Anti-factor Xa Activity Research Articles

Anti-factor Xa activity, prothrombin time, and activated partial thromboplastin time in patients treated with factor Xa inhibitors.

The regimens for factor Xa (FXa) inhibitors (apixaban, edoxaban, and rivaroxaban) vary with venous thromboembolism (VTE) or non-valvular atrial fibrillation (NVAF). The dosage and duration of FXa inhibitor therapy also differ. However, the distribution of anti-factor Xa activity (AXA) values, prothrombin time (PT), and activated partial thromboplastin time (APTT) in patients administered each FXa inhibitor has not fully been assessed. Trough and peak AXA values, PT, and APTT were measured in 85 patients taking apixaban, 105 patients taking edoxaban, and 27 patients taking rivaroxaban. The patients were further divided into three groups based on the dosage. Each FXa inhibitor showed various ranges of AXA values, and twice-daily use resulted in higher absolute AXA values than once-daily use. AXA values and PT for 20mg apixaban at both trough and peak times were significantly higher than those for 5mg or 10mg. AXA values for 60mg edoxaban at peak time were significantly higher than those for 15mg or 30mg. AXA values for 30mg of rivaroxaban at both trough and peak times were significantly higher than those for 10mg or 15mg. In a nonlinear regression model of the relationship between AXA and PT or APTT, PT was positively correlated with AXA values for each FXa inhibitor. This study obtained trough and peak levels of AXA, PT, and APTT in patients with VTE or NVAF who were administered apixaban, edoxaban, and rivaroxaban.

Impact of Renal Function on Anti-factor Xa Activity Concentrations with Edoxaban Use in Patients with Non-valvular Atrial Fibrillation

Chromogenic anti-factor Xa activity (AXA) assay is used to measure the pharmacodynamics of factor Xa inhibitors, including edoxaban. Although AXA concentrations in patients with non-valvular atrial fibrillation using edoxaban have been reported, the impact of renal function on AXA concentrations with edoxaban use in patients with non-valvular atrial fibrillation has not been fully assessed. Trough and peak AXA concentrations were measured in 93 patients with non-valvular atrial fibrillation taking edoxaban (73.6 ± 11.2 years, 48 were male). The patients were divided into three groups: patients with moderate renal dysfunction (creatinine clearance 15-49 mL/min), mild renal dysfunction (creatinine clearance 50-95 mL/min), and normal renal function (creatinine clearance >95 mL/min). Both trough and peak AXA concentrations were assessed among the groups according to the edoxaban dose (30 or 60 mg). At a 30-mg dose, patients with moderate renal dysfunction showed significantly higher trough AXA concentrations than patients with mild renal dysfunction or normal renal function. At a 60-mg dose, patients with mild renal dysfunction showed significantly higher trough AXA concentrations than patients with normal renal function. Peak AXA concentrations were not significantly different between the groups. Creatinine clearance was significantly and negatively correlated with trough AXA concentrations at a 60-mg dose, whereas the correlation of creatinine clearance with AXA concentrations was borderline significant at a 30-mg dose. No correlation was found between creatinine clearance and peak AXA concentrations at either dose. Creatinine clearance tends to be negatively correlated with trough AXA concentrations in patients with non-valvular atrial fibrillation taking edoxaban, while renal function is not correlated with peak AXA concentrations.

Deaminative-cleaved S. monotuberculatus fucosylated glycosaminoglycan: Structural elucidation and anticoagulant activity

Stichopus monotuberculatus is a tropical sea cucumber species and used as a folk medicine and tonic food. In this study, a fucosylated glycosaminoglycan (SmFG), the depolymerized SmFG (dSmFG) and its oligosaccharide fractions were prepared. The SmFG and its depolymerized products were comprised of a chondroitin-sulfate-E backbone, and various sulfated fucose side chains, including an unusual disaccharide side chain connected to the C-3 position of D-glucuronic acid (GlcA) or GlcA-ol. A peeling reaction occurred during the deaminative depolymerization process. The dSmFG and its fractions showed strong anticoagulant activity by selectively inhibiting intrinsic tenase complex, and had no anti-factor IIa, Xa and VIIa activity. The anticoagulant activity reduced with the decrease of molecular weight, and the unusual branch and novel reducing end may enhance the anticoagulant activity. These findings can provide significant information for development and utilization of depolymerized products from SmFG in food and pharmaceutical industries.

