Anti-factor Xa Research Articles

Population pharmacokinetics and pharmacodynamics of edoxaban in pediatric patients.

Edoxaban is an orally active inhibitor of activated factor X (FXa). Population pharmacokinetic (PK) and pharmacodynamic (PD) analyses were performed to characterize the PK and PK-PD relationships of edoxaban in pediatric patients to identify the covariates that may contribute to inter-subject variability in PK and PD of edoxaban in pediatric patients, and to compare the PK and PD data between pediatric and adult patients. The pediatric PK of edoxaban was best described by a two-compartment model with transit compartments, first-order oral absorption, and linear elimination. The estimated glomerular filtration rate (eGFR), body weight, and post-menstrual age were the significant covariates explaining variability in edoxaban PK among pediatric patients. A function based on renal maturation was applied to edoxaban clearance. The clearance for a 70 kg patient with an eGFR of 110 mL/min/1.73 m2 was estimated to be 42.9 L/h (CV ~ 31.8%). PK simulation showed that exposures across five pediatric age groups were comparable to that in adult patients receiving 60 mg once daily dose. The PK-PD relationship for anti-factor Xa was best fit with an Emax (8.65 IU/mL) model with an EC50 of 631 ng/mL. The PK-PD relationships for activated partial thromboplastin time and prothrombin time were best fit with linear models (slopes of 0.0467, and 0.0415 s mL/ng, respectively). In addition, due to the small number of efficacy and safety events, an exploratory analysis did not detect a correlation between efficacy events (recurrent venous thromboembolism) or safety events (clinically relevant bleeding) and edoxaban exposure.

The Efficacy of Andexanet Alfa for the Reversal of Factor Xa Inhibitors Is Not Influenced by Hemodilution with Different Volume Expanders

Background: Andexanet alfa is a specific antidote for factor Xa (FXa) inhibitors. It is licensed to treat patients under FXa inhibitor therapy with life-threatening bleeding. Concomitantly, volume expanders are used to compensate for blood loss and maintain circulation. The competitive binding of andexanet to FXa inhibitors may be disrupted due to hemodilution, as shown by laboratory assays with high sample dilution. This study investigated the efficacy of andexanet for the reversal of FXa inhibitors under hemodilution. Methods: Blood from 10 healthy volunteers was anticoagulated with rivaroxaban and subsequently treated with four different volume expanders (Ringer’s solution, 4% gelatine, 5% and 20% human albumin (HA)) at two dilution levels (20% and 50%). After anticoagulation and hemodilution, andexanet was added according to the high-dose protocol. Blood samples were analyzed using a Russell’s viper venom (RVV) test on a Clot Pro® device, a thrombin generation assay, a fully automated coagulation analyzer and a chromogenic anti-FXa activity assay. Results: After anticoagulation, the median rivaroxaban concentration was 272 ng/mL (IQR 254–353). Anticoagulation with rivaroxaban caused a significant impairment of all coagulation parameters, which was further aggravated by hemodilution. After the administration of andexanet, coagulation parameters in anticoagulated samples were reversed to near baseline in all groups. Andexanet administration decreased the rivaroxaban plasma concentration in all groups to a median of <10 ng/mL. In the anticoagulated, non-hemodiluted samples, anti-FXa activity was reduced by 98%. The anti-FXa activity in the anticoagulated, hemodiluted samples was reduced by approximately 96% in the 20% diluted samples and by about 93% in the 50% diluted samples. Conclusions: Our data indicate that FXa inhibitor reversal with andexanet is about 5% less effective with 50% hemodilution than in non-hemodiluted samples.

