Thrombin Inhibitor Dabigatran Research Articles

Effect of different anticoagulants and antiplatelets on intraoral bleeding time during professional oral hygiene session

ObjectivePatients with thromboembolic problems, prosthetic valves, or coagulation issues are commonly prescribed anticoagulants and antiplatelets. Anticoagulant and antiplatelet medication might constitute a challenge for dentists and dental hygienists since possible prolonged bleeding might interfere with dental procedures. The aim of the present study was to examine the bleeding durations associated with various anticoagulants and antiplatelets during professional dental hygiene sessions, utilizing a modified Ivy test adapted for the oral context.Materials and methodsNinety-three consecutive patients undergoing professional oral hygiene were recruited. Debridement during oral hygiene was performed using ultrasonic mechanical instrumentation, and bleeding sites were assessed and treated with gentle pressure using sterile gauzes. The time for bleeding cessation was recorded. Patients were categorized into six groups based on their drug intake, Control: no anticoagulants or antiplatelets DTI: direct thrombin inhibitors (dabigatran) AntiXa: directa factor Xa inhibitors (endoxaban, apixaban, rivaroxaban) VKA: vitamin K antagonists (warfarin, acenocoumarol) SAPT: single anti-platelet therapy (acetylsalicylic acid or clopidogrel) DAPT: dual anti-platelet therapy (acetylsalicylic acid and clopidogrel). Bleeding time was measured in seconds and mean values were assessed among the different groups. Differences between groups were investigated with Kruskal-Wallis test followed by Dunn’s post-hoc correction for multiple comparisons or two-way ANOVA followed by Dunnett post-hoc;ResultsControl patients presented the lowest bleeding time 50 s, followed by AntiXa (98), SAPT (105), DTI (120), DAPT (190) and VKA (203). A statistically significant difference was present among control and DTI (p = 0.004), VKA (p < 0.001), DAPT (p < 0.001).ConclusionsBased on the present outcomes, an increased risk of prolonged bleeding emerged in patients taking VKA and DAPT.Clinical significancebleeding did not interfere with the oral hygiene session The optimal period for dental treatment of these patients should be 2–3 h before the next dose, without the need to temporarily suspend the medication.

Attenuation of Atherosclerosis with PAR4 Deficiency: Differential Platelet Outcomes in apoE -/- vs. Ldlr -/- Mice.

Cardiovascular disease (CVD) is a significant burden globally and, despite current therapeutics, remains the leading cause of death. Platelet inhibitors are of interest in CVD treatment to reduce thrombus formation post-plaque rupture as well their contribution to inflammation throughout the progression of atherosclerosis. Protease activated receptor 4 (PAR4) is a receptor highly expressed by platelets, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4. Mice on a low-density lipoprotein receptor-deficient ( Ldlr -/- ) background were bred with Par4 deficient ( Par4 -/- ) mice to create Ldlr -/- /Par4 +/+ and Ldlr -/- /Par4 -/- cousin lines. Mice were fed high fat (42%) and cholesterol (0.2%) 'Western' diet for 12 weeks for all studies. Bone marrow transplant (BMT) studies were conducted by irradiating Ldlr -/- /Par4 +/+ and Ldlr -/- /Par4 -/- mice with 550 rads (2x, 4 hours apart) and then repopulated with Par4 +/+ or Par4 -/- bone marrow. To determine if the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the 'Western' diet. Ldlr -/- /Par4 -/- given dabigatran did not further decrease their atherosclerotic burden. Differences between apolipoprotein E deficient ( apoE -/- ) and Ldlr -/- platelets were assessed for changes in reactivity. We observed higher PAR4 abundance in arteries with atherosclerosis in human and mice versus healthy controls. PAR4 deficiency attenuated atherosclerosis in the aortic sinus and root versus proficient controls. BMT studies demonstrated this effect was due to hematopoietic cells, most likely platelets. PAR4 appeared to be acting independent of PAR1, as there werer no changes with addition of dabigatran to PAR4 deficient mice. apoE -/- platelets are hyperreactive compared to Ldlr -/- platelets. Hematopoietic-derived PAR4, most likely platelets, plays a vital role in the development and progression of atherosclerosis. Specific targeting of PAR4 may be a potential therapeutic target for CVD. Deficiency of protease-activated receptor 4 attenuates the development of diet-induced atherosclerosis in a Ldlr -/- mouse model. PAR4 deficiency in hematopoietic cells is atheroprotective. PAR4 deficiency accounts for the majority of thrombin-induced atherosclerosis in a Ldlr -/- mouse model. The examination of platelet-specific proteins and platelet activation should be carefully considered before using the apoE -/- or Ldlr -/- mouse models of atherosclerosis.

