Tailoring oral anticoagulant treatment in the era of multi-drug therapies for PAH and CTEPH.

The use of oral anticoagulants in the management of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) presents distinct therapeutic challenges and benefits. In PAH, the benefits of oral anticoagulation are uncertain, with studies yielding mixed results on their efficacy and safety. Conversely, oral anticoagulants are a cornerstone in the treatment of CTEPH, where their use is consistently recommended to prevent recurrent thromboembolic events. The choice between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) remains a significant clinical question, as each type presents advantages and potential drawbacks. Furthermore, drug-drug interactions (DDIs) with concomitant PAH and CTEPH treatments complicate anticoagulant management, necessitating careful consideration of individual patient regimens. This review examines the current evidence on oral anticoagulant use in PAH and CTEPH and discusses the implications of DDIs within a context of multi-drug treatments, including targeted drugs in PAH.

Latest advances in the reversal strategies for direct oral anticoagulants.

BACKGROUND: Since the late 2000s, Europe has granted approval for various thrombotic risk-related uses of direct oral anticoagulants (DOACs). Unlike traditional anticoagulants, DOACs do not necessitate routine coagulation monitoring. Nevertheless, clinical practice often encounters bleeding events associated with these medications, making the need for effective reversal strategies evident. OBJECTIVES: The study aims to take stock of current reversal strategies for DOACs, with a particular emphasis on the latest compounds that have been developed or are currently under development. METHODS: For obtaining information regarding the ongoing reversal strategies and the compounds under development, we referred to ClinicalTrials website, PubMed, and Google Scholar. RESULTS: In 2024, two specific antidotes to DOACs have already received approval when reversal of anticoagulation is needed owing to life-threatening or uncontrolled bleeding: idarucizumab that reverses the effects of dabigatran, and andexanet alfa, designed to counteract activated factor X inhibitors such as apixaban and rivaroxaban. Furthermore, ciraparantag, a potential universal reversal agent, is currently in advanced stages of clinical development. Concerns remain regarding the safety of specific reversal agents, especially concerning the risk of thrombosis. Additionally, the cost of these antidotes remains high. Consequently, nonspecific strategies to counteract anticoagulant medications, including activated charcoal, hemodialysis, and concentrates of coagulation factors, still have utility. CONCLUSION: With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice.

Proteomics analyses of human plasma reveal triosephosphate isomerase as a potential blood marker of methotrexate resistance in rheumatoid arthritis.

OBJECTIVES: To assess differentially expressed blood proteins between patients with active rheumatoid arthritis (RA) and patients in remission after methotrexate (MTX) treatment, with the aim of identifying a biomarker of methotrexate resistance (MTXR). METHODS: Two populations of RA patients treated with a stable dose of subcutaneous MTX for at least 3 months were constituted according to the DAS28: remission (DAS28 < 2.6; n = 24) and active disease (DAS28 > 3.2; n = 32). The two groups of RA patients were homogeneous regarding their epidemiological characteristics, except for the duration of treatment which was longer in the remission group. After collection of a blood sample, plasma protein digestion was performed, followed by untargeted proteomics analysis. Then, a targeted analysis was performed to confirm the results of the untargeted approach. RESULTS: Untargeted proteomics analysis revealed 8 plasma proteins differentially expressed between the two groups of patients. Among them, triosephosphate isomerase (TPI-1) and glucose-6-phosphate isomerase (GPI), which are main actors of glycolysis, were found down-regulated in the active group. This result was confirmed for TPI-1 in the targeted proteomics analysis. CONCLUSIONS: A first step was achieved in the search for biomarker of MTXR with identification of two actors of glycolysis (TPI-1 and GPI). The next step will be to confirm these results in a larger cohort, including samples from treatment-naive patients, to assess the predictive potential of these protein markers.

Comparative diagnosis interest of NfL and pNfH in CSF and plasma in a context of FTD-ALS spectrum.