Pregnant Woman in Outcomes with Prosthetic Heart Valves

We here sought to assess thrombotic and hemorrhagic complications and associated risk factors during pregnancy, delivery, and postpartum in women with prosthetic heart valves (PHV). Methods: The retrospective cohort study covered January 2011 to December 2022. The objective of the study was to assess the risk factors and frequency of thrombotic and hemorrhagic complications during pregnancy, delivery, and the postpartum period in women with PHV based on the experience of one perinatal center. We included 88 pregnancies with 77 prosthetic heart valves (PHV), which were divided into two groups, mechanical valve prostheses (MVP) (n = 64) and biological valve prosthesis (BVP) (n = 24). In the study we analyzed pregnancy outcomes, as well as thrombotic and hemorrhagic complication frequencies. Results: Of 88 pregnancies, 79 resulted in live births. In the MVP group, there were six miscarriages (9.4%) and two medical abortions (3.1%), including one due to Warfarin’s teratogenic effects. No miscarriages were reported in the BVP group, but one fetal mortality case (4.2%) occurred. During pregnancy, 11 MVP cases (17.2%) experienced thrombotic complications. In the BVP group, one patient (4.2%) had transient ischemic attack (TIA). Two MVP cases required surgical valve repair during pregnancy, and one in the post-delivery stage was caused by thrombotic complications. Postpartum, two MVP cases had strokes, and in one MVP patient, pulmonary embolism was registered, while no thrombotic complications occurred in the BVP group. Hemorrhagic complications affected 15 MVP cases (17.9%) in the postpartum period. There were no registered cases of maternal mortality. Conclusions: The effective control of anti-factor Xa activity reduced thrombotic events. However, the persistently high incidence of postpartum hemorrhagic complications suggests a need to reassess anticoagulant therapy regimens, lower target levels of anti-Xa, and reduce INR levels for discontinuing heparin bridge therapy. Despite the heightened mortality risk in MVP patients, our study cohort did not have any mortality cases, which contrasts with findings from other registries.

Monitoring anti-factor Xa activity in patients with chronic thromboembolic pulmonary hypertension treated with factor Xa inhibitors

Direct oral anticoagulants (DOACs) have been used clinically in patients with chronic thromboembolic pulmonary hypertension (CTEPH) for secondary prevention after acute venous thromboembolism, although the data are limited. We evaluated the effects of DOACs—especially factor Xa (FXa) inhibitors—by measuring anti-factor Xa activity (AXA). Fifty consecutive CTEPH patients treated with rivaroxaban, apixaban, or edoxaban were enrolled. Heparin-calibrated AXA was measured at peak and trough. The median peak heparin-calibrated AXA across all 50 patients was 1.90 IU/mL and was comparable among the three FXa inhibitors. At trough, heparin-calibrated AXA was significantly higher in apixaban-treated patients (median 0.70 IU/mL) than in those given rivaroxaban (median 0.11 IU/mL) or edoxaban (median 0.11 IU/mL, p < 0.001). Peak heparin-calibrated AXA was significantly lower with reduced-dosage FXa inhibitor (edoxaban 30 mg/day) than with the reference dosage (edoxaban 60 mg/day, apixaban 10 mg/day, or rivaroxaban 15 mg/day, p = 0.01). The heparin-calibrated AXA of both rivaroxaban and apixaban was strongly significantly correlated with the plasma concentration of each drug. The cumulative rate of major and clinically relevant non-major bleeding was significantly higher in patients with peak heparin-calibrated AXA ≥ 2.09 IU/mL. Heparin-calibrated AXA could provide useful information for treating CTEPH patients with FXa inhibitors.

Establishment of an Integrated Population Pharmacokinetic/Pharmacodynamics Model of Apixaban in Chinese Healthy Population Adjusting for Key Genetic Variants.

