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The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. HIGHLIGHTS: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities. PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations.

Epidural hematoma typically manifests following craniocerebral trauma, stemming from injury to the meningeal artery or venous system, predominantly on one side. Instances of spontaneous epidural hematoma are uncommon, with occurrences of spontaneous bilateral epidural hematoma being exceedingly rare. Sickle cell disease, adjacent paranasal sinusitis, and tumor metastases are the most prevalent causes of spontaneous epidural hematoma. This case study presents an individual with abdominal liposarcoma exhibiting reduced coagulation factor XII activity, who experienced sudden unconsciousness due to spontaneous acute bilateral epidural hematoma, and subsequently achieved a favorable outcome following surgical intervention. [ABSTRACT FROM AUTHOR]

Coagulation Factor XI (FXI) and Factor XII (FXII) deficiencies are rare. FXI deficiency is associated with a bleeding disorder, while FXII deficiency is not, but both can cause chronic prolongation of activated partial thromboplastin time and impair thrombus formation, posing great challenges for hemodialysis anticoagulation. Traditionally, heparin or low‐molecular‐weight heparins (LMWHs) are not considered a safe anticoagulation option for patients with increased bleeding risk. In this context, FXI and FXII have received substantial attention as targets for new anticoagulants. We present the case of a 68‐year‐old woman with combined FXI and FXII deficiencies who successfully underwent hemodialysis with anticoagulation using a low dose of LMWHs. This case highlights that FXI and FXII deficiencies are associated with anticoagulant effects, which can reduce the dosage of anticoagulant during hemodialysis. With careful monitoring, an appropriate dosage of LMWHs is still an acceptable option for patients with a bleeding risk. [ABSTRACT FROM AUTHOR]

It has been recognized that shortened activated partial thromboplastin time (aPTT) may be caused by various preanalytical conditions. As coagulation Factor VIII is included in the in vitro intrinsic coagulation cascade measured by aPTT, we hypothesized that the shortened aPTT could be a result of elevated FVIII activity. We aimed to inspect the connection of elevated FVIII with shortened aPTT, and the possible effect inflammation has on routine laboratory parameters. 40 patients from various hospital departments with aPTT measurement below the lower limit of the reference interval (<23.0 s) were included in the study. To compare the obtained results with aPTT measurements in the non-inflammatory state, samples from 25 volunteers (laboratory personnel) were collected. White blood cell count, C-reactive protein, aPTT, and FVIII values were measured in the control group. Only two samples among 40 patients with shortened aPTT (5 %) were clotted. Out of the remaining 38, 26 had FVIII activity above 150 % (upper limit of a reference interval), median value of 194 % (IQR: 143–243 %). Seven samples in the control group had shortened aPTT results (36 %). However, all coagulation samples were clot and hemolysis-free. Multiple regression identified only FVIII activity as an independent variable in predicting aPTT values (p=0.001). Our results support the thesis that shortened aPTT is rarely a consequence of preanalytical problems. Elevated FVIII activity causes shortened aPTT, not only in the inflammatory state but also in individuals with concentration of inflammatory markers within reference intervals. [ABSTRACT FROM AUTHOR]

Anticoagulation treatment for patients with high bleeding risk during hemodialysis is challenging. Contact between the dialysis membrane and the blood leads to protein adsorption and activation of the coagulation cascade reaction. Activated coagulation Factor X (FXa) plays a central role in thrombogenesis, but anticoagulant modification of the dialysis membrane is rarely targeted at FXa. In this study, we constructed an anticoagulant membrane using the polydopamine coating method to graft FXa inhibitors (apixaban and rivaroxaban) on the membrane surface. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM) were used to characterize the membranes. The apixaban- and rivaroxaban-modified membranes showed lower water contact angles, decreased albumin protein adsorption, and suppressed platelet adhesion and activation compared to the unmodified PES membranes. Moreover, the modified membranes prolonged the blood clotting times in both the intrinsic and extrinsic coagulation pathways and inhibited FXa generation and complement activation, which suggested that the modified membrane enhanced biocompatibility and antithrombotic properties through the inhibition of FXa. Targeting FXa to design antithrombotic HD membranes or other blood contact materials might have great application potential. [ABSTRACT FROM AUTHOR]

Background: Huashi Baidu Formula (HBF) is a clinical formula known for its efficacy against coronavirus disease 2019 (COVID-19). HBF may reduce the number of patients with abnormal serum creatinine while improving respiratory symptoms, suggesting that this formula may have potential for treating acute kidney injury (AKI). However, the protective effect of HBF on AKI has not been definitively confirmed, and the mechanism remains unclear. Therefore, the present study explored the renoprotective effects and molecular mechanisms of HBF and screened for its active ingredients to identify new potential applications of renoprotection by HBF. Methods: The present study first assessed the protective effects of HBF on AKI in a DOX-induced mouse model. Then, RNA-seq and bioinformatics analyses were used to explore the related pathological processes and potential molecular mechanisms, which were subsequently validated using qRT-PCR and Western blotting. Furthermore, candidate compounds with potential binding affinity to two pivotal targets, sphingosine kinase 1 (SphK1) and plasminogen activator inhibitor-1 (PAI-1), were screened from the 29 constituents present in the blood using Microscale Thermophoresis (MST). Finally, to identify the active ingredients, the candidate components were re-screened using the SphK1 kinase activity detection system or the uPA/PAI-1 substrate colorimetric assay system. Results: In the DOX-induced AKI mouse model, therapeutic administration of HBF significantly reduced the levels of CRE, BUN, TNF-α, IL-1β, IL-6, and UA in plasma and the levels of MDA, T-CHO, and TG in kidney tissue. Additionally, the levels of TP and Alb in plasma and SOD and CAT in the kidney tissue were significantly increased. Histopathological assessment revealed that HBF reduced tubular vacuolation, renal interstitial inflammatory cell infiltration, tubular atrophy, and positive staining of renal interstitial collagen. RNA-seq and bioinformatics analyses showed that oxidative stress, the immune-inflammatory response, and extracellular matrix (ECM) formation could be the pathological processes that HBF targets to exerts its renoprotective effects. Furthermore, HBF regulated the APJ/SPHK1/NF-κB and APJ/PAI-1/TGFβ signaling axes and reduced the phosphorylation levels of NF-κB p65 and SMAD2 and the expression of cytokines and the ECM downstream of the axis. Finally, six SphK1 inhibitors (paeoniflorin, astragalin, emodin, glycyrrhisoflavone, quercetin, and liquiritigenin) and three PAI-1 inhibitors (glycyrrhisoflavone, licochalcone B, and isoliquiritigenin) were identified as potentially active ingredients in HBF. Conclusion: In brief, our investigation underscores the renoprotective effect of HBF in a DOX-induced AKI model mice, elucidating its mechanisms through distinct pathological processes and identifying key bioactive compounds. These findings offer new insights for broadening the clinical applications of HBF and unravelling its molecular mode of action. [ABSTRACT FROM AUTHOR]

