Direct Thrombin Inhibitor Dabigatran Research Articles

Direct factor Xa inhibitors and the risk of cancer and cancer mortality: A Danish population-based cohort study.

Preclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran. This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period. In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort.

Is There an Alternative Oral Anticoagulation to Vitamin-K-Antagonists for Patients with Mechanical Aortic Valve Replacement? - A Literature Review.

Current guidelines exclusively recommend vitamin-K-antagonists (VKA) as anticoagulation for patients after mechanical aortic valve replacement due to the increased postoperative risk of valve thrombosis and thrombo-embolism. Strict and regular assessments are mandatory during VKA therapy to ensure a potent anticoagulatory effect within the desired range. From the patients' perspective, VKA are associated with relevant interactions and side effects reducing the quality of life and contributing to a high number of patients not achieving the optimal therapeutic target. Direct oral anticoagulants (DOAC) have replaced VKA therapy in the past for several indications, e.g., atrial fibrillation. However, it is still unclear if DOACs could replace VKA therapy in patients after mechanical aortic valve replacement. While the PROACT-Xa study did not show a sufficient anticoagulatory effect of apixaban plus aspirin compared to VKA therapy in patients after mechanical aortic valve replacement, the direct thrombin inhibitor dabigatran and the oral factor Xa inhibitors apixaban and rivaroxaban showed promising results in comparable patient cohorts in smaller studies and case reports. Factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients after mechanical aortic valve replacement. Therefore, factor Xa inhibitors or factor XI inhibitors could provide a potent alternative to VKA for patients after a mechanical aortic valve replacement.

B-174 Simple and Accurate Quantification of Four Direct Oral Anticoagulants in Plasma Using UPLC-MS/MS

Abstract Background Direct oral anticoagulants (DOACs) constitute first-line therapy used for many thromboembolic indications, such as prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. This class of medication consists of the direct thrombin inhibitor (dabigatran) or direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban). DOACs quantification may be useful in the case of critical clinical situations, including drug accumulation in long-term treatment, overdosage, thrombotic or bleeding events. This study aimed to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of four DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban in plasma. Methods The calibration curve samples were prepared by spiking drug free plasma with DOACs. The stable isotope labeled DOACs was used as an internal standard. After addition of the internal standard and protein precipitation, the supernatant was 10-fold diluted and injected into a chromatography system consisting of a UPLC BEH C18 (2.1 × 50 mm; particle size 1.7 µm) analytical column with gradient made of mobile phase (5 mM ammonium formate pH3.5 in water and methanol). The outlet of the column was connected to a triple quadrupole mass spectrometer with electrospray interface. Ions were detected in the positive multiple reaction monitoring mode. The concentration of analyte was calculated from the calibration curve and ion ratios between the analyte and the internal standard. Results The analytical range was linear with a correlation coefficient of over 0.99 in the range of 0–500 ng/mL for each analyte. Intra- and inter-assay imprecision were less than 3.1% (n = 20) and 6.0% (n = 20), respectively. The accuracy was evaluated by spike recovery and the mean recoveries were between 97.2% and 102.1% for all analytes. This assay showed no ion suppression or enhancement and no carryover. The chromatography run time was 4.5 min. The assay was applied to quantitate DOACs in plasma samples from 93 patients. Our data showed that the DOACs concentrations vary markedly individual patients after equal dose, this therapeutic drug monitoring of DOACs is essential to optimized drug efficacy. Conclusion An accurate, and cost-effective UPLC-MS/MS method for the quantification of DOACs was successfully applied for therapeutic drug monitoring in patients.

Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis

Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 ( p < 0.01; n = 5), and 66.9 ± 4.8% ( p < 0.001; n = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation. Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study.

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Exploring the Clinical Efficacy of Venous Thromboembolism Management in Saudi Arabian Hospitals: An Insight into Patient Outcomes.

