anti-FXa Levels Research Articles

Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients

PurposeCritically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20–0.50 IU/ml) in these groups is unknown.MethodsThis study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels.ResultsA total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013).ConclusionA standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin.Clinical trials registrationRetrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

Dose-Related Effectiveness of Andexanet Alfa for Reversal of Apixaban Anticoagulation in a Porcine Polytrauma Model.

Andexanet alfa (andexanet) is a reversal agent for use in patients with life-threatening or uncontrolled bleeding treated with oral factor Xa (FXa) inhibitors. There are limited data on the dose-response relationship of andexanet and FXa inhibitor-related bleeding. The aim of this study was to assess the dose-related effectiveness of andexanet in reducing blood loss, improving survival, and reversing apixaban anticoagulation in a porcine polytrauma model. Apixaban was given orally to 40 male pigs for 3 days at a dose of 20 mg/d. On day 3, following bilateral femur fractures and blunt liver injury, animals (n = 8/group) received andexanet (250-mg bolus, 250-mg bolus + 300-mg 2-hour infusion, 500-mg bolus, or 500-mg bolus + 600-mg 2-hour infusion) or vehicle (control). Total blood loss was the primary endpoint. Coagulation parameters were assessed for 300 minutes or until death. Data were analyzed with a mixed-model analysis of variance. Administration of 250-mg bolus + 300-mg infusion, andexanet 500-mg bolus, and 500-mg bolus + 600-mg infusion significantly decreased total blood loss by 37, 58, and 61%, respectively (all p < 0.0001), with 100% survival. Andexanet 250-mg bolus was ineffective in reducing total blood loss (6%) and mortality (63% survival) versus controls. Andexanet 500-mg bolus ± infusion neutralized anti-FXa activity to less than 50 ng/mL. Andexanet neutralization of thrombin generation and thromboelastometry parameters was dose and infusion time dependent. In a porcine polytrauma model with major bleeding on apixaban, andexanet dose dependently decreased anti-FXa activity. Lower anti-FXa levels (<50 ng/mL) with andexanet 500-mg bolus ± infusion were correlated with 60% less blood loss and 100% survival versus controls.

The Effectiveness of the Intermediate and Therapeutic Doses of Enoxaparin in COVID-19 Patients: A Comparative Study of Factor Xa Inhibition

Background: Management of anticoagulant therapy in COVID-19 patients is critical. Low-molecular-weight heparin (LMWH) thromboprophylaxis is already recommended, and anti-Factor Xa (anti-FXa) monitoring has been used to titrate LMWH doses. Methods: Through a cross-sectional study, we evaluated anti-FXa activity in patients admitted to the ICU, receiving intermediate dose (30, 40, 50 mg, subcutaneously [SC], twice daily) or therapeutic dose (1 mg/kg, SC, Q12h) of enoxaparin to find whether the patients in these two groups achieved anti-FXa levels in the accepted thromboprophylaxis range. Results: The occurrence of deep vein thrombosis was 26% in the therapeutic-dose group and 17% in the intermediate-dose group. D-dimer values were nearly 3.5-fold higher in those who received a therapeutic dose of anticoagulants than in those who received intermediate-dose thromboprophylaxis. Patients in the therapeutic-dose group had significantly higher IL-6 levels (p ≤ 0.001). More than one-third of the patients in the therapeutic-dose group (n = 8; 42.18%) and approximately half of the patients in the intermediate-dose group (n = 12; 52.2%) achieved the target range level of anti-FXa. Patients who received therapeutic doses were more likely to have anti-FXa levels above the expected range (47.4 vs 13% in the intermediate-dose group; p < 0.05). Conclusion: Therapeutic dose of enoxaparin in critically ill COVID-19-infected patients did not reduce the incidence of thromboembolic events and, on the other hand, may predispose these patients to increased risk of bleeding by increasing anti-FXa activity above the desired level. Administration of intermediate-dose thromboprophylaxis is suggested to achieve anti-FXa levels in the accepted thromboprophylaxis range.

Low molecular weight heparin for venous thromboembolism prophylaxis in general Intensive Care Unit patients: an anti-factor Xa level-based approach.

