anti-Xa Concentrations Research Articles

Enoxaparin Dosing at Extremes of Weight: Literature Review and Dosing Recommendations.

To review the literature on both thromboprophylaxis and treatment of venous thromboembolism (VTE) with enoxaparin in low- and high-body-weight patients and to make dosing and monitoring recommendations in these patient populations. A search using PubMed was conducted (1995 to January 2018) using the following key words: enoxaparin, body weight, AND thromboprophylaxis, or AND treatment. Additional references were identified from a review of citations. Studies included examined the effect of body weight and/or body mass index (BMI) on VTE, bleeding, enoxaparin dosing, and/or anti-Xa concentrations for thromboprophylaxis and treatment-dose enoxaparin. Studies in pediatric and pregnant patients were excluded. Optimal enoxaparin dosing strategies for VTE prophylaxis and treatment for patients at extremes of weight have not yet been elucidated by clinical trials; however, data suggest that standard dosing regimens may not be appropriate in these patients. Relevance to Patient Care and Clinical Practice: This review provides a thorough discussion on both thromboprophylaxis and treatment of VTE with enoxaparin in low- and high-body-weight patients. It includes dosing recommendations to guide clinicians caring for these patient populations. Patients at extremes of weight require special consideration to determine appropriate enoxaparin doses. Specifically, low-body-weight patients may benefit from 30 mg subcutaneously daily for VTE prophylaxis, and standard weight-based dosing for VTE treatment. Conversely, in patients with BMIs ≥40 kg/m2, 40 mg subcutaneously twice daily is recommended, with consideration for higher doses in patients with BMIs ≥50 kg/m2.

The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients.

Morbidly obese patients are at increased risk to develop venous thromboembolism (VTE), especially after bariatric surgery. Adequate postoperative thrombosis prophylaxis is of utmost importance. It is assumed that morbidly obese patients need higher doses of low molecular weight heparin (LMWH) compared to normal-weight patients; however, current guidelines based on relative efficacy in obese populations are lacking. First, we will evaluate the relationship between body weight descriptors and anti-Xa activity prospectively. Second, we will determine the dose-linearity of LMWH in morbidly obese patients. This study was performed in a general hospital specialized in bariatric surgery. Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight (TBW) of ≥ 140kg. Patients (n = 50, 64% female) received a daily postoperative dose of 5700IU of nadroparin for 4weeks. Anti-Xa activity was determined 4h after the last nadroparin administration. To determine the dose linearity, anti-Xa was determined following a preoperative dose of 2850IU nadroparin in another 50 patients (52%). TBW of the complete group was 148.5 ± 12.6kg. Mean anti-Xa activity following 5700IU nadroparin was 0.19 ± 0.07IU/mL. Of all patients, 32% had anti-Xa levels below the prophylactic range. Anti-Xa activity inversely correlated with TBW (correlation coefficient - 0.410) and lean body weight (LBW; correlation coefficient - 0.447); 67% of patients with a LBW ≥ 80kg had insufficient anti-Xa activity concentrations. No VTE events occurred. In morbidly obese patients, a postoperative dose of 5700IU of nadroparin resulted in subprophylactic exposure in a significant proportion of patients. Especially in patients with LBW ≥ 80kg, a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels.

Antepartum Venous Thromboembolism Prophylaxis Dosing With Low Molecular Weight Heparin in Obese Population [34C

INTRODUCTION: To determine adequacy of venous thromboembolism prophylaxis dosing with low-molecular-weight heparin (LMWH) in pregnant women based on anti-Xa concentrations, with focus on the obese population. METHODS: A retrospective cohort identified 50 subjects treated with prophylactic LMWH during pregnancy at the University of Kansas Medical Center between January 2012 and May 2016 were identified from the electronic medical record. Subjects were excluded if they did not deliver at our medical center, were not monitored with anti-Xa levels, or were receiving prophylaxis for proteinuria. The data abstracted from the chart included subject demographics, BMI, indication for pharmacologic thromboprophylaxis, LMWH dosing, anti-Xa levels, weight gain, and potential complications. Fischer exact test and ANOVA were used for statistical analysis. RESULTS: 31 subjects were identified who were treated with an initial starting LMWH dose of 40mg daily. Of these, only 32.26% (10/31) had a prophylactic anti-Xa level (0.2-0.4). When stratified by BMI at treatment start, 58.82% (10/17) with BMI < 30.0 compared to 0% (0/14) subjects with BMI >30.0 reached a prophylactic anti-Xa level (p=0.0008). When stratified by gestational age at treatment start, 45% (9/20) in the first trimester, 33.33% (3/9) in the second trimester, and 0% (0/2) of subjects in the third trimester were at a prophylactic anti-Xa level on daily 40mg LMWH (p=0.24). CONCLUSION: Pregnant women with initial BMI >30.0 treated with daily 40mg LMWH are not likely to achieve a prophylactic anti-Xa level. BMI or weight-based dosing should be considered and patients should be monitored with anti-Xa levels during pregnancy.

