles

Comparison of postpartum anti-Xa levels following enoxaparin administration to prevent venous thromboembolism using 2 weight-based protocols: a randomized controlled trial

During the postpartum period, enoxaparin is given to high-risk women to prevent venous thromboembolism, a leading cause of maternal mortality. Enoxaparin activity is measured by peak plasma anti-Xa levels. The prophylactic range of anti-Xa is 0.2 to 0.6 IU/mL. Values above and below this range represent subprophylactic and supraprophylactic levels, respectively. Weight-based enoxaparin administration was superior to fixed-dose enoxaparin administration in achieving an anti-Xa prophylactic range. However, it is unknown which weight-based enoxaparin administration is superior (once daily weight categories vs 1 mg/kg body weight). This study aimed to compare the efficacy in reaching prophylactic anti-Xa levels and adverse effects profile of the 2 weight-based enoxaparin dosing protocols. A randomized open-label controlled trial was conducted. Women after delivery, who were intended to receive enoxaparin, were randomized to receive either enoxaparin treatment according to 1 mg/kg (up to 100 mg) or weight categories (≤90 kg, 40 mg; 91-130 kg, 60 mg; 131-170 kg, 80 mg; >170 kg, 100 mg). Plasma anti-Xa levels were obtained 4 hours after the second enoxaparin administration (day 2 of enoxaparin treatment). If the woman was still hospitalized, anti-Xa levels were also obtained on day 4. The primary endpoint was the proportion of women with anti-Xa levels within the prophylactic range at day 2. In addition, data regarding anti-Xa levels in different weight groups and rates of venous thromboembolism and adverse effects were evaluated. Of note, 60 and 64 women received enoxaparin according to 1 mg/kg and weight categories, respectively; moreover, 55 (92%) and 27 (42%) women reached the prophylactic range of anti-Xa at day 2, respectively (P<.0001). The mean anti-Xa levels on day 2 were 0.34±0.09 and 0.19±0.06 IU/mL, respectively (P<.0001). The anti-Xa levels were higher in the 1 mg/kg group than in the weight categories group in the subanalysis of different weight categories (51-70, 71-90, and 91-130 kg). There was no difference in anti-Xa levels on day 4 compared with day 2 in both cohorts (n=25). There was no case of supraprophylactic anti-Xa levels, venous thromboembolism events, or serious hemorrhage. Postpartum enoxaparin administration at 1 mg/kg was superior to weight categories in reaching anti-Xa prophylactic levels without leading to serious adverse effects. Given the high efficacy and safety profile, enoxaparin at 1 mg/kg once daily should be considered the preferred protocol for postpartum venous thromboembolism prophylaxis.

Clinical study on low-molecular weight heparin infusion as anticoagulation for nocturnal home haemodialysis.

This study was conducted to evaluate low-molecular weight heparin (LMWH) as anticoagulation for nocturnal home haemodialysis (NHHD). While its longer half-life may cause drug accumulation in frequent dialysis, the essential need of a supplementary intra-dialytic bolus for the sleeping patients also renders LMWH's use impractical. The recruited patients, who were on alternate-day 8h haemodialysis, were randomized to receive either nadroparin or unfractionated heparin (UFH) for a week. They underwent crossover to receive the alternate anticoagulant in the next week. A nadroparin infusion regimen was adopted to enhance its practicability, which consisted of a loading dose of 35IU/kg and a continuous infusion of 10IU/kg per hour for 6h. A total of 12 NHHD patients were recruited. With nadroparin infusion, the mean anti-Xa levels at the 2nd , 4th , 6th and 8th hours of dialysis were 0.46±0.11, 0.55±0.14, 0.61±0.15 and 0.45±0.15IU/mL respectively. Comparing to UFH, which offered satisfactory anticoagulation according to the activated partial thromboplastin time, nadroparin-treated dialysis achieved similar thrombus scores and dialyser urea/creatinine clearances at the end of haemodialysis. During the post-dialysis period, one patient demonstrated residual LMWH effect (anti-Xa level 0.09IU/mL) on the next day, whereas none had detectable anti-Xa activities 2 days afterwards upon next dialysis. Low-molecular weight heparin infusion is practical and effective as anticoagulation for NHHD. It can be safely used in an alternate-day haemodialysis schedule. A close monitoring for LMWH accumulation is recommended if long dialysis is performed daily.

Association of outcomes and anti-Xa levels in the treatment of pediatric venous thromboembolism.

