Monitoring Of Unfractionated Heparin Research Articles

Anti-factor Xa and activated partial thromboplastin time strategies for unfractionated heparin dosing after HeartMate 3 left ventricular assist device implantation.

No clear guidelines exist for perioperative anticoagulation management after durable left ventricular assist device insertion. In this study, we sought to compare outcomes between anti-factor Xa (FXa) and activated partial thromboplastin time (aPTT) in monitoring unfractionated heparin (UFH) dosing after HeartMate 3 (HM3) insertion. This is a single-center retrospective review of patients who received UFH after HM3 insertion between 01/2020-12/2022. Post-operative UFH dose was titrated by aPTT goal 45-60 sec (n = 53) or FXa goal 0.1-0.2 U/mL (n = 59). Baseline differences between cohorts were balanced by inverse probability treatment weighting. At baseline, unadjusted FXa patients were more likely to be white (47.5% vs. 35.8%, p < 0.001), INTERMACS 1-2 (69.5% vs. 47.2%, p = 0.013), have history of coronary artery disease (66.1% vs. 43.4%, p = 0.026), and lower eGFR (54.1 vs. 63.7 mL/min/1.73 m2, p = 0.029) compared to the aPTT group. After adjusting for several bleeding/thrombosis risk factors, 97.5% of FXa and 91.0% of aPTT patients reached therapeutic levels with comparable UFH duration and maximum dose. Moreover, in-hospital mortality (2.5% vs. 3.1%, p = 0.842), major bleeding events (4.2% vs. 9.2%, p = 0.360), and thromboembolic events (21.8% vs. 10.1%, p = 0.151) remained without significant differences between FXa and aPTT cohorts. There was a high degree of variability in FXa (r2 = 0.20) and aPTT (r2 = 0.22) values for any given UFH dose. No differences in frequency of bleeding or thromboembolic events were observed in this study between FXa versus aPTT cohorts after HM3 implantation. More longitudinal studies are warranted to determine whether or not one assay is superior to the other.

Bleeding outcomes in critically ill patients on heparin with discordant aPTT and anti-Xa activity.

Activated partial thromboplastin time (aPTT) and unfractionated heparin (UFH) level via the anti-factor Xa activity assay (anti-Xa) are commonly used assays for UFH monitoring. While discordance between the two assays is common, its impact on critically ill patient outcomes is unclear. This study aimed to compare the incidence of major bleeding events among critically ill patients with discordant aPTT and anti-Xa activity while on UFH, to patients with no discordance. This was a single-center, retrospective cohort study of critically ill adult patients who had simultaneous anti-Xa and aPTT levels while receiving continuous UFH infusion. The primary outcome was the incidence of a major bleeding event up to 24h after UFH discontinuation. Secondary outcomes included incidence of 30-day thrombosis and hospital length of stay (LOS). Among 264 included patients, 156 patients (59%) had at least one discordant paired level. Patients with discordance had an increased risk of major bleeding events (14% versus 5%; unadjusted risk ratio, 3.0; 95% CI 1.2-7.8; p = 0.01), and increased risk of thrombotic events (4% versus 0%; p = 0.04). Hospital LOS was similar between the two groups (13.8 days versus 11.4 days; p = 0.08). In this cohort of critically ill patients receiving continuous UFH, discordance in aPTT and anti-Xa activity was frequently observed and was associated with an increased risk of major bleeding events. While both assays remain viable monitoring options, evaluating simultaneous levels may aid in the management of critically ill patients. In patients with discordance, an individualized approach balancing bleeding and thrombotic risks should be considered.

Anticoagulation Monitoring Using Activated Clotting Time in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis of Correlation Coefficients