Venous thromboembolism (VTE) in the Intensive Care Unit (ICU) is associated with significant morbidity and mortality therefore prevention is imperative to reduce its burden. VTE prophylaxis in ICU patients is primarily pharmacological using low molecular weight heparin (LMWH). Plasma anti-factor Xa (anti-FXa) levels may be used to measure LMWH activity. This study aims to determine the proportion of acutely ill patients in a general ICU receiving standard VTE prophylaxis that achieve adequate peak or trough anti-FXa prophylactic levels and to determine the effect of LMWH dose adjustment in patients not achieving adequate anti-FXa prophylactic levels. Peak and trough anti-FXa levels were measured at four and 23 hours respectively after receiving the second consecutive daily enoxaparin 40 mg sc injection. Patients in whom peak anti-FXa levels were found to be sub-prophylactic (<0.2 IU/mL), were dose escalated to enoxaparin 60 mg once daily. Peak and trough levels were repeated as above. Sixty-one percent of study patients (N.=46) were found to have sub-prophylactic peak anti-FXa levels. Twenty-seven patients received an increased enoxaparin dose of 60 mg/d. Of these, nine patients (33.3%) still failed to achieve the target prophylactic peak anti-FXa level (0.2-0.4 IU/mL). Male gender and high body mass index (BMI) were significantly and strongly correlated with sub-prophylactic anti-FXa levels. Most ICU patients in this study did not achieve recommended prophylactic anti-FXa levels while receiving a standard dose of enoxaparin and these levels failed to increase after enoxaparin dose escalation in a significant proportion of patients. High BMI and male gender are associated with sub-prophylactic levels of anti-FXa in critically ill patients.

Association of Changes in Antithrombin Activity Over Time With Responsiveness to Enoxaparin Prophylaxis and Risk of Trauma-Related Venous Thromboembolism

Venous thromboembolism (VTE) affects 2% to 20% of recovering trauma patients, despite aggressive prophylaxis with enoxaparin. Antithrombin is a primary circulating anticoagulant and crucial component of enoxaparin thromboprophylaxis. Approximately 20% of trauma patients present with antithrombin deficiency (antithrombin activity <80%). To examine time-dependent changes in antithrombin activity, responsiveness to enoxaparin, as measured by anti-factor Xa (anti-FXa) levels, and incidence of VTE after severe trauma and to assess the association of ex vivo antithrombin supplementation with patients' sensitivity to enoxaparin prophylaxis. This single-center, prospective cohort study was performed at a level 1 trauma center between January 7, 2019, and February 28, 2020. Adult trauma patients admitted to the trauma service at high risk for VTE, based on injury pattern and severity, were screened and enrolled. Patients who were older than 70 years, were pregnant, had a known immunologic or coagulation disorder, or were receiving prehospital anticoagulants were excluded. Blood samples were collected on emergency department arrival and daily for the first 8 days of hospitalization. Patients' antithrombin activity and anti-FXa levels were measured by a coagulation analyzer, and thrombin generation was measured by calibrated automated thrombography. Responsiveness to enoxaparin was assessed by measuring anti-FXa levels 4 to 6 hours after the first daily enoxaparin dose and compared between patients who developed VTE and who did not. In addition, the associations of ex vivo supplementation of antithrombin with plasma anti-FXa levels were assessed. Among 150 patients enrolled (median [IQR] age, 35 [27-53] years; 37 [24.7%] female and 113 [75.3%] male; 5 [3.3%] Asian, 32 [21.3%] Black, and 113 [75.3%] White; and 51 [34.0%] of Hispanic ethnicity), 28 (18.7%) developed VTE. Patients with VTE had significantly lower antithrombin activity on admission compared with patients without VTE (median [IQR], 91% [79%-104%] vs 100% [88%-112%]; P = .04), as well as lower antithrombin activity on hospital days 5 (median (IQR), 90% [83%-99%] vs 114% [99%-130%]; P = .011), 6 (median [IQR], 97% [81%-109%] vs 123% [104%-134%]; P = .003), 7 (median [IQR], 82% [74%-89%] vs 123% [110%-140%]; P < .001), and 8 (median [IQR], 99% [85%-100%] vs 123% [109%-146%]; P = .011). Anti-FXa levels were significantly lower in patients with VTE vs those without VTE at hospital day 4 (median [IQR], 0.10 [0.05-0.14] IU/mL vs 0.18 [0.13-0.23] IU/mL; P = .006), day 6 (median [IQR], 0.12 [0.08-0.14] IU/mL vs 0.22 [0.13-0.28] IU/mL; P = .02), and day 7 (median [IQR], 0.11 [0.08-0.12] IU/mL vs 0.21 [0.13, 0.28] IU/mL; P = .002). Multivariable analyses found that for every 10% decrease in antithrombin activity during the first 3 days, the risk of VTE increased 1.5-fold. The results of this cohort study suggest that after severe trauma, antithrombin deficiency is common and contributes to enoxaparin resistance and VTE. Interventional studies are necessary to determine the efficacy of antithrombin supplementation in the reduction of VTE incidence.

Comparison of doses of heparin for venous thromboembolism and bleeding in pregnant women

The evaluation criteria for dosage of low-molecular-weight heparin (LMWH) for pregnant women at high risk of venous thromboembolism (VTE) remain unclear. A retrospective study was performed to investigate the relative...

