anti-Xa Measurements Research Articles

Ability of Activated Clotting Time Measurements to Monitor Unfractionated Heparin Activity During NonCardiac Arterial Procedures

Activated clotting time (ACT) measurements are frequently used to monitor unfractionated heparin activity during non-cardiac arterial procedures (NCAP). Accuracy of ACT-guided heparinization is mandatory to prevent heparin under- and overdosing, thereby minimizing thrombo-embolic complications (TEC) and bleeding risk. The main objective of this study was to investigate accuracy of ACT to monitor heparin activity during NCAP using the Hemostasis Management System Plus with high-range cartridges. ACT values were compared with anti-Xa measurements, regarded as the standard test to measure active heparin. This was a single centre, prospective, observational cohort study. Perioperative blood samples of patients undergoing NCAP between December 2022 and September 2023 were used to perform bedside ACT measurements and anti-Xa assays in the clinical laboratory. Primary outcome was correlation between ACT and anti-Xa measurements. TEC, mortality and bleeding complications within 30 days postoperatively or during primary admission were also scored. 196 pairs of ACT and anti-Xa measurements were performed in 34 patients. Strong correlation was observed between anti-Xa and ACT measurements (Pearson correlation coefficient = 0.84, 95% CI = 0.79 - 0.87, p < 0.001). Apart from anti-Xa, no additional variables were associated with ACT in multivariate linear regression analyses (regression coefficient β = 36.7, 95% CI = 33.3 - 40.1, p < 0.001). Bleeding complications occurred in 29% of the patients, while both TEC and mortality were observed in one patient. strong correlation and an independent association were observed between heparin activity measured by anti-Xa and ACT using the Hemostasis Management System Plus.

How enoxaparin underdosing and sex contribute to achieving therapeutic anti-Xa levels.

Anti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels. This multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike's information criterion as metric was applied to refine the logistic regression model. A total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40-30.05, p < 0.001). Despite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies.

Anti-Xa Monitoring of Apixaban (ZyQuis) in Venous Thrombo-Embolism and Atrial Fibrillation.

Apixaban is a direct oral Xa inhibitor and is indicated for the treatment of venous thrombo-embolism (VTE) and prevention of stroke in atrial fibrillation (AF). Recently, a generic (ZyQuis, Zydus Lifesciences Limited, India) has received Food and Drug Administration approval. While bioequivalence has been demonstrated with Eliquis (Bristol-Myers Squibb/Pfizer, UK), it is necessary to monitor its effectiveness prior to acceptance in medical practice. This prospective study independently evaluated Apixaban (ZyQuis) at two accredited laboratories. Participants were converted from Warfarin or Rivaroxaban to Apixaban 5 mg bd for a duration of one month. Peak anti-Xa levels were measured 3-4 h post the morning dose. The samples were processed on the Atellica COAG 360 (Siemens Healthineers, Marburg, Germany) analyzers with a chromogenic anti-Xa assay (Innovance, reference interval 69-321 ng/mL). There were 26 participants; 5 men, 21 women; mean ± standard deviation age of 46 ± 12 years. Indications for anticoagulation included: VTE (88.5%) and AF (11.5%). 69.2% of the participants had at least one comorbidity. 96.2% of the anti-Xa levels were within the laboratory's 95% reference interval. Mean anti-Xa activity was 191 ± 69 ng/mL and 186 ± 68 ng/mL measured at respective laboratories. Mean differences in anti-Xa measurements represented by Bland-Altman statistics were small (bias of -2.6%, 95% confidence interval -1.11 to -4.09) and a strong correlation was observed on Deming regression analysis (0.995). Apixaban (ZyQuis) was effective for the management of VTE and AF as evidenced by anti-Xa activity.

Effects of anti-Xa activity monitoring on the outcome of high-risk pregnancies treated with a prophylactic dose of low-molecular-weight heparin.