ObjectiveExtracorporeal membrane oxygenation (ECMO) requires systemic anticoagulation to maintain the circuit patency. However, the use of anticoagulation carries a risk of severe haemorrhage, necessitating rigorous monitoring. Activated clotting time (ACT) is a widely used monitoring tool, however the evidence on its correlation with unfractionated heparin (UFH) infusion dose is limited. Therefore, we aimed to analyse the correlation between ACT and UFH infusion during ECMO. DesignSystematic literature review and meta-analysis of correlation coefficients (Scopus and PubMed, up to July 13, 2024). PROSPERO: CRD42023448888 SettingAll retrospective and prospective studies ParticipantsPatients receiving ECMO support InterventionAnticoagulation monitoring during ECMO support Measurements and maim resultsNineteen studies were included in the analysis, and the meta-analysis encompassed 16. The vast majority of authors (n = 16) found a weak correlation, and none reported a strong correlation between ACT and UFH infusion dose. The meta-analysis (n = 12625 samples) identified a weak correlation, with the pooled estimate of correlation coefficients being 0.132 (95% CI 0.03; 0.23). Lastly, the most common adverse events were haemorrhage (pooled 45%) and thrombosis (30%), and 47% of patients died during the hospital stay. ConclusionsDespite ACT being a widely used UFH monitoring tool in ECMO patients, our meta-analysis found a weak correlation between ACT and UFH infusion dose. New trials are required to investigate the role of emerging tools and to clarify the most appropriate monitoring strategy for patients receiving ECMO support.

Management of Therapeutic-intensity Unfractionated Heparin: A Narrative Review on Critical Points.

Nowadays, unfractionated heparin (UFH) use is limited to selected patient groups at high risk of both bleeding and thrombosis (patients in cardiac surgery, in intensive care unit, and patients with severe renal impairment), rendering its management extremely challenging, with many unresolved questions despite decades of use. In this narrative review, we revisit the fundamental concepts of therapeutic anticoagulation with UFH and address five key points, summarizing controversies underlying the use of UFH and discussing the few recent advances in the field: (1) laboratory tests for UFH monitoring have significant limitations; (2) therapeutic ranges are not well grounded; (3) the actual influence of antithrombin levels on UFH's anticoagulant activity is not well established; (4) the concept of UFH resistance lacks supporting data; (5) scarce data are available on UFH use beyond acute venous thromboembolism. We therefore identified key issues to be appropriately addressed in future clinical research: (1) while anti-Xa assays are often considered as the preferred option, we call for a vigorous action to improve understanding of the differences between types of anti-Xa assays and to solve the issue of the usefulness of added dextran; (2) therapeutic ranges for UFH, which were defined decades ago using reagents no longer available, have not been properly validated and need to be confirmed or reestablished; (3) UFH dose adjustment nomograms require full validation.

DOAC-Remove to counteract the interference of anti-Xa oral anticoagulants on the monitoring of heparin.

The monitoring of unfractionated heparin (UFH) by anti-factor Xa activity (AXA) is commonly used to ensure effective anticoagulation and prevent bleeding risk. However, in patients previously treated with an anti-Xa direct oral anticoagulant (DOAC) switching to UFH therapy, there is a risk of interference that may lead to inappropriate anticoagulation. The first objective of this study was to validate DOAC-Remove to remove DOAC for measuring UFH specific AXA. The second objective was to assess the length of DOAC interference on UFH monitoring and to identify potential predictive factors. This monocentric retrospective study included all patients admitted from April 2019 to April 2021 previously treated with anti-Xa DOAC, and for whom an interference on UFH monitoring was suspected. Interference was defined as a difference in the AXA measured before and after using DOAC-Remove >2.8-fold standard deviation of the method. Removal with DOAC-Remove was specific of DOAC (apixaban n = 42, rivaroxaban n = 41, UFH n = 20) and sufficient to avoid interference on UFH AXA measurement. The exact interference length was 6.0 days [IQR 3.0-11.0] for apixaban (n = 26) and 4.5 days [IQR 2.0-5.8] for rivaroxaban (n = 20). Among the 89 patients sorted based on an interference length ≤ or >3 days, 74 (83.1%) presented an interference greater than 3 days. Correlations were observed with age for apixaban and creatinine for rivaroxaban. Our results suggest that DOAC-Remove could be of high interest in patients receiving UFH previously treated with an anti-Xa DOAC even if DOAC was stopped for more than 3 days.

Interference of oral anti-Xa anticoagulants during monitoring of unfractionated heparin treatments: practical and future attitudes

Contrary to direct oral anticoagulants (DOAC), unfractionated heparin (UFH) requires daily monitoring when administered at therapeutic dose. At present, UFH monitoring is preferably carried out by measuring plasma anti-Xa activity, however, in patients previously treated with an anti-Xa DOAC and switched to UFH, there is a high risk of DOAC interfering with the measurement of UFH anti-Xa activity. Residual anti-Xa DOAC in the sample can lead to an overestimation of the anticoagulant activity attributed to heparin and thus to incorrect anticoagulation. This risk of interference should not be overlooked because interference may occur even at concentration of DOAC below the hemostatic safety threshold and can last several days. To overcome this issue, several alternatives are being studied. This note provides an update on anti-Xa DOAC interference and different strategies available in current practice. It also underlines the importance of communication between biologists and clinicians on anticoagulant treatments received by patients.