Clinical Feasibility of Monitoring Enoxaparin Anti-Xa Concentrations: Are We Getting It Right?

Background: Anti-Xa monitoring is utilized to measure the extent of anticoagulation in certain patient populations receiving enoxaparin. It is essential to accurately obtain this pharmacodynamic marker for safe and effective anticoagulation management. Objectives: To determine the frequency of correctly drawn anti-Xa concentrations in accordance with predefined institutional criteria and to determine the number of dose adjustments implemented based on incorrectly drawn anti-Xa concentrations. Methods: This was a retrospective, single-center, cohort study among adult patients who received treatment doses of enoxaparin with measured anti-Xa concentrations. Patients were excluded if they were pregnant, on hemodialysis, or received prophylactic dosing. Anti-Xa levels were defined as correctly measured if they were drawn 3 to 5 hours after the dose during steady state concentrations. Descriptive statistics were performed and analyzed via SPSS software. Results: Overall, 203 patients were reviewed and 59 patients with 74 anti-Xa levels were included. The majority of anti-Xa levels (57/74; 77%) were drawn incorrectly and often resulted in collection of repeat anti-Xa samples. There were 12 documented dose adjustments and approximately 42% (5/12) were based on incorrectly drawn anti-Xa levels. Anti-Xa levels were within target range approximately 45% of the time. Conclusions: Enoxaparin anti-Xa concentrations are frequently drawn incorrectly and dose adjustments are often performed based on these unsupported anti-Xa levels. This may present a potential risk to compromise patient safety.

Enoxaparin dosing after cesarean delivery in morbidly obese women.

To compare the adequacy of venous thromboembolism prophylaxis based on anti-Xa concentrations between weight-based enoxaparin dosing and body mass index (BMI)-stratified dosing in morbidly obese women after cesarean delivery. A prospective sequential cohort study of women with BMIs of 40 or greater who underwent cesarean delivery was conducted. Participants received either weight-based or BMI-stratified enoxaparin dosing to prevent venous thromboembolism formation. The weight-based regimen was 0.5 mg/kg of enoxaparin every 12 hours. In the BMI-stratified regimen, women with BMIs of 40-59.9 received 40 mg enoxaparin every 12 hours and women with BMIs of 60 or greater received 60 mg every 12 hours. The primary outcome was an anti-Xa concentration in the adequate thromboprophylaxis range (0.2-0.6 international units/mL). Secondary outcomes included enoxaparin dosage, timing of dosing and anti-Xa concentration, estimated surgical blood loss, postoperative changes in hemoglobin and platelets, wound hematoma, and adverse reactions to enoxaparin. Univariate analysis was used to compare dosing regimens. Forty-two morbidly obese women received weight-based enoxaparin, and 43 received BMI-stratified dosing. Anti-Xa concentrations were significantly higher in the weight-based group compared with the BMI-stratified group (0.29±0.08 international units/mL compared with 0.17±0.07 international units/mL, P<.001). Thirty-six participants (86%) on weight-based dosing had anti-Xa concentrations within the prophylactic range compared with 11 (26%) on BMI-stratified dosing (P<.001). No participant had an anti-Xa concentration of 0.6 international units/mL or greater, the therapeutic threshold for venous thromboembolism prophylaxis. In morbidly obese women after cesarean delivery, weight-based dosing of enoxaparin for venous thromboembolism prophylaxis is significantly more effective than BMI-stratified dosing in achieving adequate anti-Xa concentrations. II.