There are few data in the pediatric population evaluating the relationship between measured anti-Xa levels during enoxaparin therapy and thrombotic outcomes. To determine whether there is a difference in outcomes in children who receive enoxaparin with mean anti-Xa levels between 0.45 and 0.79 unit/ml (low therapeutic range) versus between 0.80 and 1.05 unit/ml (high therapeutic range) throughout their course of their treatment. We retrospectively identified subjects with uncomplicated venous thromboembolism treated with enoxaparin. Of 69 patients with any response to therapy, 48 (70%) had mean anti-Xa levels in the low therapeutic range and 21 (30%) had mean anti-Xa levels in the high therapeutic range. Of 20 patients with no documented response to therapy, 13 (65%) had mean anti-Xa levels in the low therapeutic range and 7 (35%) had mean anti-Xa levels in the high therapeutic range. Forty-eight (79%) of the 61 patients with low-range mean anti-Xa level had any response to therapy. Twenty-one (75%) of the 28 patients with high-range mean anti-Xa level had any response to therapy. Chi-square test (P = 0.080) and logistic regression (OR = 1.23, P = 0.70) demonstrated no significant association between mean anti-Xa range (lower vs. upper) and therapy response. There was no statistically significant difference between low-range versus high-range mean anti-Xa levels and thrombus resolution. Empiric clinical practices of targeting anti-Xa levels in the higher therapeutic range to achieve better outcomes may not be warranted.

Association of Outcomes and Anti-Xa Monitoring in Treatment of Pediatric Venous Thromboembolism

BACKGROUND/INTRODUCTION: With the increased use of venous catheters and improved survival from previously life-threatening pediatric disorders (e.g., congenital heart disease, cancer), the incidence of venous thromboembolism and the need for anticoagulation have also increased.While unfractionated heparin and warfarin were once considered the standards of care, enoxaparin has now become the drug of choice in many pediatric institutions, given improved efficacy, fewer bleeding complications, minimal interaction with concurrent medications, and a more favorable pharmacokinetic profile.Regular monitoring of Anti-Xa activity is generally recommended in children treated with enoxaparin. Though the published therapeutic range for Anti-Xa levels is 0.5 - 1.0 unit/mL, there is little data in the pediatric population regarding the outcomes associated with maintaining Anti-Xa levels at the higher versus lower end of the therapeutic range.OBJECTIVES: The purpose of this study was to determine whether there was a difference in diagnostic outcomes when children received enoxaparin with Anti-Xa levels between 0.5 - 0.79 unit/mL (low therapeutic range) versus between 0.8 - 1.0 unit/mL (high therapeutic range) throughout their course of their treatment.METHODS: Using the TCH DVT Registry, we retrospectively identified 107 subjects diagnosed with uncomplicated VTE and treated with enoxaparin. Demographic information, Anti-Xa levels, dose modifications, and diagnostic outcomes were abstracted using the electronic medical record (Epic®) and analyzed.RESULTS: We evaluated 103 patients with therapeutic Anti-Xa levels at the time of hospital discharge, of whom 93 had outcomes data. Of these 93 subjects, 38% (N = 35) had complete resolution after 3 months of therapy, 40% (N = 37) had partial resolution, 20% (N = 19) were unchanged, and 2% (N = 2) had progression of their initial thrombus. Of the 72 patients with any response to therapy (complete or partial resolution), 68% (N = 49) had a mean Anti-Xa level in the low therapeutic range and 32% (N = 23) had a mean Anti-Xa level in the high therapeutic range. In comparison, of the 21 patients with no documented response to therapy (unchanged or progression), 67% (N = 14) had a mean Anti-Xa level in the low therapeutic range, and 33% (N = 7) had a mean Anti-Xa level in the high therapeutic range.Of the 93 subjects with outcomes data, all but one had a mean Anti-Xa level within the therapeutic range throughout their treatment course. Of these 92 patients, 68% (N = 63) had mean Anti-Xa levels in the low therapeutic range. 78% (N = 49) had any response (complete or partial resolution) after 3 months of therapy, and 22% (N = 14) had no documented response to therapy (unchanged or progression). Of the 92 patients, 32% (N = 29) had mean Anti-Xa levels in the high therapeutic range. 76% (N = 22) had any response to therapy and 24% (N = 7) had no response to therapy.CONCLUSIONS: There does not appear to be a statistically significant difference between low versus high range mean therapeutic Anti-Xa levels and the incidence of thrombus resolution. Empiric clinical practices of targeting Anti-Xa levels in the high end of the therapeutic range may not be warranted. DisclosuresOff Label Use: Enoxaparin use as an anticoagulant in pediatric patients with venous thromboembolism.

Administration of antithrombin concentrate in infants and children on extracorporeal life support improves anticoagulation efficacy.

Unfractionated heparin (UFH) is required in children on extracorporeal life support (ECLS) to maintain circuit patency. When high-dose UFH is inadequate to maintain an anticoagulant effect, the addition of antithrombin concentrate (ATC) is considered. The objective of this study was to review clinical experience giving 1,000 units (U) of ATC to patients on ECLS and UFH anticoagulation. Specifically, antithrombin (AT) levels pre- and post-administration of high-dose ATC, estimation of the efficacy of high-dose ATC administration as measured by the level of anticoagulation, and the incidence of adverse effects were determined. A retrospective chart review of all infants and children on ECLS who received ATC between June 2008 and May 2011 at Stollery Children's Hospital, Edmonton, Canada, was performed. A total of 78 doses of ATC were administered to 36 patients with a median age of 2.9 months (interquartile range, 0.6-12.6) on ECLS. Mean dose of ATC was 241 U/kg (95% confidence interval, 199-283). Mean AT level pre- and post-administration was 0.40 and 0.93 U/ml, respectively. Mean anti-Xa level pre- and post-AT administration was 0.23 and 0.41 U/ml, respectively. There were no associated acute adverse events. The administration of high-dose ATC decreases UFH dose requirements.