European practices on antithrombotic management during percutaneous mechanical circulatory support in adults: a survey of the Association for Acute CardioVascular Care of the ESC and the European branch of the Extracorporeal Life Support Organization.

Bleeding and thrombotic complications compromise outcomes in patients undergoing percutaneous mechanical circulatory support (pMCS) with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and/or microaxial flow pumps like Impella™. Antithrombotic practices are an important determinant of the coagulopathic risk, but standardization in the antithrombotic management during pMCS is lacking. This survey outlines European practices in antithrombotic management in adults on pMCS, making an initial effort to standardize practices, inform future trials, and enhance outcomes. This online cross-sectional survey was distributed through digital newsletters and social media platforms by the Association of Acute Cardiovascular Care and the European branch of the Extracorporeal Life Support Organization. The survey was available from 17 April 2023 to 23 May 2023. The target population were European clinicians involved in care for adults on pMCS. We included 105 responses from 26 European countries. Notably, 72.4% of the respondents adhered to locally established anticoagulation protocols, with unfractionated heparin (UFH) being the predominant anticoagulant (Impella™: 97.0% and V-A ECMO: 96.1%). A minority of the respondents, 10.8 and 14.5%, respectively, utilized the anti-factor-Xa assay in parallel with activated partial thromboplastin time for UFH monitoring during Impella™ and V-A ECMO support. Anticoagulant targets varied across institutions. Following acute coronary syndrome without percutaneous coronary intervention (PCI), 54.0 and 42.7% were administered dual antiplatelet therapy during Impella™ and V-A ECMO support, increasing to 93.7 and 84.0% after PCI. Substantial heterogeneity in antithrombotic practices emerged from participants' responses, potentially contributing to variable device-associated bleeding and thrombotic complications.

Thromboelastography versus thromboelastometry for unfractionated heparin monitoring in adult patients on extracorporeal membrane oxygenation.

Background: Monitoring the anticoagulant effect of unfractionated heparin (UFH) in extracorporeal membrane oxygenation (ECMO) patients is complex but critically important to balance the risks of treatment related bleeding and circuit thrombosis. While guidelines recommend using more than one method to monitor UFH activity, the use of thromboelastometry (ROTEM) to monitor UFH in ECMO patients has not been investigated in detail.Methods: This is an observational, single-center retrospective study looking at adult ECMO patients on UFH that had ROTEM and thromboelastography (TEG) tests obtained concurrently. A total of 20 samples were obtained from nine patients during the study period, seven of which were on veno-arterial (VA) ECMO and two of which were on veno-venous (VV) ECMO.Results: Under institutional standard operating practice, when TEG and/or activated partial thromboplastin time (aPTT) were considered therapeutic, intrinsic thromboelastometry clotting time (INTEM CT) was only 1.2 times higher than the normal range. TEG based monitoring compared to aPTT based monitoring tended to result in lower anti-Xa levels and less intensive anticoagulation. For the total cohort, bleeding events, driven by the need for blood transfusions, were more common compared to ischemic events (77% vs 11%; p = 0.02).Conclusion: INTEM CT tended to be less sensitive to lower doses of UFH with a value of 1.2 times higher than the normal range when aPTT and/or TEG were considered therapeutic. Due to the relative insensitivity of ROTEM, our institution decided to continue to use TEG instead of ROTEM. Larger, multicenter trials may be helpful to validate these findings.

Pilot study examining anti-factor Xa levels for heparin monitoring and outcomes in patients with cerebral venous thrombosis.