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.

A small-molecule hemostatic agent for the reversal of direct oral anticoagulant–induced bleeding

BackgroundThe bleeding risk associated with direct oral anticoagulants (DOACs) remains a major concern, and rapid reversal of anticoagulant activity may be required. Although specific and nonspecific hemostatic biotherapies are available, there is a need for small-molecule DOAC reversal agents that are simple and cost-effective to produce, store, and administer. ObjectivesTo identify and characterize a small molecule with procoagulant activity as a DOAC reversal agent. MethodsWe sought to identify a small procoagulant molecule by screening a chemical library with a plasma clotting assay. The selected molecule was assessed for its procoagulant properties and its ability to reverse the effects of the DOACs in a thrombin generation assay. Its activity as a DOAC reversal agent was also evaluated in a tail-clip bleeding assay in mice. ResultsThe hemostatic molecule (HeMo) dose-dependently promoted thrombin generation in plasma, with dose values effective in producing half-maximum response ranging between 3 and 5 μM, depending on the thrombin generation assay parameter considered. HeMo also restored impaired thrombin generation in DOAC-spiked plasma and reversed DOAC activity in the mouse bleeding model. HeMo significantly reduced apixaban-induced bleeding from 709 to 65 μL (vs 43 μL in controls; P < .01) and dabigatran-induced bleeding from 989 to 155 μL (vs 126 μL in controls; P < .01). ConclusionHeMo is a small-molecule procoagulant that can counterbalance hemostatic disruption by a thrombin inhibitor (dabigatran) or factor Xa inhibitors (apixaban and rivaroxaban). The compound’s effective clot formation and versatility make it a possible option for managing the inherent hemorrhagic risk during DOAC therapy.

Basics for the Use of Andexanet

For life-threatening or uncontrollable bleeding in association with the thrombin inhibitor dabigatran, the monoclonal antibody fragment idarucizumab is available, and for bleeding in association with the direct factor Xa inhibitors rivaroxaban or apixaban, the modified recombinant FXa protein andexanet is available for reversal. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures. An interdisciplinary group of experienced experts in the fields of angiology, hematology, internal medicine, clinical pharmacology, laboratory medicine, transfusion medicine, anesthesiology, intensive care, and hemostaseology developed recommendations relevant to daily clinical practice based on the current scientific evidence. Reversal of oral anticoagulants should be considered for severe bleeding in the following situations: (1) life-threatening bleeding or refractory hemorrhagic shock, (2) intracerebral bleeding, or (3) endoscopically unstoppable gastrointestinal bleeding. After successful hemostasis, anticoagulation (e.g., direct oral anticoagulant, vitamin K antagonist, and heparin) should be resumed promptly, taking into account individual bleeding and thromboembolic risk. This article aims to facilitate the management of patients with andexanet by all medical disciplines involved, thereby ensuring optimal care of patients during bleeding episodes.

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.

Pharmacological Thromboprophylaxis in People with Hemophilia Experiencing Orthopedic Surgery: What Does the Literature Say in 2023?

This narrative review of the literature, consisting of papers found in PubMed and The Cochrane Library published up to 31 July 2023, analyzed those that were deemed to be closely related to the title of this paper. It was encountered that the peril of deep vein thrombosis (DVT) in people with hemophilia (PWH) after orthopedic surgery is very small, such that pharmacological thromboprophylaxis is not necessary in most cases. The hemophilia literature states that the use of pharmacological thromboprophylaxis should only be performed in PWH undergoing major orthopedic surgery (total-knee arthroplasty, total-hip arthroplasty, ankle arthrodesis) who have additional venous thromboembolism (VTE) risk factors, such as old age, prior VTE, varicose veins, general anesthesia, cancer, factor V (Leiden) mutation, overweight, and treatment with the oral contraceptive pill (in females with von Willebrand's illness). If we notice various risk factors for VTE in PWH who experience orthopedic surgery, theoretically, we should perform the identical type of pharmacological thromboprophylaxis advised for non-hemophilia patients: low-molecular weight heparins (LMWHs), such as enoxaparin (40 mg subcutaneous/24 h); or direct oral anticoagulants (DOACs), either thrombin inhibitors (dabigatran, 150 mg oral/12 h) or activated factor X (FXa) inhibitors (rivaroxaban, 20 mg oral/24 h; apixaban, 5 mg oral/24 h), or subcutaneous fondaparinux (2.5 mg/24 h subcutaneously). However, the review of the literature on hemophiliac patients has shown that only a few authors have used pharmacological prophylaxis with LMWH (subcutaneous enoxaparin) for a short period of time (10-14 days) in some patients who had risk factors for VTE. Only one group of authors used a low dose of DOAC in the dusk after the surgical procedure and the next day, specifically in individuals at elevated risk of VTE and elevated risk of bleeding after the surgical procedure.

