Chronic thromboembolic pulmonary hypertension (CTEPH) and COVID-19 share molecular pathways yet remain poorly understood in their interrelation. Using RNA-seq datasets (GSE130391 and GSE169687), we identified 645, 206, and 1,543 differentially expressed genes (DEGs) for long-COVID (16 and 24 weeks post-infection) and CTEPH, respectively. Weighted Gene Co-Expression Network Analysis (WGCNA) pinpointed 234 intersecting key module genes. Three hub genes-DNAJA1, NDUFA5, and SLC2A14-were identified with robust discriminatory capabilities (AUC ≥ 0.7). Enrichment analyses revealed shared pathways linked to immune modulation, oxidative stress, and metabolic dysfunction. Immune analysis highlighted activated CD8 T cells as critical regulators. Regulatory networks implicated TFs and miRNAs, including STAT1 and hsa-mir-23a-3p. Drug prediction identified potential therapeutic compounds with strong molecular docking interactions. These findings unravel critical molecular linkages, emphasizing shared pathogeneses and guiding experimental validations for improved diagnostic and therapeutic strategies in COVID-19 and CTEPH.

Factor V Leiden (FVL) and prothrombin G20210A mutation (PGM) are the most common types of inherited thrombophilia, predisposing to increased venous thromboembolism (VTE) risk. The homozygous and compound heterozygous forms of these mutations are extremely rare. While direct oral anticoagulants (DOACs) have replaced vitamin K antagonists (VKAs) as the primary treatment for VTE, data on their use in patients with high-risk hereditary thrombophilia are limited. To compare the efficacy and safety of DOACs vs. VKA in patients with high-risk hereditary thrombophilia, including FVL and PGM. This retrospective cohort study included adults with homozygous/compound heterozygous FVL and/or PGM who experienced a thrombotic event between 2000 and 2022. The primary outcome was the incidence of recurrent thrombosis in patients with high-risk inherited thrombophilia treated with DOACs versus VKAs. The secondary outcome included a comparison of rates of bleeding complications between these groups. The types of bleeding were defined according to the ISTH criteria. Of 56 patients included 28 received DOACs and 28 received VKAs. There was no significant difference in recurrent VTE rates (1/28, 3.6% DOAC group vs. 0/28, 0% VKA group) or major bleeding (1/28, 3.6% DOAC group vs. 1/28, 3.6% VKA group). This is the largest cohort of patients with high-risk hereditary thrombophilia, providing valuable insights into DOAC use in this group. The findings suggest that DOACs may represent an effective and safe alternative to VKAs. Further research is warranted to confirm these results and optimize anticoagulant management in this challenging patient group.

Drugs targeting factor XI may offer an alternative to heparin for preventing blood clotting in extracorporeal circulation. We investigated the effects of abelacimab, a novel monoclonal antibody targeting factor XI. We collected whole blood samples into two bags (each 240 ml, control group: enoxaparin 1.2 mg, treatment group: enoxaparin 1.2 mg plus abelacimab 5 mg) and circulated in a hemodialysis device for up to 3 h. We performed whole blood aggregation and thromboelastometry at several time points. Time to filter clotting was the primary endpoint. We included 10 volunteers. Each volunteer's blood was split into two bags (containing enoxaparin +/- abelacimab) and used simultaneously on two hemodialysis devices. The treatment group's time to filter clotting was significantly prolonged (treatment: 180 min, IQR 180-180 vs. control: 120 min, IQR 97-147, p < 0.001), and the transmembrane pressure was significantly lower at the end of the circuit flow (treatment: 13 mmHg vs. control: 65 mmHg, p = 0.001). Fibrinogen levels and median platelet counts were preserved. Platelet aggregation was better preserved in the treatment group for ristocetin (p = 0.015), thrombin receptor activating peptide (p = 0.015), and arachidonic acid (p = 0.001). Thromboelastometry showed prolonged clotting times in the treatment group at the end of the experiment (INTEM, p < 0.001; HEPTEM, p = 0.001). Abelacimab prolonged the time to filter clotting in this ex vivo model of hemodialysis. This is an aggressive model due to the frequent re-circulation of blood and a lack of endothelial cells. These data provide support for testing abelacimab in patients on hemodialysis.