There are no studies to date that examine the association between anti-factor-Xa (AFXa)-based heparin monitoring and clinical outcomes in the setting of cerebral venous thrombosis (CVT). This pilot study included adults aged ≥18 admitted with CVT between 1 January 2018 and 1 January 2021, who were treated with unfractionated heparin (UFH) and were monitored via AFXa-based nomogram within 24 h of arrival. Comparisons were made between patients with AFXa levels within the target therapeutic range (0.25-0.5 IU/mL) and patients whose levels were not within the therapeutic range within 24 h of arrival; the time (hours) from arrival to reach the therapeutic range was also examined. Outcomes were length of stay (LOS) in the hospital, major (actionable) bleeding events, and discharge home (vs. higher acuity location). Continuous data are reported in the form of the median (interquartile range). Among 45 patients, treatment with UFH was initiated 2 (1-11) h after arrival, and the majority (84%) of UFH infusions did not need dose adjustment. AFXa assays were conducted every 6 (5.5-7) h. Thirty patients (67%) fell within the therapeutic range. Outcomes were similar for patients with levels within the therapeutic range vs. not: major bleeding events, 10% vs. 0% (p = 0.54); discharge home, 77% vs. 80% (p = 1.0); LOS, 5 days in each group (p = 0.95). There was also no association between outcomes and time to reach the therapeutic range. Our findings demonstrate the practicability of monitoring UFH based on AFXa values in this population of patients with CVT, but reaching target AFXa levels within 24 h of arrival may not necessarily be prognostic.

Standardization of Anti-Xa Assay and its Comparison with Activated Partial Thromboplastin Time for Monitoring Unfractionated Heparin Therapy.

Monitoring of anticoagulant activity of unfractionated heparin (UFH) is primarily done with activated partial thromboplastin time (aPTT), which is affected by many factors. Anti-Xa assays are considered to overcome these factors and may provide a better method for monitoring patients on UFH with a narrow therapeutic range. This study aimed to compare the effectiveness of aPTT and anti-Xa assays in UFH monitoring. A prospective non-randomized study was carried out in two stages: first, the anti-Xa assay was standardized using kit instructions; each sample was then analyzed by both tests. The outcomes of the two assays were compared and assessed for agreement of maintaining therapeutic anticoagulant levels. These levels for anti-Xa assay were between 0.3 and 0.7IU/ml, while it was 1.5-2.5 times the control for aPTT assay. Below this range was regarded as subtherapeutic, and above this as supratherapeutic. A total of 90 samples were tested and analyzed using both assays. Most of them (> 70%) were noted to be in subtherapeutic levels with both tests. The overall concordance was 73.3%, and the estimated kappa value was 0.483 (0.396-0.57). The correlation between aPTT and anti-Xa assay was 0.74 (p < 0.001). With anti-Xa levels in the therapeutic range, aPTT levels were in subtherapeutic in 60% and supratherapeutic in 13.3% cases. Although both the testing strategies had a good agreement and correlation, discordance was observed in interpretative values with anti-Xa levels in therapeutic range and aPTT levels in non-therapeutic range. Its clinical implications need to be evaluated further in future studies.

PB1035 Monitoring of Unfractionated Heparin in Critical ill ICU Patients: A Prospective Study Comparing aPTT and Point-of-Care Viscoelastic Testing with IN/HI Ratio to Anti-Xa

PB1035 Monitoring of Unfractionated Heparin in Critical ill ICU Patients: A Prospective Study Comparing aPTT and Point-of-Care Viscoelastic Testing with IN/HI Ratio to Anti-Xa

Performance Assessment of Anti-Xa Assay-Based Heparin Dosing Protocol in Pediatric Patients on Extracorporeal Membrane Oxygenation.

The use of extracorporeal membrane oxygenation (ECMO) in the postoperative cardiac critical care setting is evolving. Anticoagulation monitoring is among the most challenging aspects of pediatrics. However, there is no consensus on the optimal dosing and monitoring of unfractionated heparin in this setting. To address this, we developed an anti-Xa assay-based protocol derived from the best available clinical and anecdotal evidence of ECMO use and assessed its effectiveness in achieving the anti-Xa assay therapeutic target. This prospective single-arm study was conducted in the pediatric carcardiac-surgery intensive care unit of a large tertiary hospital. We used two different anti-Xa assay intensity levels based on the patients' bleeding status. The median patient age was 7 (interquartile range [IQR]: 5-11.25) months, and the median weight was 5.7 (IQR: 3.8-13.82) kg. The median ECMO duration was 6 (IQR: 4.5-7.5) days. The bleeding protocol was used for most patients. Seventy percent achieved the anti-Xa assay therapeutic target during the study period (median: 75.5 h, IQR: 60.5-117.5 h). Hemorrhagic complications were reported in 40% of the patients, and thrombotic complications were reported in 25%. The median length of stay was 37 (IQR: 22-43) days, with a survival-to-discharge rate of 75%. Despite a failure to achieve the anti-Xa assay target within the first ECMO days, most patients achieved the target by the median ECMO duration. Moreover, using two different anti-Xa assay levels reduced thrombotic complications.

