anti-Xa Activity Research Articles

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.

Challenges to Laboratory Monitoring of Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups.

Development of a Rapid Qualitative Screen for Anticoagulant Presence.

Direct oral anticoagulants (DOACs) and fondaparinux with stable pharmacokinetics are commonly used anticoagulants for outpatient care. Due to the lack of monitoring requirements, drug-specific assays are not available in most hospital laboratories, but drug levels are needed in some urgent/emergency situations. This study describes the development of a qualitative screen for the presence of DOAC or fondaparinux using coagulation tests found in most laboratories. The DOAC screen is composed of a heparin anti-Xa activity assay and thrombin time (TT) assay. The STA®-Liquid-Anti-Xa assay calibrated with Stago Multi Hep® and STA®-TT were run on STA-R Max® analyzers. The anti-Xa activity and TT assays were repeated 5 times in samples of commercially available calibrators and controls for each drug: fondaparinux, dabigatran, rivaroxaban, apixaban, and edoxaban. Statistical analysis and correlations were performed for anti-Xa activity and TT results for each drug and pooled normal plasma. A significant correlation was found between heparin-calibrated anti-Xa levels and fondaparinux, rivaroxaban, apixiban, and edoxaban (r2 = 0.99-1.0). Dabigatran showed a strong linear correlation (r2 = 0.99) with TT. Anti-Xa levels >0.3 IU/mL and TT >25 seconds were determined as cutoffs at our lab for the detection of clinically relevant drug levels of factor Xa inhibitor and direct thrombin inhibitor, respectively. Our study demonstrates that commonly available heparin anti-Xa activity and TT assays can be used to qualitatively detect DOACs and fondaparinux and provides a method to establish a qualitative interpretation.

Quality Analysis of Lupus Anticoagulant Testing: Indeterminate and Interference

Abstract Lupus anticoagulant (LA) testing is a commonly performed test within hemostasis laboratories. Criteria for diagnosing a LA based on the International Society on Thrombosis and Hemostasis are: prolonged phospholipid-dependent (PD) clotting test, evidence of an inhibitor, evidence the inhibitor is PD, and exclusion of specific inhibitors. At our academic institution, we analyzed Lupus anticoagulant results to establish common sources of drug interference (DI), identify causes of indeterminate results, and evaluate if repeat testing was performed on patients with an initial indeterminate test. At this institution, Lupus anticoagulant evaluation includes activated partial thromboplastin time (aPTT), Anti-Xa activity, Thrombin Time (TT), diluted Russell Viper Venom Time, hexagonal phase phospholipid assay, and Platelet Neutralization Procedure. Samples with Anti-Xa activity >0.1 IU/mL and/or elevated TT are treated with hepzyme; if the Anti-Xa activity or TT does not correct, testing is not completed. Samples with elevated aPTT undergo an immediate and incubated mixing study (MS). Samples are considered positive (POS) for LA if there is a positive screening test (+ST), +MS, and evidence of PD in at least one assay. Tests are resulted as indeterminate (IND) with a +ST and either +MS or +PD. LA results are reported as unlikely (UNL) if only a single phospholipid panel is positive without +ST or +MS, and negative (NEG) if the ST, MS, and PD assays are all negative. Patients with indeterminate LA testing are recommended to have repeat LA testing after 12 weeks. A total of 3025 cases were identified over the 18-month period (July 2020 – December 2021). The majority of cases were interpreted as NEG (2310; 76%) followed by 8% POS (229), 6% IND (174), and 1% UNL (34). While the majority of IND met the ST (99%) and PD (71%) criteria, only 32% were +MS, indicating failure of an inhibitor detection in the mixing study is the major factor preventing an IND from becoming positive. Within the IND group, only 25% (43) underwent the recommended repeat LA testing. The results of repeated 43 IND tests are as follows: 16 NEG, 4 POS, 19 IND, 3UNL, 1 DI. While a significant proportion of IND repeated testing became negative, a majority remained IND, arguing for more comprehensive LA testing. This quality study demonstrates the majority of patients at this institution who receive an interpretation of IND LA do not undergo the recommended repeat testing, underscoring the importance of follow-up and education to standardize care. Prospective studies maybe needed to elucidate the clinical significance of IND LAs. Additionally, 278 (9%) cases were canceled due to drug interference, the majority (192; 69%) due to direct oral anticoagulants (DOAC). Testing for LA in patients actively receiving DOACs should be discouraged. Alternatively, methods to remove DOAC interference should be standardized.