Background: COVID19 is a pandemic that has affected millions around the world since March 2020. While many patients recovered completely with mild illness, many patients succumbed to various organ morbidities. This heterogeneity in the clinical presentation of COVID19 infection has posed a challenge to clinicians around the world. It is therefore crucial to identify specific organ-related morbidity for effective treatment and better patient outcomes. We have carried out serum-based proteomic experiments to identify protein biomarkers that can flag organ dysfunctions in COVID19 patients. Methods: COVID19 patients were screened and tested at various hospitals across New Delhi, India. 114 serum samples from these patients, with and without organ morbidities were collected and annotated based on clinical presentation and treatment history. Of these, 29 samples comprising of heart, lung, kidney, gastrointestinal, liver, and neurological morbidities were considered for the discovery phase of the experiment. Proteins were isolated, quantified, trypsin digested, and the peptides were subjected to liquid chromatography assisted tandem mass spectrometry analysis. Data analysis was carried out using Proteome Discoverer software. Fold change analysis was carried out on MetaboAnalyst. KEGG, Reactome, and Wiki Pathway analysis of differentially expressed proteins were carried out using the STRING database. Potential biomarker candidates for various organ morbidities were validated using ELISA. Results: 254 unique proteins were identified from all the samples with a subset of 12–31 differentially expressed proteins in each of the clinical phenotypes. These proteins establish complement and coagulation cascade pathways in the pathogenesis of the organ morbidities. Validation experiments along with their diagnostic parameters confirm Secreted Protein Acidic and Rich in Cysteine, Cystatin C, and Catalase as potential biomarker candidates that can flag cardiovascular disease, renal disease, and respiratory disease, respectively. Conclusions: Label free serum proteomics shows differential protein expression in COVID19 patients with morbidity as compared to those without morbidity. Identified biomarker candidates hold promise to flag organ morbidities in COVID19 for efficient patient care. [ABSTRACT FROM AUTHOR]

Exposure to the spaceflight environment causes adaptations in most human physiological systems, many of which are thought to affect women differently from men. Since only 11.5% of astronauts worldwide have been female, these issues are largely understudied. The physiological nuances affecting the female body in the spaceflight environment remain inadequately defined since the last thorough published review on the subject. A PubMed literature search yielded over 2200 publications. Using NASA's 2014 review series ‘The effects of sex and gender on adaptation to space’ as a benchmark, we identified substantive advancements and persistent knowledge gaps in need of further study from the nearly 600 related articles that have been published since the initial review. This review highlights the most critical issues to mitigate medical risk and promote the success of missions to the Moon and Mars. Salient sex‐linked differences observed terrestrially should be studied during upcoming missions, including increased levels of inflammatory markers, coagulation factors and leptin levels following sleep deprivation; correlation between body mass and the severity of spaceflight‐associated neuro‐ocular syndrome; increased incidence of orthostatic intolerance; increased severity of muscle atrophy and bone loss; differences in the incidence of urinary tract infections; and susceptibility to specific cancers after exposure to ionizing radiation. To optimize health and well‐being among all astronauts, it is imperative to prioritize research that considers the physiological nuances of the female body. A more robust understanding of female physiology in the spaceflight environment will support crew readiness for Artemis missions and beyond. [ABSTRACT FROM AUTHOR]

Introduction: Pseudoxanthoma elasticum (PXE) is an autosomal recessive ectopic calcification disorder clinically affecting the skin, eyes, and vascular system. Most cases of PXE are caused by inactivating pathogenic variants in the ABCC6 gene encoding a hepatic transmembrane efflux transporter, which facilitates the extracellular release of ATP, the precursor of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Pathogenic variants in GGCX, encoding γ-glutamyl carboxylase required for activation of vitamin K-dependent coagulation factors as well as matrix Gla protein (MGP) and Gla-rich protein (GRP), two inhibitors of ectopic calcification, have also been reported to cause cutaneous changes like those seen in PXE. While ectopic calcification in ABCC6 deficiency has been associated with reduced plasma levels of PPi due to loss of ABCC6 transport activity in the liver, plasma PPi levels have not been reported in patients with GGCX-associated phenotypes. Methods: We analyzed five patients from three unrelated families on their clinical, laboratory, and molecular findings who carry biallelic variants in GGCX and present with phenotypic characteristics associated with PXE. The variants were identified using a next-generation sequencing panel consisting of 29 genes associated with ectopic calcification. Results and conclusion: This study demonstrates that in addition to ABCC6, GGCX variants can cause the PXE phenotype, expanding PXE and perhaps other heritable ectopic calcification disorders' clinical and genetic heterogeneity. The results also show that the plasma concentrations of PPi in these patients are not reduced compared to healthy control individuals, suggesting that plasma PPi does not govern ectopic calcification in GGCX deficiency. [ABSTRACT FROM AUTHOR]

Objective: To investigate the inhibitory effect of Celastrus orbiculatus extracts (COE) on the proliferation of lymphoma cells and the immune regulation ability on inflammation and thrombophilia in vivo. Methods: The 38B9 lymphoma cells were treated with COE (160 µ g/mL) and CTX (25 µ mol/L). The apoptosis rate and cell cycle of each group were detected by flow cytometry. The secretion of inflammatory factors, including interleukin (IL)-6, IL-10, and tumor necrosis factor α (TNF-α), in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). In vivo, BALB/c mice were subcutaneously injected with 38B9 lymphoma cells to establish lymphoma model. COE (3 mg·kg−1·d−1) and CTX (40 mg·kg−1·d−1) were administered to the model mice, respectively. The expression of plasma inflammatory factors (IL-6, IL-10 and TNF-α) and thrombus indexes, including D-dimer (D-D), von Willebrand factor (vWF) and tissue factor (TF), were detected by ELISA before tumor bearing (1 d), after tumor formation (14 d) and after intervention (21 d). PicoGreen dsDNA was used to detect the level of serum neutrophil extracellular traps (NETs). Flow cytometry was used to detect the expression of platelet activation marker calcium-dependent lectin-like receptor 2 (CLEC-2). The tumor growth and survival of mice were recorded. Results: The 38B9 lymphoma cells were apoptotic after the intervention of COE and CTX. The ratio of G2-M phase cells decreased in COE intervented cells compared with the control cells (P<0.05), and S phase cells decreased in CTX intervented cells (P<0.05). Also, the secretion level of IL-6 was significantly reduced after COE or CTX intervention (P<0.05), and IL-10 was significantly increased (P<0.05). Furthermore, the tumor mass was reduced, and the median survival time was longer in COE and CTX intervented tumor-bearing mice than in non-intervented mice. The significantly lower levels of TNF-α, IL-6, NETs, TF, DD and CLEC-2, as well as higher IL-10 were observed in COE and CTX treatment mice in comparision with the control mice (P<0.05). Conclusion: COE has a mild and stable anti-tumor effect, which can reduce the secretion of inflammatory factors by lymphoma cells and regulate thrombophilic state caused by tumor inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Background: Cerebral venous thrombosis (CVT) is a rare but serious condition that can lead to significant morbidity and mortality. Virchow's triad elucidates the role of blood hypercoagulability, blood flow dynamics, and endothelial damage in the pathogenesis of CVT. Cerebral venous congestion (CVC) increases the risk of cerebral venous sinus thrombosis and can lead to recurrent episodes and residual symptoms. However, the precise mechanism by which blood congestion leads to thrombosis remains unclear. Our objective was to investigate the cellular and molecular alterations linked to CVC through analysis of the pathological morphology of venous sinus endothelial cells and transcriptomic profiling. Results: This study demonstrated a remarkable correlation between CVC and the phenotypic transformation of endothelial cells from an anticoagulant to a procoagulant state. The findings revealed that cerebral venous stasis results in tortuous dilatation of the venous sinuses, with slow blood flow and elevated pressure in the sinuses and damaged endothelial cells of the retroglenoid and internal jugular vein ligation (JVL) rat model. Mechanistically, analysis of transcriptomic results of cerebral venous sinus endothelial cells showed significant activation of platelet activation, complement and coagulation cascades pathway in the JVL rats. Furthermore, the expression of von Willebrand factor (vWF) and coagulation factor VIII (F8) in the complement and coagulation cascades and Fgg and F2 in the platelet activation was increased in the cerebral venous sinuses of JVL rats than in sham rats, suggesting that endothelial cell injury in the venous sinus induced by CVC has a prothrombotic effect. In addition, endothelial cell damage accelerates coagulation and promotes platelet activation. Significantly, the concentrations of vWF, F2 and F8 in venous sinus blood of patients with internal jugular vein stenosis were higher than in their peripheral blood. Conclusion: Collectively, our data suggest that CVC can induce endothelial cell damage, which then exhibits a procoagulant phenotype and ultimately increases the risk of CVT. This research contributes to our understanding of the pathophysiology of CVC associated with procoagulant factors and reexamines the components of Virchow's triad in the context of CVC. [ABSTRACT FROM AUTHOR]