To improve the understanding of pharmacokinetic/pharmacodynamic (PK/PD) profiles of apixaban, supporting personalised drug prescriptions for future patients. Genetic as well as nongenetic factors can affect the predictable PK and PD characteristics of apixaban. Establish a integrated popPK/PD model that adjusts for critical genetic variant. The integrated PK/PD models was characterized on the basis of PK (apixaban blood concentration) and PD (prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-FXa activity) data from 181 healthy Chinese volunteers. Other investigated covariate variables included: Meaningful intrinsic and extraneous determinants, correlated markers (ABCG2, F13A1, C3, etc.). A total of 2877 PK concentration observations were included in the modeling dataset. The PK model of apixaban is adopted by single compartment model with first-order oral absorption. The estimated values of total clearance rate (CL/F), apparent distribution volume (V/F), and absorption rate constant (KA) in the final model are 3.37 l/h, 28.2 l, and 0.781 l/h, respectively. The PK model includes significance covariates such as FOOD, RBC, WT, and gene (ABCG2). The PD model of apixaban is adopted by a linear direct effect model with additive error, which was used to describe the relationship between markers such as APTT, PT, anti-FXa, versus plasma concentration. PK simulation within the modelled dose range is similar to clinical real date, while PD simulation results also show that the simulated exposure parameters is within the range of the literature. We established a comprehensive PK/PD model and used it to simulate markers level such as APTT, PT, and anti-FXa of apixaban. Individual predictive values with a dose of 2.5 mg are basically within the expected recommended range.

Complex Antiphospholipid Syndrome Successfully Controlled for 17 Years with Personalized Enoxaparin Therapy.

This patient presented with rare manifestations of antiphospholipid syndrome (APS), such as acalculous cholecystitis, Budd-Chiari syndrome, and Addison's disease, all linked to ischemic events caused by vascular thrombosis. These atypical presentations highlight the varied and severe clinical spectrum of APS, requiring physicians to be vigilant about unusual complications.After multiple severe thrombotic and haemorrhagic events, the patient was successfully managed with long-term enoxaparin, with dose adjusted according to anti-factor Xa activity (which allowed for a significant dose reduction in comparison with the predicted empiric dose).The patient remained event-free for 17 years, reflecting the importance of personalizing anticoagulation therapy.

Pharmacodynamics of Rivaroxaban and Dabigatran in Adults with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy.

Background/Objectives: Rivaroxaban and dabigatran are commonly used for thromboembolic disease management in active cancer patients. However, limited research explores the impact of concurrent chemotherapy on the pharmacodynamics of direct oral anticoagulants (DOAC). The aim of our study was to evaluate the impact of combined chemotherapy with rivaroxaban and dabigatran on the pharmacodynamics in patients with diffuse large B-cell lymphoma (DLBCL).; Methods: This was a prospective, pharmacodynamic study. Eligible subjects were ≥18 years old, diagnosed with DLBCL and initiating R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. The enrolled adults received either rivaroxaban (10 mg once daily) or dabigatran etixalate (110 mg twice daily). Plasma anti-factor Xa (FXa) in participants on rivaroxaban and diluted thrombin time (dTT) in participants on dabigatran were assessed over the dosing interval before and after R-CHOP administration. Pharmacodynamic parameters of rivaroxaban and dabigatran were determined using a non-compartmental analysis.; Results: Twenty-six adults participated, with twelve in the rivaroxaban group and fourteen in the dabigatran group. The mean age was 59 ± 14.4 years. In the rivaroxaban group, the AUEC of FXa inhibition showed no significant change after R-CHOP (mean difference 3.8 ng·h/mL, 95% confidence interval (CI) -155.4 to 163.0, p = 0.96). Similarly, in the dabigatran group, the AUEC of dTT remained unchanged post R-CHOP (mean difference 54.41 ng·h/mL, 95% CI -99.09 to 207.9 ng/mL, p = 0.46). However, the median time-to-peak dTT was significantly faster with R-CHOP (3 h, [min-max, 1.5-8] compared to without it (4 h, [min-max, 3-8], p = 0.04); Conclusions: Concurrent R-CHOP chemotherapy did not significantly impact FXa inhibition by rivaroxaban or dTT by dabigatran. The time-to-peak dTT was faster when dabigatran was administered with R-CHOP.

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.