Adequate Antithrombin III Level Predicts Survival in Severe COVID-19 Pneumonia.

Critically ill patients with COVID-19 are at an increased thrombotic risk, hence thromboprophylaxis with heparin is considered mandatory. Antithrombin III (ATIII) is the most potent endogenous anticoagulant and is required for the clinical efficacy of heparin. Profound hypercoagulable and inflammatory state associated with COVID-19 can result in decreased ATIII levels and ineffective heparin treatment resulting in increased mortality. The present study evaluated ATIII levels in critically ill patients of COVID-19 and correlated them with other coagulation parameters and disease outcomes. A retrospective review of those critically ill COVID-19 patients was performed who were on a therapeutic dose of low molecular weight heparin (LMWH) and had serial measurements of ATIII, anti-factor Xa (antiFXa) assay and other routine coagulation parameters. A total of 27 critically ill COVID-19 patients were identified, out of these, 12 survived and 15 had disease-induced mortality. ATIII levels were found to be significantly lower in non-survivors on the third day of serial measurement along with worsening of other coagulation parameters. AntiFXa levels were found to be higher in non-survivors as compared to survivors. Further studies are required to establish ATIII as a prognostic marker and to determine the utility of monitoring antiFXa levels in COVID-19 patients on LMWH therapy.

Unfractionated heparin using actual body weight without dose capping in obese pediatric patients—Subgroup analysis from an observational cohort study

To evaluate the correlation between an uncapped, actual body weight-based unfractionated heparin dosing strategy, we performed a body mass index-based subanalysis of a previously reported pediatric cohort. Nearly half (45%) of obese patients were supra-therapeutic on initial anti-FXa assessment. Obese patients achieved therapeutic anti-FXa significantly faster than nonobese patients (median 4 vs 12hours, P=.0192) and were more likely to have any supra-therapeutic anti-FXa levels (77% vs 35%; P=.0021). There was no statistically significant difference in major or clinically relevant nonmajor bleeding rates between weight categories (P=.69). Prospective pediatric studies are warranted to confirm our findings.

Monitoring of Low Molecular Weight Heparin Thromboprophylaxis with Alternative Methods to Anti-Factor Xa

Introduction: Initiating low molecular weight heparin (LMWH) thromboprophylaxis too early in patients with traumatic braininjury increases the risk of intracranial bleeding. Therefore, it is important to monitor LMWH and asses when it is safe to initiate.The aim of this research was to study alternative monitoring methods for LMWH than the standard method anti-factor Xa (antiFXa), and to investigate the peak anti-FXa level. We hoped to answer “How do rotational thromboelastometry (ROTEM) andSonoclot change at different LMWH concentrations added in vitro to blood from intensive care patients? How do point of careparameters change after subcutaneous LMWH administration on healthy volunteers with consecutive measurements to catch thepeak effect?”.Methods: Different concentrations of enoxaparin were added in vitro to citrated whole blood from fifteen intensive care patients.The first ten patients’ coagulation was analysed with ROTEM using the INTEM and NATEM assays, and the last five withSonoclot with a kaolin activator and ROTEM INTEM. Previously collected data was used from nine healthy volunteers that hadreceived subcutaneous enoxaparin. Citrated blood samples were collected before and after LMWH initiation and analysed withSonoclot kaolin and a chromogenic anti-FXa-assay. Friedman test, Dunn’s multiple comparison test and Spearman’s correlationtest were performed.Results: ROTEM INTEM CT, CFT, A10 and MCF were significantly affected with increasing in vitro enoxaparin from 0.4anti-FXa concentration. ROTEM NATEM CT was also prolonged at this LMWH concentration. Sonoclot’s parameters didn’tsignificantly change with increasing in vitro enoxaparin. The peak of in vivo LMWH was reached after 2 to 4 hours with avariation of peak anti-FXa between 0.3-0.5 IU/mL.Conclusions: ROTEM INTEM CT performed best and was prolonged at anti-FXa from 0.4-0.6 IU/mL. ROTEM INTEM shouldbe tested in neurointensive care to increase the safety of LMWH thromboprophylaxis and possibly to individualize the dosage. (Less)

606 Oral anticoagulants in fragile patients with percutaneous endoscopic gastrostomy and atrial fibrillation: the Origami study