Evaluation of the use of a heparin dose-response test in dogs to determine the optimal heparin dose during intravascular procedures and assessment of the in vitro heparin response in healthy dogs.

No guidelines for administering and monitoring anticoagulants intraprocedurally are currently available in dogs, despite the prevalence of procedures necessitating systemic anticoagulation with heparin. To evaluate an activated clotting time (ACT)-based heparin dose-response (HDR) test to predict the individual required heparin dose in dogs during intravascular procedures, and to investigate both the in vitro heparin - ACT and in vitro heparin - factor anti-Xa activity (anti-Xa) relationships in dogs. Blood was collected from eight healthy beagles undergoing a cardiac procedure and utilised to establish baseline ACT and for in vitro evaluation. Subsequently, 100IU/kg heparin was administered intravenously (IV) and ACT was remeasured (HDR test). The required heparin dose for an ACT target response ≥300 s was calculated for each individual and ACT was remeasured after administration of this dose. For in vitro testing, a serial heparin blood dilution (0-0.5-1-2-4 international unit (IU)/mL) was prepared and ACT and anti-Xa were determined using whole blood and frozen plasma, respectively. The HDR test overestimated the required heparin dose in 3/7 dogs. In vitro, ACT and anti-Xa increased significantly with increasing blood heparin concentration. Heparin - ACT was nonlinear in 4/8 dogs at heparin concentrations >2 IU/mL, whereas heparin - anti-Xa remained linear throughout the tested range. The HDR test poorly estimated the required heparin dose in dogs. This is most likely attributed to a nonlinear heparin - ACT relationship, as observed in vitro. Anti-Xa is a promising alternative for ACT; however, unavailability as a point-of-care test and lack of in vivo target values restrict its current use.

Variation in coagulation factor activity levels cause discrepancies between activated partial thromboplastin time and anti-Xa activity for heparin monitoring: a retrospective observational study

BackgroundUnfractionated heparin (UFH) is primarily monitored using activated partial thromboplastin time (APTT). However, the recent introduction of anti-activated factor X (anti-Xa) activity testing has provided a direct evaluation of Xa inhibition by anticoagulants. This study aimed to investigate discrepancies between APTT and anti-Xa activity during UFH monitoring in critically ill patients and explore their underlying causes.MethodsThis study analyzed 271 pairs of laboratory test results from blood samples of 99 critically ill patients receiving continuous intravenous UFH. Theoretical APTT values were calculated using fitted curve equations from spiked sample measurements with anti-Xa activity. Samples were categorized into three groups based on the measurement of the APTT/theoretical APTT ratio: the lower group (< 80%), the concordant group (80–120%), and the upper group (> 120%).ResultsThe overall concordance rate between APTT and anti-Xa activity was 45%, with a 55% discrepancy rate. The lower group frequently showed apparent heparin overdoses, while coagulation factor activities in the lower and upper groups were higher and lower, respectively, than those in the concordant group. Particularly, the lower group exhibited higher factor VIII activity levels than the upper and concordant groups.ConclusionsDiscrepancies between APTT and anti-Xa activity were frequently observed, influenced by changes in coagulation factors activity levels. The lower and upper groups were classified as pseudo-heparin-resistant and coagulopathy types, respectively. Accurate monitoring of heparin in critically ill patients is crucial, especially in cases of pseudo-heparin resistance, where APTT values may wrongly indicate inadequate heparin dosing despite sufficient anti-Xa activity. Understanding these discrepancies is important for managing heparin therapy in critically ill patients.Trial registration: Not applicable.

