Anti-factor Xa Concentrations Research Articles

Evaluation of anti-factor Xa concentrations using a body mass index-based enoxaparin dosing protocol for venous thromboembolism prophylaxis in trauma patients.

The aim of this study was to evaluate the effectiveness of a body mass index (BMI)-based enoxaparin prophylaxis dosing protocol at achieving target anti-factor Xa (anti-Xa) concentrations in the trauma population. This retrospective chart review evaluated anti-Xa concentrations in adult trauma patients who received prophylactic enoxaparin over a three-month period. The primary outcome was the percentage of patients that achieved target anti-Xa concentrations after ≥3 doses of enoxaparin. Secondary outcomes included correlations of anti-Xa concentrations with enoxaparin dose per BMI, total body weight (TBW), and estimated blood volume (EBV). The prevalence of clinically relevant bleeding and venous thromboembolism was also recorded. Multivariable logistic regression was used to identify associated variables for target anti-Xa concentration attainment. Ninety-nine consecutive patients were included in the study. Included patients were predominately male (69.7%) and Black (50.5%) with a mean age of 44.1years. Target anti-Xa concentrations were achieved in 62.6% of patients. Anti-Xa concentrations were moderately correlated with enoxaparin dose per EBV (ρ=0.57), followed by dose per TBW (ρ=0.46), and dose per BMI (ρ=0.20). Multivariable logistic regression demonstrated that categorization of enoxaparin dose per EBV and per TBW were the only statistically significant predictors of reaching target anti-Xa concentrations (p=<0.001). In adult trauma patients, the rate of achieving target anti-Xa concentrations remains suboptimal and provides room for further improvement. Enoxaparin dose per EBV was more closely correlated with anti-Xa concentrations when compared to TBW and BMI. Dosing per EBV and TBW was the only variables associated with reaching target anti-Xa concentrations within the study. Further investigation is warranted to elucidate optimal EBV- and TBW-based dosing regimens.

Edoxaban Exposure in Patients With Atrial Fibrillation and Estimated Creatinine Clearance Exceeding 100mL/min.

Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose‐reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti–factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti–factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60‐75 mg) resulted in ≈25% exposure increase in the 75‐mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.

Impact of antithrombin III and enoxaparin dosage adjustment on prophylactic anti-Xa concentrations in trauma patients at high risk for venous thromboembolism: a randomized pilot trial.

The impact of antithrombin III activity (AT-III) on prophylactic enoxaparin anti-factor Xa concentration (anti-Xa) is unknown in high-risk trauma patients. So too is the optimal anti-Xa-adjusted enoxaparin dosage. This prospective, randomized, pilot study sought to explore the association between AT-III and anti-Xa goal attainment and to preliminarily evaluate two enoxaparin dosage adjustment strategies in patients with subprophylactic anti-Xa. Adult trauma patients with Risk Assessment Profile (RAP) ≥ 5 prescribed enoxaparin 30mg subcutaneously every 12h were eligible. AT-III and anti-Xa were drawn 8h after the third enoxaparin dose and compared between patients with anti-Xa ≥ 0.1IU/mL (goal; control group) or anti-Xa < 0.1IU/mL (subprophylactic; intervention group). The primary outcome was difference in baseline AT-III. Subsequently, intervention group patients underwent 1:1 randomization to either enoxaparin 40mg every 12h (up to 50mg every 12h if repeat anti-Xa < 0.1IU/mL) (enox12) or enoxaparin 30mg every 8h (enox8) with repeat anti-Xa assessments. The proportion of patients achieving goal anti-Xa after dosage adjustment were compared. A total of 103 patients were included. Anti-Xa was subprophylactic in 50.5%. Baseline AT-III (median [IQR]) was 87% [80-98%] in control patients versus 82% [71-96%] in intervention patients (p = 0.092). Goal trough anti-Xa was achieved on first assessment in 38.1% enox12 versus 50% enox8 patients (p = 0.67), 84.6% versus 53.3% on second assessment (p = 0.11), and 100% vs. 54.5% on third trough assessment (p = 0.045). AT-III activity did not differ between high-risk trauma patients with goal and subprophylactic enoxaparin anti-Xa concentrations, although future investigation is warranted. Enoxaparin dose adjustment rather than frequency adjustment may be associated with a higher proportion of patients achieving goal anti-Xa over time.