Venous thromboembolism (VTE) is a common condition that can recur, leading to multiple therapeutic strategies to prevent it. The aim of this study was to explore the clinical efficacy of VTE management in Saudi Arabian hospitals and to gain insights into patient outcomes. A retrospective single-center study was conducted that retrieved the data of all patients with VTE registered from January 2015 to December 2017. Patients of all age groups were included if they attended the thrombosis clinic at KFMC during the data collection period. The study analyzed the various therapeutic strategies used for VTE and their effect on patient outcomes. The results showed that 14.6% of the patients had provoked VTE, with a higher incidence among females and younger patients. The most commonly prescribed treatment was combination therapy, followed by warfarin, oral anticoagulants, and factor Xa inhibitor. Despite being prescribed treatment, 74.9% of the patients experienced recurrence of VTE. There was no associated risk factor for recurrence in 79.9% of the patients. Thrombolytic therapy and catheter-directed thrombolysis were found to be associated with a lower risk of VTE recurrence, while anticoagulation therapy, including oral anticoagulants, was associated with a higher risk. Vitamin K antagonist (warfarin) and factor Xa inhibitor (rivaroxaban) had a significant positive association with VTE recurrence, while the use of a direct thrombin inhibitor (dabigatran) showed a lower risk, but it was not statistically significant. The results of the study highlight the need for further research to determine the most effective therapeutic strategy for VTE management in Saudi Arabian hospitals. The findings also suggest that anticoagulation therapy, including oral anticoagulants, may increase the risk of VTE recurrence, while thrombolytic therapy and catheter-directed thrombolysis may lower the risk.

3 SAFETY OF NOVEL ORAL ANTICOAGULANTS COMPARED TO VITAMIN K ANTAGONISTS IN THE TREATMENT OF VENOUS THROMBOEMBOLISM: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background Individual randomized controlled trials (RCTs) enrolling patients with venous thromboembolism (VTE) have demonstrated that novel oral anticoagulants (NOACs) are comparable to vitamin K antagonists (VKAs) in reducing the risk of recurrent VTE but hold a safer bleeding profile. Nonetheless, pooled data from RCTs on the safety of NOACs versus VKAs in patients with VTE are still scarce. Purpose We aimed to compare the effect of NOACs versus VKA on the risk of fatal bleeding, major bleeding, clinically relevant non-major bleeding (CRNMB) and any bleeding in patients with VTE through a meta-analysis of RCTs. Methods We performed a systematic review of the literature, from January 1970 to December 2021, using PubMed database with four independent reviewers (L.R.; G.M.; V.C.; F.G.). Discrepancies were solved by consensus with a senior researcher (D.M.). Phase 3 randomized controlled trials comparing NOACs versus VKAs, either as an acute treatment or as an extended therapy, in patients with pulmonary embolism or deep vein thrombosis were selected. We performed a meta-analysis using a random-effects model with the Mantel–Haenszel method for each safety endpoint. Study outcomes were expressed as odd ratios (OR) with 95% confidence interval (CI) and illustrated in a Forest plot diagram. A two-sided p-value &amp;lt;0.05 was considered statistically significant. Heterogeneity was tested using the I2-statistic. Results Seven trials were included (n=29,879 patients), either investigating the direct thrombin inhibitor dabigatran (RE-COVER, RE-COVER II and RESONATE trials) or the factor Xa inhibitors rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE studies), apixaban (AMPLIFY study) and edoxaban (Hokusai-VTE study). Compared to VKAs, treatment with NOACs was associated with lower risk of fatal bleeding (OR 0.35; 95% CI 0.16-0.81), major bleeding (OR 0.60; 95% CI 0.45-0.80), and any bleeding (OR 0.62; 95% CI 0.54-0.72) - fig. 1. There was no significant difference between the two groups concerning the risk of CRNMB. Conclusions In patients with VTE, treatment with NOACs was associated with fewer bleeding complications compared with VKAs.

Oral Anticoagulant Use in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Review of the Evidence With Recommendations for Australian Clinical Practice.

Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with heightened risks of stroke/systemic embolisation and bleeding. In this review we outline the evidence for AF stroke prevention in kidney disease, identify current knowledge gaps, and give recommendations for anticoagulation at various stages of chronic kidney disease. Overall, anticoagulation is underused. Warfarin use becomes increasingly difficult with advancing kidney disease, with difficulty maintaining international normalised ratio (INR) in therapeutic range, increased risk of intracranial and fatal bleeding compared to non-vitamin K oral anticoagulants (NOACs), and high rates of discontinuation. Similarly, the direct thrombin inhibitor dabigatran is not recommended as it is predominantly renally excreted with consequent increased plasma levels and bleeding risk with advanced kidney disease. The Factor Xa inhibitors apixaban and rivaroxaban have less renal excretion (25-35%), modest increases in plasma levels with advancing kidney disease, and are the preferred first line choice for anticoagulation in moderate kidney disease based on strong evidence from randomised clinical trials (RCTs). In severe kidney disease there is a paucity of RCT data, but extrapolation of the pharmacokinetic and RCT data for moderate kidney disease, and observational studies, support the considered use of dose-adjusted Factor Xa inhibitors unless the bleeding risk is prohibitive. In Australia, apixaban is approved for creatinine clearance down to 25 mL/min, and rivaroxaban down to 15 mL/min. For end-stage kidney disease warfarin is the only agent approved, but we recommend against anticoagulation (except in selected cases) due to high bleeding risk, multiple co-morbidities, and questionable benefit.

Thrombin Generation Is Differentially Affected By Anticoagulants in Patients with Acute Lymphoblastic Leukemia - an Ex-Vivo Study

Background: Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). Low molecular weight heparin (LMWH) reduces the risk of VTE in ALL, but is not well tolerated in children. VTE rates remain unacceptably high in adults despite LMWH prophylaxis. Thus, novel strategies for VTE prevention are warranted. In the primary analysis of the PREVAPIX-ALL trial there was no statistically significant reduction in VTE among children treated with the oral factor Xa inhibitor, apixaban, compared to no anticoagulation (AC). Comparative data on activity of different anticoagulants are needed to guide planning of VTE prophylaxis trials. Aims: To characterize and compare the ex-vivo effect of LMWH (enoxaparin), oral direct factor Xa inhibitors (apixaban, rivaroxaban) and oral direct thrombin inhibitor (dabigatran etexilate) in ALL patients' samples using thrombin generation (TG). Methods: A prospective observational cohort study of 46 children with newly-diagnosed ALL, treated with the L-asparaginase (ASP)-based BFM protocol, at a tertiary medical center. Patients on therapeutic-dose AC at baseline were excluded. Blood samples were drawn before ASP treatment (ALL-Day0) and 7 days after (ALL-Day7). Normal pooled plasma (NP) was collected from healthy adult volunteers. Samples were spiked ex-vivo with enoxaparin [0.2 U/mL], apixaban [39 ng/mL], rivaroxaban [39 ng/mL] and dabigatran [150 ng/mL] or vehicle (i.e., control). AC concentrations chosen based on 50% peak reduction (for Xa inhibitors) or 200% LT prolongation (for dabigatran) in NP. Subsequently, TG was performed initiated using 5 pM tissue factor in the presence of 4 µM phospholipids using Calibrated Automated Thrombogram method in these samples. Results are expressed as peak height (PH) and lag time (LT) and relative reduction or prolongation (% difference in PH or LT, respectively) in plasma samples spiked with anticoagulants compared to control. Reduction in PH reflects enoxaparin, apixaban and rivaroxaban activity, while LT prolongation indicates dabigatran activity. This report focuses on measures reflecting the activity of each drug. Descriptive statistics were used to show the median [interquartile range (IQR)] for continuous variables and percentages for categorical data. T-Test / Mann-Whitney U test and paired T-test / Wilcoxon test used to compare between paired and non-paired samples, respectively. Results: Selected sample characteristics are as follows: median age, 7.75 years [IQR 3.73-11.93]; 19 (41%) females; median BMI, 16.8 [IQR 15.5-19.9]; B-cell precursor immunophenotype in 33 (71.7%) and T-cell in 13 (28.3%); prior VTE in 1 (2%). Median PH [IQR] in control samples (without AC) was 256.6 [252.6-265.3] nmol/l, 396.0 [347.2-464.7] nmol/l and 354.4 [307.1-407.4] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median LT [IQR] in control samples was 2.7 [2.5-2.83] nmol/l, 1.8 [1.7-2.3] nmol/l and 1.7 [1.6-2] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median % differences in PH and LT between samples spiked with different anticoagulants and controls are shown in Figure 1A and Figure 1B, respectively. Enoxaparin, apixaban and rivaroxaban reduced PH in NP, ALL-Day0 and ALL-Day7 samples (p<0.0005). There was less reduction in PH with enoxaparin, apixaban and rivaroxaban in ALL-Day0 samples than in NP (p=0.029, p<0.0005, p<0.0005 respectively), suggesting reduced anticoagulant activity in ALL patients compared to subjects without ALL. LT was prolonged with dabigatran in NP, ALL-Day0 and ALL-Day7 samples (p<0.05). Dabigatran resulted in a similar LT prolongation in ALL-Day0 and NP (p=0.677), suggesting a preserved AC effect in ALL. There was less LT prolongation in ALL-Day7 (134% [123-175%] than in ALL-Day0 (180% [134-238]; p=0.031). This reflects an ongoing dabigatran effect after ASP, albeit to a lesser degree. Conclusions: Our ex-vivo results suggest limited anticoagulant activity of enoxaparin and lack of anticoagulant activity of apixaban and rivaroxaban (both factor Xa inhibitors) in preventing VTE in ALL, in line with prior clinical data. In contrast, dabigatran etexilate, an oral direct thrombin inhibitor not previously tested in ALL, exhibited preserved anticoagulant activity in ALL patients, even after exposure to ASP. This may suggest that dabigatran should be investigated in clinical studies for the unmet need of VTE prophylaxis in ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity

Protease‐activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR‐1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration barrier is not clear. Anticoagulant‐related nephropathy (ARN) is a kidney disease with glomerular hematuria and red blood cell tubular casts. We validated 5/6 nephrectomy (5/6NE) in rats as a model of ARN and had demonstrated that direct thrombin inhibitor (dabigatran) induces ARN. The aim of this study was to investigate the role of PAR‐1 in the ARN pathogenesis. 5/6NE rats were treated with dabigatran (150 mg/kg/day), PAR‐1 inhibitor SCH79797 (1 and 3 mg/kg/day) and PAR‐1 agonist TFLLR‐NH2 (0.25 and 0.50 µmol/kg/day) for 7 days. Serum creatinine and hematuria were assessed daily. Kidney morphology was evaluated at the end of the study. In 5/6NE rats treated with either dabigatran or combination with a PAR‐1 modulator, there was an elevation in serum creatinine, glomerular hematuria, red blood casts in the tubules, and acute tubular epithelial cell injury. Interestingly, both PAR‐1 modulators in a dose‐depended manner had similar effects on the serum creatinine levels and hematuria as those of dabigatran. Dabigatran‐induced increase in the systolic blood pressure was not affected by PAR‐1 modulators. In conclusion, the normal function of PAR‐1 is crucial to maintain the glomerular filtration barrier integrity. Either activation or blockage of PAR‐1 leads to glomerular hematuria and subsequent acute tubular epithelial cell injury.

An Update of the Efficacy and Comparative Characteristics of Direct (New) Oral Anticoagulants (DOACs).

Direct (New-generation) Oral Anticoagulants (DOACs) have emerged as effective agents which are used in place of vitamin-K antagonists in treatment and prophylaxis of Venous Thromboembolism (VTE), atrial fibrillation and other thrombotic diseases. Among them, the FIIa- direct thrombin inhibitor dabigatran and FXa inhibitors (rivaroxaban, apixaban, edoxaban) are the most broadly used. Anticoagulant dosing may differ under special considerations. The patients' physiological reserves, organ functional status and failures should be taken into account in clinical decision-making processes. The advantages and drawbacks of each specific agent should be weighed with special regard to metabolism, pharmacokinetics and pharmacodynamics, along with the efficiency of the agents in different indications. This article aims to review the most recent literature to highlight the usage and efficacy of the agents in different clinical conditions.

Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass.

Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB. The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition. In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250-1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban. The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.

Global Research Status and Trends in Venous Thromboembolism After Hip or Knee Arthroplasty From 1990 to 2021: A Bibliometric Analysis.

BackgroundVenous thromboembolism (VTE) after hip or knee arthroplasty has attracted increasing attention over the past few decades. However, there is no bibliometric report on the publications in this field. The purpose of this study was to analyze the global research status, hotspots, and trends in VTE after arthroplasty.MethodsAll articles about VTE research after hip or knee arthroplasty from 1990 to 2021 were retrieved from the Web of Science Core Collection database. The information of each article including citation, title, author, journal, country, institution, keywords, and level of evidence was extracted for bibliometric analysis.ResultsA total of 1,245 original articles from 53 countries and 603 institutions were retrieved. The USA contributed most with 457 articles, followed by England and Canada. McMaster University in Canada was the leading institution for publications. The journals with the highest output and citation were the Journal of Arthroplasty and the Thrombosis and Haemostasis, respectively. The median number of citations was significantly different among the levels of evidence (F = 128.957, P < 0.001). The research hotspots switched from VTE diagnosis and heparin to factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran etexilate, ximelagatran), and finally to aspirin, risk factor studies, which can be observed from the keyword analysis and co-cited reference cluster analysis.ConclusionsThis study observed an increasing trend of research articles on VTE after arthroplasty. Publications with higher levels of evidence gained further popularity among researchers and orthopedic surgeons. Additionally, individualized VTE prevention and the development of new, safe, effective, and inexpensive oral agents would be emerging trends in the future.

DOAC Dipstick Testing Can Reliably Exclude the Presence of Clinically Relevant DOAC Concentrations in Circulation.

In certain clinical situations, it is necessary to determine whether clinically relevant plasma levels of direct oral anticoagulants (DOACs) are present. We examined whether qualitative testing of DOACs in urine samples can exclude DOAC plasma concentrations of ≥30 ng/mL. This prospective single-center cohort study included consecutive patients treated with an oral direct factor Xa inhibitor (DXI) (apixaban, n = 31, rivaroxaban, n = 53) and direct thrombin inhibitor (DTI) (dabigatran, n = 44). We aimed to define the negative predictive value (NPV) and other statistical parameters of detecting DXIs and DTIs by DOAC Dipstick at plasma concentrations of ≥30 ng/mL. We also determined the best-fit threshold plasma levels using chromogenic substrate assays by logistic regression analysis. Between July 2020 and July 2021, 128 eligible patients (mean age 66 years, 55 females) were included into the study. The NPVs and sensitivities for DXI and DTI of DOAC Dipstick were 100% at ≥30 ng/mL plasma, for specificities 6 and 21% and for positive predictive values 62 and 72%, respectively. All diagnostic statistical tests improved to values between 86 and 100% at best-fitting plasma thresholds of ≥14 ng/mL for DXI and ≥19 ng/mL for DTI. Visual analysis using the DOAC Dipstick was 100% in agreement with that of the optoelectronic DOASENSE Reader for all the three DOACs. DOAC Dipstick testing can reliably exclude the presence of DOACs in urine samples at best-fitting thresholds of >14 and >19 ng/mL in plasma. The performance of the DOAC Dipstick at detecting lower DOAC concentrations in plasma requires confirmation.

Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis.

Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity.

The Role of Direct Oral Anticoagulants in Advanced Chronic Kidney Disease – Questions and Future directions

With the advent of the direct oral anticoagulants (DOACs), patients requiring anticoagulation for common conditions such as atrial fibrillation and venous thromboembolism no longer need to worry about dietary restrictions or regular monitoring of the international normalized ratio which complicated warfarin treatment. Switching from warfarin to apixaban, a DOAC, has been shown to improve patient satisfaction by reducing treatment burden [1]. The clotting factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) and the direct thrombin inhibitors (argatroban and dabigatran) have shown non-inferiority in preventing thromboembolic events and a superior safety profile in terms of bleeding in several trials when compared to warfarin [2-6]. Furthermore, apixaban and dabigatran have even shown superiority in preventing stroke or systemic embolism [3,6].