Measuring anti-factor xa activity to monitor low-molecular-weight heparin in obesity: a critical review.

The choice of whether to monitor anti-factor Xa (anti-Xa) activity in patients who are obese and who are receiving low-molecular-weight heparin (LMWH) therapy is controversial. To the authors' knowledge, no systematic review of monitoring of anti-Xa activity in such patients has been published to date. To systematically ascertain the utility of monitoring anti-Xa concentrations for LMWH therapy in obese patients. MEDLINE (1946 to September 2014), the Cochrane Database of Systematic Reviews, Embase (1974 to September 2014), PubMed (1947 to September 2014), International Pharmaceutical Abstracts (1970 to September 2014), and Scopus were searched using the terms obesity, morbid obesity, thrombosis, venous thrombosis, embolism, venous thromboembolism, pulmonary embolism, low-molecular weight heparin, enoxaparin, dalteparin, tinzaparin, anti-factor Xa, anti-factor Xa monitoring, anti-factor Xa activity, and anti-factor Xa assay. The reference lists of retrieved articles were also reviewed. English-language studies describing obese patients treated with LMWH or reporting anti-Xa activity were reviewed using a 9-step decision-making algorithm to determine whether monitoring of LMWH therapy by means of anti-Xa activity in obesity is warranted. Studies published in abstract form were excluded. The analysis showed that anti-Xa concentrations are not strongly associated with thrombosis or hemorrhage. In clinical studies of LMWH for thromboprophylaxis in bariatric surgery, orthopedic surgery, general surgery, and medical patients, and for treatment of venous thrombo embolism and acute coronary syndrome, anti-Xa activity can be predicted from dose of LMWH and total body weight; no difference in clinical outcome was found between obese and non-obese participants. Routinely determining anti-Xa concentrations in obese patients to monitor the clinical effectiveness of LMWH is not warranted on the basis of the current evidence. Circumstances where measurement of anti-Xa concentration may help in clinical decision-making in either obese or non-obese patients would be cases where elimination of LMWH is impaired or there is an unexpected clinical response, as well as to confirm compliance with therapy or to identify deviation from predicted pharmacokinetics.

Clinical experience with prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment or renal failure requiring renal replacement therapy.

Fondaparinux has an increased bleeding risk in patients with a CrCl ≤ 50 mL/min and is contraindicated if CrCl < 30 mL/min. Data regarding dosing and anti-Xa monitoring are lacking in this population. To describe dosing, monitoring, and safety outcomes of prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment, including renal replacement therapy (RRT). Retrospective analysis from October 2006 to November 2012 of patients ≥ 18 years old who received fondaparinux for ≥ 72 hours with ≥ 1 dose in an intensive care unit and a CrCl ≤ 50 mL/min or RRT during therapy. Participants were divided into 4 cohorts: moderate impairment (CrCl = 30-50 mL/min), severe impairment (CrCl < 30 mL/min), hemodialysis (HD), or continuous venovenous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and thromboembolic events. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. Pharmacokinetic modeling was performed to assess drug accumulation. In all, 95 patients met inclusion criteria: 64 (67.4%) with moderate impairment, 10 (10.5%) with severe impairment, 5 (5.3%) with HD, and 16 (16.8%) with CVVH. The median defined daily doses in the moderate, severe, HD, and CVVH cohorts were 2.5, 2.5, 0.9, and 1.9 mg. Anti-Xa monitoring occurred in 19 (20%) patients, although few concentrations were peaks. Clinically significant bleeding occurred in 4 (4.2%) patients. A pharmacokinetic model demonstrated drug accumulation. Empirical dose adjustments may be prudent in critically ill patients with renal dysfunction; however, the optimal fondaparinux dosage in this population remains unknown. Peak anti-Xa concentrations may help guide therapy.

Higher doses of low-molecular-weight heparin (enoxaparin) are needed to achieve target anti-Xa concentrations in critically ill children*.

