anti-Xa Group Research Articles

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.

Comparison of Time Within Therapeutic Range Using Anti-Factor Xa Versus Activated Partial Thromboplastin Time Monitoring of Unfractionated Heparin in Children.

To compare unfractionated heparin (UFH) monitoring using time in therapeutic range of activated partial thromboplastin time (aPTT) versus anti-factor Xa activity (anti-Xa) in children. This retrospective chart review, with data between October 2015 and October 2019, included pediatric patients younger than 18 years on therapeutic UFH infusion with aPTT or anti-Xa monitoring. Patients receiving extracorporeal membrane oxygenation, dialysis, concomitant anticoagulants, prophylactic UFH, no stated goal, and UFH administered for less than 12 hours were excluded. The primary outcome compared the percentage of time in therapeutic range between aPTT and anti-Xa. Secondary outcomes included time to first therapeutic value, UFH infusion rates, mean rate adjustments, and adverse events. A total of 65 patients were included, with 33 aPTT patients and 32 anti-Xa patients, representing 39 UFH orders in each group. Baseline characteristics were similar between groups, with an overall mean age of 1.4 years and mean weight of 6.7 kg. The anti-Xa cohort demonstrated a statistically significantly higher percentage of time in therapeutic range compared with the aPTT group (50.3% vs 26.9%, p = 0.002). The anti-Xa group also demonstrated a trend toward decreased time to first therapeutic value compared with aPTT (14 vs 23.2 hours, p = 0.12). Two patients in each group experienced new or worsening thrombosis. Six patients in the aPTT cohort experienced bleeding. This study demonstrated greater time was spent within therapeutic range for children receiving UFH monitored with anti-Xa compared with aPTT. Future studies should assess clinical outcomes in a larger population.

Heparin Monitoring with an Anti-Xa Protocol Compared to Activated Clotting Time in Patients on Temporary Mechanical Circulatory Support.

Temporary mechanical circulatory support (tMCS) devices are used for patients with severe cardiac or respiratory failure; however, these patients are at high risk for clotting and bleeding. The best method to monitor heparin in these patients has not been established. To determine the risks for bleeding and clotting while monitoring heparin with either anti-Xa or activated clotting time (ACT) in tMCS patients. A retrospective cohort study was conducted on tMCS patients who received heparin adjusted according to an anti-Xa or ACT protocol. The primary outcome was incidence of major bleeding. Pertinent secondary outcomes were individual components of the primary outcome, clotting events, and time to therapeutic range. There were 103 patients included in the study: 53 in the ACT group and 50 in the anti-Xa group. Overall, there were 30 (56.6%) patients with major bleeding in the ACT group, compared with 16 (32%) patients in the anti-Xa group (P = 0.017). An anti-Xa-based protocol was associated with a decreased hazard of major bleeding (hazard ratio = 0.388 [0.215-0.701]; P = 0.002) in the univariate analysis. In the multivariable analysis, an anti-Xa protocol remained associated with a significantly lower hazard of bleeding. Findings were similar when broken down into more discrete subgroups of the entire cohort, extracorporeal membrane oxygenation life support (ECMO), and non-ECMO groups. Anti-Xa monitoring was associated with a lower hazard of bleeding during tMCS compared to an ACT-based protocol. Further studies should evaluate if anti-Xa monitoring should be preferentially used in tMCS.

Antifactor Xa Monitoring and Hematologic Complications of Pediatric Extracorporeal Membrane Oxygenation.