Impact of Weight on Anti-Xa Attainment in High-Risk Trauma Patients on Enoxaparin Chemoprophylaxis

BackgroundSerum anti-factor Xa (anti-Xa) concentration may guide low molecular weight heparin chemoprophylaxis in trauma patients. Higher total body weight (TBW) is a risk factor for subprophylactic anti-Xa and venous thromboembolism (VTE). The purpose of this study was to evaluate TBW differences in patients with subprophylactic versus prophylactic trough anti-Xa. MethodsThis retrospective study included adults admitted to the trauma service who received enoxaparin chemoprophylaxis, trough anti-Xa assessment, and screening duplex ultrasound. Initial enoxaparin dose was determined per trauma team weight-tiered protocol with subsequent 10 mg increase if anti-Xa was subprophylactic. Patients were stratified into subprophylactic (anti-Xa <0.1 IU/ml) and prophylactic (anti-Xa ≥0.1 IU/mL) groups. The primary outcome was difference in TBW. Secondary outcomes were weight-adjusted enoxaparin dose (mg/kg), VTE, red blood cell (pRBC) transfusions. ResultsA total of 887 patients were included with 681 (76.8%) having subprophylactic anti-Xa. The subprophylactic group had significantly younger age, higher proportion male sex, higher Injury Severity Score (ISS), higher BMI, and longer length of hospital stay. The subprophylactic group had higher TBW (median [IQR], 87.8 [74-102] kg vs. 78.9 [68-91.8] kg; P < 0.001) which equated to a lower weight-adjusted dose (0.34 [0.3-0.41] mg/kg vs. 0.38 (0.33-0.44) mg/kg; P < 0.001). There were no differences in VTE (10.4% vs. 9.2%; P = 0.71) or pRBC administration (17.0% vs. 16.0%; P = 0.81). ConclusionsTBW is higher and weight-adjusted enoxaparin dose is lower in high-risk trauma patients with subprophylactic anti-Xa concentrations. These data suggest TBW should be considered when determining the optimal prophylactic enoxaparin dose in high-risk trauma patients.

Prospective Analysis of the Mechanisms Underlying Ineffective Deep Vein Thrombosis Prophylaxis in Necrotizing Pancreatitis

Patients with necrotizing pancreatitis (NP) have the highest rate of venous thromboembolism (VTE) of any hospitalized patient (57%). We hypothesized that VTE prophylaxis might be inadequate in the setting of this profound inflammatory disease and that early detection of deep vein thrombosis would limit pulmonary embolism. All patients with NP treated at a single center between August 2018 and December 2019 were enrolled in prospective, weekly VTE screening, including 4-extremity duplex ultrasound. Routine chemoprophylaxis included low-molecular-weight or unfractionated heparin. Peak serum anti-factor Xa concentration was measured during weekly screening (goal prophylaxis 0.2 to 0.4 IU/mL). Eighty-five patients with NP underwent a total of 201 screening events (mean 2.4 per patient). VTE developed in 55 patients (65%), including splanchnic vein thrombosis in 41 patients (48%) and extremity deep vein thrombosis (eDVT) in 32 patients (38%). Extremity DVT was diagnosed a mean ± SD of 44 ± 30 days after NP onset. Symptomatic pulmonary embolism was prevented in all patients diagnosed with eDVT and no contraindication to anticoagulation (0 of 29). Prophylactic anti-factor Xa concentration was only achieved in 21% (12 of 57 screening events); no eDVTs developed in patients achieving prophylactic anti-factor Xa concentration. In patients with NP, identification of eDVT by screening ultrasound permits early treatment and prevents symptomatic pulmonary embolism. Fixed dosing of chemical prophylaxis is inadequate in most patients with NP and likely contributes to the mechanism of increased VTE in NP.