Assessing an enoxaparin dosing protocol in morbidly obese patients.

The effect of obesity on the pharmacokinetics of enoxaparin is not clearly understood and traditional treatment doses in morbidly obese patients (body mass index [BMI]>40kg/m(2)) can lead to over anticoagulation. Our institution developed an inpatient protocol with reduced enoxaparin doses (0.75mg/kg/dose based on actual body weight) for patients with a weight >200kg or BMI>40kg/m(2). The primary objective was to determine if modified enoxaparin treatment doses would achieve therapeutic anti-Xa levels (goal range 0.6-1.0IU/mL) in morbidly obese patients. Thirty-one patients were included in our study and had a median body weight of 138kg (range 105-197) and a median BMI of 46.2kg/m(2) (range 40.1-62). The initial peak anti-Xa levels were in therapeutic range in 15 of 31 patients (48%) with an initial mean anti-Xa level of 0.92IU/mL. Twenty-four patients (77%) achieved therapeutic anti-Xa levels in goal range during their hospitalization, with a mean enoxaparin dose of 0.71mg/kg. Bleeding and thrombotic events were minimal and all patients that achieved an anti-Xa level in goal range did so with a dose less than 1mg/kg of enoxaparin.

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Introduction: Obesity is an independent risk factor for venous thromboembolism (VTE) and a major cause of morbidity and mortality. The optimal enoxaparin dosing for VTE prophylaxis in obese patients based on Anti-Xa levels and correlation of Anti-Xa levels with clinical outcomes remains controversial. Methods: Data were collected retrospectively on 139 adult obese patients (BMI ≥ 30 kg/m2) who received enoxaparin for VTE prophylaxis with at least one appropriately timed Anti-Xa level (drawn 3-5 hours after the third dose) from February 1, 2011 through August 31, 2012. Data were analyzed using appropriate descriptive statistics. Results: The mean BMI and weight were 38.3 kg/m2 (range 30.1 - 66.4) and 116.1 kg (range 70 - 208.7), respectively. The initial mean Anti-Xa level was 0.13 IU/mL (range 0 - 0.47) and 21.6% of patients initially achieved the target peak Anti-Xa level between 0.2 and 0.5 IU/mL. The initial mean enoxaparin dose was 0.56 mg/kg/day (range 0.19 - 0.96). The overall rate of bleeding was 23.7%, but only two patients discontinued enoxaparin due to concern for bleeding. Two VTE events were detected. Conclusions: Standard dosing of enoxaparin for VTE prophylaxis in obese patients is inadequate to achieve target peak Anti-Xa levels. Although a relatively low incidence of bleeding and VTE was observed, the correlation between Anti-Xa levels and clinical outcomes remains unclear. Further studies are needed to elucidate this relationship and to develop an algorithm for enoxaparin VTE prophylactic dosing in obese patients.

Low molecular weight heparin dosing and monitoring in solid organ transplant recipients

Anti-Xa monitoring for low molecular weight heparin (LMWH) is currently recommended in obese, renally impaired, and pregnant patients. Substantial evidence indicates that solid organ transplant (SOT) patients are at an increased risk of renal impairment, thus representing a population at risk of LMWH accumulation. The purpose of this study was to review our experience with LMWH dosing and monitoring in a cohort of transplant recipients. This was a retrospective, single-center review of 96 SOT patients receiving enoxaparin treatment and anti-Xa monitoring. The percent of patients with supratherapeutic anti-Xas (>1 IU/mL) was determined, as was the relationship between enoxaparin dosages and anti-Xa levels and bleeding. The cohort had a mean age of 62 yr and creatinine clearance of 59 mL/min and was primarily lung transplant recipients (73%). The mean enoxaparin dose was 0.82 mg/kg, which resulted in a mean anti-Xa level of 0.98 IU/mL. Despite the reduced enoxaparin dose, 44% of patients experienced a supratherapeutic anti-Xa level. Patients with supratherapeutic anti-Xas had higher doses than those within the therapeutic range (0.89 mg/kg vs. 0.77 mg/kg; p = 0.002). No major bleeds occurred. Supratherapeutic anti-Xa levels are common in transplant patients receiving enoxaparin therapy. Empirically reduced dosing of enoxaparin and monitoring may warrant consideration in this population.