A-171 Novel Fluorometric Assay for Pediatric Anti-Factor Xa Testing: Minimizing Bilirubin and Hemolysis Interference in Whole Blood

Abstract Background High bilirubin levels are common in pediatric patients and are noted in patients undergoing extracorporeal membrane oxygenation (ECMO). Acute anticoagulation therapy necessitates frequent monitoring of anti-Factor Xa activity (aFXa), and high bilirubin levels cause interference in chromogenic assays. Moreover, large volumes of blood lead to iatrogenic anemia in pediatric and neonatal patients. We developed a fluorescence assay to measure aFXa activity on a near-patient digital microfluidic (DMF) platform using low volume whole blood samples (&amp;lt; 50 μL) and present the results of interference of bilirubin and hemolysis on aFXa activity. Methods aFXa assay was performed on a DMF cartridge wherein 50 μL whole blood was loaded into the cartridge which separates plasma droplets through agglutination within the cartridge followed by incubation with a droplet containing exogenous FXa and a fluorogenic substrate. The fluorescence is inversely proportional to the concentration of heparin in the sample. All required reagents for the aFXa assay are dried within the cartridge, allowing for integrated sample preparation and assay automation for point of care use. To test the interference of bilirubin, we spiked into whole blood different concentrations of unconjugated bilirubin, ranging from 0-40 mg/dL. We also tested hemoglobin interference by testing 4 different concentrations of hemolysate (0-1,000 mg/dL) on the aFXa assay. All experiments were performed with 6 replicates of each concentration. Results Across each bilirubin concentration, we saw uniform measurements of aFXa activity (see Table). We observed &amp;lt; 5% CV in aFXa activity with 0, 13.33 and 26.67 mg/dL bilirubin levels. All measured unfractionated heparin values for hemolysate interference were &amp;lt;5% CV. Conclusions Our interference results suggest that high bilirubin and hemolysate levels do not interfere with our novel aFXa fluorescence assay. Further clinical studies are underway to establish clinical performance.

Retrospective study evaluating safety, clinical effect, and dosing of dalteparin for the treatment of venous thromboembolism in term neonates.

There is an increased risk of venous thromboembolism (VTE) among neonates due to their unique hemostatic system. However, there is lack of approved treatment options for VTE in neonatal population. Importantly, dalteparin, a low molecular weight heparin approved for pediatric VTE in children ≥1month of age, has also been used for the treatment of neonatal VTE. Based on the request from the Food and Drug Administration, this retrospective study aimed to characterize the safety, clinical effects, and dosing of dalteparin for treatment of VTE among neonates. Data from electronic medical records for neonates (born ≥35weeks of gestation) treated with dalteparin for VTE between January 2010 and December 2021 were collected. The data assessed included bleeding and deterioration in hematological biomarkers among other adverse events, changes in relevant factor antifactor Xa (anti-Xa) levels and VTE status, and dosing of dalteparin and corresponding anti-Xa assay levels. Sixteen neonates from five participating sites in the United Kingdom were included. There were no bleeding events or deaths. Only one serious adverse event of hypoglycemic brain injury (unrelated to dalteparin) was documented in a patient with a history of hyperinsulinism. Median (range) daily dose of dalteparin at initiation was 309 (297-314)IU/kg. Eight of 16 neonates achieved therapeutic anti-Xa level, including two patients who did so after the first dose. Dalteparin treatment in neonates raised no major safety concerns. Larger cohort studies may help provide further insights on clinical effects of dalteparin for neonatal VTE.