To demonstrate that low-molecular-weight heparin (enoxaparin) can be used in critically ill pediatric patients to achieve target anti-factor Xa concentrations and determine appropriate dosing corrected for age and illness severity. Retrospective cohort study. Single tertiary level PICU. One hundred ninety-two children age 1 day through 18 years admitted to PICU undergoing every 12-hour enoxaparin therapy with at least one anti-factor Xa concentration obtained. Patients receiving renal replacement therapy or infants with corrected gestational age less than 37 weeks were excluded. None. We collected patient characteristics including age, weight, height/length, gender, corrected gestational age, illness severity markers, diagnosis, creatinine, enoxaparin dose and times of administration, anti-factor Xa concentrations, and collection times. Only 42% of critically ill children (80 of 192) and only 29% of children (9 of 31) on inotropes achieved recommended target range of anti-factor Xa concentrations on initial recommended enoxaparin dosing (1.5 mg/kg/dose < 2 mo; 1 mg/kg/dose > 2 mo), but 81% were ultimately within target range with dose titration. Increased enoxaparin dose was required to reach target concentrations in younger patients and those with worse illness severity as evidenced by concurrent use of inotropes, previous ICU admission, mechanical ventilation, cardiac surgery, and increased risk of mortality defined by severity-of-illness scores. Enoxaparin can be used to reach recommended target range of anti-factor Xa concentrations in the PICU patient. However, younger patients and patients with higher illness severity are less likely to achieve target concentrations using currently recommended dosing and may require higher doses of enoxaparin to reach target anti-factor Xa concentrations. Starting enoxaparin dose at least 1.3 mg/kg dosed every 12 hours for treatment of thromboembolic disease in critically ill patients aged 61 days to 1 year or those requiring inotropic support should be confirmed in prospective study.

Correlation of Treatment Dose Enoxaparin with Anti-Xa Concentrations in Adult Hemodialysis Inpatients

Enoxaparin, a low-molecular-weight-heparin, is being used in hemodialysis patients despite a lack of guideline or manufacturer dose recommendations. Due to enoxaparin’s renal excretion, the possibility of accumulating anti-Xa concentrations in hemodialysis patients using enoxaparin creates a hemorrhagic risk, calling for more research. The objectives of this study are to determine the correlation between treatment dose enoxaparin use and anti-Xa concentrations within the defined therapeutic range in patients receiving chronic, scheduled hemodialysis to determine the degree of change in anti-Xa concentrations in those cases where a concentration was obtained before and after a specific hemodialysis session, and to determine if there is evidence of enoxaparin accumulation over the course of treatment. This was a retrospective cohort study. Patients that were admitted to Indiana University Health facilities in a two-year period were identified from a Cerner query for inclusion eligibility. Inclusion criteria involved patients that received therapeutic dose enoxaparin based on actual body weight on a once daily basis, maintained a scheduled hemodialysis regimen, and had an anti-Xa concentration obtained after at least one enoxaparin dose. Despite lacking statistical significance, the data collected from this study depicts trends which can be utilized to guide future studies. The results of this study suggest that hemodialysis does not effectively remove enoxaparin.

Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients

Low anti-factor Xa (anti-Xa) concentrations with twice-daily enoxaparin are associated with venous thromboembolism (VTE) in high-risk trauma patients. Concerns have been raised with once-daily dalteparin regarding effectiveness and achievable anti-Xa concentrations. The purpose of this before-and-after study was to evaluate the effectiveness of a VTE prophylaxis protocol using anti-Xa concentrations and associated dalteparin dose adjustment in high-risk trauma patients. Adult trauma patients receiving VTE chemoprophylaxis and hospitalized for at least 3 days were prospectively followed during two 6-month epochs before (PRE) and after (POST) implementation of anti-Xa monitoring. In both groups, high-risk patients received dalteparin 5,000 U subcutaneously once daily; low-risk patients received subcutaneous unfractionated heparin. High-risk POST patients with anti-Xa less than 0.1 IU/mL 12 hours after initial dalteparin dose received dalteparin every 12 hours. All patients underwent routine VTE ultrasound surveillance of the lower extremities. The primary outcome was incidence of VTE. A total of 785 patients (PRE, n = 428; POST, n = 357) were included. Demographics, injury patterns, Injury Severity Score (ISS), red blood cell transfusions, intensive care unit and hospital stays, and mortality did not differ between groups. Overall, POST patients had lower VTE (7.0% vs. 13%, p = 0.009) including acute VTE (6.4% vs. 12%, p = 0.01) and proximal deep vein thromboembolism (2.2% vs. 5.7%, p = 0.019). Between high-risk patients, VTE occurred in 53 (16.3%) PRE compared with 24 (9.0%) POST patients (p = 0.01); there was no difference in VTE between low-risk patients (PRE, 2.0% vs. POST, 1.1%; p = 0.86). Among 190 high-risk POST patients with anti-Xa, 97 (51%) were less than 0.1 IU/mL. Patients with low anti-Xa had higher rates of VTE (14.0% vs. 5.4%, p = 0.05) and deep vein thromboembolism (14.4% vs. 3.2%, p = 0.01). Younger age (odds ratio, 0.97; 95% confidence interval, 0.95-0.99) and greater weight (odds ratio, 1.02; 95% confidence interval, 1.00-1.03) predicted low anti-Xa on multivariate regression. A VTE prophylaxis protocol using anti-Xa-based dalteparin dosage adjustment in high-risk trauma patients was associated with decreased VTE. Once-daily dalteparin 12-hour anti-Xa concentrations are suboptimal in a majority of patients and associated with VTE. Therapeutic study, level IV.