Hemorrhagic and thrombotic complications are a significant source of morbidity and mortality for pediatric patients on extracorporeal membrane oxygenation (ECMO). Optimal anticoagulation therapies and monitoring strategies remain unknown. In 2013, our institution changed the anticoagulation monitoring protocol from activated clotting time (ACT) to antifactor Xa (anti-Xa) levels. We conducted a retrospective review of patients who received anticoagulation management directed by ACT results (n = 96) or anti-Xa levels (n = 72) between January 2010 and March 2016. Hemorrhagic complications occurred in 25% of the ACT group and 39% of the anti-Xa group (p = 0.054). Thrombotic complications were observed in 12.5% of the ACT group and 14% of the anti-Xa group (p = 0.8). There was a greater incidence of extracorporeal cardiopulmonary resuscitations (E-CPR; 36% vs. 15%; p = 0.005) in the anti-Xa group as compared with the ACT group. Secondary analysis showed no difference in transfusion requirements for red blood cells (ml/kg; p = 0.32) or platelets (ml/kg; p = 0.32). There was no difference in average heparin infusion rates (unit/kg/hr) per cannulation (p = 0.17) between the groups. Management of anticoagulation based on anti-Xa levels appears to be as effective as management based on ACT results.

Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: A retrospective review.

To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion. A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient. Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay. In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.

Comparing Anti-Factor Xa and Activated Partial Thromboplastin Levels for Monitoring Unfractionated Heparin.

Background: Lab tests such as activated partial thromboplastin time (aPTT) or anti-factor Xa (anti-Xa) levels are typically used to monitor intravenous unfractionated heparin (IV heparin), with recent evidence suggesting that anti-Xa levels may provide a more accurate measure of anticoagulation. Objective: The Lexington Veterans Affairs Health Care System transitioned from using aPTT to anti-Xa levels in January 2017. This study was conducted to evaluate the efficacy and safety of this change. Methods: This was a retrospective cohort study comparing all patients receiving IV heparin per protocol for at least 24 hours from August 1, 2016, to January 31, 2017 (aPTT group), and February 1, 2017, to July 31, 2017 (anti-Xa group). The primary objective was a comparison of IV heparin doses required to achieve goal range between the 2 cohorts. Secondary objectives included a comparison of time to therapeutic goal, percentage of time within goal range, number of rate changes until therapeutic goal, and adverse outcomes, such as number of bleeds. Results: A total of 155 patients were included in this study. Significantly higher IV heparin doses were required to achieve therapeutic goal in the anti-Xa group, despite significantly fewer IV heparin rate changes required. Anti-Xa monitoring was not associated with an increased risk of adverse events. Conclusion and Relevance: Significantly higher IV heparin doses were required to achieve therapeutic anti-Xa levels after transitioning from an aPTT-based protocol in the largely unstudied veteran population. However, the transition from aPTT to anti-Xa monitoring appears safe and efficacious in these patients.

The use of activated partial thromboplastin time versus antifactor Xa assay in monitoring continuous unfractionated heparin infusion therapy in obstetric intensive care unit

BackgroundUnfractionated heparin (UFH) infusion therapy needs accurate tight control to prevent overanticoagulation that may result in hemorrhagic complications and also to prevent sub therapeutic level that may result in thrombotic complications. The aim of this study was to compare the most popular monitoring tool activated aPTT versus antifactor Xa to reach accurate monitor to UFH therapy in critically ill pregnant females.ResultsTime to reach therapeutic level as well as total heparin dose required to reach this therapeutic level were much lower in the anti-Xa group when compared to aPTT group.ConclusionThe use of anti-Xa-based protocol to monitor UFH infusion therapy resulted in better therapeutic control as it resulted in earlier achievement of therapeutic level and lower heparin dose requitments.

Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial

BackgroundAntithrombotic treatment regimen following transcatheter aortic valve replacement (TAVR) is not evidence-based. Apixaban, a non-vitamin K direct anticoagulant (NOAC) was shown to be superior to VKA and superior to aspirin to prevent cardioembolic stroke in non-valvular atrial fibrillation. It may have the potential to reduce TAVR-related thrombotic complications including subclinical valve thrombosis along with a better safety than the standard of care. DesignATLANTIS is a multicenter, randomized, phase IIIb, prospective, open-label, superiority study comparing standard of care (SOC Group) versus an apixaban-based strategy (Anti-Xa Group) after successful TAVR (ClinicalTrials.gov NCT 02664649). Randomization is stratified according to the need for chronic anticoagulation therapy for a reason other than the TAVR procedure. In the experimental arm, patients receive 5 mg bid of apixaban or a reduced dose of 2.5 mg bid according to the drug label or when apixaban is combined with antiplatelet therapy. In the control arm, patients receive VKA therapy if there is an indication for oral anticoagulation or antiplatelet therapy alone (single or dual) or the combination of both if needed. The primary study end point is the composite of all-cause death, TIA/stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep venous thrombosis, systemic embolism, life-threatening, disabling or major bleeding, according to the Valve Academic Research Consortium definitions. ConclusionsATLANTIS tests the superiority of an apixaban-based strategy versus the recommended standard of care strategy to reduce the risk of post-TAVR thromboembolic and bleeding complications in an all comer population.

Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study.

The two most common methods for monitoring unfractionated heparin (UFH) infusion are the activated partial thromboplastin time (aPTT) and the antifactor Xa heparin assay (anti-Xa). The purpose of this study is to compare the performance of an aPTT protocol vs. an anti-Xa protocol in adult patients as defined by the time to reach therapeutic range, the percentage of time the values were within the goal range and the number of times laboratory monitoring was conducted. We then analysed the discordance between paired values of anti-Xa and aPTT. This was a single-centre prospective cohort pilot study conducted from 1 September 2013 to 31 May 2014. Eighty-five patients were treated with UFH infusion, aPTT monitoring (n = 48), anti-Xa monitoring (n = 37). The number of times aPTT and anti-Xa values were ordered was (median, IQR) 14 (2-34) vs 7 (2-76); P = 0·23. The time to reach therapeutic range in hours was (mean, SD) 22 (20) aPTT vs 15 (13) anti-Xa; P = 0·08. Therapeutic range (>50-100% of the time) was achieved in only 5 (10%) patients in the aPTT group vs. 21 (57%) in the anti-Xa group; P < 0·01. Supratherapeutic values (>50-100%) were observed in 38 (78%) patients in the aPTT group vs. 14 (38%) in the anti-Xa group; P < 0·01. The discordance between aPTT and anti-Xa was evaluated using 234 paired values from 37 patients. There was discordance between anti-Xa and aPTT values 57% of the time. Two patients had bleeding complications requiring blood transfusion or discontinuation of post-pilot protocol. Utilizing an anti-Xa protocol to monitor heparin infusion showed favourable results compared with utilizing an aPTT protocol by maintaining values within the therapeutic goal range. The most common discordant pattern in our study was a disproportionate prolongation of aPTT to anti-Xa values. Patients with discordant values presenting with high aPTT to normal anti-Xa values may have an increased risk of bleeding complications.

Kidney graft outcome using an anti-Xa therapeutic strategy in an experimental model of severe ischaemia-reperfusion injury.

Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model. The effect of an anti-Xa compound (fondaparinux) was evaluated using an autotransplanted kidney model in pigs. Kidneys were clamped for 60 min (warm ischaemia) and then preserved for 24 h at 4 °C in University of Wisconsin solution (UW). The anti-Xa compound was injected intravenously before warm ischaemia and used during cold storage, and its effects were compared with those of intravenous injection of unfractionated heparin (UFH) before warm ischaemia and use during cold storage, or use of UW alone during cold storage. At 3 months after transplantation, anti-Xa treatment improved recovery of renal function and chronic serum creatinine levels compared with UW and UFH (mean(s.e.m.) 89(4), 250(4) and 217(8) µmol/l respectively). The anti-Xa treatment also reduced fibrosis, and decreased tissue expression of markers of the epithelial-mesenchymal transition compared with UW and UFH. Cleaved protease-activated receptor 2 was overexpressed in the UW group compared with the anti-Xa and UFH groups. Leucocyte infiltrates were decreased in the anti-Xa group compared with the UW and UFH groups. Macrophage invasion was also decreased by anticoagulation treatment. Peritransplant anticoagulation therapy was beneficial to graft outcome, in both the acute and chronic phases. Moreover, specific inhibition of coagulation Xa protease further protected kidney grafts, with better recovery and decreased expression of chronic lesion markers. Surgical relevance The increasing use of marginal donors highlights the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury (IRI), which includes a deleterious activation of coagulation, plays a central role in determining graft quality and outcome. Using an established porcine renal autotransplantation preclinical model with high clinical relevance, the benefits of anticoagulation therapy using an antifactor Xa molecule were evaluated. Peritransplantion anticoagulation treatment, specifically with an anti-Xa compound, protected marginal kidney grafts, improving functional recovery and reducing chronic lesions. This study demonstrates the benefits of anticoagulation therapy at the time of organ collection, particularly for marginal organs, encountered in cases of extended criteria and deceased after circulatory death donors. This anticoagulation strategy could be an important addition to current donor and organ management protocols in order to limit IRI and improve outcome.