Background: Coronary artery bypass grafting (CABG) is often performed with hypothermic cardiopulmonary bypass (CPB) to reduce metabolic demands and protect the myocardium. However, hypothermia can increase bleeding risks and other complications. Methods: This is a prospective, multi-center, randomized controlled trial. From September 2023 to December 2024, a total of 336 eligible patients planning to undergo on-pump CABG will be enrolled. All participants will be randomly divided into mild hypothermia CPB group (target oxygenator arterial outlet blood temperature at 32–33℃) or normothermia CPB group (target oxygenator arterial outlet blood temperature at 35–36℃). The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2–4. Secondary endpoints are class of UDPB, levels of coagulation and inflammatory factors, in-hospital mortality, perioperative related complications, ICU length of stay, and hospital length of stay. Discussion: This clinical trial aims to compare the effects of different target temperature during CPB on postoperative bleeding and to explore optimal temperature strategy to provide new clinical evidence. Trial registration: Chictr.org.cn: ChiCTR2300075405. The trial was prospectively registered on 4 September 2023. [ABSTRACT FROM AUTHOR]

Although hypercoagulability is commonly associated with malignancies, whether coagulation factors directly affect tumor cell proliferation remains unclear. Herein, by performing single-cell RNA sequencing (scRNA-seq) of the prostate tumor microenvironment (TME) of mouse models of castration-resistant prostate cancer (CRPC), we report that immunosuppressive neutrophils (PMN-MDSCs) are a key extra-hepatic source of coagulation factor X (FX). FX activation within the TME enhances androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells. Genetic and pharmacological inhibition of factor Xa (FXa) antagonizes the oncogenic activity of PMN-MDSCs, reduces tumor progression, and synergizes with enzalutamide therapy. Intriguingly, F10 high PMN-MDSCs express the surface marker CD84 and CD84 ligation enhances F10 expression. Elevated levels of FX, CD84, and PAR2 in prostate tumors associate with worse survival in CRPC patients. This study provides evidence that FXa directly promotes cancer and highlights additional targets for PMN-MDSCs for cancer therapies. [Display omitted] • PMNs are a key source of coagulation factor X (FX) in the tumor microenvironment • PMN-derived FX directly fuels tumor growth and CRPC • CD84 marks F10 high Cxcr2 low PMNs in CRPC • High FX, CD84, and PAR2 levels predict poorer survival in PCa patients Calì et al. demonstrate that CD84+ immunosuppressive PMNs release in the tumor microenvironment of castration-resistant prostate cancer the coagulation factor X (FX). FX promotes androgen-independent cell proliferation and therapy resistance, independently from the coagulation cascade, by binding PAR2 on prostate cancer cells. This research reveals a new interplay between coagulation factors, immune cells, and cancer. [ABSTRACT FROM AUTHOR]

Bleeding events in patients receiving direct oral anticoagulation (DOAC) can be life-threatening even at therapeutic DOAC plasma concentrations, as anticoagulation impairs hemostasis and should therefore be identified immediately after hospital admission. The anticoagulatory effects of DOAC are typically not measurable in standard coagulation tests, such as PT or aPTT. Specific calibrated anti-FXa-tests allow specific drug monitoring, but they are too time-consuming for critical bleeding events and are commonly not available for 24 h/7 days in routine care. However, recent advances in point-of-care (POC) viscoelastic testing (VET) have shown a promising approach for rapid and quantitative detection of DOAC plasma concentrations using the Russell viper venom factor V activator (RVV for FXa-inhibitors) test or the ecarin clotting time (thrombin inhibitors). In acute bleeding situations, direct FXa inhibitors can be reversed by specific antidote andexanet alfa or hemostasis can be improved by prothrombin complex factor concentrates (PCCs). After reversal, confirmation of reversal efficacy is often requested, but no routine assays are currently available. Thus, the emergency management of bleeding DOAC patients is usually "blinded" with regard to reversal efficacy. POC VET laboratory assays might therefore also be helpful for measuring DOAC effects after reversal. We present a case series demonstrating the usefulness of RVV-clotting time post-DOAC reversal with andexanet alfa. [ABSTRACT FROM AUTHOR]

Introduction: Endothelial dysfunction (ED) promotes the development of atherosclerosis, and studies suggest an association with age-related neurocognitive disorders. It is currently unclear whether ED is also associated with the risk of perioperative neurocognitive disorders. Method: We included 788 participants aged ≥ 65 years of the BioCog study. Patients were scheduled to undergo elective surgery with expected duration > 60 min. Blood was collected before surgery for measurement of 5 biomarkers of ED: asymmetric and symmetric dimethylarginine (ADMA; SDMA), intercellular and vascular adhesion molecule (ICAM-1, VCAM-1), and von Willebrand factor (vWF). Patients were monitored for the occurrence of postoperative delirium (POD) daily until the 7th postoperative day. 537 (68.1%) patients returned for a 3-month follow-up. Post-operative cognitive dysfunction (POCD) was defined from the change in results on a battery of 6 neuropsychological tests between baseline and 3 months, compared to the change in results of a control group during the 3-month interval. The associations of each of the 5 ED biomarkers with POD and POCD respectively were determined using multiple logistic regression analyses with adjustment for age, sex, surgery type, pre-morbid IQ, body mass index, hypertension, diabetes, HbA1C, triglyceride, total and HDL cholesterol. Results: 19.8% of 788 patients developed POD; 10.1% of 537 patients had POCD at 3 months. Concentrations of ED biomarkers were not significantly associated with a POD. A higher VCAM-1 concentration was associated with a reduced POCD risk (adjusted odds ratio 0.55; 95% CI: 0.35–0.86). No further statistically significant results were found. Conclusion: Pre-operative concentrations of ED biomarkers were not associated with POD risk. We unexpectedly found higher VCAM-1 to be associated with a reduced POCD risk. Further studies are needed to evaluate these findings. [ABSTRACT FROM AUTHOR]