Analysis of Anti-Xa Concentrations in Patients on Treatment Dose Enoxaparin: A Retrospective Chart Review

The purpose of this retrospective chart review was to determine the correlation between full weight-based enoxaparin use and the frequency of anti-Xa concentrations within the defined therapeutic range; to ascertain if anti-Xa monitoring is being appropriately ordered in relation to the timing of enoxaparin dose (after 3 consistent therapeutic doses and 3-5 hours post-dose); to establish if the evidence-based recommended dose adjustment protocol that was studied in the pediatric population was utilized; and if this yielded anti-Xa concentrations within the target range (0.6 - 1.1 IU/mL) for an adult population. The data may suggest a lack of correlation between BMI and whether or not the anti-Xa concentration is within the therapeutic range. Further prospective studies are needed to confirm this finding, and to determine the utility of the available dose adjustment nomogram.

Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient

BackgroundLimited data exist regarding the efficacy of weight-based dosing of low–molecular weight heparin for venous thromboembolism (VTE) prophylaxis in obese trauma patients. MethodsConsecutive obese trauma patients were placed on a weight-based protocol for VTE prophylaxis (enoxaparin .5 mg/kg subcutaneously every 12 hours). Peak anti-Xa levels were drawn, and bilateral lower extremity duplex ultrasound was performed. The incidence of VTE and bleeding complications were recorded. ResultsEighty-six patients met the study criteria. Seventy-four patients achieved target prophylactic anti-Xa concentrations, with a mean level of .42 ± .01 IU/mL. Eighteen patients were found to have deep vein thrombosis. However, in 16 of these patients, deep vein thrombosis was diagnosed before weight-based low–molecular weight heparin initiation. No bleeding complications occurred, and no symptomatic pulmonary emboli were identified. ConclusionsIn obese trauma patients, weight-based enoxaparin is an efficacious regimen that provides adequate VTE prophylaxis, as measured by anti-Xa levels, and appears to be safe without bleeding complications.

High-Risk Non-ST Elevation Acute Coronary Syndrome Outcomes in Patients Treated with Unfractionated Heparin Monitored Using Anti-Xa Concentrations Versus Activated Partial Thromboplastin Time.

While the activated partial thromboplastin time (aPTT) is the most widely used assay to monitor unfractionated heparin (UFH), providing a general measure of the extent of anticoagulation, it does not reliably correlate with the blood concentration of heparin or its antithrombotic effect. While cost and availability have limited the widespread use of UFH in hospitals, monitoring UFH with heparin levels has been shown to reduce both the number of monitoring tests and the time to a therapeutic range. To compare outcomes in patients with non-ST elevation acute coronary syndrome (ACS) treated with weight-based UFH monitored with anti-Xa concentrations versus aPTT. A retrospective chart review was completed in patients admitted with high-risk ACS and compared to the UFH arm of the SYNERGY trial. The primary outcome included the clinical endpoint of all-cause death or non-fatal myocardial infarction until time of hospital discharge. Safety endpoints evaluated included incidence of stroke and major bleeding. The primary endpoint occurred in 6.3% of patients in the study cohort compared to 6.5% of patients in the heparin arm of the SYNERGY trial at 48 hours (P = .006). Bleeding was reduced in the study cohort with a significant decrease in GUSTO severe bleeding (P = .007). Additionally the study cohort had significantly fewer patients with an absolute drop in hemoglobin or hematocrit. Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeding, rate of transfusion, and platelet counts were similar between groups. Outcomes for high-risk ACS patients receiving heparin monitored by anti-Xa concentrations are noninferior to heparin monitored by aPTT.