CytoSorb hemoadsorption of apixaban during cardio-pulmonary bypass for heart transplantation

IntroductionHeart transplantation is an emergency surgery requiring cardio-pulmonary bypass (CPB) and its timing is unpredictable. Patients on the transplant waiting list often have multiple reasons for being anticoagulated. Direct oral anticoagulants (DOACs) such as apixaban are very popular due to their well-known advantages. Intraoperative removal of apixaban using CytoSorb® (CytoSorbents Inc., Princeton, NJ, USA), seems to be an interesting solution for patients on DOACs requiring an emergency CPB intervention. The aim of this short communication is to describe the perioperative effects of the use of the CytoSorb® hemoadsorption device during emergency CPB for a heart transplant patient Case presentationA 61-year-old male patient (75kg/173cm) wait-listed for heart transplantation was admitted to our hospital (Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France) to benefit from a heart transplantation. This patient, with many comorbidities, has an end-stage heart failure with multiple episodes of decompensation over the previous year. He was anticoagulated with a Vitamin K antagonist (VKA) due to atrial fibrillation and was switched to apixaban (5mg twice daily) 9 days before surgery based on poor clotting control. A NaCl 0.9% primed CytoSorb cartridge was inserted into the CPB circuit. Hemoadsorption was performed during the entire CPB duration. Anti-Factor Xa Activity (AFXaA) levels were taken at multiple time points before, during and after surgery in order to monitor anticoagulation. Results. Preoperatively, activated Clotting Time (ACT) was 146 seconds. The ACT reached 545 seconds after administration of 25,000IU of unfractionated heparin (UFH). Surgery consisted of an orthotopic heart transplantation with bi-caval anastomoses.CPB duration was 133 minutes with 83 minutes of aortic cross clamping. Total graft ischemic time was 249 minutes. At the time of anesthesia induction and after UFH administration, AFXaA levels were 330ng/mL and 317ng/mL, respectively. Thereafter, AFXaA decreased to 137ng/mL during CPB and to 57ng/mL after the end of CPB and 250mg (=25,000IU) of protamine administration.After surgery, AFXaA levels stabilized over 50ng/mL over the next 14 hours. Postoperative anticoagulation was performed with the use of UFH starting 6 hours after surgery.No primary graft dysfunction (PGD) was observed, and during the post-operative period of 72 hours, the patient did not have any bleeding events requiring reintervention or transfusion. ConclusionIn conclusion, we observed that CytoSorb® could be a potential solution to remove apixaban intraoperatively. If this efficacy is confirmed in larger trials, it would allow transplant candidates to be treated with DOACs without requiring a switch to VKAs.

Evaluating chemical venous thromboembolism prophylaxis in trauma patients at a single Australian center.

Trauma patients are at an elevated risk of developing venous thromboembolism (VTE), with the subsequent mortality in patients requiring intensive care unit admission ranging from 25% to 38%. There remains significant variability in clinical practice related to VTE prophylaxis in trauma patients due to the frequent presence of contraindications impacting the timing and consistency of application. This study aimed to assess the effectiveness of the current practice of chemical VTE prophylaxis in trauma patients at a single Australian center. A prospective review was conducted on patients admitted to the ACT Trauma Service (Canberra, Australia) from July to November 2022. The included patients were 18 years or older, without a direct contraindication to anticoagulation, who received chemical VTE prophylaxis with low-molecular-weight heparin (enoxaparin) for at least three doses and underwent subsequent testing of anti-factor Xa (aFXa) levels. During the study period, 187 patients were admitted, of whom 63 were included in the study. Of these, 47 patients achieved therapeutic levels of anticoagulation as determined by their aFXa levels, while 16 were subtherapeutic. The only statistically significant difference between the two groups was in weight, with patients in the subtherapeutic group weighing an average of 91.9 kg compared to 79.1 kg in the therapeutic group (P<0.05). A fixed-dose enoxaparin regimen was utilized, with limited individualization based on patient factors, such as injuries, comorbidities, and other biological factors. Sixteen patients (25%) had subtherapeutic VTE prophylaxis, as measured by aFXa levels. Higher weight was significantly correlated with inadequate VTE prophylaxis dosing. While age, sex, and smoking status might play important roles in clinical decision-making, weight-based dosing of low-molecular-weight heparin may be more effective in achieving adequate VTE prophylaxis.

Heparin-Calibrated Anti-Factor Xa Assay for the Measurement of Direct Anticoagulants such as Apixaban, Rivaroxaban, and Edoxaban.