Usefullness of Heparin Calibrated Anti-Xa Activity to Assess Anticoagulant Activity of Apixaban and Rivaroxaban in Emergency Patients Scheduled for Acute Interventions.

(1) Background: Direct oral anticoagulants (DOACs) require monitoring in some critical clinical situations. The specific tests for DOAC monitoring are not yet available in all labs. The aim of this study was to evaluate if a unique, more widespread heparin-calibrated anti-Xa assay could be suitable to estimate the concentrations of apixaban and rivaroxaban in order to establish an algorithm helping our clinicians in their therapeutic decision for patients treated with DOACs in emergencies. (2) Methods: A first retrospective part allowed us to determine of a conversion factor between the measured DOAC concentration and the deducted anti-Xa heparin activity based on optic density. During the second prospective part, both DOAC concentration (ng/mL) and anti-Xa activity heparin (UI/mL) were measured on the same sample, and the previously determined conversion factor was applied to each UI/mL value. We then compared the calculated and measured DOAC concentration values. (3) Results: The analysis of the derivation cohort confirmed a good correlation, especially between the anti-Xa heparin activity and the apixaban concentrations (r = 0.97). Additionally, we determined heparin-calibrated anti-Xa assay cut-offs for invasive procedures at 0.3 UI/mL and for intravenous thrombolysis at 0.51 UI/mL using ROC curves with a sensitivity at 98% and specificity at 95% for 0.3 UI/mL and a sensitivity at 97.7% and specificity at 88.2% for the cut-off of 0.51 UI/mL. In the validation cohort, we confirmed the agreement between measured and calculated DOAC concentrations for the low values, especially around cut-offs with an excellent negative predictive value for 0.51 UI/mL (94% for apixaban and 100% for rivaroxaban) and a good negative predictive value for 0.3 UI/mL (83.3% for apixaban and 85.7% for rivaroxaban). (4) Conclusions: Our results confirm that it is possible to correctly predict or exclude the presence of apixaban/rivaroxaban in emergency situations when specific tests are not readily available.

PO40 Hyperfiltration Syndrome as a Cause of Low Anti-Xa Activity Levels during Enoxaparin Treatment in a Critically Ill Patient

PO40 Hyperfiltration Syndrome as a Cause of Low Anti-Xa Activity Levels during Enoxaparin Treatment in a Critically Ill Patient

СРАВНИТЕЛЬНЫЙ МОНИТОРИНГ АНТИКОАГУЛЯНТНОЙ ТЕРАПИИ У РАНЕНЫХ С ТРОМБОЗАМИ ГЛУБОКИХ ВЕН НИЖНИХ КОНЕЧНОСТЕЙ

Introduction. Deep vein thrombosis of the lower extremities (DVT) currently remains one of the most important problems affecting not only vascular surgeons, but also doctors of other specialties. Target. Carry out a comparative monitoring of methods for monitoring the effectiveness of anticoagulant therapy in the wounded using the Thrombodynamics test and determining anti-Xa activity. Materials and methods. The study included 30 wounded individuals with established DVT, hospitalized for examination and treatment at the Military Medical Academy. CM. Kirov. Against the background of treatment with enoxaparin sodium (hereinafter referred to as enoxaparin) at therapeutic doses, depending on body weight, all patients were assessed the parameters of the "Thrombodynamics" (TD) test and the determination of anti-Xa activity at the peak of the drug's action (after 3-4 hours), and on outcome (before the next injection) of the drug. Statistical data processing was carried out using the Statistica 10.0 application package. Results and discussion. A strong inverse correlation was established between the clot growth rate (V) of the TD test and the determination of anti-Xa activity at the peak (-0.777; p&lt;0.05) and at the end (-0.715; p&lt;0.05) of anticoagulant therapy. With the standard prescription of doses of anticoagulant therapy depending on body weight, it was found that 30% of patients did not reach the target values of the V TD test and anti-Xa activity and were in the hypercoagulable zone. Conclusion. The indicator of clot growth rate of the "Thrombodynamics" test correlates with the level of anti-Xa activity and can be used as another tool for laboratory monitoring of ongoing therapy with low molecular weight heparins (LMWH) in the wounded. The standard use of LMWH in therapeutic doses by body weight in the wounded does not always lead to the achievement of target coagulation parameters, which requires the development of a personalized approach to LMWH titration, which can be based on the indicators of TD tests and anti-Xa activity.

