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Discovery of a new lead molecule to develop a novel class of human factor XIIa inhibitors.

Factor XIIa (FXIIa) is a plasma serine protease within the contact activation pathway. Inhibiting FXIIa could offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks that accompany the use of existing anticoagulants. Therefore, we investigated the anticoagulant properties of an amidine-containing molecule (inhibitor 1) to identify a potential lead molecule for subsequent development of FXIIa inhibitors. Results indicated that inhibitor 1 primarily inhibits human FXIIa with an IC50 value of ~30 µM. The inhibitor demonstrated variable selectivity against thrombin, factor IXa, factor Xa, factor XIa, and activated protein C. Michaelis-Menten kinetics indicated that the molecule is an active site inhibitor of FXIIa. Molecular modeling studies revealed that the molecule recognizes residues His57, Asp189, and Ala190 in FXIIa's active site. The inhibitor selectively and concentration-dependently prolonged the clotting time of human plasma under activated partial thromboplastin time assay conditions. The inhibitor did not exhibit significant cytotoxicity in human HEK293 cells and the in silico pharmacokinetics and toxicology data were comparable to known anticoagulants. This study introduces inhibitor 1 as a lead platform for further development as an anticoagulant to provide a more effective and safer approach to preventing and treating thromboembolic diseases.

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3-Factor prothrombin complex concentrate versus 4-factor prothrombin complex concentrate for the reversal of oral factor Xa inhibitors.

Multiple agents exist for the reversal of oral Factor Xa inhibitor (FXa) associated bleeding, including Coagulation FXa Recombinant, Inactivated zhzo (andexanet alfa) and 4-factor prothrombin complex concentrate (4F-PCC). While classified as a 3F-PCC product, Profilnine contains up to 35IU of Factor VII (per 100IU of Factor IX) in addition to therapeutic levels of Factors II, IX, and X, and has demonstrated a similar impact on prothrombin time and blood product usage in non-warfarin related bleeding. This was a retrospective, multicenter study at four medical centers of adult patients who presented with major bleeding associated with oral FXa inhibitors and received either 4F-PCC (n = 64) or 3F-PCC (n = 61). The primary outcome was hemostatic effectiveness. Secondary outcomes included the incidence of thromboembolism, in-hospital mortality, and length of stay. The most common indication for reversal was intracranial bleeding. For the primary outcome, 84% of all patients were rated as effective with no difference noted between the groups (p = 0.81). No significant difference between groups was found in the multivariable analysis adjusting for baseline differences between groups including race, total body weight, type of bleeding, and the use of antiplatelet therapy. There was no difference in the length of stay, in-hospital mortality, or the incidence of thromboembolism between the groups. Overall, no significant differences were found in the effectiveness or safety of 4F-PCC and 3F-PCC use in the management of oral FXa inhibitor-associated bleeding. Further investigations are warranted to explore the use of 3F-PCC for this indication and its safety and effectiveness.

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Development of the Pulmonary Embolism Progression (PEP) score for predicting short-term clinical deterioration in intermediate-risk pulmonary embolism: a single-center retrospective study.

Accurate risk stratification in acute intermediate-risk pulmonary embolism (PE) is essential. Current prediction scores lack the ability to forecast impending clinical decline. The Pulmonary Embolism Progression (PEP) score aims to predict short-term clinical deterioration (respiratory failure or hemodynamic instability within 72h) in patients with intermediate-risk PE. This single-center retrospective cohort study analyzed patients with intermediate PE. The outcome of interest was respiratory failure or hemodynamic instability within 72h. A multivariate logistic regression identified five predictive variables for the final PEP score: use of > 4L/min of supplemental oxygen above baseline, lactate > 2.0 mmol/L, high-sensitivity cardiac troponin T (hs-cTnT) > 40 ng/L, tricuspid annular plane systolic excursion (TAPSE) < 13mm, and the combination of central and subsegmental clot. The derivation cohort included 117 patients, and the validation cohort included 70 patients. The area under the receiver operating characteristic (AUROC) curve for the derivation cohort was 0.8671 (95% CI: 0.7946, 0.9292), and for the validation cohort, it was 0.9264 (95% CI: 0.8680, 0.9847). A PEP score of 4 points yielded the highest combination of sensitivity (93%) and specificity (65%). Each incremental point increase in the PEP score raised the probability of clinical deterioration by a factor of 1.933. The PEP score is a reliable tool for predicting the likelihood of clinical deterioration in intermediate-risk PE patients within 72h, potentially aiding in timely clinical decision-making and improving patient outcomes.