Factor Xa Inhibitors for Patients after Mechanical Heart Valve Replacement?

Patients with a mechanical heart valve need a lifelong anticoagulation due to the increased risk of valve thrombosis and thrombo-embolism. Currently, vitamin K antagonists (VKA) are the only approved class of oral anticoagulants, but relevant interactions and side effects lead to a large number of patients not achieving the optimal therapeutic target international normalized ration (INR). Therefore, steady measurements of the INR are imperative to ensure potent anticoagulation within a distinctive range. Direct oral anticoagulants (DOACs) with newer agents could serve as a possible alternative to VKAs in this patient cohort. DOACs are approved for several indications, e.g., atrial fibrillation (AF). They only have a minor interaction potential, which is why monitoring is not needed. Thereby, DOACs improve the livability of patients in need of chronical anticoagulation compared with VKAs. In contrast to dual platelet inhibition using aspirin in combination with an ADP receptor antagonist and the direct thrombin inhibitor dabigatran, the oral factor Xa inhibitors apixaban and rivaroxaban show promising results according to current evidence. In small-scale studies, factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients with mechanical heart valves. Finally, DOACs seem to represent a feasible treatment option in patients with mechanical heart valves, but further studies are needed to evaluate clinical safety. In addition to the ongoing PROACT Xa trial with apixaban in patients after aortic On-X valve implantation, studies in an all-comer collective with rivaroxaban could be promising.

Point-of-care detection and differentiation of anticoagulant therapy - development of thromboelastometry-guided decision-making support algorithms

BackgroundDOAC detection is challenging in emergency situations. Here, we demonstrated recently, that modified thromboelastometric tests can reliably detect and differentiate dabigatran and rivaroxaban. However, whether all DOACs can be detected and differentiated to other coagulopathies is unclear. Therefore, we now tested the hypothesis that a decision tree-based thromboelastometry algorithm enables detection and differentiation of all direct Xa-inhibitors (DXaIs), the direct thrombin inhibitor (DTI) dabigatran, as well as vitamin K antagonists (VKA) and dilutional coagulopathy (DIL) with high accuracy.MethodsFollowing ethics committee approval (No 17–525-4), and registration by the German clinical trials database we conducted a prospective observational trial including 50 anticoagulated patients (n = 10 of either DOAC/VKA) and 20 healthy volunteers. Blood was drawn independent of last intake of coagulation inhibitor. Healthy volunteers served as controls and their blood was diluted to simulate a 50% dilution in vitro. Standard (extrinsic coagulation assay, fibrinogen assay, etc.) and modified thromboelastometric tests (ecarin assay and extrinsic coagulation assay with low tissue factor) were performed. Statistical analyzes included a decision tree analyzes, with depiction of accuracy, sensitivity and specificity, as well as receiver-operating-characteristics (ROC) curve analysis including optimal cut-off values (Youden-Index).ResultsFirst, standard thromboelastometric tests allow a good differentiation between DOACs and VKA, DIL and controls, however they fail to differentiate DXaIs, DTIs and VKAs reliably resulting in an overall accuracy of 78%. Second, adding modified thromboelastometric tests, 9/10 DTI and 28/30 DXaI patients were detected, resulting in an overall accuracy of 94%. Complex decision trees even increased overall accuracy to 98%. ROC curve analyses confirm the decision-tree-based results showing high sensitivity and specificity for detection and differentiation of DTI, DXaIs, VKA, DIL, and controls.ConclusionsDecision tree-based machine-learning algorithms using standard and modified thromboelastometric tests allow reliable detection of DTI and DXaIs, and differentiation to VKA, DIL and controls.Trial registrationClinical trial number: German clinical trials database ID: DRKS00015704.

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.