Enzymatic synthesis of low molecular weight heparins from N-sulfo heparosan depolymerized by heparanase or heparin lyase

Low-molecular-weight heparin (LMWH) is prepared from the controlled chemical or enzymatic depolymerization of animal sourced heparins. It has been widely used as an anticoagulant. Concerns about the shortcomings of animal-derived heparin and the contamination of supply chain demand biochemical approaches for synthesizing LMWH. In the present study, two LMWHs were enzymatically synthesized from low molecular weight N-sulfated heparosan (LMW-NSH) cleaved by recombinant hydrolase, endo-β-glucuronidase, (HepBp) or heparin lyase III (HepIII), followed by subsequent sulfotransferase modifications. Structural characterization shows that LMWH chains prepared using HepBp had a saturated uronic acid residue at their reducing ends, while chains of LMWH prepared using HepIII had an unsaturated uronic acid residue at their non-reducing end. Both LMWHs had anti-factor Xa and anti-factor IIa activities comparable to enoxaparin. This approach demonstrates that the hydrolase, HepBp, can be used to prepare a new type of LMWH that has no unsaturated uronic acid at its non-reducing end.

Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients.

Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity. A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti-factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty-nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high-performance liquid chromatography-tandem mass spectrometry. The typical population values (inter-individual variability%) of the oral volume of distribution and clearance for a one-compartment model were 61.2 L (21%) and 3.68 L·h-1 (61%), respectively. Creatinine clearance and Child-Turcotte-Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng-1 , respectively. The selected model for anti-factor Xa activity consisted of a direct link inhibitory Emax model with Hill coefficient. The maximum level of inhibition (Emax ) was 4 IU·ml-1 . The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50 ) was 180 (24%) ng·ml-1 , and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti-factor Xa activity. Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics-pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.

Anti-factor Xa Activity Is Not Associated With Venous Thromboembolism in Critically Ill Patients Receiving Enoxaparin for Thromboprophylaxis: A Retrospective Observational Study.

BackgroundAnti-factor Xa activity has been suggested as a surrogate parameter for judging the effectiveness of pharmacological thromboprophylaxis with low molecular weight heparins in critically ill patients. However, this practice is not supported by evidence associating low anti-factor Xa activity with venous thromboembolism.MethodsWe performed a retrospective observational study including 1,352 critically ill patients admitted to 6 intensive care units of the Medical University of Vienna, Austria between 01/2015 and 12/2018. Included patients received prophylactically dosed enoxaparin (≤100 IU/kg body weight per day). We analyzed median peak, 12-h trough and 24-h trough anti-factor Xa activity per patient and compared anti-factor Xa activity between patients without vs. with venous thromboembolic events.Results19 patients (1.4%) developed a total of 22 venous thromboembolic events. We did not observe a difference of median (IQR) anti-factor Xa activity between patients without venous thromboembolism [peak 0.22 IU/mL (0.14–0.32); 12-h trough 0.1 IU/mL (<0.1–0.17), 24-h trough < 0.1 IU/mL (<0.1– <0.1)] vs. patients with venous thromboembolism [peak 0.33 IU/mL (0.14–0.34); 12-h trough 0.12 IU/mL (<0.1–0.26); 24-h trough < 0.1 IU/mL (<0.1–<0.1)].ConclusionPatients who developed venous thromboembolism had anti-factor Xa activities comparable to those who did not suffer from venous thromboembolism.