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The protective effects of annexin A1 against oxidized-LDL-induced monocytes adhesion to endothelial cells: implication in atherosclerosis.

Oxidized low-density lipoprotein (ox-LDL)-associated endothelial dysfunction is a critical factor in the initiation and progression of Atherosclerosis (AS). Annexin A1 is an important member of the annexin family. Despite its wide range of biological functions across various tissues and cells, the role of Annexin A1 in AS remains largely unexplored. In this study, we demonstrate that Annexin A1 treatment effectively reduced the expression of LOX-1 at both the mRNA and protein levels in HUVECs exposed to ox-LDL. Annexin A1 also ameliorated oxidative stress (OS) by decreasing mitochondrial ROS levels and restoring reduced GSH levels. Moreover, Annexin A1 decreased the expression of pro-inflammatory cytokines, including IL-6 and MCP-1. Importantly, Annexin A1 inhibited ox-LDL-induced expressions of the endothelial adhesion molecules, such as E-selectin and VCAM-1 in HUVECs, which leads to reduced attachment of THP-1 monocytes to HUVECs. Mechanically, we found that Annexin A1 reversed the expression of KLF2 against ox-LDL mediated by the PI3K/Akt axis. Notably, the silencing of KLF2 abrogated the protective effects of Annexin A1 on E-selectin and VCAM-1 expression and the attachment of THP-1 monocytes to HUVECs. Our findings suggest that Annexin A1 is a potential therapeutic agent for atherosclerosis, offering a novel approach to mitigate endothelial dysfunction and inflammation.

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ASTRAL scale for predicting prognosis following intravenous thrombolysis with anterior versus posterior circulation acute ischemic stroke.

In this study, we compared whether there was any difference between the ASTRAL(Acute Stroke Registry and Analysis of Lausanne, ASTRAL) scale in predicting prognosis after IVT(Intravenous Thrombolysis, IVT) in patients with AIS(Acute Ischemic Stroke, AIS) in the ACI(Anterior Circulation Infarction, ACI) and PCI(Posterior Circulation Infarction, PCI), with the aim of providing more guiding information. Statistical analysis was performed using SPSS 25.0. When comparing the baseline characteristics, the normal distribution test was carried out first, which did not conform to the normal distribution. The continuous variables were expressed in the median and interquartile, and the nonparametric double-independent sample test was carried out. MedCalc software was used to plot ROC(Receiver Operating Characteristic, ROC) curves, calculate AUC(Area Under the Receiver Operating Characteristic Curve, AUC), and compare the prediction performance of the ASTRAL score by Delong text, and the difference of P < 0.05 was statistically significant. The AUCs of ASTRAL in predicting poor prognosis of ACI and PCI patients after IVT were 0.768 and 0.773, respectively. There was no difference in the AUC of ASTRAL score between ACI and PCI(P > 0.05). The ASTRAL scale has consistent prognostic predictive value for AIS in the anterior and posterior circulatory systems and is a reliable tool for predicting poor prognosis of patients with ACI and PCI after IVT.

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Risk of venous thromboembolism after discontinuing prophylactic or therapeutic anticoagulation in patients with haematologic malignancies because of thrombocytopenia.

Although the rates of thrombocytopenia in patients with hematologic malignancies are well known, clinical reports of patients with haematological malignancies presenting with thrombocytopenia who developed venous thromboembolism (VTE) are rare. Defining the risk of VTE in patients with hematologic malignancies in whom anticoagulation is discontinued could help to individualize concepts of anticoagulation. We performed a retrospective analysis of medical records of patients with hematologic malignancies and thrombocytopenia grade 3 (25 × 109/L to < 50 × 109/L) or more severe in 2019-2022 in the Department of Haemato-Oncology at HELIOS Klinikum Krefeld. Data from 67 patients (34 (51%) males, 33 (49%) females) aged between 22 and 82years (38 leukaemia, 23 lymphoma, 6 other) were included. Prophylactic anticoagulation was performed in 59 (88%) patients and therapeutic due to atrial fibrillation in 8 (12%). Anticoagulation was discontinued in 37 (55%) patients due to thrombocytopenia. Thrombotic events occurred in eight (12%) and minor bleeding in two (3%) patients. Seven patients developed a deep vein thrombosis (DVT) or superficial vein thrombosis (SVT) of the upper limbs, only one patient had a thrombosis of the femoral veins. Thrombotic event were much more frequent in patients suffering from leukaemia compared to lymphoma. Two thrombotic events occurred despite continued prophylaxis (2 of 30, 6.6%), the other six after discontinuing of anticoagulation (6 of 37, 16.2%). Both bleedings occurred in the group with continued anticoagulation. Five of the six patients with a thrombotic event, but without anticoagulation, received anticoagulation again despite a low platelet count and no bleeding was observed. Only one patient with jugular vein thrombosis and a platelet count around 4 × 109/L remained without anticoagulation and no thrombus formation was observed. Risk of VTE in our patients with haematologic malignancies in whom anticoagulation is discontinued due to thrombocytopenia grade 3 is about 2.5 times higher than in patients in whom anticoagulation is continued and predominantly affects patients with leukaemia and upper extremity.