To evaluate if anti-Xa level monitoring and dose adjustment in women using a prophylactic dose of enoxaparin can decrease placenta-mediated pregnancy complications. This retrospective observational cohort study included pregnant women receiving enoxaparin prophylaxis, who were followed at the Thrombosis and Hemostasis Outpatient clinic between 2010 and 2017. The dose was adjusted according to enoxaparin anti-Xa levels in the study group or the weight of individuals in the control group. Of 585 women surveyed, 110 met the inclusion criteria; 63 of them were included in the study group and 47 in the control group. Mean starting dose was 46 versus 43 mg (p = .25), mean final dose was 52 mg versus 45 mg (p = .03) and dose adjustment was required in 37% versus 11% (p = .002) in the study and control groups, respectively. Twenty-eight percent of anti-Xa measurements in the second trimester were beneath the prophylactic threshold, compared to 11% and 16% in the first and third trimesters, respectively (p = .02). Labors ended with live birth in 91% versus 94% of cases (p = .5), 85% versus 68% of pregnancies were term (p = .05), 11% versus 23% of newborns were low birth weight (p = .1) and placenta-mediated pregnancy complications were documented in 9% versus 19%, (p = .17) in the study group relative to controls, respectively. The most prominent decrease in anti-Xa levels was observed in the second trimester. Monitored women had significantly more term deliveries and demonstrated a trend toward higher birth weight and fewer placenta-mediated pregnancy complications. Larger studies are needed to confirm improved pregnancy outcome in monitored women.

Applications of rotational thromboelastometry in heparin monitoring in critical COVID-19 disease: Observations in the Maastricht Intensive Care COVID cohort

BackgroundCritically ill COVID-19 patients are at risk for venous thromboembolism (VTE). Therefore, they receive thromboprophylaxis and, when appropriate, therapeutic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). To monitor heparins in COVID-19 disease, whole-blood rotational thromboelastometry (ROTEM) may be a promising alternative to the aPTT and anti-Xa assays. ObjectiveTo evaluate the ROTEM INTEM/HEPTEM ratios in mechanically ventilated COVID-19 patients treated with UFH and therapeutic LMWH. Material and methodsA subcohort of mechanically ventilated COVID-19 patients of the prospective Maastricht Intensive Care Covid (MaastrICCht) cohort was studied. Anti-Xa, aPTT, and ROTEM measurements following treatment with UFH or therapeutic dose of LMWH (nadroparin) were evaluated using uni- and multivariable linear regression analysis and receiver operating characteristics. ResultsA total of 98 patients were included, of which 82 were treated with UFH and 16 with therapeutic LMWH. ROTEM-measured INTEM/HEPTEM CT ratio was higher in patients using UFH (1.4 [1.3–1.4]) compared to patients treated with LMWH (1.0 [1.0–1.1], p < 0.001). Both the aPTT and anti-Xa were associated with the CT ratio. However, the β-regression coefficient (95%CI) was significantly higher in patients on UFH (0.31 (0.001–0.62)) compared to therapeutic LMWH (0.09 (0.05–0.13)) for comparison with the anti-Xa assay. Furthermore, ROC analysis demonstrated an area under the curve for detecting UFH of 0.936(0.849–1.00), 0.851(0.702–1.000), and 0.645(0.465–0.826) for the CT ratio, aPTT, and anti-Xa, respectively. ConclusionThe ROTEM INTEM/HEPTEM CT ratio appears a promising tool to guide anticoagulant therapy in ICU patients with COVID-19 disease, but associations with clinical endpoints are currently lacking.

Creatinine Clearance May Predict Goal Enoxaparin Dose in Trauma.