Single and Repeated Doses of EGb 761® do not Affect Pharmacokinetics or Pharmacodynamics of Rivaroxaban in Healthy Subjects

The present drug-drug interaction study investigates whether single or repeated doses of 240 mg Ginkgo biloba extract EGb 761® alter the pharmacokinetics or pharmacodynamics of rivaroxaban in healthy subjects. This was a single-centre, two-period, fixed-sequence trial. In Period 1, rivaroxaban was taken alone. In Period 2, rivaroxaban was given on the first and last of 8 days of EGb 761® treatment. Plasma concentrations of rivaroxaban and anti-Factor Xa activity were determined until 48 h after each rivaroxaban intake. The data of forty-one healthy subjects (25 males, 16 females) aged 21–70 years were evaluable. Geometric mean ratios (90% confidence intervals) for rivaroxaban administered concomitantly with a single or multiple doses of EGb 761® vs. rivaroxaban administered alone were 97.97 (91.78, 104.58) and 96.78 (90.67, 103.31) for maximum concentration (Cmax), 98.55 (94.43, 102.84) and 97.82 (93.73, 102.08) for area under the concentration-time curve (AUC0-∞) of rivaroxaban in plasma (primary endpoints), 98.19 (92.00, 104.80) and 99.78 (93.43, 106.55) for maximum effect (Emax), 99.46 (93.63, 105.66) and 99.12 (93.25, 105.35) for area under the effect curve (AUEC0-48). All 90% confidence intervals were within the prespecified range of 80%–125%. Neither adverse events related to haemorrhages nor clinically significant findings in haematology or coagulation parameters were observed. The treatments were safe and well-tolerated. Single and repeated doses of EGb 761® neither affect plasma concentrations of rivaroxaban nor anti-Factor Xa activity in healthy subjects.

Efficacy and Safety of Two Different Enoxaparin Doses for Thromboprophylaxis in Non-critically Ill Patients: A Randomized Controlled Trial.

Recently, a few studies based on anti-factor Xa activity levels have propounded doubtful and sub-prophylactic levels by the usual dose of enoxaparin in surgical and critically ill patients. In this study, we assessed two doses of enoxaparin in adult non-critically ill patients. Patients were randomly assigned into two groups of intervention and control. While the intervention group received enoxaparin with a daily dose of 60 mg, the control group received enoxaparin 40 mg. Anti-factor Xa activity was measured based on the peak steady-state levels. The level of 0.2 to 0.4 IU/mL was considered as a prophylactic goal. All individuals were followed for bleeding or thromboembolic events during admission. The mean levels of anti-factor Xa were 0.29 ± 0.13 IU/mL in the control group (n = 31) and 0.44 ± 0.19 IU/mL in the intervention group (n = 29). More patients in the control group had an optimal level of anti-factor Xa compared to the patients in the intervention group (62.1% vs. 29%). No adverse outcomes were detected in any of the groups. Enoxaparin dose of 60 mg daily provided anti-factor Xa level higher than desired in most patients. In non-critically ill patients, the dose of 40 mg is the proper dose for thromboprophylaxis.

Monitoring of Anticoagulant Activity of Dabigatran and Rivaroxaban in the Presence of Heparins.

The routine monitoring of direct oral anticoagulants (DOACs) may be considered in patients with renal impairment, patients who are heavily obese, or patients requiring elective surgery. Using the heparin-binding copolymer (HBC) and polybrene, we aimed to develop a solution for monitoring the anticoagulant activity of DOACs in human plasma in the interfering presence of unfractionated heparin (UFH) and enoxaparin. The thrombin time (TT) and anti-factor Xa activity were monitored in pooled plasma from healthy volunteers. In these tests, plasma with dabigatran or rivaroxaban was mixed with UFH or enoxaparin and then incubated with HBC or polybrene, respectively. HBC and polybrene neutralized heparins and enabled monitoring of anticoagulant activity of dabigatran in the TT test. Both agents allowed for accurate measurement of anti-factor Xa activity in the plasma containing rivaroxaban and heparins in the concentration range reached in patients’ blood. Here, we present diagnostic tools that may improve the control of anticoagulation by eliminating the contamination of blood samples with heparins and enabling the monitoring of DOACs’ activity.

A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration. Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters. Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range. Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.