Growing evidence suggests inflammatory bowel disease (IBD) is linked to ischemic stroke (IS); however, the results are inconclusive. Therefore, it remains uncertain whether the association between IBD and IS is causal. Herein, we performed a bidirectional Mendelian randomization (MR) study to examine the causal association of IBD with IS. We obtained summary-level data for IBD and IS from several publicly released genome-wide association studies to conduct a two-sample bidirectional Mendelian randomization (MR) analysis. Herein, the inverse-variance weighted method was utilized as the primary approach. Then, we applied the weighted median and MR-Egger estimators for the follow-up sensitivity analyses. In addition, the MR-Egger intercept test was performed to detect the potential directional pleiotropy. Genetically predicted IBD was not causally associated with IS and IS subtypes (IS: OR = 0.99, 95% CI 0.98-1.01, p = 0.49; large artery atherosclerosis stroke: OR = 1.00, 95% CI: 0.96-1.05, p = 0.88; cardioembolic stroke: OR = 0.99, 95% CI 0.96-1.03, p = 0.75; small-vessel occlusion stroke: OR = 1.02, 95% CI 0.99-1.05, p = 0.16). Moreover, we did not find a significant causal effect of UC or CD on IS and IS subtypes. Furthermore, there was no significant association observed between IS and IBD in the reverse MR analysis. The estimates were consistent across sensitivity analyses. Our MR analysis does not support a bidirectional causal association between IBD and IS, despite observational studies reporting an association of IBD with IS.

Thrombin generation (TG) is reduced after cardiac surgery using cardiopulmonary bypass (CPB), contributing to coagulopathy and bleeding. Plasma transfusion or four-factor prothrombin complex concentrate (PCC) are commonly used to treat coagulopathic bleeding after CPB without knowledge of how each may restore TG. To determine the effect of PCC infusion on restoration of thrombin generation compared with plasma transfusion, we performed a laboratory-based secondary analysis of a randomized, controlled trial of adult patients undergoing cardiac surgery to assess efficacy and safety of 4 F-PCC versus plasma for treatment of perioperative coagulopathic bleeding after CPB. Participants were randomized to receive either PCC (15 IU/kg) or plasma (10-15 ml/kg) after separation from CPB. Participant blood samples were obtained at pre-specified serial timepoints, with laboratory assays for TG and factor levels subsequently performed. The primary outcome was change in thrombin generation (TG) parameters after each randomized treatment through postoperative day 5. Secondary outcomes included serially derived clotting factor levels. Of 100 randomized participants, 99 were included in this laboratory analysis (PCC group, N = 51; plasma group, N = 48). After treatment, participants in the PCC group compared with those in the plasma group showed higher endogenous thrombin potential (ETP, Median, Interquartile range, IQR: 688 [371-1069] vs. 1088 [550-1691] nM minutes, P = 0.01), a greater increase din ETP (P = 0.002) and peak TG (P = 0.01) in the timepoints between heparin reversal and after treatment administration. Both groups demonstrated similar values in all TG assays by postoperative day 1 (P > 0.05). The PCC group also demonstrated higher levels of proteins C, S, and Factors II, VII, IX and X, early after treatment (P < 0.001 for all comparisons). Antithrombin levels were initially higher in the plasma group after treatment (Median, IQR: 66% [61-71%] vs. 56% [51-65%], P = 0.002) but differences did not persist beyond postoperative day 3. In this laboratory analysis from a recent randomized trial in adult cardiac surgery, PCC administration restored thrombin generation more rapidly than plasma in the early postoperative period without laboratory evidence of hypercoagulability. ClinicalTrials.gov identifier: NCT02557672 [1].