Peak plasma anti-Xa levels after first and third doses of enoxaparin in women receiving weight-based thromboprophylaxis following caesarean section: a prospective cohort study

BackgroundWomen undergoing caesarean section are at higher risk for thromboembolic complications following delivery than other parturients. The aim of this study was to determine whether higher doses of enoxaparin based on body weight are safe and more likely to achieve plasma anti-Xa levels within the accepted thromboprophylactic range. MethodsWe undertook a prospective cohort study of 80 women undergoing caesarean section in a tertiary obstetric hospital with >6000 deliveries per year. Enoxaparin was administered after caesarean section using the Royal College of Obstetricians and Gynaecologists weight-adjusted dosing guidelines. Plasma anti-Xa levels were measured at baseline and 3–4h after enoxaparin administration on days one and three postoperatively. The main outcomes of interest were plasma anti-Xa levels and the proportion of patients with plasma anti-Xa levels in the range of 0.2–0.4IU/mL. ResultsThe proportion of women with anti-Xa levels between 0.2 and 0.4IU/mL was 72% (95% CI 60–81%). Unadjusted mean anti-Xa levels were 0.26±0.09IU/mL and 0.28±0.08IU/mL on day one and day three respectively. No woman had levels >0.48IU/mL. ConclusionThe majority of women receiving weight-based enoxaparin thromboprophylaxis following caesarean section achieved plasma anti-Xa levels within the putative thromboprophylactic range. No woman achieved levels associated with an increased risk of bleeding (>0.8IU/mL). These findings provide a safety basis for a large prospective study using this regimen.

Tinzaparin Versus Dalteparin for Peri-Procedure Thromboembolic Prophylaxis in Patients with Dialysis Dependent Renal Disease.

Abstract 3136Poster Board III-73 BackgroundLow-molecular-weight heparins (LMWHs) can be administered in fixed subcutaneous doses permitting predictable parenteral anticoagulation in an out-of-hospital setting. The renal clearance of LMWHs leads to uncertainty about the safety of use of LMWHs in patients on hemodialysis given the potential for bioaccumulation of anticoagulant effect which may lead to bleeding. MethodsWe conducted a randomized open label trial to investigate the feasibility and safety of a perioperative anticoagulation protocol in hemodialysis patients comparing two LMWHs preparations as outpatient bridging therapy when warfarin is interrupted for invasive procedures. The primary objective of the study was to compare if tinzaparin and dalteparin differentially bioaccumulate in hemodialysis (HD) patients after three therapeutic doses. Warfarin therapy was discontinued in these patients 5 to 6 days prior to surgery. Patients were randomized to either 3 doses of tinzaparin (175 IU/kg/day) or dalteparin (200 IU/kg/day) with two dialyses in the interval between the first dose of study drug and inavsive procedure. Primary outcome was pre-dialysis anti-Xa levels 20-24hrs post third therapeutic LMWH dose to determine if these LMWHs accumulated in HD patients, and if they differentially accumulated. After procedure, patients received a daily prophylactic dose of tinzaparin (4500 IU) and dalteparin (5000 IU) for 3 to 4 days along with dialysis. Post- procedure pre- and post- dialysis anti-Xa levels were also monitored. ResultsOf 29 eligible and consenting patients, 17 patients (58.6%) received tinzaparin sodium and 12 patients (41.4%) received dalteparin sodium. Two patients were withdrawn prior to invasive procedure and the invasive procedures were canceled (1 for important bio-accumulation in the dalteparin arm; 1 for major bleed in the tinzaparin arm). Primary outcome anti-Xa samples were not analyzable in 2 patients (1 contaminated with heparin; 1 drawn too early). There was important and significant bioaccumulation in both study drug arms. The mean primary outcome pre-dialysis anti-Xa level 20-24hrs post third tinzaparin dose was 0.40 IU/ml (SD= 0.21). The mean primary outcome pre-dialysis anti-Xa level 20-24hrs post third dalteparin dose was 0.57 IU/ml (SD= 0.43). There was no statistically significant difference between the two study drug groups (student's t-test (p value = 0.33). Postoperatively 16/21 (76%) of patients tested had undetectable pre-dialysis anti-Xa levels 20-24hrs post prophylactic dose, with the remaining 5 patients having a mean anti-Xa level of 0.23 IU/ml (SD = 0.25). During subsequent follow-up, 2 patients experienced serious adverse events (one non-STEMI in patient who died of sepsis (tinzaparin group) and one upper extremity DVT (dalteparin group)). ConclusionsTinzaparin and Dalteparin significantly accumulate at therapeutic doses in HD patients with no statistically significant difference detected in accumulation between the drugs. Neither drug importantly accumulates at prophylactic doses in HD patients. “Bridging therapy” with LMWHs at therapeutic doses in patients on hemodialysis who require temporary interruption of warfarin for invasive procedures is risky and of uncertain risk benefit. DisclosuresRodger:Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding.