Chemical synthesis and pharmacological properties of heparin pentasaccharide analogues

The pentasaccharide fondaparinux is a synthetic anticoagulant based on heparin antithrombin-binding sequence. Fondaparinux improves safety and predictable pharmacodynamics compared with heparins; however, it requires a complicate synthesis process which contain more than 50 steps of synthesis. Herein, we designed and synthesized four fondaparinux analogues (compounds 1, 2, 3, 4) using a [2+3] convergent synthetic method, which greatly simplified the synthetic process, improved the product yield, and curtailed the expenditures. These synthesized compounds showed stronger anticoagulant activities by factor Xa inhibition (IC50 725–1126 nM vs. 1909 nM for fondaparinux) in the AT-dependent manner. After subcutaneous (s.c.) administration to rats, the compounds displayed long-lasting anti-factor Xa activities and inhibition of thrombin generation ex vivo. Compared with fondaparinux, these compounds were slowly eliminated after s.c. administration to rats, the half-lies (t1/2) were more than 2-fold of that of fondaparinux. These results suggested the pentasaccharide analogues may exhibit better pharmacokinetic and predictable pharmacodynamic characteristics.

Oral anticoagulants in fragile patients with percutaneous endoscopic gastrostomy and atrial fibrillation: the ORIGAMI pilot investigation.

Extensive data support the superior safety without any trade-off in efficacy of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation, deep venous thrombosis or pulmonary embolism. Whether DOACs may be successfully used to treat complex and fragile patients with percutaneous endoscopic gastrostomy (PEG) remains to be proven. The purpose of this pilot study was to evaluate the feasibility, anticoagulant effect, and preliminary safety/efficacy profile of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation. In this prospective, single-arm, pilot study, 12 patients with PEG and guideline-recommended indication for anticoagulation for nonvalvular atrial fibrillation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. Quantitative measures of edoxaban's antifactor Xa activity were performed at steady state. Thromboembolic and bleeding events were assessed at one-month follow-up. Steady state edoxaban plasma levels were at therapeutic range in all patients; mean plasma concentration was 208.5 (±78.6) ng/mL. At one month follow-up, none had suffered a thromboembolic event; one developed minor bleeding, and one died from non-cardiovascular death, owing to sudden worsening of a pre-existing underlying severe condition. In this pilot investigation, we report for the first time that crushed edoxaban, administered at approved doses through PEG in fragile and complex patients, is feasible, results in therapeutic edoxaban concentrations, and is apparently effective and safe.

Comparison of the injection of low-molecular weight heparin in the arterial vs. venous blood line for preventing extracorporeal circuit clotting during hemodialysis.

Low-molecular weight heparins (LMWH) are widely used for preventing clotting during hemodialysis (HD). Although injection in the venous blood line is recommended to avoid initial loss of LMWH through the dialyzer, LMWH is still frequently administered in the arterial blood line at the start of dialysis. This study aimed to compare the safety and efficacy of the same enoxaparin dose administered through the venous blood line or arterial blood line. We also evaluated antifactor Xa (aXa) activity according to the injection route and dialysis modalities: high-flux (HF) HD, medium cut-off (MCO) HD, and online hemodiafiltration (OL-HDF). Forty-three patients were studied over 18 consecutive dialysis sessions using a fixed enoxaparin dose (20 or 40 mg), first administered through the arterial blood line bolus and then through the venous blood line for another 18 sessions. Compared to arterial blood line administration, venous blood line bolus resulted in a significant increase in median post-dialysis aXa activity: 0.16 (0.1-0.6) IU/ml versus 0.31 (0.1-1.3) IU/ml, respectively, p=0.006. After arterial blood line bolus of 40 mg enoxaparin, median post-dialysis aXa activity was significantly lower with OL-HDF compared to HF-HD: 0.14 (0.1-0.35) versus 0.32 (0.15-0.49), p=0.02. A trend for lower clotting within lines and bubble trap using venous blood line bolus was observed. In conclusion, venous blood line enoxaparin injection is safe in OL-HDF patients. However, in HF-HD and MCO-HD, venous blood line injection of 40 mg enoxaparin may increase overdosing risk. Thus, aXa activity should be monitored in HF-HD and MCO-HD patients at risk of bleeding and/or on vitamin K antagonists and careful surveillance is required when administering a 40 mg enoxaparin dose through the venous blood line route.

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban.

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population ( n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Maternal mortality due to valvular heart disease: a population-based study in Turkey.