Abstract Aims Randomized trials support the safety and efficacy of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation (AF), leading to increased use of these compounds. Crushed forms of DOACs have shown to be reliable, but evidence supporting percutaneous endoscopic gastrostomy (PEG) delivery is lacking. PEG is a long-term option for enteral food and drug delivery in patients unable to maintain oral intake, bypassing the risks and disadvantages of parenteral nutrition. We investigate the safety and efficacy of Edoxaban administered via PEG in patients with atrial fibrillation and a clinical indication for a long-term anticoagulation. Methods and results In this prospective, single centre observational study, 12 PEG-treated patients with indication to anticoagulation will receive edoxaban via PEG and will be followed-up to 6 months. Plasma anti-Factor Xa activity and edoxaban concentrations will be assessed. Thromboembolic (ischaemic stroke, systemic embolism, venous thromboembolism) and bleeding events (Bleeding Academic Research Consortium and Thrombolysis in Myocardial Infarction) will be recorded at 1 and 6 months. A retrospective analysis of 5 AF cases undergoing PEG-implantation at our Institution, who received edoxaban via PEG, showed plasma anti-FXa levels at steady state of 146 ± 15 ng/ml, without major adverse event at a mean follow-up of 6 months. Conclusion We prospectively investigate PEG-administration of edoxaban in PEG-treated patients requiring long term anticoagulation. Our preliminary retrospective data support this route of DOAC administration.

ORal anticoagulants In fraGile patients with percutAneous endoscopic gastrostoMy and atrIal fibrillation: the (ORIGAMI) study.

The ORal anticoagulants In fraGile patients with percutAneous endoscopic gastrostoMy and atrIal fibrillation (ORIGAMI) study investigates the safety and efficacy of Edoxaban administered via PEG in patients with atrial fibrillation and a clinical indication for a long-term anticoagulation. In this prospective, single-centre observational study, 12 PEG-treated patients with indication to anticoagulation will receive edoxaban via PEG and will be followed up to 6 months. Plasma antifactor Xa activity and edoxaban concentrations will be assessed. Thromboembolic (ischaemic stroke, systemic embolism, venous thromboembolism) and bleeding events (Bleeding Academic Research Consortium and Thrombolysis in Myocardial Infarction) will be recorded at 1 and 6 months. A retrospective analysis of five atrial fibrillation cases undergoing PEG implantation at our Institution who received edoxaban via PEG showed plasma anti-FXa levels at a steady state of 146 ± 15 ng/ml, without major adverse event at a mean follow-up of 6 months. ORIGAMI prospectively investigates PEG-administration of edoxaban in PEG-treated patients requiring long-term anticoagulation. Our preliminary retrospective data support this route of DOAC administration. NCT04271293.

Validation of a Modified Anti-FXa Assay on STA-Compact Analyzer for Measuring FXa Inhibitor Levels in the Presence of Andexanet Alfa

Introduction: The anticoagulants rivaroxaban and apixaban inhibit Factor Xa (FXa) activity and are effective therapeutic agents for the prevention and treatment of thromboembolism. Andexanet alfa (andexanet) is the only specific reversal agent approved for anticoagulation reversal in patients presenting with life-threatening bleeding treated with rivaroxaban or apixaban. Anti-FXa assays are functional assays used for measuring direct and indirect FXa inhibitor levels in plasma. Current commercially available anti-FXa assays are not suitable for accurately measuring anti-FXa activity in patient samples in the presence of andexanet due to the high sample dilutions (e.g.,1:44 with STA-Liquid Anti-Xa), which causes dissociation of the inhibitor from andexanet (due to reversible binding). This results in substantial underestimation of the reversal activity of andexanet, and in some cases with erroneously elevated anti-FXa levels in patient samples following andexanet treatment. Therefore, we modified the current anti-FXa assays to measure apixaban and rivaroxaban anti-FXa levels in the presence of andexanet. Methods: The modified anti-FXa assays were performed on STA®-Compact analyzer using reagents from STA-Liquid Anti-Xa assay kits (Stago). Andexanet was provided as a 10 mg/mL frozen stock. Plasma samples with FXa inhibitor in the presence or absence of andexanet were prepared using Stago Calibrator 1 and pooled normal human plasma (Precision Biologic). Previous anti-FXa assays (calibrator range: 0-500 ng/mL) employed 1:4 dilution of test plasma in Owren-Koller buffer followed by addition of FXa substrate and bovine FXa with an overall 1:44 sample dilution. In the modified assays, calibration curves for the anti-FXa assay were generated using apixaban or rivaroxaban calibrators in the range of 0 to 80 ng/mL; test samples were analyzed neat with an overall 1:2.6 sample dilution. Rivaroxaban and apixaban concentrations in the test samples were interpolated from the respective assay specific calibration curves. Validation of the modified anti-FXa assays was performed by assessing a) linearity and precision of the calibration curve and controls, b) lower limit of quantitation (LLOQ), c) inter-assay precision and d) sample stability. Results: The calibration curves for both apixaban and rivaroxaban assays demonstrated good correlation with a mean "r" value of 0.997 and 0.998, respectively (n=6). The percent recovery and precision of the modified anti-FXa assay are summarized in Table 1. The LLOQ for apixaban and rivaroxaban using the modified assays were &amp;lt;18.8 and &amp;lt;20.6 ng/mL, respectively, based on the preliminary results. Both apixaban and rivaroxaban assays demonstrated potent reversal of anti-FXa activity in presence of andexanet. Samples containing 232 ng/mL apixaban (0.5 µM) treated with equimolar andexanet (0.5 µM) resulted in 77.18 ng/mL of quantifiable apixaban (~66.7% reversal). Similarly, samples containing 242 ng/mL rivaroxaban (0.5 µM) treated with equimolar andexanet (0.5 µM) resulted in 29.44 ng/mL quantifiable rivaroxaban (~87.8% reversal). The short-term stability study with the modified anti-FXa assay included storage of plasma samples at 2-8oC up to 24 hours and under frozen conditions at -20oC up to 2 weeks. Conclusions: The modified anti-FXa assays intended for measuring FXa inhibitor levels in the presence of andexanet produced acceptable analytical performance characteristics. Application of the modified anti-FXa assays in plasma samples from andexanet-treated human subjects has yet to be studied. Table 1 Disclosures Cardenas: CirQuest Labs/MLM Medical Labs: Current Employment. Kotha:CirQuest Labs/MLM Medical Labs: Current Employment. Lu:Portola Pharmaceuticals, Inc.: Current Employment. Conley:Portola Pharmaceuticals, Inc.: Current Employment. Bourdin:Diagnostica Stago: Current Employment. Herve:Diagnostica Stago: Current Employment. Jennings:CirQuest Labs/MLM Medical Labs: Current Employment, Current equity holder in private company.