Different Coagulation Indicators in Predicting Clinical Outcomes for Patients With Direct Oral Anticoagulants: A Systematic Review and Meta-analysis

PurposeThere are many anticoagulant test indexes available for direct oral anticoagulants (DOACs), but how to select the appropriate index and the index cutoff values are still controversial. This is the first study, to our knowledge, to assess the association of different coagulation indicators with clinical outcomes among DOACs using a meta-analysis of observational studies. MethodsA medical literature search was conducted using PubMed, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Library from inception to February 2020. Studies that reported relationships between coagulation indexes and clinical outcomes or the diagnostic value of coagulation assays were included in the analysis. FindingsA total of 17 articles (7 meta-analyses and 10 systematic reviews) from 8904 citations were included in the analysis. In the analysis of bleeding events with coagulation indexes for DOACs, for peak prothrombin time level (cutoff value of 19–25 s), the pooled results found a sensitivity of 0.61 (95% CI, 0.44–0.75) and a specificity of 0.71 (95% CI, 0.49–0.86). For rivaroxaban, the trough anti–factor Xa concentration (AXA-C) (cutoff value of 400–500 ng/mL) had a sensitivity of 0.53 (95% CI, 0.16–0.87) and a specificity of 0.87 (95% CI, 0.71–0.94), with a diagnostic odds ratio of 7 (95% CI, 2–32). For apixaban, trough AXA-C had a sensitivity of 0.85 (95% CI, 0.60–0.96) and a specificity of 0.83 (95% CI, 0.52–0.95). The AUC of the AXA-C peak was higher than that of the trough AXA-C for apixaban, with a higher sensitivity and specificity. Compared with trough concentration of anti–factor IIa for dabigatran, the peak concentration had a higher specificity (98%) at the cutoff value of 484 ng/mL. In the analysis of thromboembolic events with coagulation indexes for DOACs, peak and trough prothrombin time values were not typically correlated with subsequent symptomatic venous thromboembolism, without a sensitivity or specificity higher than 90%. Trough AXA-C had a sensitivity of 100% and but a low specificity (<50%) for rivaroxaban-apixaban. Trough AXA-C had a sensitivity of 100% and a specificity of 32% with a cutoff value of 108 ng/mL for dabigatran. ImplicationPeak prothrombin time (19–25 s) and AXA-C had a better predictive value on bleeding outcomes for rivaroxaban and apixaban, whereas peak concentration of anti–factor IIa activity can be an indicator for dabigatran. Coagulation indexes might not be a good indicator of thromboembolic events of DOACs. Because the limited studies focused on association of coagulation indicators and clinical outcomes, more studies are needed to verify this in the future.

Direct Oral to Parenteral Anticoagulants: Strategies for Inpatient Transition.

The primary objective of this study was to describe the impact on bleeding rates of 2 different strategies for transitioning from a direct oral anticoagulant (DOAC) to a parenteral anticoagulant: a delayed, clinically driven strategy versus the standard per-package-insert strategy. This was a single-center descriptive cohort study conducted at a large academic medical center. Included patients were 18 years or older, admitted as an inpatient, and had received at least 1 dose of a DOAC prior to initiation of therapeutic parenteral anticoagulation. The primary end point was the incidence of major bleeds on the transition from a DOAC to a parenteral anticoagulant via a standard versus an intentionally delayed strategy. The secondary outcomes evaluated renal function, reason for delay, DOAC anti-factor Xa concentration, international normalized ratio values, blood product administration, and thrombotic complications. A total of 300 patients were included. The primary end point of bleeding was higher in the delayed group than the standard group, 25% and 12%, respectively (odds ratio, 0.39; P < .05). In both groups, patients who bled had a higher severity of illness, a greater incidence of acute kidney injury, and, when available, higher median DOAC anti-factor Xa concentrations. Despite a more conservative approach, patients in the delayed group experienced more bleeding, most likely attributable to a higher severity of illness, which highlights emerging challenges of inpatient anticoagulation management. Further prospective studies analyzing DOAC pharmacodynamics and pharmacokinetics in acutely ill patients are warranted.

Portal Vein Thrombosis a Rare but Life-threatening Complication after Laparoscopic Sleeve Gastrectomy: A 5 Years Study in a Bariatric Center of Excellence.