Guidelines for enoxaparin dosing after trauma recommend an initial dose of 40 mg twice daily for most patients and then adjusting by anti-Xa levels. Previous studies indicated higher enoxaparin doses are necessary with higher levels of creatinine clearance (CrCl). We sought to determine if the goal enoxaparin dose correlates with the admission CrCl to reduce the reliance on measuring anti-Xa levels. A retrospective review was conducted of patients admitted to an urban, academic Level 1 trauma center from April 2017 to February 2020. Patients started on enoxaparin who reached goal anti-Xa trough levels were included, and patients were excluded if they did not reach goal anti-Xa levels. Data collection included patient demographics, injury characteristics, admission CrCl, and final enoxaparin dose. CrCl was then correlated with the final enoxaparin dose. Of 421 patients included, the mean age was 46.6 years and 73% were male. The median goal enoxaparin dose was 40 mg twice daily. The mean CrCl significantly increased with increasing twice-daily doses of enoxaparin (20 mg: 69.2 mL/min; 30 mg: 89 mL/min; 40 mg: 112.8 mL/min; 50 mg: 140.5mL/min; 60 mg: 147.4 mL/min; and 70 mg: 140 mL/min; p < 0.01). Admission CrCl may predict the enoxaparin dose required to achieve adequate anti-Xa levels. Our data indicate that CrCls of approximately 70, 90, 110, 140, and 150 mL/min may predict the twice-daily enoxaparin doses of 20, 30, 40, 50, and 60 mg, respectively. CrCl dosing guidance may reduce the time to goal anti-Xa levels and the frequency of anti-Xa measurements. Further research is necessary, and enoxaparin dosing should continue to be monitored by anti-Xa levels.

Stability of Rivaroxaban and Apixaban Anti-Xa Activities in Whole Blood Samples: A French Bicentric Study.

Over the last 10 years, the use of direct oral anticoagulants (DOACs) in the management of venous thromboembolism and atrial fibrillation grew significantly, and in particular direct factor Xa inhibitors rivaroxaban and apixaban. Clinical trials of these molecules did not underline the necessity of systematic laboratory monitoring, and the measurement of anti-Xa activity was only indicated in urgent situations such as trauma or prior to acute surgery.[1] [2] [3] [4] However, in 2021, the International Council for Standardization in Haematology (ICSH) updated these recommendations and added several nonurgent indications for anti-Xa activity measurement: advanced age, severe renal failure, ahead of a surgical procedure at high bleeding risk, body mass index >40 kg/m2, and drug interactions.[5] [6] The 2018 ICSH recommendations stated that citrated whole blood samples for anti-Xa activity measurement should be processed within 4 hours of collection, but without providing evidence. Moreover, the French Working Group on Hemostasis and Thrombosis recommendations indicated a shorter stability, of 2 hours, in accordance with the only study then published in the literature.[7] [8] [9] In practice, some laboratories may find it difficult to comply with these short delays.

Prevalence and Impact of Lupus Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation.

Monitoring of blood coagulation is essential in ECMO patients. We investigated the prevalence of lupus anticoagulant (LA) and its association with coagulation testing and hemostaseologic complications in patients treated with ECMO. This is a retrospective analysis including adult patients who received ECMO at a medical intensive care unit at the Medical University of Vienna. The primary outcome was the prevalence of LA. Secondary outcomes included conditions associated with LA positivity, rates of bleeding and thromboembolic events, as well as the proportions of aPTT and antiXa measurements within the target range. Between 2013 and 2021 193 patients received ECMO, in 62 (32%) of whom LA diagnostics were performed. Twenty-two (35%) patients tested positive. LA positive patients had more frequently received VV ECMO (77.3% vs 34.3%; p = 0.002), were more frequently diagnosed with viral respiratory infections (SARS-CoV2: 45.5% vs 20%; p = 0.041, influenza virus: 22.7% vs 0%; p = 0.003), had a longer ECMO treatment duration (25 vs 10 days; p = 0.011) and a longer ICU stay (48 vs 25 days; p = 0.022), but similar rates of bleeding and thromboembolic events.