Do Anti-Factor Xa Levels have any Impact on Pregnancy Outcome in Women with Previous Adverse Outcomes?

Low-molecular-weight heparin (LMWH) is used during pregnancy in women diagnosed with thrombophilia for prevention of thromboembolic events and prevention of recurrent pregnancy loss. Prophylactic dosing does not always achieve target anti-FXa levels of 0.2-0.6 IU/ml. We aimed to determine if anti-FXa levels, measured in the first trimester, have an influence on pregnancy outcome. Eighty-one first-trimester women with a history of adverse pregnancy outcomes under LMWH therapy during pregnancy were enrolled in this study. Anti-FXa levels were measured in the first trimester, and fetal and maternal outcomes were recorded. The mean age of women was 28±4 (19-40) and mean anti-FXa level 0.44±0.93 IU/ml. No bleeding or clotting complications were associated with LMWH administration. Anti-FXa levels did not have a relationship with gestational age at birth, fetal weight, type of delivery, cesarean indications, postpartum bleeding, APGAR scores, or admission to the neonatal intensive care unit (p>0.005). Anti-FXa levels were not correlated with live birth rates. Anti-FXa levels did not have an influence on pregnancy and fetal outcomes. The effect of LMWH on pregnancy outcomes may not be due to anticoagulant activity but other mechanisms.

Supplementation with antithrombin III ex vivo optimizes enoxaparin responses in critically injured patients

BackgroundThe high incidence of venous thromboembolism (VTE) following trauma persists in spite of aggressive thromboprophylaxis strategies. Approximately half of VTE patients do not achieve the recommended anti-FXa response to enoxaparin anticoagulation (0.1–0.4 IU/mL), however, research to explain or correct this phenomenon is lacking. We hypothesized that antithrombin III (AT) deficiency is associated with poor enoxaparin responsiveness in trauma patients that develop VTE which can be reversed through supplementation with AT. Methods and findingsA retrospective cohort study was performed on plasma collected from trauma patients who did and did not develop pulmonary embolism (PE) as well as healthy volunteers. AT levels, thrombin generation, and anti-FXa levels were measured in the collected plasma at baseline and in response to supplementation with AT concentrate at 120–200% or plasma (30% volume). A total of 54 PE patients and 46 non-PE patients were enrolled in this study for analysis. Compared to healthy volunteers, trauma patients had lower levels of AT, elevated thrombin generation, and lower anti-FXa levels in response to enoxaparin. Moreover, thrombin generation was higher and responses to enoxaparin were lower in patients who developed PE compared to those who did not develop PE. We found that supplementation with AT, but not plasma, increased AT levels and improved enoxaparin-mediated inhibition of thrombin generation. ConclusionsSupplementation with AT may provide a novel adjunct therapy to increase the effectiveness of enoxaparin thromboprophylaxis and reduce the incidence of VTE in the trauma population.