Epidural hematoma typically manifests following craniocerebral trauma, stemming from injury to the meningeal artery or venous system, predominantly on one side. Instances of spontaneous epidural hematoma are uncommon, with occurrences of spontaneous bilateral epidural hematoma being exceedingly rare. Sickle cell disease, adjacent paranasal sinusitis, and tumor metastases are the most prevalent causes of spontaneous epidural hematoma. This case study presents an individual with abdominal liposarcoma exhibiting reduced coagulation factor XII activity, who experienced sudden unconsciousness due to spontaneous acute bilateral epidural hematoma, and subsequently achieved a favorable outcome following surgical intervention. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that the coagulation system plays a role in mammalian innate defense by entrapping bacteria in clots and generating antibacterial peptides. So, it is very important for the survival of bacteria to defend against the host coagulation system, which suggests that bacterial exotoxins might be a new source of anticoagulants. In this study, we analyzed the genomic sequences of Acinetobacter baumannii and a new bacterial exotoxin protein, F6W77, with five Kunitz-domains, KABP1-5, was identified. Each Kunitz-type domain features a classical six-cysteine framework reticulated by three conserved disulfide bridges, which was obviously similar to animal Kunitz-domain peptides but different from plant Kunitz-domain peptides. Anticoagulation function evaluation showed that towards the intrinsic coagulation pathway, KABP1 and KABP5 had apparently inhibitory activity, KABP4 had weak inhibitory activity, and KBAP2 and KABP3 had no effect even at a high concentration of 20 μg/mL. All five Kunitz-domain peptides, KABP1-5, had no inhibitory activity towards the extrinsic coagulation pathway. Enzyme-inhibitor experiments showed that the high-activity anticoagulant peptide KABP1 had apparently inhibitory activity towards two key coagulation factors, Xa and XIa, which was further confirmed by pull-down experiments that showed that KABP1 can bind to coagulation factors Xa and XIa directly. Structure-function relationship analyses of five Kunitz-type domain peptides showed that the arginine of the P1 site of three new bacterial anticoagulants, KABP1, KABP4 and KABP5, might be the key residue for their anticoagulation activity. In conclusion, with bioinformatics analyses, peptide recombination, and functional evaluation, we firstly found bacterial-exotoxin-derived Kunitz-type serine protease inhibitors with selectively inhibiting activity towards intrinsic coagulation pathways, and highlighted a new interaction between pathogenic bacteria and the human coagulation system. [ABSTRACT FROM AUTHOR]

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Percutaneous liver biopsy is essential for diagnosing hepatic amyloidosis. Post biopsy hemorrhage is unusual but can occur. The potential for bleeding can result from various factors, such as the deposition of amyloid in the hepatic parenchyma or vessel wall, deficiencies in coagulation factors, hyperfibrinolysis, and platelet dysfunction. Transarterial embolization can be a safe and effective method for achieving hemostasis. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) increases the risk for venous thromboembolism. Tissue factor (TF) initiates the extrinsic coagulation pathway (ECP). Aims: To investigate the correlation of UC severity with latent ECP activation and TF expression in primary colonic stromal cells (PCSC). Methods: In plasma of 38 UC patients (31 males, disease duration 151 ± 25 months) and 28 healthy controls, exosomes and microparticles (EM) were counted. Moreover, TF protein concentration, activities of EM-bound TF (EM-TFa) and coagulation factor VII (FVIIa) were assessed. In PCSC in culture, TF mRNA (F3) from 12 patients with active UC and 7 controls was evaluated. Results: UC patients had 4– and 3.7– times more exosomes and microparticles, respectively, than controls. TF protein in UC was correlated with several disease severity indices, such as partial Mayo score (pMs; r 0.443), albumin (− 0.362), ESR (0.353), PLT (0.575), and endoscopic Ms (eMs 0.468). EM-TFa was also significantly higher in UC and was correlated to SIBDQ (− 0.64), albumin (− 0.624), disease extent and eMs (0.422). Refractory-to-treatment patients had significantly higher TF protein, EM-TFa and FVIIa. Even within responders, the need for steroids or biologics correlated with a 2.2–times higher EM-TFa. PCSC from active UC maintained higher F3 than controls, which was correlated to pMs (0.56), albumin (− 0.543) and eMs. Treatment with cytokines further upregulated F3. P for all comparisons was < 0.05. Conclusion: Low-grade activation of the ECP associates with clinical, endoscopic UC activity and response to treatment. TF in PCSC mirrors its systemic activity and points to them as a source. [ABSTRACT FROM AUTHOR]

Coagulation factor XIII (FXIII) is an enzyme that strengthens hemostatic clots, and its deficiency can cause life-threatening bleeding. We immunized mice with human plasma-derived FXIII to generate monoclonal antibodies (mAbs) against the B subunit (FXIII-B), which stabilizes the A subunit (FXIII-A) of FXIII, and analyzed their properties. The epitopes of the seven mouse antihuman FXIII-B mAbs obtained were found to be the 3rd, 5th, 6th, 9th, and 10th Sushi domains. One of these mAbs, mAb 5–6C, recognized the 10th Sushi domain and inhibited the fibrin cross-linking reaction without affecting the amine incorporation activity of FXIII. We previously reported that the 10th Sushi domain is the site where FXIII-B binds to fibrin and functions to bring FXIII-A closer to the substrate fibrin. Except for mAb 5–6C, mouse mAbs with high yields were used to measure the amount of FXIII-B antigen by an immunochromatography test (ICT), which showed a high correlation with enzyme-linked immunosorbent assay–obtained results. In addition, we developed a prototype ICT to detect anti-FXIII-B autoantibodies using mAb 1–3C, which showed good results in measuring the amount of FXIII-B antigen. Thus, mouse mAbs may be useful for clinical applications. mAb 5–6C targeting the 10th Sushi domain may also be useful for inhibiting thrombosis progression when humanized as antibody medicines. [ABSTRACT FROM AUTHOR]

Background and Objectives: Quantifying the contribution of individual coagulation factors to haemostasis may aid our understanding of the haemostatic function in patients with rare coagulation deficiencies (RCDs) and the exploration of suitable treatments. Materials and Methods: Reconstituted blood prepared from specific coagulation factor‐deficient plasma (factor [F]II; prothrombin, FV, FVII, FVIII, FIX, FX, FXI or FXII) and red blood cell/platelet products were used to simulate the whole blood of patients with RCD. We prepared in vitro treatment models for patients with prothrombin deficiency using coagulation factor agents and fresh frozen plasma. Haemostatic function was measured using a microchip flow chamber system at 600 s−1. Results: The haemostatic function was low, especially in blood samples reconstituted with prothrombin‐ and FX‐deficient plasma. In a plasma transfusion model of prothrombin deficiency, haemostatic function recovered after 10% replacement with normal plasma and reached a plateau at ≧60% replacement. A treatment model of prothrombin deficiency with prothrombin complex concentrates revealed dose‐dependent therapeutic effects in the range of 0–50 IU/kg. Conclusion: Microchip flow chamber system‐based quantification of haemostatic function using reconstituted blood could predict haemostasis and therapeutic effects of treatments in patients with prothrombin deficiency. [ABSTRACT FROM AUTHOR]