The first purpose of this study was to determine whether a measurement of the level of direct oral anticoagulants (DOACs) was possible with heparin-calibrated chromogenic anti-factor Xa activity (AXA). The second purpose of this study was to evaluate whether the antidote treatment decision level (30 or 50 ng/mL of DOAC) can be determined by unfractionated heparin (UHF)/low molecular weight heparin (LMWH)-calibrated AXA. AXA was measured by using two reagents and dedicated analyzers (Sysmex CS-5100 analyzer and STA R Max3). Four types of calibrators were used: 1) Stago DOAC (rivaroxaban, edoxaban, and apixaban)-specific calibrator, 2) Stago LMWH calibrator, 3) Sysmex UHF calibrator, and 4) Sysmex LMWH calibrator. Regression analysis was used between assays. Receiver operating characteristic (ROC) curves were performed, and the concordance rate was calculated. The correlation coefficients were in the range of 0.75 - 0.91 for rivaroxaban and 0.81 - 0.94 for apixaban. The correlation coefficient between edoxaban-calibrated AXA and Sysmex LMWH/Sysmex UHF calibrator-calibrated AXA was low (r = 0.47). Overall correlation between DOAC-calibrated AXA and Stago LMWH-calibrated AXA was linear, at only low concentration in all three DOACs. The concordance rate (89.3 - 100%) is good for de-termining the antidote management level by UFH/LMWH-calibrated AXA, compared with those of DOAC-calibrated AXA in rivaroxaban and apixaban. The concordance rate ranged from 63% to 67% between Sysmex UFH/ LMWH-calibrated AXA and edoxaban-calibrated AXA. The findings of our study suggest limitations in calculating accurate concentrations, when using UFH/LMWH-calibrated AXA to measure DOAC. This study demonstrates that UFH/LMWH-calibrated AXA may be useful in determining the presence of DOACs at the cutoff level for the antidote treatment in rivarovaban and apixaban. However, in edoxaban, UFH/LMWH-calibrated AXA could not accurately measure the presence of DOACs at the cutoff for antidote treatment.

Finding individualised treatment in obese needing enoxaparin (FIT ONE): a multicentre study of therapeutic enoxaparin and the role of anti-factor Xa monitoring.

Enoxaparin is dosed according to actual body weight in treatment of arterial and venous thrombosis. Due to its hydrophilic nature, it distributes according to lean body mass which may be problematic when dosing obese patients as this may increase the risk of bleeding events in this population. The aimwasto evaluate current therapeutic enoxaparin dosing strategies, including Antifactor Xa (AFXa) level monitoring, in obese patients and to identify factors that contribute to treatment failure and excess anticoagulation. A retrospective cohort study was conducted reviewing patients administered therapeutic enoxaparin between May 2020 and April 2021. Data were collected on patient characteristics, enoxaparin therapy, AFXa monitoring, and outcomes. Regression models were constructed to assess variables of interest to estimate any association with AFXa levels. In total 762 patients were included in the analysis. The mean initial weight-based dose was 0.95mg/kg twice daily (SD: ± 0.12, IQR 0.92-1.01) and 1.04mg/kg once daily (SD: ± 0.26, IQR 0.93-1.12) and 14.4% of patients had AFXa monitoring. Treatment failure was experienced by 2.2%, 5% experienced bleeding. There was no association between the mean actual milligram per kilogram weight-based twice daily doses and subtherapeutic, therapeutic and supratherapeutic AFXa levels(P = 0.135). Obesity was not includedin the final regression models due to lack of significance. At a mean therapeutic enoxaparin dose of 0.95mg/kg twice daily and 1.04mg/kg once daily no excess in treatment failure or bleeding events were observed in obese patients compared to the product information. Obesity was not an independent variable that affected the achievement of target AFXa levels.

Distribution of anti-factor Xa activity in patients with nonvalvular atrial fibrillation receiving 15 mg dose of edoxaban.