The utility of thromboelastography in monitoring low molecular weight heparin therapy in the coronary care unit

Low molecular weight heparins (LMWHs) are used for prevention and management of vascular thrombosis. In general, monitoring of anticoagulant activity is not required, however, certain populations may be susceptible to overdosing or underdosing. As anti-activated factor X(anti-Xa) activity testing is not readily available, it was our aim to investigate the usefulness of thromboelastography (TEG; Haemoscope Corporation, Skokie, Illinois, USA) for the assessment of coagulation in patients on LMWH. All patients admitted to the coronary care unit on therapeutic dose of enoxaparin were included (1 mg/kg twice daily). Blood samples were collected 4 h after the morning dose of enoxaparin once the participant had received at least three doses. When anti-Xa activity was classified as low (0-0.5), correct (0.5-1.0) or high (>1.0), the distribution of reaction time (R) and dose per kg showed little association with anti-Xa activity. The difference between mean R for the high anti-Xa group and the correct anti-Xa group was statistically nonsignificant using two-sample t-test (P = 0.26). A linear regression model showed no evidence of association between dose per kg and anti-Xa (P = 0.95). However, there was evidence of positive association between dose per kg and R (P = 0.011) wherein a 10% increase in dose per kg was associated with an increase in R of 2.7 (95% confidence interval 0.6-4.7). There was no evidence of association between R and anti-Xa (P = 0.38). TEG was unable to be used to predict anti-Xa activity. However, TEG R was prolonged in more than 90% patients and correlated with dose of enoxaparin. As enoxaparin dose correlated poorly with anti-Xa activity, a more global test might be necessary to adjust dosing of LMWH in sick, hospitalized patients.

Increased fibrinolysis increases bleeding in orthopedic patients receiving prophylactic fondaparinux

We evaluated hemostatic markers in patients who underwent major orthopedic surgery, including total hip and total knee arthroplasty, and were treated for the prophylaxis of deep vein thrombosis (DVT) with or without fondaparinux (anti-Xa group, n = 98 and without anti-Xa group, n = 20). The frequency of DVT was significantly higher in the without anti-Xa group than in the anti-Xa group, but the reduction of hemoglobin and fibrinolytic marker levels was significantly lower in the without anti-Xa group than in the anti-Xa group. Eighteen patients in the anti-Xa group showed a reduction in hemoglobin of more than 2 g/dl, and those individuals were considered to be the increased bleeding (IB) group. The concentration of fibrinolytic markers in the anti-Xa group was significantly higher in the IB group than in the non-IB group. There were also no significant differences in the levels of anti-Xa activity, plasminogen activator inhibitor-I, soluble fibrin and antithrombin between the IB and non-IB groups. In conclusion, elevated fibrinolysis induced by increased bleeding may lead to further increases in bleeding in patients receiving thromboprophylaxis with fondaparinux following major orthopedic surgery.