Laparoscopic sleeve gastrectomy (LSG) is actually the most performed bariatric procedures in the world, and porto-mesenteric vein thrombosis (PVT) has been increasingly reported as a rare but serious complication. The best algorithm for PVT's prevention and therapy is still under discussion. The aim of this study is to explore the incidence and the outcomes of the PVT after LSG in a Bariatric Surgery Center of Excellence (BS-CoE) and elaborate a diagnostic and therapeutic algorithm for PVT after LSG. Methods: We retrospectively reviewed all the consecutive patients who underwent elective LSG within the last five years, between November 2014 and October 30th 2019, in Ponderas Academic Hospital, Bucharest, Romania. All the patients received an extended DVT prophylaxis protocol with adjusted doses of LMWH. Anti-factor Xa concentrations measurement to monitor the activity of LMWH in all the high-risk patients was used for the last two years. The patients suspected of PVT were scanned by computed tomography using IV contrast. All PVT patients were initially treated with systemic anticoagulation (Heparin), further interventions, such as systemic thrombolysis or surgery, being considered. After the acute stage, the PVT patients received longterm anticoagulation. Results: Of the 3861 patients who underwent elective LSG, three were readmitted 7-60 days after the bariatric procedure for PVT, equating to an incidence of 0.077%. The average age of the patients developing PVT was 40 years (SD 11.97), the average body mass index (BMI) was 40.34 (SD 7.994) kg/m2 and all of them underwent the same protocol for LSG. Two patients underwent conservative therapy with heparin anticoagulation and no surgery was needed. The third patient had a fulminant evolution in ICU, due to an extensive PVT, with death within two hours from his admission despite all resuscitation measures taken. The two patients remained on long life anticoagulant therapy. A high clinical suspicion of PVT after LSG is required with prompt diagnosis and treatment. The BS-CoE protocol with adjusted doses of LMWH and extended prophylaxis proved to be very efficient showing a very low incidence of PVT.

Establishment of prophylactic enoxaparin dosing recommendations to achieve targeted anti-factor Xa concentrations in children with CHD.

Enoxaparin may be used to prevent central venous catheter-related thrombosis in patients with CHD. We aimed to determine whether current enoxaparin dosing regimens effectively achieve anti-factor Xa concentrations within prophylactic goal ranges in this patient population. We implemented a formal protocol aimed at reducing central venous catheter-related thrombosis in children with CHD in January, 2016. Standard empiric prophylactic enoxaparin dosing regimens were used - for example, 0.75 mg/kg/dose every 12 hours for patients <2 months of age and 0.5 mg/kg/dose every 12 hours for patients ⩾2 months of age - with anti-factor Xa goal range of 0.25-0.49 IU/ml. Patients <2 years of age who received enoxaparin and had at least one valid steady-state anti-factor Xa measurement between 25 January, 2016 and 31 August, 2016 were retrospectively reviewed. During the study period, 47 patients had 186 anti-factor Xa concentrations measured, of which 20 (11%) were above and 112 (60%) were below the prophylactic goal range. Anti-factor Xa concentrations within the goal range were ultimately achieved in 31 patients. Median dose required to achieve anti-factor Xa concentrations within the prophylactic range was 0.89 mg/kg/dose (25, 75%: 0.75, 1.11) for patients <2 months (n=23 patients) and 0.79 mg/kg/dose (25, 75%: 0.62, 1.11) for patients ⩾2 months (n=8 patients). Enoxaparin doses required to achieve prophylactic anti-factor Xa concentrations in young children with CHD were consistently higher than the currently recommended prophylactic dosing regimens. Further study is needed to determine whether dose titration to achieve prophylactic anti-factor Xa concentrations is effective in preventing central venous catheter-related thrombosis.

Performance of Anti-Factor Xa Versus Activated Partial Thromboplastin Time for Heparin Monitoring Using Multiple Nomograms.

The purpose of this study was to compare the performance of anti-factor Xa concentration versus activated partial thromboplastin time (aPTT) monitoring with multiple indication-specific heparin nomograms. This was a prospective, nonrandomized study with historical control at a large academic medical center. A total of 201 patients who received intravenous heparin in the cardiology units were included. The prospective cohort included patients (n = 101) with anti-factor Xa (anti-Xa) monitoring, and the historical control group included patients (n = 100) who had aPTT monitoring. Patients in the prospective group had both anti-Xa and aPTT samples drawn, but anti-Xa was used for dosing adjustment. The anti-Xa cohort achieved a significantly faster time to therapeutic range (P < .01) and required fewer dose adjustments per 24-hour period compared to the aPTT control (P = .01). Results were consistent across heparin nomograms. The overall discordance rate between the 2 tests was 49%. No significant differences in clinical outcomes were observed. In summary, anti-Xa monitoring improved the time to therapeutic anticoagulation and led to fewer dose adjustments compared to the aPTT with multiple indication-based heparin nomograms.