To assess the clinical and demographic features of maternal mortality cases among patients with cardiac valvular diseases between 2012 and 2019. Maternal mortality due to valvular heart disease between January 2012 and December 2019 in Turkey was retrospectively analyzed. The cases were classified according to New York Heart Association (NYHA) classification based on the severity of the heart disease. NYHA classification groups were divided into two; as class I-II (n = 34) and class III-IV (n = 31). Two groups were compared in terms of demographic and clinical characteristics. Valvular heart disease was diagnosed in 41 (63.1%) of the cases before pregnancy. It was found that 100% (n = 21) of the warfarin users had switched to low molecular weight heparin treatment due to concerns about warfarin embryopathy after the diagnosis of pregnancy, and only 14.2% (n = 3) of them had been monitorized with Antifactor Xa activity to evaluate the effectiveness of the medication. Two NYHA groups had similar clinical characteristics. Intensive care unit admission rate, frequency of prosthetic valve, rate of thromboprophylaxis, type of valvular disease and reasons of maternal death were similar between the NYHA groups (p < 0.05). Maternal mortality may be observed in cases with NYHA class I-II in almost similar rates with NYHA class III-IV. Therefore, it is crucial to adequately assess the mortality risk of pregnant women with cardiac valvular pathologies and to achieve early diagnosis and appropriate treatment in order to reduce maternal mortality.

Comparison of Anti-factor Xa Levels in Female and Male Patients with Obesity After Enoxaparin Application for Thromboprophylaxis

PurposeVenous thromboembolic events (VTEs) are common complications after bariatric surgery, and enoxaparin is commonly used to prevent VTEs. The risk for VTEs is sex-specific. Whether enoxaparin application results in similar anti-factor Xa activities (aFXa) in males and females with obesity remains to be determined. We investigated whether our dosage regimen of enoxaparin resulted in similar serum aFXa levels in female and male patients undergoing bariatric surgery.Materials and MethodsWe administered enoxaparin twice daily in patients undergoing bariatric surgery. Patients with a body mass index (BMI) > 60 kg/m2 (n = 11) received 60 mg enoxaparin (group 2), and patients with lower BMI (n = 86) received 40 mg per dose (group 1). Peak aFXa levels were measured 3 days after surgery. The primary outcome was the aFXa level. As a secondary outcome, we detected VTEs and major bleeding events and explored the possible influencing factors of aFXa.ResultsWomen had higher aFXa than men, but after matching for anthropometric values, the two groups were similar (females: 0.17 ± 0.08 U/ml; males: 0.18 ± 0.08 U/ml). Linear regression revealed a moderate relationship between weight and aFXa levels. The 3-month follow-up was attended by 94.9%, at which one patient had pulmonary embolism.ConclusionIndividual enoxaparin dosage regimens for men and women do not seem to be required. Weight-based dosing regimen seems to be a more reasonable choice.Graphical abstract

Patients' Plasma Activity of Heparin, low-Molecular-Weight Heparin or no Anticoagulants on Urine Based DOAC Test Strips.

DOAC Dipstick determines specifically the presence and absence of direct oral anticoagulants (DOACs) from patients’ urine samples and handmade test strips performed as well as the commercial version. To compare plasma activity (chromogenic substrate assays) from plasma samples with results from urine samples (DOAC test strips) of patients treated with heparin, low-molecular weight heparin (LMWH) and without anticoagulation. Plasma anti-factor Xa (aXa) activity was determined by Coamatic chromogenic substrate assay and compared to the presence of anticoagulants in urine by DOAC test strips. Patients were treated for least 5 days and samples were taken 4 hrs after administration in comparison to no treatment with an anticoagulant (n = 42). A total of 100 patients were included treated with heparin (n = 29), LMWH nadroparin (n = 29) or no anticoagulants (n = 42). Plasma aXa levels of patients treated with heparin (2 × 7.500 IU daily subcutaneously, 12 male, age 67.4 ± 11.5 years) were 0,18 IU/ml ± 0,15 IU/ml (mean, standard deviation), with LMWH (1 × 3000 IU daily subcutaneously, 15 male, age 64.2 ± 14.1 years) 0,17 IU/ml ± 0,16 IU/l, and with no anticoagulants (28 male, age 64.2 ± 15.6 years) 0,02 IU/ml ± 0.01 IU/ml. All factor Xa and thrombin inhibitor pad results of test strips were negative. We conclude that DOAC Dipstick has a high probability of not detecting heparin and LMWH in patients on treatment as well as in urine samples of patients not treated with an anticoagulant.