Comparison of two low-molecular-weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery

Venous thromboembolic events (VTE) are a morbidity and mortality concern for patients undergoing laparoscopic bariatric surgery. Although VTE prophylaxis is recommended in bariatric surgery, data with regard to monitoring and appropriate dosing of low-molecular-weight heparin are limited. Enoxaparin prophylactic doses ranging from 30 to 60 mg every 12 h have been used for this population. The authors hypothesized that higher prophylactic enoxaparin doses (60 mg) would yield more appropriate heparin antifactor Xa (anti-Xa) concentrations than the 40-mg dosage for bariatric surgery patients. Patients undergoing laparoscopic bariatric surgery by two surgeons during a 5-month period at one institution received enoxaprin 40 or 60 mg every 12 h. Anti-Xa levels were obtained 4 h after the first and third doses. Therapeutic levels were defined as 0.18 to 0.44 U/ml. Paired and unpaired t-tests and chi-square tests were used for statistical analysis as appropriate. The first-dose mean anti-Xa concentration was 0.173 U/ml in the 40-mg group and 0.261 U/ml in the 60-mg group (p < 0.005), compared with the third-dose mean anti-Xa levels of 0.21 and 0.43 U/ml, respectively (p < 0.001). After the third dose of enoxaparin, the percentage of patients with anti-Xa concentrations who remained subtherapeutic showed a statistically significant difference: 44% in the 40-mg group versus 0% in the 60-mg group (p = 0.02). However, no supratherapeutic anti-Xa concentrations were observed in the 40-mg group, whereas 57% of the third-dose levels in the 60-mg group were supratheraputic. The highest anti-Xa level was 0.54 U/ml, but none of the patients with this level experienced bleeding events. Enoxaparin 60-mg every 12 h was superior to a dosage of 40 mg every 12 h in achieving therapeutic anti-Xa concentrations and avoiding subtherapeutic anti-Xa levels. However, the 60-mg group had a number of supratherapeutic levels. Future studies evaluating the relationship of anti-Xa concentrations and outcomes with larger numbers of morbidly obese patients are needed.

Prevention of Early Arteriovenous Fistula Failure Due to Thromosis: Experience with Primary Thromboprophylaxis.

Background: Arteriovenous fistula (AVF) is the preferred vascular access for children with end stage renal disease (ESRD) requiring hemodialysis. Once AVF is surgically created, it takes 6 to 12 weeks to mature. Nearly 20 to 50% of AVFs fail to mature due to development of primary or secondary thrombosis. Currently there is no uniform strategy to prevent the thrombosis at AVF. We report our experience of using primary thromboprophylaxis (PTP) for prevention of thrombosis at AVF.Methods & Results: A strategy of PTP constituted an infusion of unfractionated heparin (UFH, 10 IU/kg/hr) for the first 24 hours after AVF surgery followed by subcutaneous injection of low molecular weight heparin (LMWH, 0.5 to 1 mg/kg/dose) twice daily until AVF was matured and successfully accessed. LMWH therapy was monitored by peak and trough anti-Xa levels. Target anti-Xa levels were maintained in therapeutic range (0.5 to 1.0 IU/ml) for those with history of thrombosis or associated risk factors for thrombosis while remaining patients were maintained in prophylactic range (0.2 to 0.5 IU/ml). Trough anti-Xa level was aimed to be les than 0.2 IU/ml. Total of 26 AVF were performed on 18 children from January 2001 to July 2006: 19 (73%) historical controls; 7 (27%) received PTP. Mean time for AVF maturation was 60 days (range: 33 to 88). Among 19 children, 14 received no thromboprophylaxis while 5 received aspirin (81 mg once daily). Eleven (79%) of 14 AVF in no treatment group failed: 9/14 (65%) due to thrombosis, 2/14 (14%) due to poor growth of venous segment. Among 5 children who received aspirin prophylaxis, 2 (40%) AVFs failed, 1 (20%) developed hematoma and 1 (20%) had poor growth. In PTP group, 2/7 (29%) AVF failed: 1 due to hematoma, 1 due to poor growth. Additional events in PTP group included: vasospasm-induced thrombosis requiring thrombectomy (n=1) and hematoma (n=2, one was salvaged by surgical evacualtion). Two children who developed hematoma had anti-Xa levels at 1.56 IU/ml and 0.6 IU/ml respectively. Presently 4/7 (57%) AVFs in PTP group are functioning well (Figure 1). The 7th patient does not require hemodialysis. Three of the 5 children in the PTP group are still on LMWH (mean duration 6 months, mean anti-Xa level 0.6 IU/ml). Mean AVF survival was higher in children who received PTP (Day 100 survival: 57.14±18.7% versus 42.10±11.32% respectively; p 0.20; Figure 2). Small sample size thus far limits the meaningful statistical analysis.Conclusion: Our experience of LMWH thromboprophylaxis appears encouraging for prevention of AVF failure due to thrombosis. Close clinical and laboratory monitoring is required to prevent bleeding complications related to LMWH. More prospective data to expand our sample size will be required to clarify our observation. [Display omitted] [Display omitted]