Low molecular weight heparin in patients undergoing free tissue transfer following head and neck ablative surgery: review of efficacy and associated complications

Most microsurgeons report the use of anticoagulants in their routine practice. Anti-Xa concentrations are preferentially used to monitor treatment with low molecular weight heparin (LMWH). The aim of this retrospective study was to measure the therapeutic response to standard dosing with LMWH (using anti-Xa) in patients after ablative and reconstructive surgery for head and neck cancer, and to review the associated risk of bleeding. We retrospectively reviewed 153 patients who had undergone resection of primary or recurrent tumours of the head and neck with free flap reconstruction. In total, 173 free flap procedures were completed. Medical records were reviewed to find the anticoagulation regimen used, anti-Xa result, patients’ weight, and any associated complications. Fourteen patients returned to theatre because of bleeding; of these no cause was identified in 6 and a haematoma was evacuated. The distribution of unexplained haematoma was similar for all dose regimens of dalteparin. Anti-Xa results were available in 47 cases, and of these, 22 (47%) were within the prophylactic range (0.2IU/ml or more). Our results highlight the high incidence of inadequate response to standard prophylactic doses of LMWH in patients with head and neck cancer. Increasing the dose of dalteparin does not seem to increase the risk of bleeding or formation of a haematoma. These findings may be transferable to other surgical specialties.

Dosing and monitoring of enoxaparin therapy in children

Pediatric deep vein thrombosis (DVT) is an emerging problem in tertiary care hospitals, recent reviews shows a rate of 40.2/10,000 admissions. Experts affirm that enoxaparin has become in the drug of choice for DVT therapy. Despite this, there is a little information regarding the optimal dose schedule for enoxaparin therapy in children and the therapeutic guidelines for enoxaparin use in children are extrapolated from adult guidelines. Monitoring by antifactor Xa (anti-Xa) measurement and target concentrations between 0.5-1 U/ml at 4-6 h postdose are recommended. This study was designed to analyse our experience in paediatric-specific dosage requirements for enoxaparin therapy. A retrospective study was performed with patients less than 16 years old, who were treated with enoxaparin for DVT and monitored by anti-Xa concentration, between January 2005 and March 2012. Demographic and clinical characteristics and outcomes were obtained. Fourteen patients were analyzed: boy/girl ratio, 8/4; median age, 3.5 months. Cerebral venous sinus thrombosis was the most common indication for therapy. All patients presented thrombosis risks factors. Dose increases were necessary only in patients less than 6 years old. Target anti-Xa concentrations were achieved in 12 (85%) patients. Children younger than 1 year required a higher dose of enoxaparin/kg (1.5-2.7 mg/kg per 12 h). Complete resolutions of DVT were registered in all cases. The mean number of dose increases was three and a median of 11 days to achieve target anti-Xa concentration. This study indicates that an initial higher enoxaparin dose may be necessary in neonates and infants, but other factors must be considered to improve management.