Reversal of Apixaban Anticoagulation with Reduced Doses of Andexanet Alfa in a Porcine Polytrauma Model

Background: Prompt reversal of factor Xa (FXa) anticoagulation is essential in clinical situations with major bleeding or urgent surgery. Andexanet alfa (Andexxa, AnXa) is approved in the US for reversal of rivaroxaban or apixaban anticoagulation when necessary due to life-threatening or uncontrolled bleeding. In ANNEXA-4 interim report, ~85% of patients had good or excellent hemostasis after AnXa treatment (bolus + 2-h infusion). However, the minimum extent and duration of anticoagulation reversal required for a clinically relevant reduction in bleeding in humans have not been fully characterized.Purpose: The impact of escalating doses of AnXa on reversing bleeding in a porcine polytrauma model with apixaban anticoagulation was investigated.Method: After ethical approval, 40 anesthetized male pigs underwent a standardized polytrauma by blunt liver injury and bilateral femur fractures following 3-day apixaban administration (20 mg/day). 12 min post-trauma, animals were randomized (n=8 per group) to 5 groups: 250 mg bolus (AnXa 250 B), 500 mg bolus (AnXa 500 B), 250 bolus + 300 mg 2-h infusion (AnXa 250 B+), 500 mg bolus + 600 mg 2-h infusion (AnXa 500 B+), or vehicle (control). Blood loss (BL), hemodynamics and coagulation profiles were monitored over 5 h or until death; the primary outcome was total BL. Coagulation profiles consisted of apixabananti-FXa activity, global coagulation assays (PT, aPTT), rotational thromboelastometry (ROTEM) and thromboelastography (TEG). For differentiated risk assessment, thrombin generation, thrombin-antithrombin (TAT) and D-Dimer levels were measured. Data were analyzed by two-way ANOVA and log-rank tests (mean ± SD).Results: Before the polytrauma, anti-FXa levels were 178.2 ± 52.7 ng/mL (similar among 5 groups). Trauma led to comparable BL at 12 min after injury (814 ± 79 mL). Compared with control (3464 ± 719 mL) and AnXa 250 B (3155 ± 364 mL; p=0.99 vs control), a significant reduction in total BL was observed in AnXa 250 B+ (2113 ± 297 mL; p<0.01 vs all other groups), AnXa 500 B (1427 ± 119 mL; p< 0.01 vs control, AnXa 250 B and AnXa 250 B+) and AnXa 500 B+ (1312 ± 213 mL; p=0.99 vs AnXa 500 B), with 100% survival. The mortality in the control group was 100%, whereas 62% of AnXa 250 B animals survived throughout the observation period. The reduction in total BL post-injury aligned with a dose-dependent reversal of anti-FXa activity (Figure 1). 5 min post-intervention, AnXa 500 B and AnXa 500 B+ regimens reduced the level of anti-FXa activity to 40.7 ± 14.6 and 33.8 ± 10.1 ng/mL, respectively. In contrast, reduction of anti-FXa activity to 84.3 ± 28.9 and 65.9 ± 14.9 ng/mL was seen in AnXa 250 B and AnXa 250 B+ regimens, respectively. This anti-FXa activity could be measured by the viscoelastic point of care tests on a specific FXa channel on a TEG. Activation of coagulation was indicated by dose-dependent increases in TAT and D-Dimer levels. This activation was in line with the recovery of the impaired thrombin generation following administration of AnXa. Clinically no adverse events were observed and the necropsy revealed no evidence of thromboembolic complications.Conclusion: Dose-dependent reversal of apixaban by AnXa in this animal model was associated with decreased BL and mortality. The results indicate that AnXa regimens that decreased anti-FXa activity below a certain level (approx. 50 ng/mL), whether temporarily or sustained, was sufficient to prevent exsanguination in this animal model. This remaining low level of anticoagulation after apixaban reversal does not prevent activation of coagulation, allowing for sufficient hemostasis. Our results warrant further investigation of the extent and duration of reversal of FXa inhibition required to achieve adequate hemostasis in humans.Figure 1: Anti-FXa activity in control, AnXa 250 B and AnXa 250 B+ groups (A). Anti-FXa activity in control, AnXa 500 B and AnXa 500 B+ groups (B). Initially n=8 per group. *P<0.05 vs. all other groups; Ω<0.05 vs. control; § P<0.05 vs. AnXa 250 B+; †P<0.05 vs. AnXa 500 B; ‡P<0.05 vs. AnXa 500 B+. BL: baseline (after 3-days oral apixaban administration and before the polytrauma) [Display omitted] DisclosuresGrottke:Pfizer: Honoraria; Sanofi: Honoraria; Octapharma: Consultancy, Research Funding; Portola: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding. Conley:Portola: Employment. Rossaint:CSL Behring: Honoraria; Boehringer Ingelheim: Honoraria.