27 Prevention of Arteriovenous Fistula Failure Due to Thromosis: Is there a Role for Thromboprophylaxis?

Background: Development of thrombosis is the commonest cause of arteriovenous fistula (AVF) failure in children with end stage renal disease (ESRD) requiring hemodialysis. We report our experience of using primary thromboprophylaxis (PTP) for prevention of thrombosis at AVF. Methods & Results: A strategy of PTP constituted an infusion of unfractionated heparin (UFH, 10 IU/kg/hr) for the first 24 hours after AVF surgery followed by subcutaneous injection of low molecular weight heparin (LMWH, 0.5 to 1 mg/kg/dose) twice daily until AVF was matured and successfully accessed. LMWH therapy was monitored by peak and trough anti-Xa levels. Target anti-Xa levels were maintained in therapeutic range (0.5 to 1.0 IU/ml) for those with history of thrombosis or associated risk factors for thrombosis while remaining patients were maintained in prophylactic range (0.2 to 0.5 IU/ml). Total of 26 AVF were performed on 18 children from Jan 2001 to July 2006: 19 (73%) historical controls; 7 (27%) received PTP. Mean time for AVF maturation was 60 days (range: 33 to 88). Among 19 children, 14 received no thromboprophylaxis while 5 received aspirin (81 mg once daily). Eleven (79%) of 14 AVF in no treatment group failed: 9/14 (65%) due to thrombosis, 2/14 (14%) due to poor growth of venous segment. Among 5 children who received aspirin prophylaxis, 2/5 (40%) AVFs failed. One (20%) developed hematoma and 1 (20%) had poor growth. In PTP group, 2/7 (29%) AVF failed: 1 due to hematoma, 1 due to poor growth. Additional events in PTP group included: vasospasm-induced thrombosis requiring thrombectomy (=1) and hematoma (=2). Two children who developed hematoma had anti-Xa levels at 1.56 IU/ml and 0.6 IU/ml respectively. Presently 4/7 (57%) AVFs in PTP group are functioning well. The 7th patient does not require hemodialysis. Three of the 5 children in the PTP group are still on LMWH (mean duration 6 months, mean anti-Xa level 0.6 IU/ml). Mean AVF survival was higher in children who received PTP (Day 100 survival: 57.14±18.7% versus 42.10±11.32% respectively; p 0.20; Figure). Small sample size thus far limits the meaningful statistical analysis. Conclusion: Our experience of LMWH thromboprophylaxis appears encouraging for prevention of AVF failure due to thrombosis. Close clinical and laboratory monitoring is required to prevent bleeding complications related to LMWH. More prospective data to expand our sample size will be required to clarify our observation.

A Protocol for the Use of Enoxaparin During Pregnancy: Results from 85 Pregnancies Including 13 Multiple Gestation Pregnancies

Many practitioners consider low-molecular-weight heparin (LMWH) an alternative to unfractionated heparin, although there are limited safety data regarding maternal and fetal outcomes in patients using an LMWH during pregnancy. A retrospective chart review was performed on 72 patients with thrombophilia exposed to the LMWH, enoxaparin, during pregnancy. Eighty-five pregnancies resulted in 93 of 99 potential live births. Eleven of 12 twin pregnancies and one triplet pregnancy were successful. One preterm live birth infant of 33 weeks' gestation did not survive. Three patients with thrombophilia spontaneously aborted. A patient receiving injectable fertility treatment had spontaneously aborted one twin at 5 weeks' gestation. One patient terminated the pregnancy after discovering the presence of Down's syndrome. The mean maximum dose required to achieve a therapeutic anti-Xa level of 0.2-0.4 IU/mL at 5 to 6 hours following administration, was 38.1 mg every 12 hours (median 35 mg, range 30-75 mg every 12 hours). The mean anti-Xa level was 0.28 IU/mL (median 0.3, range 0.05-0.8 IU/mL). A total of nine patients experienced bleeding events, two requiring discontinuation of enoxaparin for the remainder of the pregnancy. Two patients experienced injection site reactions requiring discontinuation of enoxaparin. Three patients developed preeclampsia, two placenta abruptio, and one placenta previa. No thromboembolic complications or osteoporotic fractures had occurred. Enoxaparin was safe and effective for preventing thromboembolism and adverse obstetrical complications in our patients, including 12 of 13 multiple gestation pregnancies.