Prolonged aPTT Relative to Anti-Xa Is Associated with Increased 30-Day Mortality in Hospitalized Patients Treated with Unfractionated Heparin

Abstract 1248 BACKGROUND:Historically, unfractionated heparin (UFH) has been monitored using the aPTT, a global measurement of the ability of the heparin-antithrombin complex to inactivate the relevant clotting factors. However, the aPTT response to heparin depends on patient variables and reagent and instrument factors. Anti-Xa activity is routinely used to calibrate aPTT for heparin therapy nomograms, and some institutions use anti-Xa activity directly in heparin dosing nomograms. In general, there is a lack of data correlating these methods of measuring heparin effect in patients and outcome data validating any particular approach. We sought to determine the concordance of aPTT and anti-Xa measurements and its impact on patient outcomes in adult hospitalized patients treated with UFH. METHODS: All simultaneously drawn aPTT and anti-Xa values from patients 18 years and older receiving UFH while hospitalized at Stanford between February 2009 and August 2009 were extracted from Stanford’s patient database. We created an aPTT/anti-Xa reference curve using normal pooled plasma with heparin added at increasing concentrations from 0.05 u/mL to 1.0 u/mL, with simultaneous measurement of aPTT and anti-Xa activity. We designed a polynomial fit correlating aPTT and anti-Xa activity with a 99% confidence limit. We then grouped paired aPTT/anti-Xa values into one of three groups according to whether the paired values fell within or outside of the correlation area: 1) aPTT<anti-Xa: discordant pairs, with low aPTT to anti-Xa value, 2) aPTT> anti-Xa: discordant pairs, with high aPTT to anti-Xa value, and 3) aPTT= anti-Xa: concordant pairs, with aPTT and anti-Xa values within the correlation area. In addition, each aPTT/anti-Xa data pair which had an INR from the same date was categorized as associated with either a low (< 1.5) or high (>= 1.5) INR. Because individual patients could have data pairs that fell into multiple groups, we further narrowed the aPTT > anti-Xa and aPTT= anti-Xa groups into patient subgroups to assess outcomes, wherein each patient had data pairs only in one group. RESULTS: A total of 2321 paired values from 539 patients were studied. Data pairs were frequently discordant: 413 (18%) data pairs were in the aPTT < anti-Xa group, 971 (42%) were in the aPTT > anti-Xa group, and 937 (40%) were in the aPTT=anti-Xa group.1337 of 2321 (58%) aPTT/anti-Xa data pairs had an INR value from the same date. The aPTT>anti-Xa group had the highest proportion of data pairs associated with an INR >= 1.5 (68%, see Figure, p< 0.0001 for comparison between the three groups). Patient clinical outcomes were compared between the aPTT > anti-Xa and aPTT=anti-Xa patient subgroups. The 30-day mortality was 19 of 87 (21%) in the aPTT > anti-Xa patient group, higher than in the aPTT=anti-Xa group (6 out of 112, 5%) (p < 0.001). As warfarin use is known to increase the sensitivity of the aPTT to heparin, we compared those patients on concomitant warfarin and heparin to those on heparin alone. Patients with consistent aPTT> anti-Xa on heparin alone had the highest 30-day mortality (16 of 39, 41%), compared to a 30-day mortality of 6% (3 of 48) for aPTT > anti-Xa patients who were on both heparin and warfarin (p < 0.001). The 30-day mortality was not significantly different between those in the aPTT=anti-Xa group on heparin alone (5 of 89, 6%) compared to those on heparin and warfarin (1 of 23, 4%, p>0.05), nor was the 30-day mortality significantly different between those in the aPTT>anti-Xa on heparin and warfarin (3 of 48, 6%) compared to those in the aPTT=anti-Xa on heparin and warfarin (1 of 23, 4%, p>0.05). DISCUSSION: Simultaneously measured aPTT and anti-Xa values in a large cohort of hospitalized adult patients treated with UFH were discordant the majority of the time. The most common discordant pattern was a high aPTT to anti-Xa value. This group was associated with an INR >= 1.5 68% of the time, indicating that a baseline prolongation of the PT is associated with an increased sensitivity of the aPTT to UFH. Increased sensitivity to heparin as demonstrated by an aPTT > anti-Xa in the absence of warfarin appeared to be an indicator of poor health with significantly higher 30-day mortality from underlying disease conditions. Further study is needed to determine whether the aPTT or anti-Xa should preferentially be used in heparin dosing nomograms when the values are discrepant. [Display omitted] Disclosures:No relevant conflicts of interest to declare.