Laboratory Assessment of Unfractionated Heparin (UFH) with Activated Clotting Time (ACT) and Anti-Xa Activity during Peripheral Arterial Angiographic Procedure

Activated clotting time (ACT) is used in cardiac surgery for monitoring unfractionated heparin (UFH). In endovascular radiology, ACT use is less established. We aimed to test the validity of ACT in UFH monitoring in endovascular radiology. We recruited 15 patients undergoing endovascular radiologic procedure. ACT was measured with ICT Hemochron® device as point-of-care (1) before standard UFH bolus, (2) immediately after the bolus, and in some cases (3) 1 h into the procedure or a combination thereof (altogether 32 measurements). A total of two different cuvettes, ACT-LR and ACT+ were tested. A reference method of chromogenic anti-Xa was used. Blood count, APTT, thrombin time and antithrombin activity were also measured. UFH levels (anti-Xa) varied between 0.3-2.1 IU/mL (median 0.8) and correlated with ACT-LR moderately (R2 = 0.73). The corresponding ACT-LR values were 146-337 s (median 214). ACT-LR and ACT+ measurements correlated only modestly with one another at this lower UFH level, with ACT-LR being more sensitive. Thrombin time and APTT were unmeasurably high after the UFH dose, rendering them of limited use in this indication. We adopted an ACT target of >200-250 s in endovascular radiology based on this study. While ACT correlation with anti-Xa is suboptimal, the readily available point-of-care nature increases its suitability.

Monitoring heparin therapy: stability of two different anti-Xa assays using blood samples collected in citrate-containing and CTAD tubes

BackgroundAnti-factor Xa assays and activated partial thromboplastin time (aPTT) are mainly employed to monitor patients treated with heparins. According to the Clinical and Laboratory Standards Institute and the French Working Group on Haemostasis and Thrombosis, anti-factor Xa activity and aPTT should be tested within 2 h of blood sampling for unfractionated heparin (UFH) monitoring. However, discrepancies exist depending on the used reagents and collecting tubes. The study aim was to determine the stability of aPTT and anti-factor Xa measurements using blood samples collected in citrate-containing or citrate-theophylline-adenosine-dipyridamole (CTAD) tubes and stored for up to 6 h.MethodsPatients receiving UFH or low molecular weight heparin (LMWH) were enrolled; aPTT and anti-factor Xa activity were tested using two different analyser/reagent pairs (Stago and reagent without dextran sulfate; Siemens and reagent with dextran sulfate) after 1, 4 and 6 h of sample storage as whole blood or as plasma.ResultsFor UFH monitoring, comparable anti-factor Xa activity and aPTT results were obtained with both analyser/reagent pairs when samples were stored as whole blood before plasma isolation. With samples stored as plasma, anti-factor Xa activity and aPTT were not affected up to 6 h after sampling when using the Stago/no-dextran sulfate reagent pair. With the Siemens/dextran sulfate-containing reagent, aPTT was significantly altered after 4 h of storage. For LMWH monitoring, anti-factor Xa activity remained stable (whole blood and plasma) for at least 6 h. Results were comparable with citrate-containing and CTAD tubes.ConclusionsAnti-factor Xa activity in samples stored as whole blood or plasma was stable for up to 6 h, regardless of the reagent (with/without dextran sulfate)/collection tube. Conversely, aPTT was more variable because other plasma parameters can influence its measure and complicate the interpretation of its variations after 4 h.

136: EVALUATION OF OUTCOMES IN THE MANAGEMENT OF UNFRACTIONATED HEPARIN IN IMPELLA HEART PUMPS.