OBJECTIVE: The 'Frontotemporal dementia-Amyotrophic lateral sclerosis Spectrum' (FAS) encompasses different phenotypes, including cognitive disorders (frontotemporal dementia, FTD) and/or motor impairments (amyotrophic lateral sclerosis, ALS). The aim of this study was to apprehend the specific uses of neurofilaments light chain (NfL) and phosphorylated neurofilaments heavy chain (pNfH) in a context of FAS. METHODS: First, NfL and pNfH were measured in 39 paired cerebrospinal fluid (CSF) and plasma samples of FAS and primary psychiatric disorders (PPD) patients, considered as controls. Secondly, additional plasma samples were included to examine a larger cohort of 81 samples composed of symptomatic FAS and PPD patients, presymptomatic and non-carrier relatives individuals. The measures were performed using Simoa technology. RESULTS: There was a positive correlation between CSF and plasma values for NfL (p < 0.0001) and for pNfH (p = 0.0036). NfL values were higher for all phenotypes of symptomatic FAS patients compared to PPD patients (p = 0.0016 in CSF; p = 0.0003 in plasma). On the contrary, pNfH values were solely increased in FAS patients exhibiting motor impairment. Unlike symptomatic FAS patients, presymptomatic cases had comparable concentrations with non-carrier individuals. CONCLUSION: NfL, but not pNfH, appeared to be useful in a context of differential diagnosis between FTD and psychiatric patients. Nevertheless, pNfH seem more specific for the diagnosis and follow-up of motor impairments. In each specific indication, measures in CSF and plasma will provide identical interpretations.

Development of an automated capillary nano-immunoassay-Simple Western assay-to quantify total TDP43 protein in human platelet samples.

Frontotemporal lobar degeneration syndrome is the second cause of young-onset dementia. Unfortunately, reliable biomarkers are currently lacking for the diagnosis of this disease. As TDP43 protein is one of the proteins pathologically involved in frontotemporal lobar degeneration, many studies have been performed to assess TDP43 protein diagnostic performances. Mixed results were obtained using cerebrospinal fluid and plasma samples so far. The aim of the study was to develop an automated capillary nano-immunoassay-Simple Western assay-to detect and quantify TDP43 protein simultaneously in human blood-based samples. Simple Western assay was developed with two different cell lysates used as positive controls and was compared to Western blot. TDP43 protein profiles in plasma samples were disappointing, as they were discordant to our positive controls. On the contrary, similar TDP43 patterns were obtained between platelet samples and cell lysates using both assays. Simple Western assay provided good quantitative performances in platelet samples: a linearity of signals could be observed (r2 = 0.994), associated to a within-run variability at 5.7%. Preliminary results based on a cohort of patients suffering from frontotemporal lobar degeneration showed large inter-individual variations superior to Simple Western's analytical variability. Simple Western assay seems to be suitable for detecting and quantifying TDP43 protein in platelet samples, providing a potential candidate biomarker in this disease. Further confirmation studies should now be performed on larger cohorts of patients to assess diagnostic performances of TDP43 protein in platelet samples.

Effect of Activated Charcoal on Rivaroxaban Complex Absorption.

OBJECTIVE: To quantify the impact of activated charcoal (AC) on rivaroxaban exposure in healthy volunteers. METHODS: This was an open-label study with an incomplete cross-over design of single-dose rivaroxaban (40 mg) administered alone or with AC in 12 healthy volunteers. The study comprised three treatment periods in randomised sequence, one with rivaroxaban administered alone and two with AC given at 2, 5 or 8 h post-dose. Rivaroxaban plasma concentration was measured in blood samples drawn at 16 time points. The pharmacokinetic model of rivaroxaban alone or with AC administration was built using a non-linear mixed-effect modelling approach. RESULTS: The pharmacokinetic model was based on a one-compartment model with an absorption rate described by the sum of three inverse Gaussian densities to reproduce multiphasic and prolonged absorption. The inclusion in the model of each AC administration schedule significantly improved objective function value. AC reduced the area under the rivaroxaban concentration-time curve by 43% when administered 2 h post-dose, by 31% when administered 5 h post-dose and by 29% when administered 8 h post-dose. Based on the estimated pharmacokinetic model, simulations suggested that AC might have an impact even after 8 h post-dose. CONCLUSION: AC administration significantly reduces exposure to rivaroxaban even if AC is administered 8 h after rivaroxaban. These results suggest that AC could be used in rivaroxaban overdose and accidental ingestion to antagonise absorption. CLINICALTRIAL. GOV REGISTRATION NO: NCT02657512.