The distribution of anti-factor Xa activity (AXA) in patients with nonvalvular atrial fibrillation (NVAF) taking edoxaban 15 mg has not been fully elucidated. The trough and peak AXA were measured in 19 NVAF patients taking edoxaban 15 mg. We compared these results with those in patients taking edoxaban 30 mg. The peak AXA differed significantly between the 15 mg and the 30 mg groups (0.74 ± 0.40 IU/mL vs. 1.25 ± 0.48 IU/mL, respectively; p < 0.0001). Peak but trough AXA in the patients receiving edoxaban 15 mg were significantly lower than those in patients receiving edoxaban 30 mg.

Dried plasma spot as an innovative approach to therapeutic drug monitoring of apixaban: Development and validation of a novel liquid chromatography-tandem mass spectrometry method.

Apixaban, a direct oral anticoagulant drug (DOAC), typically does not require routine therapeutic drug monitoring (TDM), yet recent guidelines propose its use in specific clinical scenarios. While various antifactor Xa (anti-FXa) chromogenic assays serve as useful proxies for measuring plasma exposure to apixaban in emergencies, they lack specificity compared with chromatographic methods. This research project is intended to the development and validation of a standardized protocol of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conformity with the ICH guidelines M10 for the measurement of apixaban in both plasma and dried plasma spots (DPSs). Samples preparation included protein precipitation after the addition of a deuterated internal standard (IS), and the chromatographic separation was carried out on a Thermo Scientific™ Accucore™ Polar Premium column (50 mm × 2.1mm, i.d. 2.6 m). The newly developed LC-MS/MS method for apixaban mesurement from both plasma and DPS resulted linear over a wideconcentration range (31.25-500 ng/mL), accurate, and reproducible without matrix effects, allowing for specific and rapid quantification. Stability was assessed on quality controls and a real sample, allowing the setting up of a robust TDM protocol that was applied to five anonymized plasma samples obtained from adult patients undergoing apixaban treatment at steady-state. In conclusion our novel LC-MS/MS method is adequate for accurate apixaban quantitation from both plasma and DPS matrixes, andmay thus facilitate the guidelines suggested implementation of apixaban TDM, even in peripheral hospitals through shipment of DPS at reference laboratories.

An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency.

Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia. To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity. We screened for anti-ZPI sdAbs in a llama-derived phage display immune library of sdAbs. The sdAbs that bound ZPI were produced and purified for characterization. The binding of sdAbs to ZPI or other serpins was evaluated using ELISAs, and ZPI inhibition was measured in an anti-FXa or anti-FXIa chromogenic assay. The sdAbs's procoagulant activity was assessed in a thrombin generation assay in normal plasma, factor VIII- and FXI-deficient plasma. Of the four sdAbs found to bind to ZPI, one (referred to as ZPI-sdAb2) dose-dependently inhibited ZPI's anti-FXa and anti-FXIa activities with a mean half-maximal inhibitory concentration of 1.8 and 1.3 µM, respectively. ZPI-sdAb2 did not cross-react with other plasma serpins, such as antithrombin and α1-antitrypsin. ZPI-sdAb2 induced a significant increase in thrombin generation in plasma samples from healthy donors, patients with severe hemophilia A, and patients with FXI deficiency. ZPI-sdAb2 is the first specific, direct ZPI inhibitor found to exhibit procoagulant activity in plasma. This sdAb might have potential as a treatment for hemophilia or other bleeding disorders.

Heparanase inhibitor improves clinical study in patients with septic cardiomyopathy.