The use of weight-based unfractionated heparin (UFH) infusions is the standard of care in hospital management of venous thromboembolism (VTE). Initial dosing strategies for UFH in older adults and higher body weight patients remain uncertain given differences in pharmacokinetics and concerns for over-anticoagulation. Methods: This was a single-center, retrospective, pre-post study involving older adults aged ≥ 65 years and patients weighing ≥ 100 kg with suspected or confirmed VTE to determine if the use of adjusted body weight (AdjBW)-based UFH regimens improves time to therapeutic anti-Xa levels compared to total body weight (TBW)-based regimens Patients received weight-based UFH infusions, dosed according to either TBW or AdjBW, to target a therapeutic anti-Xa level. Each cohort consisted of 40 patients, stratified by whether they met age or weight criteria to ensure equal representation of elderly and higher body weight patients between cohorts. The median time to therapeutic anti-Xa levels was shorter in the AdjBW group compared to the TBW group (13.6 h versus 20.9 h; point estimate 5.3 h (95% CI 0.2 to 9.9)). This finding was driven by those aged ≥ 65 years and those who received a bolus dose at the start of the infusion. Among older adults and higher weight adults with suspected or confirmed VTE, the use of AdjBW to guide heparin infusion initiation was associated with shorter time to therapeutic anti-Xa levels. This finding driven by the older adult sample and the subgroup analyses did not find a statistically significant difference in time to therapeutic anti-Xa levels in higher body weight patients aged less than 65 years.

Animal models of thrombosis play a critical role in research, helping us understand the mechanisms of hemostasis and thrombus formation, as well as in the screening of anti-thrombotic drugs. This study aimed to evaluate the safety profile of two anticoagulants in murine research and to assess coagulation parameters, including prothrombin time (PT) and activated partial thromboplastin time (aPTT), using the VETSCAN VSpro coagulation analyzer in wild-type (C57BL/6) mice following administration of anticoagulants. Two experiments were conducted involving a total of sixty wild-type mice that received two common anticoagulants. Warfarin was administered in the drinking water at varying dosages, while dabigatran was incorporated into a custom-chow diet at two dosages (10 mg/g and 15 mg/g chow). The VSpro was used to establish a reference range for PT and aPTT values in untreated wild-type mice and to monitor coagulation changes in mice undergoing anticoagulant therapy. Dabigatran was well tolerated at both concentrations (10 mg/g and 15 mg/g chow), while warfarin was safe at a concentration of 2.5 mg/L, resulting in a doubling of PT and aPTT compared to baseline levels. Although the VSpro effectively detected coagulation abnormalities in murine models, certain limitations were observed, including out-of-range measurements in cases of coagulopathy. This study provides insights into safe anticoagulant dosages for murine models, supporting the use of dabigatran at 10 mg/g and 15 mg/g chow and warfarin at 2.5 mg/L. The VSpro analyzer was able to monitor coagulation parameters under these conditions, making it a feasible tool for murine research.

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 IC 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.

While the association between coronavirus disease-19 (COVID-19) and neutrophils extracellular traps (NETs) is recognized, uncertainties remain regarding its precise onset, timing of resolution and target therapy. To assess changes in inflammatory and NET markers during the first week of COVID-19 hospitalization, and the association with disease severity. "In vitro" experiments investigated the effect of antiplatelets, anticoagulants, and cyclic nucleotide stimulators on NETs release. Prospective cohort study, changes in interleukin (IL)-6, IL-8, IL-17, TNF-α, RANTES, PF4, and citrullinated-H3 (citH3) levels within each outcome group was evaluated using ANOVA. Differences between moderately ill, critically ill, and non-survivors were determined using Kruskal-Wallis and logistic regression. Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. The proportion of NETosis was assessed using IncuCyte Cell Imager. Of the 125 patients, 40.8% had moderate COVID-19, 40.8% had critical COVID-19 but recovered, and 18.4% died. From admission to hospitalization day 8, IL-6 levels decreased in moderately and critically ill, but not in non-survivors, while citH3 levels increased in critically ill and non-survivors. IL-6, IL-8, and TNF-α levels were associated with critical and fatal COVID-19. The release of NETs by neutrophils stimulated with PMA or COVID-19 sera was decreased in the presence of ASA, UFH, LMWH and cyclic nucleotide stimulators in a dose-dependent manner. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis.