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Bleeding outcomes in critically ill patients on heparin with discordant aPTT and anti-Xa activity.

Activated partial thromboplastin time (aPTT) and unfractionated heparin (UFH) level via the anti-factor Xa activity assay (anti-Xa) are commonly used assays for UFH monitoring. While discordance between the two assays is common, its impact on critically ill patient outcomes is unclear. This study aimed to compare the incidence of major bleeding events among critically ill patients with discordant aPTT and anti-Xa activity while on UFH, to patients with no discordance. This was a single-center, retrospective cohort study of critically ill adult patients who had simultaneous anti-Xa and aPTT levels while receiving continuous UFH infusion. The primary outcome was the incidence of a major bleeding event up to 24h after UFH discontinuation. Secondary outcomes included incidence of 30-day thrombosis and hospital length of stay (LOS). Among 264 included patients, 156 patients (59%) had at least one discordant paired level. Patients with discordance had an increased risk of major bleeding events (14% versus 5%; unadjusted risk ratio, 3.0; 95% CI 1.2-7.8; p = 0.01), and increased risk of thrombotic events (4% versus 0%; p = 0.04). Hospital LOS was similar between the two groups (13.8 days versus 11.4 days; p = 0.08). In this cohort of critically ill patients receiving continuous UFH, discordance in aPTT and anti-Xa activity was frequently observed and was associated with an increased risk of major bleeding events. While both assays remain viable monitoring options, evaluating simultaneous levels may aid in the management of critically ill patients. In patients with discordance, an individualized approach balancing bleeding and thrombotic risks should be considered.

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Construction and validation of a nomogram prediction model for the catheter-related thrombosis risk of central venous access devices in patients with cancer: a prospective machine learning study.

Central venous access devices (CVADs) are integral to cancer treatment. However, catheter-related thrombosis (CRT) poses a considerable risk to patient safety. It interrupts treatment; delays therapy; prolongs hospitalisation; and increases the physical, psychological and financial burden of patients. Our study aims to construct and validate a predictive model for CRT risk in patients with cancer. It offers the possibility to identify independent risk factors for CRT and prevent CRT in patients with cancer. We prospectively followed patients with cancer and CVAD at Xiangya Hospital of Central South University from January 2021 to December 2022 until catheter removal. Patients with CRT who met the criteria were taken as the case group. Two patients with cancer but without CRT diagnosed in the same month that a patient with cancer and CRT was diagnosed were selected by using a random number table to form a control group. Data from patients with CVAD placement in Qinghai University Affiliated Hospital and Hainan Provincial People's Hospital (January 2023 to June 2023) were used for the external validation of the optimal model. The incidence rate of CRT in patients with cancer was 5.02% (539/10 736). Amongst different malignant tumour types, head and neck (9.66%), haematological (6.97%) and respiratory (6.58%) tumours had the highest risks. Amongst catheter types, haemodialysis (13.91%), central venous (8.39%) and peripherally inserted central (4.68%) catheters were associated with the highest risks. A total of 500 patients with CRT and 1000 without CRT participated in model construction and were randomly assigned to the training (n = 1050) or testing (n = 450) groups. We identified 11 independent risk factors, including age, catheterisation method, catheter valve, catheter material, infection, insertion history, D-dimer concentration, operation history, anaemia, diabetes and targeted drugs. The logistic regression model had the best discriminative ability amongst the three models. It had an area under the curve (AUC) of 0.868 (0.846-0.890) for the training group. The external validation AUC was 0.708 (0.618-0.797). The calibration curve of the nomogram model was consistent with the ideal curve. Moreover, the Hosmer-Lemeshow test showed a good fit (P > 0.05) and high net benefit value for the clinical decision curve. The nomogram model constructed in this study can predict the risk of CRT in patients with cancer. It can help in the early identification and screening of patients at high risk of cancer CRT.

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