Trough anti-Xa activity after intermediate dose nadroparin for thrombosis prophylaxis in critically ill patients with COVID-19 and acute kidney injury

Our objective was to assess the incidence of drug bioaccumulation in critically ill COVID-19 patients with AKI receiving intermediate dose nadroparin for thrombosis prophylaxis. We conducted a Prospective cohort study of critically ill COVID-19 patients. In patients on intermediate dose nadroparin (5700 IU once daily) we assessed the incidence of bioaccumulation (trough anti-Xa level > 0.2 IU/mL) stratified according to presence of AKI. We quantified this association using multilevel analyses. To assess robustness of our observations, we explored the association between AKI and anti-Xa activity in patients receiving high dose nadroparin (> 5700 IU). 108 patients received intermediate dose nadroparin, of whom 24 had AKI during 36 anti-Xa measurements. One patient with AKI (4.2% [95%CI 0.1–21%]) and 1 without (1.2% [95%CI 0.03–6.5%]) developed bioaccumulation (p = 0.39). Development of AKI was associated with a mean increase of 0.04 (95%CI 0.02–0.05) IU/ml anti-Xa activity. There was no statistically significant association between anti-Xa activity and AKI in 51 patients on high dose nadroparin. There were four major bleeding events, all in patients on high dose nadroparin. In conclusion, Bioaccumulation of an intermediate dose nadroparin did not occur to a significant extent in critically ill patients with COVID-19 complicated by AKI. Dose adjustment in AKI may be unnecessary.

Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.

Prospective cohort study on the use of low molecular weight heparin calibrated anti-Xa assay for measurement of direct oral Xa inhibitors in ex vivo patient samples

Drug-specific anti-Xa chromogenic assays are recommended for measurement of direct anti-Xa inhibitor levels but are not routinely available in many institutions. We performed a prospective study to determine: (1) the relationship between low molecular weight heparin (LMWH) calibrated anti-Xa measurements and apixaban or rivaroxaban levels measured using drug-specific anti-Xa assays and, (2) if a LMWH calibrated anti-Xa assay can be used to detect clinically significant apixaban or rivaroxaban levels. Haematology outpatients on rivaroxaban or apixaban for at least 72 h were recruited for this study. Anti-Xa LMWH assay was performed using the Innovance Heparin Anti-Xa kit/calibrator. Drug-specific levels were determined using STA-Liquid anti-Xa kit/STA-Apixaban or STA-Rivaroxaban calibrators. Serial dilutions with pooled normal plasma were performed for specimens with anti-Xa LMWH activity greater than 1.50 ng/mL to obtain anti-Xa levels within the reportable range (0.10-1.50 ng/mL) and multiplied by the dilution factor to determine actual anti-Xa level. Seventy-five (39 rivaroxaban, 36 apixaban) specimens from 67 patients (mean age 60.3 years; 53.3% males) were available for analysis. Rivaroxaban levels ranged from <25 to 500 ng/mL while apixaban levels ranged from <20 to 236.1 ng/mL. For both rivaroxaban and apixaban, there was linear and good correlation (R2= 0.96) between direct oral anticoagulants and anti-Xa LMWH levels. Using the correlation equation from our data, a rivaroxaban concentration of 50 ng/mL [International Society on Thrombosis and Haemostasis (ISTH) threshold for consideration of antidotes in bleeding patients] and 30 ng/mL (ISTH threshold for consideration of reversal agents prior to interventions), corresponds to anti-Xa LMWH levels of 0.50 and 0.35 IU/mL, respectively. For apixaban the corresponding anti-Xa LMWH levels were 0.35 and 0.20 IU/mL, respectively. In conclusion, LWWH calibrated anti-Xa assay can be used in emergency situations to screen for clinically significant apixaban or rivaroxaban levels when drug-specific calibrators are not available.

Accuracy of a Single, Heparin-Calibrated Anti-Xa Assay for the Measurement of Rivaroxaban, Apixaban, and Edoxaban Drug Concentrations: A Prospective Cross-Sectional Study.