The circadian system regulates 24‐h time‐of‐day patterns of cardiovascular physiology, with circadian misalignment resulting in adverse cardiovascular risk. Although many proteins in the coagulation‐fibrinolysis axis show 24‐h time‐of‐day patterns, it is not understood if these temporal patterns are regulated by circadian or behavioral (e.g., sleep and food intake) cycles, or how circadian misalignment influences these patterns. Thus, we utilized a night shiftwork protocol to analyze circadian versus behavioral cycle regulation of 238 plasma proteins linked to cardiovascular physiology. Six healthy men aged 26.2 ± 5.6 years (mean ± SD) completed the protocol involving two baseline days with 8‐h nighttime sleep opportunities (circadian alignment), a transition to shiftwork day, followed by 2 days of simulated night shiftwork with 8‐h daytime sleep opportunities (circadian misalignment). Plasma was collected for proteomics every 4 h across 24 h during baseline and during daytime sleep and the second night shift. Cosinor analyses identified proteins with circadian or behavioral cycle‐regulated 24‐h time‐of‐day patterns. Five proteins were circadian regulated (plasminogen activator inhibitor‐1, angiopoietin‐2, insulin‐like growth factor binding protein‐4, follistatin‐related protein‐3, and endoplasmic reticulum resident protein‐29). No cardiovascular‐related proteins showed regulation by behavioral cycles. Within the coagulation pathway, circadian misalignment decreased tissue factor pathway inhibitor, increased tissue factor, and induced a 24‐h time‐of‐day pattern in coagulation factor VII (all FDR < 0.10). Such changes in protein abundance are consistent with changes observed in hypercoagulable states. Our analyses identify circadian regulation of proteins involved in cardiovascular physiology and indicate that acute circadian misalignment could promote a hypercoagulable state, possibly contributing to elevated cardiovascular disease risk among shift workers. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) is a rare, potentially life‐threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)‐driven kallikrein–kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first‐line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa‐targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long‐term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE. [ABSTRACT FROM AUTHOR]

Background: Four-factor prothrombin complex concentrate (4F-PCC) is indicated for vitamin K antagonist (VKA) reversal but is associated with thrombotic events (TE). In 2018, the institution revised 4F-PCC dosing for VKA reversal from INR and weight-based dosing to a fixed-dose of 1500 units. Objective: The purpose of this study was to compare hemostatic efficacy and TE rate of fixed-dose 4PCC to weight-based dosing. Methods: This was a retrospective, single-center, quasi-experimental study of adult patients who received 4F-PCC for VKA reversal from January 2014 through May 2016 (INR and weight-based dosing) or April through October 2018 (fixed-dosing). The primary endpoint was hemostatic efficacy, defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. The key secondary endpoint was TE within 14 days of 4F-PCC administration. Data were analyzed using descriptive statistics, chi-squared for nominal data and Mann-Whitney U for ordinal and continuous data. Results: The study included 163 patients who received weight-based dosing and 45 who received fixed-dose 4F-PCC. Hemostatic efficacy was 76.9% of patients in the weight-based group and 77.4% of patients in the fixed-dose group (P =.229). TE occurred in 13.5% of the weight-based vs 6.7% of the fixed-dose group (P =.181). Conclusion: This study found no difference in hemostatic efficacy with fixed-dose 4F-PCC for VKA reversal compared to INR and weight-based dosing. The occurrence of TE was reduced by 50% with the 4F-PCC fixed-dose strategy; however, this difference was not statistically significant. Further randomized studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background: Recombinant factor VIIa (rFVIIa) and prothrombin concentrate complex (PCC) are used for uncontrolled bleeding in cardiac surgery (CS), however, there are limited direct comparisons of these agents. Objective: To evaluate the efficacy and safety of rFVIIa and PCC in CS related bleeding. Methods: This retrospective study included adult CS patients who received either low dose rFVIIa (< 30 mcg/kg) or 4-factor PCC. The primary outcome was transfusion requirements of packed red blood cells (pRBC) within 6 hours of factor administration. Secondary efficacy outcomes included transfusion requirements 0-18 hours, doses of additional factor product, thrombotic events, and acute kidney injury (AKI). Results: A total of 179 patients were included (n = 78 rFVIIa; n = 101 PCC). Of patients who received blood products, there was no difference in the requirement of pRBCs within 6 hours (73.8 vs 68.9%, P =.5359) or in the median amount of pRBC transfused (500 mL vs 640 mL, P =.0723) in the rFVIIa and PCC groups respectively. Patients in the PCC group were more likely to require additional factor products (24.4% vs 47.5%, P =.0015), develop AKI (12.8% vs 25.7%, P =.0325), have longer ICU lengths of stay [2 (IQR 1-5) vs 4 (IQR 2-6), P =.0487] and greater in-hospital mortality (2.6% vs 10.9%, P =.033). There was no difference in thrombotic events. Conclusion: Although, there was no difference in pRBC transfusion requirements between PCC and rFVIIa, more patients in the PCC group required additional factor products and had increased adverse effects. Further comparisons of PCC and rFVIIa are warranted. [ABSTRACT FROM AUTHOR]

For decades, it was considered that plasma kallikrein's (PKa) sole function within the coagulation cascade is the activation of factor (F)XII. Until recently, the two key known activators of FIX within the coagulation cascade were activated FXI(a) and the tissue factor–FVII(a) complex. Simultaneously, and using independent experimental approaches, three groups identified a new branch of the coagulation cascade, whereby PKa can directly activate FIX. These key studies identified that (1) FIX or FIXa can bind with high affinity to either prekallikrein (PK) or PKa; (2) in human plasma, PKa can dose dependently trigger thrombin generation and clot formation independent of FXI; (3) in FXI knockout murine models treated with intrinsic pathway agonists, PKa activity results in increased formation of FIXa:AT complexes, indicating direct activation of FIX by PKa in vivo. These findings suggest that there is both a canonical (FXIa-dependent) and non-canonical (PKa-dependent) pathway of FIX activation. These three recent studies are described within this review, alongside historical data that hinted at the existence of this novel role of PKa as a coagulation clotting factor. The implications of direct PKa cleavage of FIX remain to be determined physiologically, pathophysiologically, and in the context of next-generation anticoagulants in development. [ABSTRACT FROM AUTHOR]

Hemorrhage remains a major complication of anticoagulants, with bleeding leading to serious and even life-threatening outcomes in rare settings. Currently available anticoagulants target either multiple coagulation factors or specifically coagulation factor (F) Xa or thrombin; however, inhibiting these pathways universally impairs hemostasis. Bleeding complications are especially salient in the medically complex population who benefit from medical devices. Extracorporeal devices—such as extracorporeal membrane oxygenation, hemodialysis, and cardiac bypass—require anticoagulation for optimal use. Nonetheless, bleeding complications are common, and with certain devices, highly morbid. Likewise, pharmacologic prophylaxis to prevent thrombosis is not commonly used with many medical devices like central venous catheters due to high rates of bleeding. The contact pathway members FXI, FXII, and prekallikrein serve as a nexus, connecting biomaterial surface-mediated thrombin generation and inflammation, and may represent safe, druggable targets to improve medical device hemocompatibility and thrombogenicity. Recent in vivo and clinical data suggest that selectively targeting the contact pathway of coagulation through the inhibition of FXI and FXII can reduce the incidence of medical device-associated thrombotic events, and potentially systemic inflammation, without impairing hemostasis. In the following review, we will outline the current in vivo and clinical data encompassing the mechanism of action of drugs targeting the contact pathway. This new class of inhibitors has the potential to herald a new era of effective and low-risk anticoagulation for the management of patients requiring the use of medical devices. [ABSTRACT FROM AUTHOR]

Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important. [ABSTRACT FROM AUTHOR]