The Impact of Continuous Veno-Venous Hemodiafiltration on the Efficacy of Administration of Prophylactic Doses of Enoxaparin: A Prospective Observational Study.

Critically ill patients frequently require continuous renal replacement therapy (CRRT). During CRRT, particles up to 10 kDa in size, such as enoxaparin, may be removed. The aim of this study was to determine if patients receiving prophylactic doses of enoxaparin and treated with continuous veno-venous hemodiafiltration (CVVHDF) reach prophylactic values of anti-Xa factor activity. In this observational trial, we compared two groups: 20 patients treated with CVVHDF and 20 patients not treated with CVVHDF. All of them received prophylactic doses of 40 mg of enoxaparin subcutaneously. Anti-Xa factor activity was determined on the third day of receiving a prophylactic dose of enoxaparin. The first blood sample was taken just before the administration of enoxaparin, and other samples were taken 3 h, 6 h, and 9 h after the administration of a prophylactic dose of enoxaparin. At 3 and 6 h after administration of enoxaparin in both groups, we observed a significant increase in anti-Xa factor activity from baseline, with the peak after 3 h of administration. There were no significant differences in the numbers of patients who had anti-Xa factor activity within the prophylactic range between CVVHDF and control groups. CVVHDF has only a mild effect on the enoxaparin prophylactic effect measured by anti-Xa factor activity. Thus, it seems there is no need to increase the dose of enoxaparin for patients requiring CVVHDF.

Need to determine the residual concentrations of direct oral anticoagulants in patients with atrial fibrillation undergoing transcatheter implantation of the aortic valve

Introduction. Lengthening the period of direct oral anticoagulant (DOAC) withdrawal before intervention is not allowed. Chronic kidney disease (CKD), impaired liver function, extremely low or high body mass, chronic heart failure (CHF), and age &gt; 90 years can increase blood DOAC levels. DOAC therapy does not require routine laboratory monitoring. However, there are coagulation tests that can be used to detect the presence of a drug in blood. Duration of DOAC discontinuation and the appropriateness of assessing residual anticoagulant concentrations before intervention with a high bleeding risk in a special category of patients is to be defined.Aim. To measure residual concentrations of anticoagulants and their association with perioperative bleeding risk in patients with AF using DOACs in blood samples collected immediately before TAVI.Materials and methods. The 94 patients with atrial fibrillation (AF) included in the study were characterized by senile age, a high risk of thromboembolic complication (ТС), many comorbidities, and a high prevalence of senile asthenia. The apixaban and rivaroxaban concentrations were measured according to the value of anti-Xa activity and control plasmas with normal levels of coagulation factors (Diagnostica Stago, France).Results. The median time of DOAC withdrawal before TAVI was 60 hours [47.5; 72]. However, the DOAC concentration exceeded 30 ng/ml in 1/5 patients (19.2%), and stage 3 or more CKD was more common in these patients. Our study showed the relationship between DOAC concentration and the duration of DOAC withdrawal period. However, the relationship between DOAC concentration and bleeding that occurred in the perioperative period could not be found. Patients with signs of CKD were older and had a lower BMI as compared to patients without CKD.Conclusion. Our data showed the relationship between the DOAC concentration and the duration of DOAC withdrawal period. No relationship was found between DOAC concentrations and bleeding.

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.