BackgroundApplying a single anti-Xa assay, calibrated to unfractionated heparin to measure rivaroxaban, apixaban, and edoxaban would simplify laboratory procedures and save healthcare costs.AimWe hypothesized that a heparin-calibrated anti-Xa assay would accurately measure rivaroxaban, apixaban, and edoxaban drug concentrations and correctly predict clinically relevant drug levels.MethodsThis analysis is part of the Simple-Xa study, a prospective multicenter cross-sectional study conducted in clinical practice. Patients treated with rivaroxaban, apixaban, or edoxaban were included. Anti-Xa activity was measured using the Siemens INNOVANCE® Heparin assay. Drug concentrations were determined using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cut-off levels were determined in a derivation dataset (50% of patients) and sensitivities and specificities were calculated in a verification dataset (50% of patients).ResultsOverall, 845 patients were available for analysis. Correlation coefficients (rs) between the heparin-calibrated anti-Xa assay and drug concentrations were 0.97 (95% CI 0.97, 0.98) for rivaroxaban, 0.96 (0.96, 0.97) for apixaban, and 0.96 (0.94, 0.99) for edoxaban. The area under the receiver operating characteristics curve (ROC) was 0.99 for all clinically relevant drug concentrations. In the verification dataset, the sensitivity was 94.2% (95% CI 90.8–96.6) for 30 μg L–1, 95.8% (92.4–98.0) for 50 μg L–1, and 98.7% (95.5–99.9) for 100 μg L–1. Specificities were 86.3% (79.2–91.7), 89.8% (84.5–93.7), and 88.7% (84.2–92.2), respectively.ConclusionIn a large prospective study in clinical practice, a strong correlation of heparin-calibrated anti-Xa measurements with LC-MS/MS results was observed and clinically relevant drug concentrations were predicted correctly.

Effects of dalteparin on anti-Xa activities cannot be predicted in critically ill COVID-19 patients.

Critically ill COVID‐19 patients are at high risk of thromboembolic events despite routine‐dosed low‐molecular‐weight heparin thromboprophylaxis. However, in recent randomized trials increased‐intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti‐Xa activities on frequent timepoints in 15 critically ill COVID‐19 patients receiving dalteparin and performed PK analysis by nonlinear mixed‐effect modelling. A linear one‐compartment model with first‐order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased‐intensity dalteparin to result in anti‐Xa activities well over prophylactic targets (0.2‐0.4 IU/mL) in the majority of patients. Therapeutic‐intensity dalteparin results in supratherapeutic anti‐Xa levels (target 0.6‐1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti‐Xa measurements should guide high‐intensity dalteparin in critically ill COVID‐19 patients.

Agreement between Anti-Factor Xa and Activated Partial Thromboplastin Time Measurements in Syncardia Total Artificial Heart Recipients Receiving Postoperative Anticoagulation with Unfractionated Heparin

<h3>Purpose</h3> The Activated Partial Thromboplastin Time (aPTT) has been the historical method of choice for anticoagulation monitoring in patients undergoing mechanical circulatory support with intravenous unfractionated heparin (IVUFH). However, the assay is susceptible to interference effects and is being progressively superseded by the anti-Factor Xa (anti-Xa) method. The study aim was to investigate the agreement between aPTT and anti-Xa measurements in patients receiving post-operative anticoagulation with IVUFH following Syncardia Inc. Total Artificial Heart (TAH) implantation. <h3>Methods</h3> A retrospective single arm, single centre analysis of 20 patients who underwent TAH implantation from July 2014 to October 2018 entailed simultaneous determinations of aPTT and anti-Xa. Agreement between these parameters was assessed using a novel statistical approach based on the Bland-Altman method. <h3>Results</h3> In spite of a positive correlation between aPPT and anti-Xa measurements, normal target ranges were poorly aligned: from 5^th to 30^th post-operative day, for anti-Xa values of 0.2 and 0.4 U/mL corresponding APTT values were 51.1 and 64.3 seconds, respectively. Moreover, white blood cell count was associated with a trend towards lower aPTT levels with respect to anti-Xa. Conversely, bilirubin level was significantly associated with an increase in aPTT levels with respect to anti-Xa values. <h3>Conclusion</h3> A novel method developed to investigate the agreement between aPTT and anti-Xa in the peri-operative phase of TAH therapy showed comparatively low levels of anticoagulation (with respect to historical target aPTT range) were not associated with thromboembolic sequalae. Methodology developed for this study is generalisable to other forms of mechanical circulatory support.