Unfractionated Heparin Use in Children: Clinical Outcomes in a Pediatric Cohort Managed Using an Anti-Factor Xa Based Nomogram

Background: Given its short half-life and immediate, complete reversibility with protamine sulfate, unfractionated heparin (UFH) remains the anticoagulant of choice for critically-ill children. The American College of Chest Physicians recommends that a therapeutic activated partial thromboplastin time (APTT) range in children on treatment doses of UFH should reflect an anti-FXa level of 0.35-0.7 IU/mL. A previous study from our institution showed moderate correlation between APTT and anti-FXa, prompting an institution-wide change to an anti-FXa based nomogram. Per the new nomogram, APTT and anti-FXa levels were simultaneously collected at pre-specified time points, though dose titrations were made on anti-FXa levels alone. In this study, we present our 20-month experience using this nomogram.Objectives: To assess the utility of anti-FXa based UFH dosing guidelines in children over a 20-month period (September 2015-May 2017).Methods: Permission for this study was obtained from the Institutional Review Board. Data was abstracted for all pediatric patients (age<21 yrs.) receiving therapeutic dosing of UFH (≥18 u/kg/hr) at Nationwide Children's Hospital (NCH) over the study period. Patients receiving UFH for <24 hrs, patients with mechanical circuits (ECMO and ventricular assist devices), and patients receiving concomitant anti-platelet therapy were excluded. Data were analyzed using descriptive statistics and comparisons were made using non-parametric methods. Correlations were assessed using the Bland-Altman method for repeated measures.Results: Over a 20-month period, 176 patients received UFH therapy at NCH. Of these, 95 patients met our pre-specified inclusion criteria. These 95 patients had 1102 simultaneous APTT and anti-FXa measurements performed. Baseline demographic information is described in Table 1. Mean duration of UFH therapy was 5.2 days (range: 1-45 days). Median UFH dose required to reach therapeutic anti-FXa goal was 22 units/kg/hr (range: 18-55 units/kg/hr), and was significantly higher in infants (<1yr of age) compared to older children (33.9 u/kg and 20 u/kg respectively; p<0.0001). Median time to achieve therapeutic anti-Xa was 10 hours (range: 2-96 hours), and was significantly shorter in patients who received a bolus (n=44) compared to those who did not (5 hrs and 12 hrs respectively; p=0.03). Five patients never achieved therapeutic anti-FXa levels. In patients with thrombo-embolism (n=75), 65 had end-of-therapy imaging (complete response: 36; partial or no response: 29). Time to achieve therapeutic anti-FXa was not predictive of radiological response (p=0.27). Moderate linear correlation between the APTT and anti-FXa (r = 0.74; 95% CI = 0.71-0.77) (Figure 1) was noted for the entire cohort. Eleven (10.6%) major and non-major bleeding events and 10 (10.5%) minor bleeding events were noted. When comparing coagulation parameters of patients with major and non-major bleeding to those with no-bleeding and minor bleeding age, indication for anticoagulation, peak anti-FXa, peak APTT, lowest platelet count and fibrinogen were not predictive of bleeding. Critically high APTT (>250 sec) was noted on 43 occasions in 21 unique patients and not associated with an increased risk of major and non-major bleeds (p=0.07).Conclusions: UFH monitoring is challenging in children. Time to achieve therapeutic anticoagulation and bleeding risk in our cohort is consistent with previous publications. Contrary to previous publications, extreme elevation of APTT was not associated with increased bleeding risk. [Display omitted] DisclosuresO'Brien:Pfizer: Consultancy, Other: study of direct oral anticoagulant in treatment of pediatric VTE; Glaxo Smith Kline: Other: DSMB for Arixtra Study in Pediatric VTE; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - von Willebrand Disease diagnosis & management; Bristol Myers Squibb: Other: study of direct oral anticoagulant in prevention of pediatric VTE, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - VWD diagnosis and management. Dunn:Alnylam: Other: Unrestricted educational grant; Bayer: Consultancy, Other: Unrestricted educational grant; Kedrion: Other: Unrestricted educational grant; NovoNordisk: Other: Unrestricted educational grant; Octapharma: Other: Unrestricted educational grant; Shire: Consultancy, Other: Unrestricted educational grant, Research Funding; Biogen: Other: Unrestricted educational grant, Research Funding; CSL Behring: Consultancy, Other: Unrestricted educational grant; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees. Kumar:Bayer: Consultancy; CSL Behring: Consultancy.