Introduction: The Impella® is a percutaneous ventricular assist device indicated for the management of cardiogenic shock or hemodynamic support in high-risk percutaneous coronary intervention. An Impella® requires anticoagulation with unfractionated heparin (UFH) and monitoring to prevent bleeding or thrombotic events. Available methods for monitoring include activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-Xa, but the ideal method of monitoring UFH with Impella® is not identified. This study evaluates concomitant ACT and aPTT values for 36 hours after Impella® implantation to determine if either predicts bleeding or thrombotic events. Methods: This single center study included adult patients with an Impella® anticoagulated with UFH. The primary outcome was evaluated with receiver operating characteristic (ROC) curve using concomitant ACT and aPTT values to determine the impact on bleeding and thrombotic events. A linear regression was used to correlate concomitant ACT and aPTT values. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, need for renal replacement therapy, and in-hospital mortality. Results: Of 50 patients included, 15 (30%) had a bleeding event and 15 (30%) had a thrombotic event. The duration of Impella® implant was 56 hours (IQR 28, 78), with 59% of bleeding events occurring while the Impella® was in place and 55% of thrombotic events occurring after device removal. For events that occurred during the 36 hours evaluated, the area under the ROC curve did not exceed 0.85 for the ACT and aPTT for bleeding or thrombotic events. Linear regression of concomitant ACT and aPTT showed an r2 of 0.4255. Median ICU and hospital length of stay were 10 and 11.5 days, respectively, 17 (34%) patients required renal replacement therapy and the in-hospital mortality rates were 36%. Conclusions: ACT and aPTT values show poor correlation in patients with an Impella® and neither demonstrated greater predictability on bleeding or thrombotic events during hospitalization. Patients demonstrated similar mortality rates when compared to previously published literature.

Validation of high concentrated thrombin time assay for unfractionated heparin monitoring.

BackgroundThe high concentrated thrombin time (hcTT), a thrombin time modified by increasing the thrombin concentration, is a possible alternative assay to activated partial thromboplastin time (aPTT) in unfractionated heparin (UFH) monitoring. This study aimed to determine the optimal thrombin concentration used in the hcTT assay for UFH monitoring.MethodsA total of 30 blood samples obtained from healthy volunteers were included in this study. Thrombin concentrations of 10.0, 15.0, 20.0, and 25.0 IU/ml were used in the hcTT assay. The consistency between the hcTT and anti‐FXa assays was evaluated. To validate the hcTT assay, linearity, repeatability, reproducibility, and diagnostic performance of the assay were assessed.ResultsThe hcTT assay using thrombin concentration of 15.0 IU/ml showed a strong correlation to the anti‐FXa assay with R2 of 0.72 and the Spearman's correlation coefficient (rs) of 0.97 (95% CI, 0.96–0.98). Within‐run and day‐to‐day run variabilities of the assay were satisfactory (all coefficients of variation <10%). We found an excellent correlation between the results which were measured using different reagents with intra‐ or inter‐laboratory instruments. Notably, as compared to the aPTT assay, the hcTT assay showed a significantly better performance in identifying the samples which contain UFH at the supratherapeutic level, with an AUC of 0.97 vs. 0.91, p = 0.049.ConclusionThe hcTT assay can be used as an alternative assay for UFH therapy monitoring. A further study using clinical samples is recommended to confirm the appropriateness of the hcTT assay for clinical application.

Lack of Inter-Laboratory Agreement in the Monitoring of Unfractionated Heparin Using the Anti-Factor Xa Activity and the Anti-Factor Xa-Correlated Activated Partial Thromboplastin Time

