Search Results (11)

Background/objectives: In some cases of concomitant use of direct oral anticoagulants (DOAC) and certain anticancer medications, pharmacokinetic interactions are expected; however, clinical data is scarce. This report reviews the recommendations on the use of DOAC concurrently with anticancer drugs according to different clinical decision support systems and sources, with a focus on discrepancies. Methods: We reviewed the recommendations from the American Heart Association (AHA), European Heart Rhythm Association (EHRA), summary of product characteristics (SPC) in FASS (Swedish medicine information portal), the Swedish clinical decision support system Janusmed, and information from the Food and Drug Administration (FDA) on the concomitant use of apixaban, edoxaban, and rivaroxaban (activated factor X (FXa) inhibitors) and 80 anticancer drugs from 11 categories (240 drug pairs). Results: No warnings of expected pharmacokinetic drug interactions between FXa inhibitors and anticancer drugs were found for 155 drug pairs (65%) across all sources. The remaining 35% of drug pairs were flagged as having possible interactions with FXa inhibitors according to at least one source. Discrepancies in the recommendations from the different sources were reported. The reported discrepancies were, for the most part, associated with different assessments of the mechanism and the extent of pharmacokinetic interactions of each anticancer medication. Also, knowledge sources have different approaches to reporting potential interactions, in some cases reporting clinically relevant strictly pharmacokinetic interactions, whereas others include even patient-specific factors. Conclusions: The lack of clinical data and different recommendations can make clinical decisions on the concomitant use of DOAC and anticancer drugs difficult. Our compilation is meant to assist clinicians in making decisions based on the available evidence, even if it is scarce. Full article

Direct oral anticoagulants (DOACs) are increasingly being used due to their improved efficacy/safety ratio and lower clinical and economic burden when compared to vitamin K antagonists. However, bleeding is still the most frequent complication associated with DOACs, and although rare, bleeding episodes can be life-threatening or critical. The impact of DOAC anticoagulation activity during a bleeding event must be evaluated according to patient clinical assessment, dosage and time from last intake, the presence of comorbidities (especially kidney and liver dysfunction), and, whenever possible, coagulation tests. Unfortunately, DOACs’ anticoagulation activity is not easily or usually detectable in routine common coagulation testing. Specific DOAC tests allow for specific drug monitoring, but they are too time consuming, and are usually unavailable in routine emergency practice. If a clinically relevant DOAC plasma concentration is assumed or proven in a severe bleeding scenario, DOAC reversal is needed to restore hemostasis. This experts’ consensus provides a narrative review about DOAC reversal and practical life-threatening bleeding management in several scenarios (trauma, intracranial hemorrhage and gastrointestinal bleeding), focusing on the selection of patients to whom specific reversal agents should be given. Full article

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug–drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa. Full article

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. Full article

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents. Full article

Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban, edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies. The interaction of active compounds with human serum albumin (HSA), the most abundant protein in blood plasma, is a key research area and provides crucial information about drugs’ pharmacokinetics and pharmacodynamic properties. This research focuses on the study of the interactions between HSA and four commercially available direct oral FXa inhibitors, applying methodologies including steady-state and time-resolved fluorescence, isothermal titration calorimetry (ITC), and molecular dynamics. The HSA complexation of FXa inhibitors was found to occur via static quenching, and the complex formation in the ground states affects the fluorescence of HSA, with a moderate binding constant of 10⁴ M⁻¹. However, the ITC studies reported significantly different binding constants (10³ M⁻¹) compared with the results obtained through spectrophotometric methods. The suspected binding mode is supported by molecular dynamics simulations, where the predominant interactions were hydrogen bonds and hydrophobic interactions (mainly π–π stacking interactions between the phenyl ring of FXa inhibitors and the indole moiety of Trp214). Finally, the possible implications of the obtained results regarding pathologies such as hypoalbuminemia are briefly discussed. Full article

Although preclinical research and observer studies on patients with atrial fibrillation concluded that direct oral anticoagulants (DOACs) can protect against dementia like Alzheimer’s disease (AD), clinical investigation towards therapeutical approval is still pending. DOACs target pathological thrombin, which is, like toxic tau and amyloid-ß proteins (Aß), an early hallmark of AD. Especially in hippocampal and neocortical areas, the release of parenchymal Aß into the blood induces thrombin and proinflammatory bradykinin synthesis by activating factor XII of the contact system. Thrombin promotes platelet aggregation and catalyzes conversion of fibrinogen to fibrin, leading to degradation-resistant, Aß-containing fibrin clots. Together with oligomeric Aß, these clots trigger vessel constriction and cerebral amyloid angiopathy (CAA) with vessel occlusion and hemorrhages, leading to vascular and blood–brain barrier (BBB) dysfunction. As consequences, brain blood flow, perfusion, and supply with oxygen (hypoxia) and nutrients decrease. In parenchymal tissue, hypoxia stimulates Aß synthesis, leading to Aß accumulation, which is further enhanced by BBB-impaired perivascular Aß clearance. Aß trigger neuronal damage and promote tau pathologies. BBB dysfunction enables thrombin and fibrin(ogen) to migrate into parenchymal tissue and to activate glial cells. Inflammation and continued Aß production are the results. Synapses and neurons die, and cognitive abilities are lost. DOACs block thrombin by inhibiting its activity (dabigatran) or production (FXa-inhibitors, e.g., apixaban, rivaroxaban). Therefore, DOAC use could preserve vascular integrity and brain perfusion and, thereby, could counteract vascular-driven neuronal and cognitive decline in AD. A conception for clinical investigation is presented, focused on DOAC treatment of patients with diagnosed AD in early-stage and low risk of major bleeding. Full article