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Introduction: Traditional measures of anticoagulation, including the activated clotting time (ACT), have been poorly correlated with circuit thrombosis in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). The purpose of the present study was to test the association between anti-Factor Xa (anti-Xa) concentration and circuit thrombosis, as indicated by need for circuit or membrane oxygenator change, in pediatric patients supported with ECMO. Hypothesis: We hypothesized that increased frequency of extracorporeal circuit change was associated with “sub-therapeutic” anti-Xa concentration on repeated days of measurement. Methods: Retrospective record review of 62 pediatric patients supported with ECMO from 2009-2011. Standard demographic data, reason for ECMO, hours on ECMO, ACT measurements, anti-Xa measurements, and heparin infusion rate (HIR) were collected. Univariate and multivariate logistic regression models were used to describe the relationship between anti-Xa concentrations and need for change of either entire circuit or membrane oxygenator secondary to thrombus formation. Results: Sixty-two patients met study inclusion criteria. Group 1 (46/62) required no circuit change while supported with ECMO. Group 2 (16/62) required change of circuit or membrane oxygenator due to thrombus formation. Mean age was 3.1 years for Group 1 and 0.2 years for Group 2 (p = NS). Group 1 consisted of 54% male and Group 2 69% (p = NS). Group 1 contained 13/46 and Group 2 5/16 patients supported with ECMO for primary cardiac failure (p = NS). ECMO was used in the remainder for either respiratory failure or as rescue during CPR (ECPR). Survival to hospital discharge occurred in 28/46 (61%) Group 1 and 11/16 (69%) Group 2 (p = NS). Multivariate analysis of daily anti-Xa measurements throughout duration of ECMO support, accounting for age at ECMO deployment, showed mean anti-Xa concentration = 0.22 IU/ml [95% CI: (0.20, 0.31)] in Group 1 vs. 0.14 IU/ml [95% CI: (0.11, 0.17)] in Group 2 (p < 0.001). Neither mean daily ACT measurement (p = 0.93) nor mean daily HIR (p = 0.62) were significantly different between the two groups. Conclusions: Higher anti-factor Xa concentrations were associated with freedom from circuit change due to thrombus formation in pediatric ECMO patients. Neither ACT measurements nor HIR differed significantly between groups with or without circuit change. This is the first study to link anti-Xa concentrations with a clinically relevant measure of thrombosis in pediatric ECMO patients. Further prospective study is warranted.

Fluctuations of anti‐Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis

To evaluate fluctuations in anti-Xa concentrations in infants treated with enoxaparin for thrombosis and describe clinical outcomes. A retrospective chart review was performed on infants treated with enoxaparin in the Neonatal Intensive Care Unit, and data on enoxaparin doses, anti-Xa concentrations, clinical characteristics and outcomes were abstracted. Our cohort (n = 26) had a median gestation of 36 (range, 23-41) weeks, birthweight of 2522 (510-3912) grams and 5-min Apgar score of 8(4-9). Fifteen (57.7%) infants were males. Thromboses was diagnosed at a median age of 22 (range, 1-97) days; enoxaparin was initiated at 27.5 (range, 4-98) days at a mean (SD) dose of 1.4 (0.3) mg/kg every 12 h. Therapeutic anti-Xa concentrations (0.5-1 U/mL) were achieved at a mean (SD) dose of 2.1 (0.6) mg/kg at 12.5 (12.2) days of treatment. Of the 143 anti-Xa concentrations, 39 (27%) were within the therapeutic range. During maintenance therapy following initial therapeutic anti-Xa concentration, 40% concentrations were therapeutic. Minor bleeding was noted in four infants and intracranial bleed in one infant; four infants died. During treatment, thrombocytopenia, renal and hepatic impairment during treatment were noted in 7, 2 and 4 infants, respectively. Clot resolution was observed in 21 (81%) infants. Anti-Xa concentrations fluctuate during maintenance enoxaparin therapy, with therapeutic levels being achieved only sporadically in young infants. Despite this, enoxaparin appears efficacious in thrombosis resolution. Further studies on the impact of stringent control of concentrations on outcomes in this population are warranted.

Two Cases of Valvular Thrombosis Secondary to Heparin-Induced Thrombocytopenia Managed Without Surgery

A 83-year-old woman underwent aortic valvular replacement with a bioprosthesis for symptomatic aortic stenosis. Anesthesia and surgery were uneventful. Unfractionated heparin (UFH) had been administered for cardiopulmonary bypass followed by anticoagulation on day 0 (surgery), and had been continued thereafter. Routine postoperative blood count showed an increase in platelet counts to >200 g/L on day 6. On the ninth day, the patient complained of paresthesia of the left foot. A computed tomography scan with intravenous radiocontrast material was performed. Thrombosis of both iliofemoral axes and a thrombus on the ascending aorta were found (Figure 1 and Figure 2). A blood count on day 9 revealed thrombopenia at 44 G/L; antiPF4 antibodies (Enzyme-Linked ImmunoSorbent Assay HPIA is Heparin Platelet Factor 4 Induced Antibodies [ELISA] Asserachrom HPIA Stago, Asnieres France) were positive (optical density >2), and the platelet aggregation test confirmed the diagnosis of heparin-induced thrombocytopenia. Anticoagulation with UFH was stopped and replaced with intravenous sodium danaparoid targeted to anti-Xa concentration of 0.5 to 0.8 IU/mL. The patient underwent surgical iliofemoral thrombectomy that was uneventful. Figure 1. Computed tomography …