Anti-Xa Activity of Enoxaparin for Prevention of Venous Thromboembolism in Severe Nephrotic Syndrome-A Single Center Prospective Study.

Severe nephrotic syndrome (NS) is associated with high risk of venous thromboembolic events (VTE), as well as presumably altered heparin pharmacokinetics and pharmacodynamics. Although prophylactic anticoagulation is recommended, the optimal dose is not established. The aim of the study was to test two co-primary hypotheses: of reduced enoxaparin effectiveness and of the need for dose-adjustment in NS. Forty two nephrotic patients with serum albumin ≤2.5 g/dL were alternately assigned to a standard fixed-dose of enoxaparin (NS-FD: 40 mg/day) or ideal body weight (IBW)-based adjusted-dose (NS-AD: 1 mg/kg/day). Twenty one matched non-proteinuric individuals (C-FD) also received fixed-dose. Co-primary outcomes were: the achievement of low- and high-VTE risk threshold of antifactor-Xa activity (anti-FXa) defined as 0.2 IU/mL and 0.3 IU/mL, respectively. Low-VTE-risk threshold was achieved less often in NS-FD than C-FD group (91 vs. 62%, p = 0.024), while the high-VTE-risk threshold more often in NS-AD than in NS-FD group (90 vs. 38%, p < 0.001). Two VTE were observed in NS during 12 months of follow-up (incidence: 5.88%/year). In both cases anti-FXa were 0.3 IU/mL implying the use of anti-FXa >0.3 IU/mL as a target for dose-adjustment logistic regression models. We determined the optimal dose/IBW cut-off value at 0.8 mg/kg and further developed bivariate model (termed the DoAT model) including dose/IBW and antithrombin activity that improved the diagnostic accuracy (AUC 0.85 ± 0.06 vs. AUC 0.75 ± 0.08). Enoxaparin efficacy is reduced in severe NS and the dose should be adjusted to ideal body weight to achieve target anti-FXa activity.

Coagulation markers in patients with venous thromboembolism treated with 10 mg apixaban twice daily.

Apixaban is used to treat venous thromboembolism (VTE) at 10 mg twice daily (BID) for 7 days, followed by 5 mg BID without dose adjustment, and non-valvular atrial fibrillation (NVAF) at 5 mg BID or 2.5 mg BID with dose adjustment criteria (DAC) including age, body weight, and renal function. The anti-factor Xa activity (AXA), prothrombin time (PT), and activated partial thromboplastin time (APTT) in patients with VTE receiving 10 mg BID of apixaban remains unclear. Twenty-six patients (70.8±15.4 years, 10 males) with VTE receiving 10 mg BID of apixaban were enrolled. The patients were divided into two groups based on whether they met the DAC of NVAF: DAC group (n=8) and non-DAC group (n=18). Trough and peak AXA values, PT, and APTT were measured at 10 mg BID dosage and then at 5 mg BID dosage. Coagulation markers in recipients of 10 mg BID therapy were significantly higher than those of 5 mg BID recipients. A significant and strong positive correlation was observed between AXA and PT at trough and peak times. The AXA values and PT in the DAC group were significantly higher than those in the non-DAC group. No significant inter-group differences were seen in APTT. This study provides the first report of AXA distribution in VTE patients receiving 10 mg BID of apixaban. Our findings indicate that coagulation markers may differ in patients with VTE-prescribed higher doses of apixaban and a DAC may be warranted in such patients.

Association between anti F-Xa activity and plasma levels in patients with non valvular atrial fibrillation on apixaban

Apixaban, a Factor Xa inhibitor, has been shown to confer superior net clinical benefit compared to warfarin in the management of patients with non-valvular atrial fibrillation (NVAF). While warfarin effect can be easily monitored using INR measurements, assessment of anti-Factor Xa activity level is currently not readily available. Effects of direct oral anticoagulants have been shown to be related to their plasma levels.