Background: Unfractionated heparin (UFH) has been in clinical use for more than half a century. Due to the risk of hemorrhage in case of over dosage and the risk of thrombosis in case of under dosage, monitoring UFH treatments is mandatory. The activated partial thromboplastin time (aPTT) is the most widely used method as it is simple, cheap, and readily available. However, it is also poorly standardized and affected by many parameters, both analytic and pre-analytic, that are unrelated to the heparin effect. Particularly, the UFH-induced prolongation of aPTT is highly dependent on the reagent and analyzer used. In an effort to improve inter-laboratory agreement in the monitoring of UFH, the College of American Pathologists (CAP) recommends that the aPTT therapeutic range must be defined in each laboratory through correlation with a direct measure of heparin activity such as the factor Xa (FXa) inhibition assay. Such a strategy was endorsed years ago by the American College of Chest Physicians (ACCP) and the 9thACCP Consensus guideline recommends monitoring UFH treatments by using either the anti-FXa activity, with the therapeutic range between 0.30 and 0.70 IU/mL, or the anti-FXa-correlated aPTT. However, whether and to what extent this approach enhances the inter-laboratory agreement of UFH monitoring has been weakly evaluated, so far.Objectives: To compare the inter-laboratory agreement of the anti-FXa activity and the anti-FXa-correlated aPTT for monitoring therapeutic UFH treatment, we conducted a cross-validation study among 3 accredited coagulation laboratories that used different technical conditions.Patients and Methods: 125 inpatients treated with UFH were sampled in one of the centers. Blood was collected into evacuated polymer tubes containing 3.2% tri-Na citrate. Tubes were centrifuged twice within 2 h after collection, and plasma was stored frozen in aliquots at -70°C that were shipped in dry ice to the 2 other centers to be locally evaluated. Anti-FXa activity (in IU/mL) was evaluated using 4 chromogenic assays i.e. Biophen Heparin LRT (Hyphen BioMed), HemosIL Liquid Anti-Xa (Instrumentation Laboratory, IL), Innovance Heparin (Siemens), and STA-Liquid Anti-Xa (Stago). APTT (expressed as the patient-to-control ratio) was evaluated using 4 reagents i.e. HemosIL SynthASil and HemosIL APTT SP (IL), Pathromtin SL (Siemens), and STA-PTT Automate 5 (Stago). With some exceptions, participating centers used combinations of reagents and analyzers from the same manufacturer i.e. ACL TOP 700 (IL), CS-5100 (Siemens) and STAR (Stago).Results: In the studied population, anti-FXa test results were found to be highly variable depending of the assay used, with the median activity ranging from 0.57 IU/mL with one reagent to 0.37 IU/mL with another, the two other reagents giving intermediate results (Table). Test results obtained using the different reagents were well correlated (r>0.91 in all cases) even though some comparisons performed according to Bland-Altman demonstrated unacceptable bias. If 0.30 to 0.70 IU/mL was used as the therapeutic range of anti-FXa activity, such a discrepancy in test results led to a lack of agreement as to whether a sample was subtherapeutic, therapeutic or supratherapeutic in more than 25% of the patients.The median aPTT test result (ratio) ranged from 2.22 with the less sensitive to 2.93 with the most sensitive reagent. Using the anti-FXa-correlation method, aPTT therapeutic ranges were found to be highly different from one combination of reagent/analyzer to another (Table), and the same applied when correlations were made between one single aPTT reagent and different anti-FXa assays performed on the same analyzer. Consequently, agreement among all aPTT reagents was found in in less than 40% of the patient samples.Conclusions: The reported discrepancy between test results evaluated using commercially available anti-FXa assays are consistent with the results of various national and international EQA programs, and clearly suggests a lack of standardization of that assay. As the consequence, the anti-FXa-correlated aPTT therapeutic range could be significantly impacted. In addition, the anti-FXa-correlation method did not appear to enhance interlaboratory agreement in UFH monitoring as it produces considerable disparity in UFH dosing decisions among different centers, although the clinical impact of this disparity is not known. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Novel Laboratory Assay for Monitoring Unfractionated Heparin in Patients Taking Direct Oral Anticoagulants Prior to Hospital Admission