Effect of Plasmapheresis on the Anti-Factor Xa Activity of Enoxaparin in an Obese Adolescent Patient

To our knowledge, the effect of plasmapheresis on the anti-factor Xa activity of enoxaparin has never been reported. We describe a 13-year-old, obese (92-kg) girl who was treated with enoxaparin for a pulmonary embolism while receiving plasmapheresis for suspected autoimmune encephalitis and who experienced clinically significant reductions in anti-factor Xa activity after plasmapheresis. She received five courses of plasmapheresis, with the final two administered during treatment with enoxaparin. Her anti-factor Xa concentrations were highly variable, and we hypothesized that plasmapheresis was affecting these levels. To test this hypothesis, anti-factor Xa concentrations were measured before and immediately after the patient's last plasmapheresis treatment, and then again 2 days after plasmapheresis. The rate of anti-factor Xa activity decline was 0.28 IU/mL/hour with plasmapheresis and only 0.088 IU/mL/hour on the day without plasmapheresis, representing a greater than 3-fold difference. The changes in anti-factor Xa activity due to plasmapheresis altered the final enoxaparin dosage required to remain in the therapeutic range of 0.5-1 IU/mL (0.98 mg/kg/dose while receiving plasmapheresis vs 0.69 mg/kg/dose without plasmapheresis). Our patient's data suggest that plasmapheresis can significantly alter enoxaparin's anticoagulant effect as measured by anti-factor Xa concentrations, which could cause a decreased anticoagulant effect during plasmapheresis and an increased risk of bleeding on plasmapheresis discontinuation. If concurrent enoxaparin-based anticoagulation and plasmapheresis are necessary, close monitoring of anti-factor Xa levels is advisable. Dose escalations and reductions of enoxaparin may be necessary when initiating and discontinuing plasmapheresis, respectively.

Stability and Sterility of Enoxaparin 8 mg/mL Subcutaneous Injectable Solution.

BACKGROUND: Enoxaparin is often diluted to accurately deliver doses to neonatal and infant patients. Current recommendations for dilutions may not be adequate for the smallest patients. METHODS: Review of dosing at our institution occurred, and an 8 mg/mL concentration of enoxaparin was chosen. A concentration of 8 mg/mL was compounded by diluting 0.4 mL of enoxaparin (100 mg/mL) into 4.6 mL of sterile water for injection into an empty sterile vial. Four syringes of the 8 mg/mL concentration were prepared by 5 technicians (20 total syringes). Stability and sterility testing occurred a 0, 7, 14, and 30 days. One-way repeated-measures analysis of variance was used to detect significant differences in Anti-Factor Xa concentrations at the testing time points. RESULTS: The dilution of enoxaparin was sterile at 30 days but exhibited significant degradation at the 30-day point (p < 0.05). CONCLUSION: A dilution of enoxaparin 8 mg/mL is stable and sterile for 14 days refrigerated but is not stable at 30 days.

Evaluation of therapeutic enoxaparin in a pregnant population at a tertiary hospital.

Therapeutic anticoagulation with enoxaparin in pregnancy is complex due to varying pharmacokinetics and the increasing prevalence of obesity. There is limited evidence to support current dosing and monitoring strategies of enoxaparin in this population. To describe the current practice in therapeutic anticoagulation in the pregnant population at a tertiary institution. A retrospective study of pregnant women on therapeutic enoxaparin between January 2007 and December 2011. Forty-four pregnant women requiring therapeutic anticoagulation were identified and divided into two groups, monitored with anti-factor Xa (AXA) concentrations and unmonitored. Fifty-five percent of monitored women were initiated on the recommended 1 mg/kg twice a day (bd) enoxaparin dose-strategy. Eighty-two percent of women were monitored; however, there was variability regarding the timing, frequency and subsequent dose adjustments from monitoring. Overall, as pregnancies progressed, there was both increasing dose adjustments and increasing frequency of monitoring. Fourteen women had a BMI over 30 kg/m(2) , and 13 of these women were monitored. Nine monitored obese women required doses less than 1 mg/kg/bd to maintain a therapeutic AXA level. Management appeared to be individualised. There were small numbers of toxicity events. Variation exists in dosing and monitoring practices for therapeutic enoxaparin in the pregnant population. Dosing obese patients using 1 mg/kg twice daily can lead to toxic AXA concentrations, and dose reductions are required to maintain a therapeutic range. A larger prospective study reviewing dose, AXA concentrations and outcome data is necessary to make dosing recommendations in this group.