Is specific anti-factor Xa activity measurement a way to predict relevant bleeding in non-valvular atrial fibrillation (NVAF) patients?

Anti-Xa direct oral anticoagulants (DOACs) are first line therapy for stroke prevention in NVAF patients. There is no need of regular anticoagulation monitoring and dose reduction may be indicated in patients showing a high bleeding risk. However, we still estimate 2 to 5% of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) in NVAF patients. Thereupon, we must identify other bleeding risks such as biological overdose. The goal of this study was to investigate specific anti-Xa activity measurement as a mean to predict bleeding complications in NVAF patients. One hundred and forty-six patients (either on apixaban or rivaroxaban) were enrolled from 2017 to 2019. The DOACs measurements were performed the day of inclusion. We determined an overdose and therapeutic underdose thresholds according to expected anti-Xa plasma range levels filled in the European heart rhythm association guide use of DOACs. MB, CRNMB and minor bleedings and strokes occurring during the follow up (up to 3 years) were recorded. We analysed the correlation between therapeutic overdose and the studied endpoints. To this day, the statistical analyses are still being conducted. The first results show that among the 146 patients, more or less 14% were considered overdosed. Moreover, a statistical trend was found between overdosed patients and MB or CRNMB. In routine clinical practice, anti-Xa activity measurement could be used to predict bleeding risk in a selected population in order to adapt doses or to consider a change of molecule.

Effective use of fondaparinux in patient with unresponsiveness to nadroparin

Fondaparinux exhibits a similar mechanism of action as LMWH. Since both of these drugs bind to antithrombin and increase its affinity to factor Xa, fondaparinux is not expected to be an effective alternative anticoagulant to LMWH in case of LMWH resistance. We report on a case of effective anticoagulation using fondaparinux following total unresponsiveness to high doses of nadroparin administered twice daily, as confirmed via repeated anti-Xa measurements. The antithrombin levels were within the normal range. To the best of our knowledge, this is the first report of the effective use of fondaparinux in the case of unresponsiveness to LMWH.

Australian and New Zealand Registry of Anticoagulation in the Obese: Prescribing Patterns, Drug Levels and Patient Outcomes