Introduction: As conditions like atrial fibrillation and venous thromboembolism (VTE) become more prevalent in the United States, the use of direct oral anticoagulants (DOACs) is increasing. Patients presenting to the hospital with indications of thrombosis are often started on unfractionated heparin (UFH) infusion, which has traditionally been monitored using laboratory based PTT and anti-Xa assays. While monitoring UFH with anti-Xa assays have been shown to correlate with better outcomes than dose adjustments guided by PTT, anti-Xa assays are susceptible to interferences from DOACs taken prior to admission and can result in inappropriate dose adjustments that can negatively impact patient care.Methods: We derived a novel assay, termed corrected heparin (CH), using quantified values from a chromogenic anti-Xa assay with heparin calibrators prior to and following heparinase treatment to detect any residual DOAC still present within the patient sample. We retrospectively assessed 79 adult patients admitted to our institution who had their UFH infusion monitored using the CH assay due to known DOAC use. These patients were continually monitored by the CH assay and the PTT (unreported) if they had detectable DOAC levels (>0.1 IU/mL by anti-Xa). Of the patients included in the study, 92% were administered apixaban, while 8% were administered rivaroxaban prior to admission and all received UFH while admitted.Results: To assess linearity of anti-Xa assay for this purpose, patient samples with both UFH and apixaban present were diluted with drug-free plasma and displayed good correlation (R2=0.999) throughout the linear range of the assay. Of the 79 patients, 53 patients reached the therapeutic range by the PTT and CH assays, 17 reached the therapeutic range by the CH assay only, 2 reached the therapeutic range by PTT only, and 2 never reached the therapeutic range with either assay. The average time to therapeutic dosing level for the CH assay was 9 hours after initiation of UFH infusion. Using the CH assay, we were able to determine how long the DOAC persisted and was detected by the anti-Xa assay. At 12 hours after the last DOAC dose, more than 80% of patients still had detectable DOAC levels capable of interfering with the anti-Xa assays. The majority of patients (80%) still had measurable anti-Xa assay interference from the DOAC until 72 hours after the last dose. We evaluated the role of kidney function as a predictor for prolonged interference in the anti-Xa assay however, clearance rates of apixaban were difficult to predict based on kidney function status alone.Conclusions: Our CH assay has provided clinicians with an assay that accounts for the presence of residual DOAC and allows patients to reach therapeutic heparin levels faster. Our study also highlights the delayed clearance of commonly prescribed DOACs, which can be longer than expected and independent of kidney function status resulting in prolonged interference in anti-Xa assays that can lead to improper dose adjustments and potentially negative outcomes for patients on UFH infusion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Optimal Tests to Minimise Bleeding and Ischaemic Complications in Patients on Extracorporeal Membrane Oxygenation.

Patients supported with extracorporeal membrane oxygenation (ECMO) experience a very high frequency of bleeding and ischaemic complications, including stroke and systemic embolism. These patients require systemic anticoagulation, mainly with unfractionated heparin (UFH) to prevent clotting of the circuit and reduce the risk of arterial or venous thrombosis. Monitoring of UFH can be very challenging. While most centres routinely monitor the activated clotting time and activated partial thromboplastin time (aPTT) to assess UFH, measurement of anti-factor Xa (anti-Xa) level best correlates with heparin dose, and appears to be predictive of circuit thrombosis, although aPTT may be a better predictor of bleeding. Although monitoring of prothrombin time, platelet count and fibrinogen is routinely undertaken to assess haemostasis, there is no clear guidance available regarding the optimal test.Additional tests, including antithrombin level and thromboelastography, can be used for risk stratification of patients to try and predict the risks of thrombosis and bleeding. Each has their specific role, strengths and limitations. Increased thrombin generation may have a role in predicting thrombosis. Acquired von Willebrand syndrome is frequent with ECMO, contributing to bleeding risk and can be detected by assessing the von Willebrand factor activity-to-antigen ratio, while the platelet function analyser can be used in urgent situations to detect this, with a high negative predictive value. Tests of platelet aggregation can aid in the prediction of bleeding.To personalise management, a selection of complementary tests to collectively assess heparin-effect, coagulation, platelet function and platelet aggregation is proposed, to optimise clinical outcomes in these high-risk patients.

Impact of a Nurse-Driven Heparin Monitoring Protocol for Ventricular Assist Devices.

Ventricular assist devices require anticoagulation to reduce thrombosis risk. Nurse-driven unfractionated heparin monitoring protocols have been validated for various indications, although data in patients with ventricular assist devices are lacking. To evaluate a nurse-driven protocol for managing unfractionated heparin therapy in stable patients with ventricular assist devices. This was a retrospective analysis of adult patients with ventricular assist devices requiring unfractionated heparin therapy, divided into 2 groups: before and after protocol implementation. The primary outcome was time to first therapeutic activated partial thromboplastin time. Each group included 29 patients. There was no difference between the preintervention and postintervention groups in time to therapeutic activated partial thromboplastin time (25 vs 23 hours, P = .95) or proportion of patients with therapeutic activated partial thromboplastin time within the first 24 hours (45% vs 34%, P = .42). Suspected pump thrombosis and bleeding events were similar in the 2 groups. A nurse-driven heparin monitoring protocol was similar in time to therapeutic activated partial thromboplastin time compared with provider-driven monitoring and adjustments in patients with ventricular assist devices.