Background: The distribution of anti‐factor Xa activity (AXA) in patients with nonvalvular atrial fibrillation (NVAF) taking edoxaban 15 mg has not been fully elucidated. Methods and Results: The trough and peak AXA were measured in 19 NVAF patients taking edoxaban 15 mg. We compared these results with those in patients taking edoxaban 30 mg. The peak AXA differed significantly between the 15 mg and the 30 mg groups (0.74 ± 0.40 IU/mL vs. 1.25 ± 0.48 IU/mL, respectively; p < 0.0001). Conclusions: Peak but trough AXA in the patients receiving edoxaban 15 mg were significantly lower than those in patients receiving edoxaban 30 mg. [ABSTRACT FROM AUTHOR]

Background: Platelet-leukocyte aggregates have been implicated in various infectious and inflammatory diseases. The Interferon-induced transmembrane protein 3 (IFITM3) protein plays a role in eliminating viral infections, but its role in the severity of COVID-19 is not well understood. Objectives: We aimed to investigate the correlation between IFITM3 mRNA expression and platelet-monocyte complex levels with the severity of COVID-19, as well as various inflammatory and coagulation markers. Methods: We conducted a cross-sectional study on 54 COVID-19 patients, classified into severe and mild/moderate subgroups. Demographics and laboratory findings were extracted from patients' medical records. We measured IFITM3 mRNA expression in patients' buffy coats using q-RT-PCR and used flow cytometry with CD61 and CD14 markers to measure platelet-monocyte aggregates. Results: No significant difference was found in IFITM3 mRNA expression levels or platelet-monocyte complexes between severe and mild/moderate groups (P = 0.067 and P = 0.056). Lymphocyte counts were significantly higher in the mild/moderate subgroup (21.7 ± 8.9 vs 16.3 ± 10.9, P = 0.02), while neutrophil counts were significantly higher in severe patients (78.3 ± 12.2 vs 72.3 ± 9.9, P = 0.01). Additionally, levels of CRP and LDH were significantly higher in severe COVID-19 patients (P = 0.01 and P = 0.001, respectively). A strong positive correlation was observed between the hospitalization period and CRP, CRP with neutrophils and LDH, as well as between O2 saturation and lymphocytes (P < 0.001, P = 0.0003, P = 0.002, and P = 0.005, respectively). Conclusions: Our findings suggest that IFITM3 gene expression and platelet-monocyte aggregate levels do not correlate with disease outcomes in COVID-19. However, further investigations with larger sample sizes are needed to better understand the mechanisms involved. Monitoring inflammatory and coagulation markers remains important for managing COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Early severe cerebral edema and chronic hydrocephalus are the primary cause of poor prognosis in patients with subarachnoid hemorrhage (SAH). This study investigated the role of cerebrospinal fluid (CSF) inflammatory cytokines and coagulation factors in the development of severe cerebral edema and chronic hydrocephalus in patients with SAH. Methods: Patients with SAH enrolled in this study were categorized into mild and severe cerebral edema groups based on the Subarachnoid Hemorrhage Early Brain Edema Score at admission. During long-term follow-up, patients were further classified into hydrocephalus and non-hydrocephalus groups. CSF samples were collected within 48 h post-SAH, and levels of inflammatory cytokines and coagulation factors were measured. Univariate and multivariate logistic regression analyses were performed to identify independent factors associated with severe cerebral edema and chronic hydrocephalus. The correlation between inflammatory cytokines and coagulation factors was further investigated and validated in a mouse model of SAH. Results: Seventy-two patients were enrolled in the study. Factors from the extrinsic coagulation pathway and inflammatory cytokines were associated with both severe cerebral edema and chronic hydrocephalus. Coagulation products thrombin-antithrombin complexes (TAT) and fibrin, as well as inflammatory cytokines IL-1β, IL-2, IL-5, IL-7, and IL-4, were independently associated with severe cerebral edema. Additionally, Factor VII, fibrin, IL-2, IL-5, IL-12, TNF-α, and CCL-4 were independently associated with chronic hydrocephalus. A positive correlation between extrinsic coagulation factors and inflammatory cytokines was observed. In the SAH mouse model, tissue plasminogen activator was shown to alleviate neuroinflammation and cerebral edema, potentially by restoring glymphatic-meningeal lymphatic function. Conclusions: Elevated levels of inflammatory cytokines and extrinsic coagulation pathway factors in the CSF are associated with the development of early severe cerebral edema and chronic hydrocephalus following SAH. These factors are interrelated and may contribute to post-SAH glymphatic-meningeal lymphatic dysfunction. [ABSTRACT FROM AUTHOR]

Background: Hemophilia A (HA) is an X-linked recessive bleeding disorder characterized by reduced or absent coagulation factor (F) VIII activity. The empirical evidence on the prevalence of HA in Africa has reported inconsistent findings and seems to present such a wide range of prevalence that it is hard to swiftly ascertain its average extent. Hence, this review aimed to pool the results of primary studies reporting the prevalence of HA into a single estimate in the region. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published in EMBASE, PubMed, Web of Science, SCOPUS, Science Direct, and Cochrane Library databases were searched. Observational studies revealing the prevalence of HA in Africa between 2010 and 2023 were incorporated. We assessed the quality of each study using the Newcastle-Ottawa quality assessment tool. The prevalence of HA was estimated as the cases (the sample size) per 100,000 population multiplied by 1000. To produce the pooled estimate, Der Simonian random-effects models were computed with Metaprop on the STATA command. The studies' heterogeneity was assessed using the I-squared (I2) value test and the Galbraith plot. A funnel plot was conducted to evaluate publication bias. Results: Of the 337 studies accessed, we included 15 that fulfilled the eligibility criteria. The random-effect model meta-analysis demonstrated the overall pooled prevalence of HA was 6.82 cases per 100,000 persons (95% confidence interval: 5.16, 8.48) with heterogeneity (I2 = 0.00%, p < 0.001). Conclusions: This systematic review and meta-analysis revealed that HA is an alarming problem that may pose a future threat to public health in Africa. Given the detrimental effects of the disease on health and the complications involved, we recommended that African regions increase patient access to factor VIII medication, improve carrier detection rates, and take the initiative toward the development and access to gene therapy. [ABSTRACT FROM AUTHOR]

The mortality rate of sepsis remains high and further increases when complicated by disseminated intravascular coagulation (DIC). Consequently, early detection and appropriate management of DIC will be helpful for the management of sepsis. Although overt DIC criteria are often used for diagnosing definitive DIC, it was not designed to detect early-phase DIC. The criteria and scoring system for sepsis-induced coagulopathy (SIC) were developed and introduced in 2017 to detect early-stage DIC, and they were subsequently adopted by the International Society on Thrombosis and Haemostasis in 2019. The objective of detecting SIC was not to miss the patients at high risk of developing overt DIC at an earlier time. Although anticoagulant therapies are potential options for the treatment of sepsis-associated DIC, their effectiveness has not been established, and further research is warranted. For that purpose, an international collaborative platform is required for future clinical trials, and SIC criteria have been suggested for such studies. Calculating the SIC score is straightforward and suitable for use in clinical settings. This review aims to introduce SIC criteria and its scoring system for better management of sepsis-associated DIC. We also intended to update the current knowledge regarding this novel diagnostic criterion. [ABSTRACT FROM AUTHOR]