Pharmacokinetics of dalteparin and nadroparin for thromboses in children with oncological diseases

Objective: evaluate the pharmacokinetics and pharmacodynamics of nadroparin and dalteparin in thrombosis that occurred in children with malignant neoplasms. Materials and methods: The results of 52 pharmacokinetic studies involving 34 patients with oncological diseases, whose treatment was complicated by venous thrombosis, were analyzed. The median age of patients was 14.5 (7–18) years. Depending on the daily dose and the type of heparin administered, the results of pharmacokinetic studies were divided into 6 groups. Dalteparin sodium: against the background of chemo-induced thrombocytopenia, subcutaneous administration of dalteparin at a dose of 51.0 (40.0–72.0) anti-Xa IU/kg every 12 hours – 6 observations; subcutaneous injection every 12 hours at a dose of 100.5 (91.0–141.0) anti-Xa IU/kg – 18 observations; long-term continuous intravenous infusion at a constant rate at a daily dose of 201.0 (180.0–265.0) anti-Xa IU/kg - 6 observations. Nadroparin calcium: 62.0 (53.0-71.0) anti-Xa IU/kg every 12 hours - 6 observations; 93.5 (80.0–117.0) anti-Xa IU/kg every 12 hours – 10 observations; subcutaneous injection at a dose of 203.0 (170.0–236.0) anti-Xa IU/kg once a day - 6 observations. Results: We confirmed that in the acute period of thrombosis in children, the most optimal way to administer low molecular weight heparin is intravenous infusion of dalteparin sodium at a constant rate. Subcutaneous injection of 50% of the daily dose of LMWH at intervals of 12 hours is preferable to a single injection of 100% of the daily dose every 24 hours. There were no significant advantages of nadroparin compared with dalteparin when using anticoagulants in comparable doses in case of venous thrombosis, which complicated the treatment of children with malignant neoplasms. Conclusion: Control over the adequacy of the dose of LMWH can be performed at any stage of treatment. The specific anti-Xa activity of nadroparin and dalteparin needs to be checked before the next subcutaneous injection and between 3 and 4 hours after administration. An increase in chronometric indicators of blood coagulation indirectly reflects the presence of an anticoagulant in the blood, but does not allow an objective assessment of the achievement of a therapeutic effect.

Comparative Studies of Complex Products Based on Heparins of Animal and Plant Origin

Complex preparations based on heparins of animal and vegetable origin with the inclusion of glutamic acid in a weight ratio of 1 : 4 were obtained. High molecular weight (HMН) and low molecular weight (LMWH) commercial preparations of heparins were used as heparins of animal origin, heparinoid was used as heparin of plant origin, isolated from the roots of the peony Akademik Sadovnichy (heparinoid). Their influence on the state of plasma hemostasis under in vitro conditions was studied in a comparative aspect. It has been established that all complex compounds have anticoagulant activity, which, according to the results of our studies, is realized by a different mechanism of their action on blood coagulation – on the internal, external, or general pathways of blood coagulation. HMН complexes with glutamic acid had an antithrombin effect, affecting the internal and general coagulation pathways, while LMWH complexes with glutamic acid, exerting anti-Xa activity, affected the internal pathway of coagulation activation, and the combination of heparinoid with glutamic acid inhibited factors not only internal, but also external ways of blood coagulation. In addition, the latter compound exhibited weak antithrombin activity. It was also shown that all heparin complexes prevented fibrin polymerization, increasing the fibrin depolymerization activity of plasma, and in the heparinoid compound, this activity was higher by 10–17% compared to other commercial agents. Thus, the best anticoagulant in terms of efficacy and safety is the heparinoid complex with glutamic acid.

Reduced anticoagulation strategy is associated with a lower incidence of intracerebral hemorrhage in COVID-19 patients on extracorporeal membrane oxygenation