Anti-Xa effect of a low molecular weight heparin (dalteparin) does not accumulate in extended duration therapy for venous thromboembolism in cancer patients

Many patients with venous thromboembolism are being treated with low molecular weight heparin for extended periods of time. It is not certain if it is necessary to assess anti-Xa levels for extended treatment periods. This study is a prospective assessment of anti-Xa levels in patients on long-term therapy for acute venous thromboembolism who have active cancer. Consecutive consenting patients from one center in a multicenter trial that compared 6 months of low molecular weight heparin with oral anticoagulant therapy were treated with therapeutic doses of dalteparin (200 IU per kilogram) subcutaneously daily. Anti-Xa levels were assessed at the end of weeks 1 and 4,4-6 hours after injection of dalteparin. Patients were followed for bleeding and recurrent venous thromboembolism. There were 24 patients who had anti-Xa levels measured at weeks 1 and 4. Two other patients had week 1 measurements performed but died before the week 4 sample was collected due to their underlying cancer. The mean anti-Xa levels at weeks 1 and 4 were 1.11 and 1.03 anti-Xa units/ml respectively (P=0.13). These results suggest that for patients with active cancer receiving extended duration therapy with low molecular weight heparin (dalteparin) there is no accumulation of anti-Xa effect over the first month of therapy. Monitoring of anti-Xa levels in this situation is usually not required.

A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy.

To assess the maternal response to low molecular weight heparin during pregnancy, by estimation of plasma anti-Xa activity, at three specified gestation points and in the nonpregnant state. A longitudinal, prospective, observational study was set in a tertiary referral recurrent miscarriage clinic. Twenty-four women, attending consecutively, were invited to participate and gave informed consent. Each woman had a history of recurring pregnancy loss and positive preconception screening for antiphospholipid syndrome. After confirmation of a viable pregnancy all subjects began taking 5000 IU of dalteparin once daily subcutaneously. Serial measurement of plasma anti-Xa activity after administration of dalteparin was performed at three standard gestation points (12, 24, and 36 weeks) and in the nonpregnant state (6 weeks postpartum). Peak anti-Xa levels occurred at 4 hours postbolus in pregnancy, as compared with 2 hours in the nonpregnant state. The mean anti-Xa levels at 12, 24, and 36 weeks' gestation were significantly reduced, at 2 hours postinjection, as compared with the nonpregnant state (P <.001, P <.01, P <.001, respectively). The lowest dose-response curve was at 36 weeks' gestation. A repeated-measures analysis of variance found a significant difference (P <.05) between the 36-week group and the postterm group but not between any of the other groups. During pregnancy, differences in the pharmacokinetics of low molecular weight heparin were observed, with an overall reduction in anti-Xa activity. On the basis of this study it is questionable to extrapolate dosing and lack of dose monitoring, in pregnant women, using data derived from a nonpregnant population.

Use of a low-molecular-weight heparinoid (danaparoid sodium) for continuous renal replacement therapy in intensive care patients.

The purpose of this study was to evaluate the efficacy and safety of danaparoid in the treatment of critically ill patients with acute renal failure and suspected heparin-induced thrombocytopenia (HIT) needing renal replacement therapy (RRT). We conducted a retrospective analysis of 13 consecutive intensive care patients with acute renal failure and suspected HIT who were treated with danaparoid for at least 3 days during RRT. In eight patients, continuous venovenous hemofiltration was performed. The mean infusion rate of danaparoid was 140 +/- 86 U/hour. Filter exchange was necessary every 37.5 hours. In five patients, continuous venovenous hemodialysis was used. A bolus injection of 750 U danaparoid was followed by a mean infusion rate of 138 +/- 122 U/hour. Filters were exchanged every 24 hours. In 7 of 13 patients, even a low mean infusion rate of 88 +/- 35 U/hour was efficient. Mean anti-Xa (aXa) levels were approximately 0.4 +/- 0.2 aXa U/mL. Persistent thrombocytopenia despite discontinuation of heparin treatment was observed in 9 of 13 patients, owing to disseminated intravascular coagulation (DIC). HIT was confirmed by an increase in platelet count and positive heparin-induced antibodies in 2 of 13 patients. No thromboembolic complications occurred, but major bleeding was observed in 6 of 13 patients, which could be explained by consumption of coagulation factors and platelets due to DIC in 5 of 6 patients. Nine of 13 patients died of multiorgan failure or sepsis, or both. In none of these patients was the fatal outcome related to danaparoid treatment. In critically ill patients with renal impairment and suspected HIT, a bolus injection of 750 U danaparoid followed by a mean infusion rate of 50 to 150 U/hour appears to be a safe and efficient treatment option when alternative anticoagulation is necessary.

Enoxaparin treatment in women with mechanical heart valves during pregnancy

Objective: This prospective audit reports pregnancy outcomes, anticoagulation complications, and anti-Xa levels in women with mechanical heart valves who were treated with therapeutic enoxaparin plus aspirin during pregnancy. Study Design: Between 1997 and 1999, 11 women with mechanical heart valves were treated with enoxaparin, 1 mg/kg twice daily, and aspirin, 100 to 150 mg daily during 14 pregnancies. Predose and 4-hour postdose anti-Xa levels were monitored monthly. Results: There were 9 live births, 3 miscarriages, and 2 terminations. In 48 months of enoxaparin treatment, one woman who had a documented valve thrombosis when she presented at 8 weeks’ gestation also had a valve thrombosis at 20 weeks’ gestation. There were no enoxaparin-related hemorrhagic complications. Mean (SD) anti-Xa levels were 0.46 (0.12) U/mL predose and 0.89 (0.22) U/mL 4 hours postdose. Conclusion: Successful pregnancy outcome may be achieved with therapeutic subcutaneous enoxaparin, but its efficacy at preventing valve thrombosis remains uncertain. Further data are required before use of enoxaparin during pregnancy in women with mechanical heart valves can be recommended. (Am J Obstet Gynecol 2001;185: 633-7.)