Background: There is limited data to guide prescribing of all available anticoagulants in obese patients, in particular those weighing &amp;gt; 150kg or with a BMI &amp;gt; 40kg/m2. We aimed to examine anticoagulant prescribing patterns in obese patients in Australia and New Zealand including choice of agent and dosing, determine whether patients with obesity achieve appropriate direct oral anticoagulant (DOAC) levels and evaluate the efficacy and safety of anticoagulation in obese patients. Methods: Patients with a BMI &amp;gt; 35kg/m2 or weight &amp;gt; 120kg receiving anticoagulant therapy are prospectively identified at 7 sites in Australia and New Zealand. Demographic data, indication for anticoagulation and choice of anticoagulant are collected at baseline. At follow-up visits, drug specific levels, dose adjustments and clinical progress (symptoms, imaging, recurrent thrombosis and adverse events) are recorded. Results: 155 patients have been recruited across seven sites (recruitment ongoing). The median age of patients was 53 (range 22-85) and 49% of patients were male. 77 (50%) of patients were anticoagulated for pulmonary embolus (PE) while 40% were anticoagulated for deep vein thrombosis (DVT) without PE. Initial anticoagulant prescribed was apixaban in 37 patients, dabigatran in 4 patients, rivaroxaban in 57 patients, low molecular weight heparin (LMWH) in 29 patients and warfarin in 28 patients (Table 1). A subset of patients initially received LMWH for 5-14 days prior to transition to a DOAC (rivaroxaban in 7, dabigatran in 6). There was cross-over between agents during the study period. Table 2 demonstrates median peak and trough DOAC levels. All peak apixaban levels and 25 of 37 (68%) peak rivaroxaban levels were within the therapeutic ranges published by the International Council for Standardization in Haematology (Gosselin, Thromb Haemost. 2018). Assessment of appropriate trough levels was limited by the limit of detection at different laboratories. 27 patients receiving enoxaparin had at least one peak Anti-Xa level (target peak 0.5-1.2U/ml). The median enoxaparin dose to achieve therapeutic peak Anti-Xa was 0.9mg/kg (range 0.52-1.3). 15 patients weighing &amp;gt; 150kg had a recorded peak Anti-Xa, 10 of these patients were prescribed a capped dose of 150mg BD (weight range 155-290kg) and nine had a therapeutic Anti-Xa and one had a supratherapeutic Anti-Xa measurement. One patient had a PE on apixaban 5mg twice daily (in the setting of suspected non-compliance), one patient had a new confirmed PE after 4 days of non-compliance with rivaroxaban 20mg daily and another patient had a confirmed recurrence on therapeutic warfarin. 1 patient had a PE when warfarin was withheld for emergency surgery. An equivocal recurrence occurred on enoxaparin with a supratherapeutic Anti-Xa (1.76 U.ml) and 1 DVT occurred on dabigatran for a cardiac indication (no drug level available). One patient had recurrent superficial thrombophlebitis on rivaroxaban 20mg daily (peak 301ng/L and trough &amp;lt;30ng/L). There was one episode of life-threatening gastrointestinal bleeding on dabigatran. Conclusion: There is limited data to guide prescribing of all anticoagulants in obese patients, in particular in patients weighing &amp;gt; 150kg or BMI &amp;gt; 40kg/m2. There is increasing use of DOACs in Australia and New Zealand in patients with obesity given the ease of administration and lack of monitoring required. Despite the recommendation to perform DOAC levels in this group of patients, interpretation of levels is difficult due to a lack of well validated therapeutic ranges with clinical correlation. Further data regarding the clinical utility of DOAC levels, appropriate dosing strategy for enoxaparin, and clinical outcomes in this population is required. Our registry provides data regarding drug levels in this population, prescribing characteristics and clinical outcome data. Disclosures No relevant conflicts of interest to declare.

Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19: A longitudinal controlled before-after study

IntroductionAn individualised thromboprophylaxis was implemented in critically ill patients suffering from coronavirus disease 2019 (COVID-19) pneumonia to reduce mortality and improve clinical outcome. The aim of this study was to evaluate the effect of this intervention on clinical outcome. MethodsIn this mono-centric, controlled, before-after study, all consecutive adult patients with confirmed COVID-19 pneumonia admitted to ICU from March 13th to April 20th 2020 were included. A thromboprophylaxis protocol, including augmented LMWH dosing, individually tailored with anti-Xa measurements and twice-weekly ultrasonography screening for DVT, was implemented on March 31th 2020. Primary endpoint is one-month mortality. Secondary outcomes include two-week and three-week mortality, the incidence of VTE, acute kidney injury and continuous renal replacement therapy (CRRT). Multiple regression modelling was used to correct for differences between the two groups. Results46 patients were included in the before group, 26 patients in the after group. One month mortality decreased from 39.13% to 3.85% (p < 0.001). After correction for confounding variables, one-month mortality was significantly higher in the before group (p = 0.02, OR 8.86 (1.46, 53.75)). The cumulative incidence of VTE and CRRT was respectively 41% and 30.4% in the before group and dropped to 15% (p = 0.03) and 3.8% (p = 0.01), respectively. After correction for confounding variables, risk of VTE (p = 0.03, 6.01 (1.13, 32.12)) and CRRT (p = 0.02, OR 19.21 (1.44, 255.86)) remained significantly higher in the before group. ConclusionMortality, cumulative risk of VTE and need for CRRT may be significantly reduced in COVID-19 patients by implementation of a more aggressive thromboprophylaxis protocol. Future research should focus on confirmation of these results in a randomized design and on uncovering the mechanisms underlying these observations. Registration numberNCT04394000.