BackgroundOptimal anticoagulation strategies for COVID-19 patients with the acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) remain uncertain. A higher incidence of intracerebral hemorrhage (ICH) during VV ECMO support compared to non-COVID-19 viral ARDS patients has been reported, with increased bleeding rates in COVID-19 attributed to both intensified anticoagulation and a disease-specific endotheliopathy. We hypothesized that lower intensity of anticoagulation during VV ECMO would be associated with a lower risk of ICH. In a retrospective, multicenter study from three academic tertiary intensive care units, we included patients with confirmed COVID-19 ARDS requiring VV ECMO support from March 2020 to January 2022. Patients were grouped by anticoagulation exposure into higher intensity, targeting anti-factor Xa activity (anti-Xa) of 0.3–0.4 U/mL, versus lower intensity, targeting anti-Xa 0.15–0.3 U/mL, cohorts. Mean daily doses of unfractionated heparin (UFH) per kg bodyweight and effectively measured daily anti-factor Xa activities were compared between the groups over the first 7 days on ECMO support. The primary outcome was the rate of ICH during VV ECMO support.Results141 critically ill COVID-19 patients were included in the study. Patients with lower anticoagulation targets had consistently lower anti-Xa activity values over the first 7 ECMO days (p < 0.001). ICH incidence was lower in patients in the lower anti-Xa group: 4 (8%) vs 32 (34%) events. Accounting for death as a competing event, the adjusted subhazard ratio for the occurrence of ICH was 0.295 (97.5% CI 0.1–0.9, p = 0.044) for the lower anti-Xa compared to the higher anti-Xa group. 90-day ICU survival was higher in patients in the lower anti-Xa group, and ICH was the strongest risk factor associated with mortality (odds ratio [OR] 6.8 [CI 2.1–22.1], p = 0.001).ConclusionsFor COVID-19 patients on VV ECMO support anticoagulated with heparin, a lower anticoagulation target was associated with a significant reduction in ICH incidence and increased survival.

Evaluating residual anti-Xa levels following discontinuation of treatment-dose enoxaparin in patients presenting for elective surgery: a prospective observational trial

IntroductionPrior studies have demonstrated that patients presenting for elective surgery may have higher-than-expected residual anti-Xa level activity at or beyond 24 hours following their last treatment dose of enoxaparin. Given...

Use of heparin calibrated anti-Xa assay for apixaban and rivaroxaban measurement in the context of regional telestroke activity

In Bordeaux University Hospital, neurologists are required to prescribe thrombolysis using telemedicine (telethrombolysis) for anticoagulated stroke patients admitted in peripheral centers in the Nouvelle-Aquitaine region. However, due to the bleeding risk, the maximum concentration of DOAC authorizing thrombolysis is 30, 50 or 100 ng/mL (depending on the sources and the patient-specific benefit-risk ratio). Most of the time, specific assays of Direct Oral Anticoagulants (DOACs) are not available in these peripheral centers. We therefore studied an alternative test: the Unfractionated Heparin (UFH) anti-Xa activity which is available in most laboratories and could be used to estimate the DOAC concentration. Five centers were included in our study: three centers using the Liquid Anti-Xa HemosIL® Werfen reagent and two centers using the STA-Liquid Anti-Xa® Stago reagent. For each reagent, we established correlation curves between DOAC and UFH anti-Xa activities and determinated UFH cut-offs for the thresholds of 30, 50 and 100 ng/mL respectively. A total of 1455 plasmas were tested. There is an excellent correlation between DOAC and UFH anti-Xa activities using a third-degree modeling curve, independently the reagent used. However, a significant inter-reagent variability is observed concerning the obtained cut-offs. Our study makes unsuitable the use of a universal cut-off. In opposition to recommendations made by other publications, the UFH cut-offs must be adapted to the reagent used locally by the laboratory, and to the considered DOAC.

Correlation between heparin anti-Xa activity and thromboelastography in adult critically ill COVID-19 patients.

Severe coronavirus disease 2019 (COVID-19) increases the risk of thrombotic complications with unfractionated heparin (UFH) as a commonly used agent in managing venous thromboembolism (VTE). The optimal anticoagulation intensity and monitoring parameters in intensive care unit (ICU) COVID-19 patients remains controversial. The primary study aim was to evaluate the relationship between anti-Xa and thromboelastography (TEG) reaction (R) time in patients with severe COVID-19 receiving therapeutic UFH infusions. Single-center, retrospective study conducted over a 15-month period (2020-2021). Academic medical center (Banner University Medical Center Phoenix). Adult patients with severe COVID-19 administered therapeutic UFH infusions with one or more corresponding TEG, and anti-Xa assessments drawn within ≤2 hours of each other were included. The primary end point was the correlation between anti-Xa and TEG R time. Secondary aims were to describe the correlation between activated partial thromboplastin time (aPTT) and TEG R time, as well as clinical outcomes. Pearson's coefficient was used to evaluate the correlation using a kappa measure of agreement.