Objective: To explore the distribution of thrombin–antithrombin complex (TAT), plasmin-α2-antiplasmin inhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) in healthy older Chinese adults, and establish the reference intervals (RIs). Methods: The Biotech Shine i2900 chemiluminescence immune assay was used to measure the plasma concentrations of TAT, PIC, TM, and t-PAIC in 1628 adults ≥ 60 years. The RIs were established using the 2.5th and 97.5th percentiles of the distribution. Results: TAT levels were lower in males than females across all ages. Differences between the ages of 60–79 and ≥ 80 in both sex groups were statistically significant, with an upward trend with age. PIC levels showed no difference between the sexes but increased with age in both groups. TM levels did not differ between the sex groups, with slight fluctuation with age. The level in females aged 60–69 was slightly higher than that in the other groups; the difference was statistically significant. T-PAIC levels were not significantly different between the sex groups, with less fluctuation with sex and age. The level in males ≥ 80 years old was slightly lower than that in the other groups; the difference was statistically significant. The RIs for all markers in healthy older Chinese adults were determined and statistically reported by age and sex. For TAT, the RIs for males aged 60–79 and ≥ 80 are 0.51–2.30 ng/mL and 0.88–3.72 ng/mL, respectively, whereas for females aged 60–79 and ≥ 80, the RIs are 0.68–2.82 ng/mL and 1.02–3.67 ng/mL, respectively. For PIC, the RIs for the age groups 60–69, 70–79, and ≥ 80 are 0.10–0.89 µg/mL, 0.12–1.00 µg/mL, and 0.21–1.04 µg/mL, respectively. The RI of TM for females aged 60–69 is 3.32–13.22 TU/mL, whereas it is 2.96–13.26 TU/mL for the other groups. The RI of t-PAIC for males aged ≥ 80 is 1.63–10.68 ng/mL, whereas it is 2.33–11.34 ng/mL for the other groups. Conclusions: Discrepancies exist in thrombus markers among different sex and age groups. The RIs of TAT, PIC, TM and t-PAIC for healthy older Chinese adults were successfully established. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion The post‐thaw shelf‐life of cryoprecipitate is 6 h, leading to high wastage. Storage of thawed cryoprecipitate at refrigerated temperatures may be feasible to extend the shelf‐life. This study aimed to evaluate the quality of thawed cryoprecipitate stored at 1–6°C for up to 14 days.Cryoprecipitate (mini‐ and full‐size packs derived from both apheresis and whole blood [WB] collections) was thawed, immediately sampled and then stored at 1–6°C for up to 14 days. Mini‐packs were sampled at 6, 24, 48 and 72 h, day 7 and 14; full‐size cryoprecipitate was sampled on day 3, 5 or 7. Coagulation factors (F) II, V, VIII, IX, X and XIII, von Willebrand factor (VWF) and fibrinogen were measured using a coagulation analyser. Thrombin generation was measured by calibrated automated thrombogram.FVIII decreased during post‐thaw storage; this was significant after 24 h for WB (p = 0.0002) and apheresis (p < 0.0001). All apheresis and eight of 20 WB cryoprecipitate met the FVIII specification (≥ 70 IU/unit) on day 14 post‐thaw. Fibrinogen remained stable for 48 h, and components met the specification on day 14 post‐thaw. There were no significant differences in VWF (WB p = 0.1292; apheresis p = 0.1507) throughout storage. There were small but significant decreases in thrombin generation lag time, endogenous thrombin potential and time to peak for both WB and apheresis cryoprecipitate.Whilst coagulation factors in cryoprecipitate decreased after post‐thaw storage, the thawed cryoprecipitate met the Council of Europe specifications when stored at refrigerated temperatures for 7 days. [ABSTRACT FROM AUTHOR]

Background: The effect of acidemia on blood coagulation remains inadequately understood in veterinary medicine. Therefore, we assessed the effect of in vitro acidification of canine whole blood on coagulation and investigated whether acidemia-induced coagulopathy could be reversed by reversing acidemia. Methods: Citrated whole blood samples were taken from six healthy Beagle dogs and categorized, based on pH adjustment, into neutral, weak acidemia (WA), strong acidemia (SA), and reversal from SA. Then, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, conventional thromboelastography (TEG) parameters, and velocity curve (V-curve) variables of TEG were assessed. Results: The PT, aPTT, and most TEG parameters showed significant coagulopathy in the SA group compared to the neutral group, with additional significant changes in reaction time (R), clot kinetic (K), maximum amplitude (MA), split point (SP), elasticity (E), thrombodynamic potential index (TPI), and coagulation index (CI) between the SA and WA groups. Among V-curve variables, the maximum rate of thrombus generation (MRTG) and total thrombus generation were significantly inhibited in the SA group compared to the neutral group, with significant differences in the time to maximum rate of thrombus generation (TMRTG) between the WA and SA groups. In the reverse group, aPTT, R, K, α-angle, MRTG, TMRTG, SP, TPI, and CI exhibited significant recovery compared to the SA group. Conclusion: The in vitro induction of acidemia in canine whole blood leads to impairment of coagulation profiles, and pH correction can reverse most acidemia-induced coagulopathy. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to characterize the safety profiles of rivaroxabanassociated suspected adverse events by mining the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: A disproportionality analysis of spontaneously reported suspected adverse drug reactions (ADRs) was conducted. The reports in FAERS from 2014 to 2024 were compiled. Frequentist and Bayesian statistics were both applied to calculate drug-AE combinations in system organ classes and preferred-term levels. Reporting odds ratio (ROR), proportional reporting ratio (PRR), the Medicines and Healthcare products Regulatory Agency (MHRA), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) methods were analyzed and used to compare the suspected AEs. Results: Of 77,384 ADR reports, 66,705 (86.20%) were serious rivaroxaban AE reports. The most common age group was above 65 years. The suspected adverse effects of rivaroxaban emerging for system organ classes (SOCs) primarily included "Gastrointestinal disorders"; "Injury, poisoning, and procedural complications", "Nervous system disorders" and "Vascular disorders". Ranked by EBGM, the top signal strength of suspected AE signals of rivaroxaban under ROR algorithm at the preferred-term (PT) level were "Haemorrhagic arteriovenous malformation" (N = 571, ROR = 756.520, PRR = 754.029, Information Component (IC) = 7.197, Empirical Bayesian Geometric Mean (EBGM) = 146.725), "Gastrointestinal vascular malformation haemorrhagic" (N = 197, ROR = 211.138, PRR = 210.950, IC = 6.614, EBGM = 97.923), and "Diverticulum intestinal haemorrhagic" (N = 722, ROR = 169.898, PRR = 169.210, IC = 6.458, EBGM = 97.920). Moreover, uncommon but significantly suspected AE signals, such as "Coagulation factor X level increased", "Basal ganglia haematoma", and "Proctitis haemorrhagic" were observed. Notably, "Gastrointestinal haemorrhage" (N = 13,436, ROR = 80.477, PRR = 74.460, IC = 5.729, EBGM = 53.042), "Upper gastrointestinal haemorrhage"(N = 2,872, ROR = 73.978, PRR = 72.797, IC = 5.706, EBGM = 52.198) and "Internal haemorrhage" (N = 2,368, ROR = 91.979, PRR = 80.899, IC = 5.813, EBGM = 56.212) exhibited relatively high occurrence rates and signal strengths. From 2014 to 2024, the IC values of rivaroxaban-associated suspected AEs for "Surgical and medical procedures" and "Cardiac disorders" showed an annual increasing trend in the time-span analysis. Based on the various visulization plots, a key discovery is that "Gastrointestinal hemorrhage" emerged as the most significant suspected AE across five algorithms. The exciting finding was that the MGPS algorithm revealed a higher risk of suspected AEs under the "Investigations" category. However, the results of the analyses of the other algorithms at the SOC level were not akin to this. Moreover, the results of signal mining for the three main types of indication populations with adverse drug reactions (ADRs), including Atrial fibrillation, Cerebrovascular accident prophylaxis, and Deep vein thrombosis were shown that "Gastrointestinal haemorrhage", "Epistaxis", "Haematuria", "Rectal haemorrhage", and "Upper gastrointestinal haemorrhage" were detected as the most common and significant signals of suspected adverse events. Conclusion: Rivaroxaban has risks of various suspected adverse reactions while providing therapeutic effects and being used widely. Our pharmacovigilance study may provide valuable hints that practitioners should closely monitor occurrences of "Gastrointestinal disorders", "Injury, poisoning, and procedural complications" and "Nervous system disorders", and other events in clinical applications. Consequently, it remains to persist in monitoring rivaroxaban, assessing the associated risks in the future. [ABSTRACT FROM AUTHOR]