Real-world data on venous thromboembolism (VTE) in Japanese patients with gynecological cancer are lacking. The GOTIC-VTE trial aimed to evaluate the frequency of VTE-associated events and risk factors at the time of cancer diagnosis and during 1-year follow-up. From July 2017 to February 2019, patients with endometrial, cervical, ovarian, tubal, or peritoneal cancer who underwent VTE screening within 2 months before registration, were enrolled. Of the 1008 patients enrolled, 881 were included in the analysis set, 51 (5.8%) had VTE at the time of cancer diagnosis (baseline), 7 (0.8%) had symptomatic VTE, and the majority had asymptomatic VTE (n = 44; 5.0%). Patients with ovarian, tubal, or peritoneal cancer had a higher incidence of VTE (13.7%) than those with other cancer types. During the 1-year follow-up, 0.9% (n = 8) of the patients had symptomatic VTE, 3.5% (n = 31) had composite VTE (symptomatic VTE and incidental VTE requiring treatment), 0.2% (n = 2) had bleeding events, and 4.3% (n = 38) had all-cause death, all of which were significantly higher in the VTE group at baseline. In the multivariate analysis, chemotherapy was an independent risk factor for composite VTE during the 1-year follow-up (hazard ratio 3.85, 95% confidence interval 1.39-13.63, p = 0.018). Among gynecological cancers, VTE incidence is particularly high in ovarian, tubal, or peritoneal cancer, and patients undergoing chemotherapy should be cautioned against VTE occurrence during treatment.The GOTIC-VTE trial Unique identifier, jRCTs031180124; Registration date, April 06, 2017.

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) pose a substantial risk of thrombosis, leading to significant morbidity and mortality. Anticoagulant therapy, historically based on vitamin K antagonists (VKAs), has limitations in preventing recurrent thrombotic events and managing bleeding complications. Direct oral anticoagulants (DOACs) offer a potential alternative with improved pharmacokinetics and compliance. However, evidence on DOAC efficacy and safety in MPNs remains limited, necessitating further investigation. In this multicenter retrospective study in Türkiye, we assessed real-world usage patterns and outcomes of DOACs in MPN patients. Data from 220 patients with PV, ET, or PMF receiving DOACs or VKAs for thrombosis or nonvalvular atrial fibrillation (NVAF) were collected from medical records. Thrombotic events and bleeding episodes were documented based on ISTH criteria. DOACs were used in 126 patients as first-line anticoagulant therapy or following VKAs. Ninety-four patients were on VKAs, of which 83 as a first-line treatment. There were eight thromboses (6.3%) seen in 126 DOAC patients, and similarly, seven episodes (9.4%) of thrombosis were observed in 94 patients using VKA. Major bleeding occurred in seven patients (5.6%) on DOAC and 3 (3.2%) in VKA. Thrombotic and bleeding risks were comparable between DOACs and VKAs (p = 0.708 and p = 0.158, respectively). The incidence rate of thrombosis in the VKA group is 1.1% and in the DOAC group is 1.9%. The incidence of major bleeding in the VKA group is 0.6% and 1.6% in the DOAC group. To the best of our knowledge, our study included the largest number of MPN patients to date, comparing DOACs with VKA in terms of both efficacy and safety, which suggests DOACs as promising alternatives to VKAs for managing thrombotic risk in MPNs with manageable toxicity. Despite the limitations of retrospective studies, DOACs' benefits in terms of efficacy and compliance warrant further investigation through prospective trials. Individualized treatment decisions should consider patient-specific factors, emphasizing collaborative efforts between specialists to optimize DOAC therapy in patients with MPNs. Comparable efficacy and safety between DOACs and VKAs were observed in MPN patients.

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.

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 72 h) 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 72 h. A multivariate logistic regression identified five predictive variables for the final PEP score: use of > 4 L/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) < 13 mm, 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 72 h, potentially aiding in timely clinical decision-making and improving patient outcomes.

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 35 IU of Factor VII (per 100 IU 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.