Septic cardiomyopathy (SCM), a prevalent and critical condition in individuals suffering from sepsis and septic shock, remains elusive in terms of its intricate pathogenesis, thereby lacking definitive diagnostic standards. Current clinical management predominantly revolves around addressing the underlying disease and alleviating symptoms, yet mortality rates persist at elevated levels. This research endeavors to delve into the effects of low molecular weight heparin on Heparanase (HPA) levels in SCM patients, while assessing the clinical significance of HPA as a diagnostic marker in this patient population. A comprehensive cohort of 105 patients diagnosed with SCM was recruited from the Department of Critical Care Medicine at the First Hospital of Lanzhou University, spanning the period from September 2022 to October 2023, serving as the primary research subjects for this investigation. A prospective, randomized controlled trial was undertaken, wherein 53 SCM patients were randomly allocated to a control group receiving standard therapy, while 52 patients were randomly assigned to an intervention group receiving conventional treatment augmented with low molecular weight heparin (LMWH). On the 1st, 3rd, and 7th days post-treatment, the following parameters were measured and documented: HPA levels, syndecan-1 levels, IL-6, TNF-α, CD4+/CD8+ cell ratio, anti-Xa factor, antithrombin III (AT-III) levels, left ventricular ejection fraction (LVEF), fractional shortening (FS), E/e' ratio, stroke volume (SV), cardiac performance index (CPI), global end-diastolic volume index (GEDVI), N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac troponin I (CTnI), heart-type fatty acid-binding protein (H-FABP), lactate (Lac) levels, central venous oxygen saturation (ScvO2), Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, ICU length of stay, and 28-day mortality rate. In comparison to the control group, the LMWH group demonstrated significantly lower levels of HPA and syndecan-1 (p < 0.05), along with reduced levels of IL-6, TNF-α, E/e', NT-proBNP, CTnI, H-FABP, GEDVI, SOFA score, APACHE II score, ICU length of stay, and 28-day mortality (p < 0.05). Additionally, the LMWH group exhibited increased levels of anti-Xa factor, AT-III, CD4+/CD8+ cell, LVEF, FS, SV, and CPI (p < 0.05). ROC curve analysis indicated that HPA can be combined with NT-proBNP, CTnI and H-FABP to improve the diagnostic efficiency of SCM. In SCM patient management, the integration of LMWH into conventional treatment significantly reduced HPA levels, mitigated syndecan-1 loss, attenuated inflammatory responses, enhanced immune function, improved microcirculation, cardiac systolic and diastolic functions, myocardial contractility, heart index, and end-diastolic volume. These interventions correlated with decreased clinical severity, ICU stays, and 28-day mortality rates in SCM patients. https://www.chictr.org.cn.

Intracardiac ultrasound-guided transseptal puncture in horses: Outcome, follow-up, and perioperative anticoagulant treatment.

Cardiac catheterizations in horses are mainly performed in the right heart, as access to the left heart traditionally requires an arterial approach. Transseptal puncture (TSP) has been adapted for horses but data on follow-up and closure of the iatrogenic atrial septal defect (iASD) are lacking. To perform TSP and assess postoperative complications and iASD closure over a minimum of 4 weeks. Eleven healthy adult horses. Transseptal puncture was performed under general anesthesia. Serum cardiac troponin I concentrations were measured before and after puncture. Weekly, iASD closure was monitored using transthoracic and intracardiac echocardiography. Relationship between activated clotting time and anti-factor Xa activity during postoperative enoxaparin treatment was assessed in vitro and in vivo. Transseptal puncture was successfully achieved in all horses within a median duration of 22 (range, 10-104) minutes. Balloon dilatation of the puncture site for sheath advancement was needed in 4 horses. Atrial arrhythmias occurred in 9/11 horses, including atrial premature depolarizations (N = 1), atrial tachycardia (N = 5), and fibrillation (N = 3). Serum cardiac troponin I concentrations increased after TSP, but remained under the reference value in 10/11 horses. Median time to iASD closure was 14 (1-35) days. Activated clotting time correlated with anti-factor Xa activity in vitro but not in vivo. Transseptal puncture was successfully performed in all horses. The technique was safe and spontaneous iASD closure occurred in all horses. Clinical application of TSP will allow characterization and treatment of left-sided arrhythmias in horses.