Use of specific antidotes in DOAC-associated severe gastrointestinal bleeding - an expert consensus - Antagonozation of direct oral anticoagulants in gastrointestinal hemorrhages

Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.

Management of major bleeding for anticoagulated patients in the Emergency Department: an European experts consensus statement.

An increasing number of patients presenting to the emergency department (ED) with life-threatening bleeding are using oral anticoagulants, such as warfarin, Factor IIa and Factor Xa inhibitors. Achieving rapid and controlled haemostasis is critically important to save the patient's life. This multidisciplinary consensus paper provides a systematic and pragmatic approach to the management of anticoagulated patients with severe bleeding at the ED. Repletion and reversal management of the specific anticoagulants is described in detail. For patients on vitamin K antagonists, the administration of vitamin K and repletion of clotting factors with four-factor prothrombin complex concentrate provides real-time ability to stop the bleeding. For patients using a direct oral anticoagulant, specific antidotes are necessary to reverse the anticoagulative effect. For patients receiving the thrombin inhibitor dabigatran, treatment with idarucizamab has been demonstrated to reverse the hypocoagulable state. For patients receiving a factor Xa inhibitor (apixaban or rivaroxaban), andexanet alfa is the indicated antidote in patients with major bleeding. Lastly, specific treatment strategies are discussed in patients using anticoagulants with major traumatic bleeding, intracranial haemorrhage or gastrointestinal bleeding.

Construction of an Antithrombotic and Anti-Inflammatory Polyethersulfone Membrane.

In addition to being the core factor in thrombosis, thrombin is involved in various inflammatory disease responses, but few studies have examined whether and how it is involved in membrane-related inflammation. In this study, the thrombin inhibitor dabigatran is used to modify a polyethersulfone dialysis membrane. The modified membrane shows good hydrophilic properties and dialysis performance. It reduces the thrombin level in a targeted manner, thereby significantly inhibiting coagulation factor activation (based on the prothrombin time, international normalized ratio, activated partial thromboplastin time and thrombin time) and reducing the fibrinogen level and platelet adhesion. On thromboelastography, it shows excellent dynamic antithrombotic capacity. The modified membrane inhibited membrane-related inflammation by inhibiting the production of the inflammatory mediators C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1β (IL-1β) via the thrombin/complement C5a pathway. Moreover, it is found to be safe in an in vivo study. Thus, the dabigatran-modified polyethersulfone membrane may reduce dialysis-related complications through its dual antithrombotic and anti-inflammatory effects.

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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.

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.

Reversal agents for current and forthcoming direct oral anticoagulants

Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials.

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.

Non-vitamin K antagonist oral anticoagulants for COVID-19 thrombosis

Thrombotic complications appear to be a major predictor of death in COVID-19 patients, and multiple studies have shown that anticoagulants can help to improve the outcome. The Food and Drug Administration’s acceptance of non-vitamin K antagonist oral anticoagulants (NOACs) has sparked much excitement about their potential as a replacement for existing oral anticoagulants. NOACs target a single clotting factor, often activated factor X or thrombin, and involve the coagulation factor Xa inhibitors including apixaban, edoxaban, and rivaroxaban, and the thrombin inhibitor dabigatran. COVID-19 is an infectious disease that causes thrombotic events by inducing a pro-inflammatory and prothrombotic condition. This article provides a comprehensive overview of the mechanism behind enhanced thrombogenicity accompanying COVID-19, the clinical range of NOACs, and the role of NOACs in treatment of COVID-19 based on recent investigations and clinical trials.

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.