Evaluation of Enoxaparin Dosing and Monitoring in Pediatric Patients at Children's Teaching Hospital.

The primary objective of this study was to evaluate whether empirical enoxaparin doses according to Chest guidelines resulted in therapeutic antifactor Xa concentrations in pediatric patients. Secondary objectives were to determine the median enoxaparin dose that resulted in therapeutic anticoagulation, the median time to therapeutic concentrations, and the percentage of patients who experienced major bleeding. Patients in a tertiary medical center who were <18 years of age and received treatment doses of enoxaparin between July 2007 and June 2010 were included. Patients with <2 antifactor Xa concentrations or with only supratherapeutic concentrations and doses that were higher than recommended by the guidelines were excluded. Subgroup analysis was conducted by dividing children into 4 age groups: <2 months of age, 2 months to <1 year of age, 1 year to <3 years of age, and 3 to 17 years of age. Thirty-two patients were included in the study. Thirty-seven percent of the patients achieved a therapeutic drug level with empirical dosing. The therapeutic dose ranged from 1 to 1.9 mg/kg in patients <1 year old, and 0.6 to 1.5 mg/kg in those =1 year of age. Comparison of the median therapeutic doses for patients 2 months to <1 year to that for patients =1 year old using the Mann-Whitney U test showed the median doses to be significantly difierent between the 2 groups (p=0.01). The antifactor Xa level became therapeutic on day 5 (median). There were no major bleeding events. Less than 40% of patients were therapeutic with empirical dosing, which supports findings from other studies that suggest a need for modification of empirical treatment dosing of enoxaparin in children.

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.

Unfractionated Heparin Activity Measured by Anti-Factor Xa Levels Is Associated With the Need for Extracorporeal Membrane Oxygenation Circuit/Membrane Oxygenator Change

Investigate whether anti-Factor Xa levels are associated with the need for change of circuit/membrane oxygenator secondary to thrombus formation in pediatric patients.Retrospective single institution study.Retrospective record review of 62 pediatric patients supported with extracorporeal membrane oxygenation from 2009 to 2011.Data on standard demographic characteristics, indications for extracorporeal membrane oxygenation, duration of extracorporeal membrane oxygenation, activated clotting time measurements, anti-Factor Xa measurements, and heparin infusion rate were collected. Generalized linear models were used to associate anti-Factor Xa concentrations and need for change of either entire circuit/membrane oxygenator secondary to thrombus formation.Sixty-two patients met study inclusion criteria. No-circuit change was required in 45 of 62 patients. Of 62 patients, 17 required change of circuit/membrane oxygenator due to thrombus formation. Multivariate analysis of daily anti-Factor Xa measurements throughout duration of extracorporeal membrane oxygenation support estimated a mean anti-Factor Xa concentration of 0.20 IU/mL (95% CI, 0.16, 0.24) in no-complete-circuit group that was significantly higher than the estimated concentration of 0.13 IU/mL (95% CI, 0.12, 0.14) in complete-circuit group (p = 0.001). A 0.01 IU/mL decrease in anti-Factor Xa increased odds of need for circuit/membrane oxygenator change by 5% (odds ratio = 1.105; 95% CI, 1.00, 1.10; p = 0.044). Based on the observed anti-Factor Xa concentrations, complete-circuit group had 41% increased odds for requiring circuit/membrane oxygenator change compared with no-complete-circuit group (odds ratio = 1.41; 95% CI, 1.01, 1.96; p = 0.044). Mean daily activated clotting time measurement (p = 0.192) was not different between groups, but mean daily heparin infusion rate (p < 0.001) was significantly different between the two groups.Higher anti-Factor Xa concentrations were associated with freedom from circuit/membrane oxygenator change due to thrombus formation in pediatric patients during extracorporeal membrane oxygenation support. Activated clotting time measurements did not differ significantly between groups with or without circuit/membrane oxygenator change. This is the first study to link anti-Factor Xa concentrations with a clinically relevant measure of thrombosis in pediatric patients during extracorporeal membrane oxygenation support. Further prospective study is warranted.