The optimized anticoagulation strategy in prolonged hemodialysis.

During extended (nocturnal) hemodialysis (ENHD), the dose of low-molecular-weight heparin (LMWH) can be administered as a single injection or as a divided dose over different time points. Our hypothesis was that a single injection might be sufficient to maintain dialyzer fiber patency. In addition, we investigated whether the biochemical clotting parameter anti-Xa accurately predicts fiber blocking. Our hypothesis was tested in 20 stable patients on ENHD in a random cross-over setting during two consecutive midweek sessions. The regular total dose of LMWH (i.e. enoxaparin, Clexane® 40-100 mg, Sanofi, Belgium) was either given (i) in a single injection at the dialysis start or (ii) divided over two injections, at the start and halfway the dialysis session. Blood samples were taken from the arterial blood line at different time points to determine plasma anti-Xa activity levels. Post-dialysis, the rinsed and dried hemodialyzers were scanned with a reference micro-computed tomography (µCT) scanning technique, and non-blocked fibers were counted in a central cross-section of the dialyzer outlet potting (ImageJ, NIH, USA). The percentage of open fibers in the dialyzers after a single injection of LMWH [91 (61-96)%] versus divided administration [94 (79-98)%] was not different. Time averaged anti-Xa activity levels were clinically not significantly different between both sessions. Anti-Xa activity levels correlated with the administered anticoagulation doses normalized for body weight, but not with the percentages open fibers in the dialyzers. Our results indicate that there is no need to administer enoxaparin over two injections for ENHD up to 8 h. The usefulness of monitoring anti-Xa levels to predict fiber patency, assessed by µCT, can be questioned, but further clinical trials are needed.

The right time to measure anti-Xa activity in critical illness: pharmacokinetics of therapeutic dose nadroparin

BackgroundPeak anti-Xa activity of low-molecular-weight heparin nadroparin is measured 3 to 5 hours after subcutaneous injection. In critically ill patients, physiological changes and medical therapies may result in peak activities before or after this interval, possibly impacting dosing. ObjectivesThe primary objective was to determine the percentage of critically ill patients with adequately estimated peak activities drawn 3 to 5 hours after subcutaneous administration of a therapeutic dose of nadroparin. Adequate was defined as a peak activity of ≥80% of the actual peak anti-Xa activity. If ≥80% of patients had adequately estimated peak activities in the 3- to 5-hour interval, measurement in this interval was regarded as acceptable. The secondary objective was to determine the pharmacokinetic profile of nadroparin. MethodsIn this single-center, prospective study, we evaluated anti-Xa activities in patients admitted to a general intensive care unit. After ≥4 equal doses of nadroparin, anti-Xa activity was measured according to a 12- to 24-hour sampling scheme. ResultsIn 25 patients, anti-Xa activities drawn between 3 and 5 hours after administration ranged 80% to 100% of the actual peak activity. Compared to the threshold level of an adequate estimation in at least 20 patients (≥80%), measuring anti-Xa activities in the 3- to 5-hour interval is an acceptable method (1-tailed binomial test; P < .02). We found a large interindividual variability for nadroparin exposure (mean ± SD area-under-the-curve0-12h, 10.3 ± 4.8 IU·h/mL) and delayed elimination (t1/2 range, 4.0-120.9 hours) despite adequate renal function. ConclusionIn critically ill patients, measuring anti-Xa activity in a 3- to 5-hour interval after subcutaneous injection of therapeutic nadroparin is an acceptable method to estimate the actual peak anti-Xa activity.