Anti-factor Xa levels in patients undergoing laparoscopic sleeve gastrectomy: 2 different dosing regimens of enoxaparin

BackgroundMorbidly obese patients undergoing bariatric surgery are at risk for developing venous thromboembolic events. Data regarding the appropriate dosing strategy in this special population is limited. ObjectiveTo evaluate 2 different dosing regimens of enoxaparin in a prospective cohort of patients undergoing laparoscopic sleeve gastrectomy. SettingUniversity hospital, Israel MethodsThe study cohort consisted of 54 patients divided into 2 groups. Group I received 40 mg enoxaparin every 24 hours, and group II received 60 mg enoxaparin every 24 hours. Anti-factor Xa (FXa) levels from each patient were obtained 3 to 4 hours after administration of the third dose of enoxaparin. Levels between .2 and 0.5 U/mL were considered appropriate. Five additional patients were selected as controls. ResultsThere were 31 patients in group I and 23 patients in group II. There was a statistically significant difference between anti-FXa levels achieved in each group: .247 U/mL in group I (range, .15–.39) versus .346 U/mL (range, .24–.8) in group II. Both groups achieved mean anti-FXa levels in the range designated appropriate with a high proportion of patients achieving appropriate levels (group I: 80.6%; group II: 91.3%). Univariate analyses found that total weight and sex were significantly correlated with anti-FXa levels. However, a multivariate analysis including enoxaparin dose found that only enoxaparin dose remained significantly correlated with anti-FXa levels. ConclusionIn the absence of sufficient data regarding clinical efficacy and safety of different dosing regimens both dosing regimens studied are reasonable choices for venous thromboembolic events prophylaxis after bariatric surgery.

Therapeutic monitoring of unfractionated heparin – trials and tribulations

ABSTRACTIntroduction: Heparin is one of the oldest biological medicines with an established role in prevention and treatment of arterial and venous thromboembolism. Published therapeutic ranges for unfractionated heparin (UFH) mostly precede the large increase in the number of activated partial thromboplastin time (APTT) reagent/instrument combinations that now show wide variability.Areas covered: This paper explores the use of UFH, the development of heparin therapeutic ranges (HTRs), and the strengths and limitations of the methods used to monitor heparin’s anticoagulant effect.Expert commentary: Despite longstanding use of UFH for management of thromboembolic conditions, the optimal test for monitoring UFH remains undetermined. Although used extensively for monitoring UFH, routine APTT-derived HTRs are based on limited science that may have little relevance to current laboratory practice. Anti-FXa levels may provide better and more reliable HTRs; however, even these levels show considerable inter-laboratory variation, and there are insufficient clinical studies proving improved clinical efficacy. Alternative tests for monitoring UFH reported over time have not been proven effective nor feasible, secondary to technical or cost issues, or lack of general adoption. Thus, despite limited evidence of clinical utility, an uncomfortable marriage of convenience represented by heparin laboratory monitoring is unlikely to be terminated in the immediate future.

Anti‐activated factor II assay for monitoring unfractionated heparin in children: results of the HEARTCAT study

Background Unfractionated heparin (UFH) is used for the prophylaxis and treatment of thrombosis in children. Laboratory monitoring of UFH is needed to prevent over-anticoagulation or under-anticoagulation. Objectives To investigate the association between UFH dose and UFH effect as monitored with the anti-activated factor II (FIIa) assay, the relationship between anti-FIIa and anti-activated factor X (FXa) effects, and the influence of patient age and other factors on UFH effect. Patients and methods This was a randomized controlled trial in children during cardiac catheterization, comparing high-dose UFH (100 units kg-1 bolus) with low-dose UFH (50 units kg-1 bolus). Blood samples were drawn at baseline, and after 30 min, 60 min, and 90 min. For the purpose of this study, 49 children and 117 blood samples were evaluated. Results The anti-FIIa assay discriminated well between high-dose and low-dose UFH. Multiple regression demonstrated significant influences of UFH dose and age on anti-FIIa levels. Younger children had lower anti-FIIa levels than older children, an effect that was more pronounced with low-dose UFH. Anti-FXa/anti-FIIa ratios were equal with low-dose UFH. However, anti-FXa levels were relatively increased over anti-FIIa levels in infants and after high-dose UFH bolus administration. Conclusion The UFH effect on anti-FIIa levels is lower in infants than in older children. This influence of age appears to be dose-dependent, being more pronounced with low-dose UFH. Anti-FXa and anti-FIIa levels are not equal, particularly in infants and after high-dose UFH. Monitoring UFH solely with anti-FXa assays may not be sufficient in children, and the anti-FIIa assay may provide important complementary information.

794: Placental findings following adjusting enoxaparin dosage according to anti-FXa levels in thrombophilic women. a randomized controlled trial

794: Placental findings following adjusting enoxaparin dosage according to anti-FXa levels in thrombophilic women. a randomized controlled trial