Individualized Dosing of Enoxaparin for Subjects With Renal Impairment Is Superior to Conventional Dosing at Achieving Therapeutic Concentrations

Enoxaparin is an anticoagulant used in the treatment of thromboembolic diseases. It is a hydrophilic molecule that is, predominantly, eliminated renally with few data to support dosing for subjects with renal impairment and/or obesity. A recently conducted randomized controlled clinical trial compared individualized enoxaparin doses based on lean body weight and renal function to conventional dosing. During this trial, anti-Xa concentrations were collected using a sparse sampling design and a population pharmacokinetic model was developed to describe the data. The current study evaluated the ability of the individualized dose to achieve and maintain anti-Xa concentrations within the therapeutic range (0.5-1.0 IU/mL) in subjects with renal impairment and/or obesity. A matched comparison of the two dosing strategies was undertaken using individual model predicted anti-Xa concentrations generated every 30 minutes to 120 hours post initiation of therapy. Concentration-time curves were generated for each subject and the proportion of time in the therapeutic, supratherapeutic, and subtherapeutic ranges were determined. When compared with conventional dosing, individualized dosing in subjects with renal impairment resulted in a significantly greater proportion of time in the therapeutic range (median [range] = 69.9% (11.3-91.8) versus 42.6% [13.9-71.4], P = 0.02) and a significantly reduced proportion of time in the supratherapeutic range (median [range] = 9.3% (0%-67.0%) versus 37.1% (0%-85.7%), P = 0.02). Although there was a trend toward a greater proportion of time in the therapeutic range in obese subjects, this did not achieve statistical significance. Individualized dosing in subjects with renal impairment is more effective than conventional dosing at achieving and maintaining therapeutic anti-Xa concentrations, which could decrease the risk of bleeding events and mortality in these subjects.

Determination of enoxaparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent

Drug monitoring of low molecular weight heparin is generally not recommended, but could be reasonable in critically ill patients, whose risk for bleeding or thrombosis shows a high interpatient variability. Anti-Xa assays are not available around the clock even in central hospitals, whereas rotational thrombelastometry (ROTEM) becomes increasingly used at the bedside. Prothrombinase-induced clotting time (PiCT) reagent allows determination of factor Xa-inhibition in plasma. The aim of our study was to evaluate enoxaparin determination in whole blood with the ROTEM using specific test modifications, including PiCT. After ethics committee's approval, citrated whole blood obtained from overall 16 healthy volunteers was incubated with enoxaparin at 16 different anti-Xa concentrations. Main endpoint was the clotting time (CT) in ROTEM representing initial activation of clot formation. CT was determined in the new PiCT-ROTEM test, in a low-tissue factor-activated modification (LowTF-ROTEM) as well as in the commercially available heparin-sensitive ROTEM assays (HEPTEM and INTEM). In the absence of enoxaparin, CT values were 168.6 +/- 6.1 s (PiCT-ROTEM), 247.3 +/- 18.6 s (LowTF-ROTEM), and -6.2 +/- 7.9 s (INTEM-HEPTEM). A linear dependency (P < 0.01) between anti-Xa concentration and CT was found for PiCT-ROTEM, LowTF-ROTEM, and for INTEM-HEPTEM with correlation coefficients of 0.93 for PiCT-ROTEM, 0.94 for LowTF-ROTEM, and 0.81 for INTEM-HEPTEM. This in-vitro experiment demonstrates a strong correlation between enoxaparin anti-Xa concentrations and specific ROTEM tests. These promising assays should be further evaluated for monitoring anticoagulation in high-risk patients in clinical studies.