Direct oral anticoagulants (DOACs) are safe and effective in cancer patients treated for venous thromboembolism (VTE) or atrial fibrillation (AF). Gastrectomy is the treatment of choice in patients with localized upper gastrointestinal cancer. DOACs are absorbed in the upper gastrointestinal tract, but to what extent is unclear. In a retrospective analysis, hospital data were searched for adult patients who underwent gastrectomy for gastroesophageal or pancreatic cancer, and DOAC therapy for VTE or AF after gastrectomy. DOAC blood levels were determined by chromogenic assays before and after administration, and thromboembolic and bleeding complications were recorded. Eleven patients (median age 76 years) received a factor Xa inhibitor (FXaI; apixaban (3), edoxaban (3), rivaroxaban (4)) or the factor IIa inhibitor dabigatran (1) for VTE (7) or AF (4) after gastrectomy. Eight patients on FXaI had anti-Xa (aXa) trough levels within the expected range (ER). In all of them, aXa levels increased upon DOAC administration. Two patients on 30 mg edoxaban had low aXa trough levels. Administration of 20 mg of rivaroxaban resulted in trough levels in the ER in one of them. None of the FXaI patients had thromboembolism, while two experienced bleeding (arterial puncture site, gastrointestinal). One dabigatran AF patient with trough and peak concentrations below the ER had strokes during 110 mg and 150 mg dabigatran administration. While on apixaban, aXa levels were in the ER, and no clinical complications occurred. DOACs, particularly FXaI, were adequately absorbed in cancer patients after gastrectomy. Our observation of recurrent thromboembolic events in a patient treated with dabigatran warrants cautious use in this specific patient population. Full article

Atrial fibrillation (AF) catheter ablation is performed in patients receiving direct oral anticoagulants (DOACs) with intra-procedural unfractionated heparin (UFH) administration to achieve activated clotting time (ACT) at 300 s, as for vitamin K antagonist (VKA). We determined whether ACT monitoring might be transposed from VKA to DOAC-treated patients. Blood was taken from 124 patients receiving uninterrupted dabigatran, rivaroxaban, apixaban, or VKA or being untreated. DOAC concentration or INR (VKA) were measured. ACT was determined at baseline, and after spiking with UFH doses equivalent to 1000, 2500, 5000 and 10000 IU in vivo. At baseline, anticoagulants prolonged ACT differently, ACT was longer with dabigatran and shorter with apixaban despite similar concentrations. ACT strongly correlated with INR and dabigatran concentration, but not with apixaban or rivaroxaban concentrations. Moreover, UFH effects on ACT prolongation depended on the anticoagulant: dose-response curves in samples with VKA and dabigatran were parallel whereas ACT prolongation in response to UFH was significantly smaller with rivaroxaban and especially apixaban. Therefore, UFH to achieve ACT at 300 s might be transposed from VKA to uninterrupted dabigatran-treated patients but not to patients receiving FXa-inhibitors, especially apixaban. Targeting 300 s might expose to UFH overdosing and bleeding, questioning the current anticoagulation strategy. Full article

Background: The direct oral anticoagulant rivaroxaban inhibiting specifically activated factor X (FXa) causes delayed thrombin generation (TG) as measured by calibrated automated thrombography (CAT). The implications of these changes for assessing bleeding or residual prothrombotic risks of patients are unclear in the absence of a better understanding of the underlying mechanism. Methods: We compared platelet rich plasma (PRP) without or with prior collagen-induced platelet aggregation (agPRP) in the CAT assay to better characterize TG in the presence of rivaroxaban. Results: In the presence of rivaroxaban, TG curves in agPRP showed a distinct profile with a rapidly ascending phase followed with a protracted phase. Inhibition of tissue factor pathway inhibitor amplified the first phase of the curve which was also modulated by procoagulant phospholipids. Inhibition of FXIIa-dependent FXI activation revealed that aggregated platelets influenced the first phase by a combination of extrinsic and intrinsic coagulation pathway initiations. Thrombin-dependent amplification of TG (even prior collagen activation) was responsible for the second phase of the TG curve. Conclusions: AgPRP fully includes platelet ability to support TG and reveal distinct TG phases in the presence of direct FXa inhibitors highlighting its potential use in an anticoagulated setting. Full article

Factor Xa (FXa) plays a significant role in the blood coagulation cascade and it has become a promising target for anticoagulation drugs. Three oral direct FXa inhibitors have been approved by the FDA for treating thrombotic diseases. By structure-activity relationship (SAR) analysis upon these FXa inhibitors, a series of novel anthranilamide-based FXa inhibitors were designed and synthesized. According to our study, compounds 1a, 1g and 1s displayed evident FXa inhibitory activity and excellent selectivity over thrombin in in vitro inhibition activities studies. Compounds 1g and 1s also exhibited pronounced anticoagulant activities in in vitro anticoagulant activity studies. Full article