The Anti-xa assay, fragmin (LMWH) and prophylaxis for thrombosis in orthopaedic surgery

Over the last few years various studies have reported the advantage of low molecular weight heparin (LMWH) over standard unfractionated heparin (UFH). The advantages are stated to be ease of administration (once daily injection), the suggested non-requirement of monitoring for prophylaxis, fewer bleeding episodes and a greatly roduced risk of venous thrombotic episodes when used in orthopaedic surgery. LMWH has greater bioavailability and greater duration of activity when Injected subcutaneously, with a longer biological half-life than UFH. the anti-thrombotic effects being due to the Inhibition of factor Xa. The commercial chromogenic assay tor measuring Anti-Xa activity (BERICHROM-HEPARIN) has been used as an Indicator of Fragmin activity. The method utilizes the principle that Factor Xa is inactivated by ATIII which Is catalysed by heparin. A pilot study of twenty patients undergoing either hip or knee surgery was undertaken to assess the standard dose recommended by the manufacturer (5000 IU/day lor high-risk' patients). In our study S.C. Fragmin 2500 U was given pre-operatively, with the premedication, followed by 2500 IU immediately post opetatively. The day following surgery and daily, for a total of 7 days Fragmin 50CO IU was administered at 6.00 a.m. and Anti-Xa assays collected 4 hours latee batched, and tested retrospectively. Other laboratory investigations included FBE and baseline APTT and INR. On day seven, photographs and ultrasound examination of the operated leg were undertaken. In the study 60% of patients had Anti-XA levels > 0.4 U/ml and all patients had levels > 0.2 U/mi. The mean Anti Xa level was 0.46 U/ml. These results were higher than expected. Patients with levels >0.4 U/ml being above the prophylactic range may have a higher risk of bleeding. Associated with these levels was significant blood loss. For knee surgery, the average blood loss was 1170 mis, with an average of 3.4 units transfused; for hip surgery the average toss was 1255 mis, with an average of 3.2 units transfused. In three patients unusual Wound blistering' was noted, and In 50% significant bruising was present at the operative site, with distal extension, uncharacteristic for the procedure. No clinical venous thrombosis was detected. In all patients, ultrasound was negative for thrombosis. In one patient only a DVT subsequently occurred three weeks post-operatively. In this study subjectively significant bleeding occurred with the recommended daily dose of 5000 IU SC. which may be substantiated by the higher than expected Anti-Xa levels. In order to avoid monitoring FRAGMIN for prophylaxis and m view of the above findings it is recommended that a dose reduction to 2S00 IU day be considered for knee surgery, and possibly for hip surgery. For the latter, this must be balanced against the thrombotic risks, and can only be elucidated by further studies.

Identification of Risk Factors for Bleeding During Treatment of Acute Venous Thromboembolism With Heparin or Low Molecular Weight Heparin

In a prospective double-blind trial, we treated 194 patients with acute venous thromboembolism with heparin or low molecular weight heparin (LMWH; Fragmin). To evaluate the most important prognostic factors for bleeding, the presenting clinical features of the patients, the patients' anticoagulant responses, and the doses of the drugs were analyzed using univariate and multivariate regression analyses. No significant differences in clinical risk factors associated with bleeding were observed between heparin and LMWH. The univariate analyses ranked the parameters in the following order of importance: World Health Organization (WHO) performance status, history of bleeding tendency, cardiopulmonary resuscitation, recent trauma or surgery, leukocyte counts, platelet counts, duration of symptoms, and body surface area. Patients with WHO grade 4 had an eightfold increase in risk of bleeding as compared with WHO grade 1. Assessment of the individual contribution of each variable using multivariate regression analysis showed that the WHO performance status was the most important independent factor predicting major bleeding. A history of a bleeding tendency, recent trauma or surgery, and body surface area were also independent risk factors. The risk of bleeding was influenced by two factors related to the treatment, the patient's anticoagulant response as measured with the anti-Xa assay and the dose of the drug expressed as U/24 h/m2. An increased risk of bleeding was only observed at mean anti-Xa levels greater than 0.8 U/mL for both drugs. Significantly more major bleedings occurred in patients treated with high doses of the drugs, an observation that was independent of the concomitant anti-Xa levels. It should be considered whether choosing an appropriate initial dose adapted to the patient's body surface area and clinical risk factors can improve the efficacy to safety ratio of heparin treatment.