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.

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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.

Retrospective Evaluation of Enoxaparin Dosing in Patients 48 Weeks' Postmenstrual Age or Younger in a Neonatal Intensive Care Unit

Enoxaparin is the anticoagulant of choice in neonates because of the ease of administration, predictable pharmacokinetics, and reduced adverse effects when compared to heparin. The Chest guidelines recommend that therapy in patients younger than 2 months should be initiated with enoxaparin 1.5 mg/kg administered subcutaneously twice daily. This starting dosage may be inadequate, leading to a delay in achieving therapeutic anti-factor Xa plasma concentrations. To determine an enoxaparin dose for neonatal patients that achieves a therapeutic anti-factor Xa plasma concentration and compare that dose to the recommended enoxaparin dose per published guidelines for this patient population. The study was designed as a single-center chart review. Eligible patients were identified by pharmacy anticoagulation records or a search of the electronic medical record for enoxaparin orders. Patients must have received enoxaparin subcutaneously twice daily and have had a postmenstrual age of 48 weeks or younger. Patients diagnosed with renal failure and those receiving prophylactic doses of enoxaparin were excluded. The mean (SD) initial dose of enoxaparin was 1.4 (0.3) mg/kg subcutaneously twice daily, resulting in 27 of 33 patients (81.8%) having a subtherapeutic anti-factor Xa concentration. A mean enoxaparin dose of 2.0 (0.5) mg/kg was required to achieve a therapeutic anti-factor Xa plasma concentration (p < 0.001). Patients born prematurely required a higher enoxaparin dose (2.2 [0.5] mg/kg) than did those born at full-term gestation (1.8 [0.4] mg/kg; p < 0.05). For patients 48 weeks' postmenstrual age or younger who are treated in a neonatal intensive care unit, a higher initial dose of enoxaparin than that suggested by the Chest guidelines is required to attain a therapeutic antifactor Xa plasma concentration. Premature neonates require a larger starting dose of enoxaparin than do infants born at full-term gestation.

Dalteparin dose-dependently increases ROTEM® thrombelastography parameters only at supratherapeutic anti-factor Xa levels: An in vitro study

1. The low molecular weight heparin (LMWH) dalteparin is used, for example, to prevent primary venous thromboembolism in patients undergoing surgery or in medically ill patients. The anticoagulant activity of dalteparin can be monitored by measuring anti-factor Xa levels and activated partial thromboplastin time (aPTT); however, aPTT is an unreliable parameter in this case. The aim of the present in vitro study was to evaluate the thrombelastograph ROTEM(®) (Tem International, Munich, Germany) with respect to determining the anticoagulant activity of dalteparin at therapeutic and supratherapeutic plasma concentrations. 2. The ROTEM(®) parameters, namely coagulation time (CT), clot formation time (CFT) and maximum clot firmness (MCF), were measured using the reagents EXTEM and INTEM (Pentapharm, Munich, Germany) at increasing concentrations of dalteparin (0.01-10 μg/mL, which corresponded to anti-factor Xa levels of 1-1000 U/mL, respectively). 3. The mean CT measured using EXTEM was found to increase from 65.4 ± 27.9 s at baseline to 173.3 ± 112.2 s and 332.2 ± 200.7 s at drug concentrations of 1 and 10 μg/mL, respectively (P < 0.0001 for both). Moreover, the mean CFT value (EXTEM) increased from 97.7 ± 21.5 s at baseline to 187.6 ± 115.2 s (P = 0.0001) at a drug concentration of 10 μg/mL, which is greater than the therapeutic anti-factor Xa concentrations for LMWH. The results obtained when INTEM was used as the reagent were similar to those obtained using EXTEM. 4. In conclusion, the results indicate that the thrombelastograph ROTEM(®) can detect the anticoagulant effects of dalteparin only at supratherapeutic levels of anti-factor Xa.