Evaluation of the anticoagulant effect of low-molecular-weight heparins based on the anti-Xa level during haemodialysis.

Evaluate the relationship between anti-Xa activity and anticoagulant effect, and ascertain whether accumulation of low-molecular-weight heparins (LMWH) occurs during haemodialysis. There was an observational, single-centre study among participants who received the LMWH dalteparin, enoxaparin or nadroparin. A standard haemodialysis session lasted 4 hours. All included participants had anti-Xa activity measures at 0.5 and 4 hours. Extracorporeal circuit (ECC) clotting was evaluated by visual inspection of the haemodialyser and bubble trap after each haemodialysis session. The same person was tested at three consecutive haemodialysis sessions. Overall, 90 participants were enrolled and 259 haemodialysis sessions assessed. There was no significant difference in the mean anti-Xa activity at 0.5 and 4 hours for three consecutive sessions, so LMWH accumulation did not occur. There were 69 (26.6%) sessions in which, ECC clotting was visible. Compared with the group where circuit clotting did not occur, the LMWH dose and anti-Xa activity in the group where circuit clotting occurred were significantly lower. At 0.5 hour, anti-Xa <0.88 IU/mL had significantly higher odds of ECC clotting than that at ≥0.88 IU/mL. At 4 hours, anti-Xa <0.35 IU/mL had significantly higher odds of ECC clotting than that at ≥0.35 IU/mL. We found that over three haemodialysis sessions, no significant accumulation of LMWH was evident in subjects receiving a LMWH dose of between 2000 and 5000 IU for regular. Anti-Xa activity measurement can be used to adjust the dosage of LMWH and predict the anticoagulant effect during haemodialysis.

Detection of early incomplete heparin reversal following congenital cardiac surgery: A single-center retrospective observational study

BackgroundThe monitoring of unfractionated heparin (UFH) reversal with protamine plays a crucial role for bleeding management after cardio-pulmonary bypass (CPB) in congenital cardiac surgery. The current standard for the monitoring of UFH and its reversal is the activated clotting time (ACT). While the ACT is affected by other CPB-associated pathologies a bedside technique with more specific heparin-related results would be very helpful. The new point-of-care viscoelastic test Haemonetics TEG® 6s, which is based on small blood samples may fulfill these requirements. This study aimed to compare the new TEG with laboratory assays. MethodsA retrospective observational study was performed on 40 children with a median age of 130 days (interquartile range 13 to 310 days) undergoing congenital cardiac surgery. After separation of CPB, test results of the TEG® 6s, ACT, anti-Xa for UFH and PTT were compared and correlated with each other. ResultsNo clinically relevant correlation was found for heparin specific TEG-derived parameters (CK/CKH R-time ratio) with ACT, PTT and anti-Xa measurements. After grouping in dependence to the CK/CKH R-time in patients with and without successful heparin reversal again no significant difference of anti-Xa-UFH-levels, post-/pre-CPB ratio of the PTT and ACT was observed. ConclusionsIn pediatric patients undergoing cardiac surgery using CPB there is no association of conventional coagulation tests and TEG-derived results. While bedside viscoelastic tests deliver rapid results, further studies are needed to compare whether the TEG based management of incomplete heparin reversal is sufficient to monitor heparin reversal and to reduce blood loss.