Background/Objectives: Through the past several years, a constant interaction has been implicated between complement and coagulation cascades. SARS-CoV-2 infection and bacterial sepsis are potent activators of both cascades. This study aims to compare the extent of complement and intrinsic coagulation pathway activation (and the interplay between them) among patients with COVID-19 and bacterial sepsis. Methods: Serum and plasma samples were collected from 25 ICU patients (11 patients with COVID-19 and 14 patients with bacterial sepsis) at two time points (on admission and either on improvement or deterioration). The activities of coagulation factors XI and XII and complement factors C3a and C5a were measured at both time points. Results: The activities of factors XI and XII were increased in both groups of patients and at both time points. However, there were no statistically significant differences between SARS-CoV-2 and bacterial sepsis patients. On the other hand, both C3a and C5a were significantly higher in the COVID-19 group on admission. This correlation was preserved on reassessment. Conclusions: Complement activation seems to be more enhanced in COVID-19 than bacterial sepsis. However, the lack of statistical significance in factors XI and XII indicates t the presence of additional pathways for complement activation in SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Alcohol-associated liver disease (ALD) is a prevalent medical problem with limited effective treatment strategies. Although many biological processes contributing to ALD have been elucidated, a complete understanding of the underlying mechanisms is still lacking. The current study employed a proteomic approach to identify hepatic changes resulting from ethanol (EtOH) consumption and the genetic ablation of the formyl peptide receptor 2 (FPR2), a G-protein coupled receptor known to regulate multiple signaling pathways and biological processes, in a mouse model of ALD. Since previous research from our team demonstrated a notable reduction in hepatic FPR2 protein levels in patients with alcohol-associated hepatitis (AH), the proteomic changes in the livers of Fpr2−/− EtOH mice were compared to those observed in patients with AH in order to identify common hepatic proteomic alterations. Several pathways linked to exacerbated ALD in Fpr2−/− EtOH mice, as well as hepatic protein changes resembling those found in patients suffering from AH, were identified. These alterations included decreased levels of coagulation factors F2 and F9, as well as reduced hepatic levels of glutamate-cysteine ligase catalytic subunit (GCLC) and total glutathione in Fpr2−/− EtOH compared to WT EtOH mice. In conclusion, the data suggest that FPR2 may play a regulatory role in hepatic blood coagulation and the antioxidant system, both in a pre-clinical model of ALD and in human AH, however further experiments are required to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Combining antitumor proprietary Chinese medicine (pCm) with radiotherapy and chemotherapy can effectively improve tumor cure rates and enhance patients' quality of life. Gastric cancer (GC) severely endangers public health. Despite satisfactory therapeutic effects achieved by using antitumor pCm to treat GC, its underlying mechanism remains unclear. Objective: To integrate existing research data, construct a database of antitumor pCm, and study the intervention mechanisms in GC by focusing on their monomer components. Methods: We constructed an antitumor pCm database based on China's medical insurance catalog, and employed network pharmacology, molecular docking methods, cell experiments, transcriptomics, and bioinformatics to investigate the intervention mechanisms of effective pCm components for GC. Results: The study built an antitumor pCm database including 55 pCms, 171 Chinese herbal medicines, 1955 chemical components, 2104 targets, and 32 disease information. Network pharmacology and molecular docking technology identified norcantharidin as an effective component of antitumor pCm. In vitro experiments showed that norcantharidin effectively inhibited GC cell proliferation, migration, and invasion; blocked the G2/M cell cycle phase; and induced GC cell apoptosis. Transcriptomic results revealed that norcantharidin affected biological processes, such as cell adhesion, migration, and inflammatory responses by influencing PI3K-AKT, NF-κB, JAK-STAT, TNF-α signaling pathways, and EMT-related pathways. Core molecules of norcantharidin involved in GC intervention include SERPINE1, SHOX2, SOX4, PRDM1, TGFR3, TOX, PAX9, IL2RB, LAG3, and IL15RA. Additionally, the key target SERPINE1 was identified using bioinformatics methods. Conclusion: Norcantharidin, as an effective component of anti-tumor pCm, exerts its therapeutic effects on GC by influencing biological processes such as cell adhesion, migration, and inflammation. This study provides a foundation and research strategy for the post-marketing re-evaluation of antitumor pCms. [ABSTRACT FROM AUTHOR]

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases. The role of coagulation factor FXII in diabetic kidney disease (DKD) remains unknown. Here, the authors show that zymogen FXII induces kidney injury via receptor (uPAR)-mediated signaling by inducing oxidative DNA damage and senescence, identifying new potential therapeutic targets for DKD. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion Di (2‐ethylhexyl) phthalate (DEHP) plasticizer must be removed from polyvinylchloride (PVC) medical devices due to toxicity. DEHP/PVC blood bags were shown to provide stable quality under blood component production and to create good storage conditions for red blood cells concentrate (RBC). It is important that substitution of the DEHP maintains the RBC quality during storage, which should be achieved with Di (isononyl) cyclohexane‐1,2‐dicarboxylate (DINCH), although substitution of the plasticizer has been challenging.A DEHP‐free Top & Bottom in‐line RBC set was validated in a tertiary hospital blood bank facility. Volunteer blood donors were randomly allocated for blood collection into DINCH/PVC or DEHP/PVC set. The groups were additionally divided according to additive solution/filter combination: PAGGS‐M + DINCH/PVC filter (only with DINCH/PVC set), and SAG‐M + DINCH/PVC filter and SAG‐M + DEHP/PVC filter (only with DEHP/PVC set). Processing and storage effects were assessed in all components.RBC concentrates, platelet concentrates and plasma that was processed and stored in DEHP‐free set fulfilled European requirements for quality. The cells stored in PAGGS‐M after filtration through DEHP‐free PVC filter showed the same low haemolysis compared with conventional set at 49 days of storage. Platelets stored in DINCH/PVC bag provided a sufficient quality of platelets after 7 days of storage. Plasma maintained the coagulation factors during 12 months of storage.A new DINCH/PVC set allows production of blood components of satisfactory quality in DEHP‐free environment. [ABSTRACT FROM AUTHOR]

Background Nephrotic syndrome (NS) is characterized by urinary loss of proteins, including hormones and their carrier proteins, potentially resulting in endocrine disorders. This study aimed to assess thyroid dysfunction frequency and potential implications in NS. Methods In this case–control study, patients with severe NS (serum albumin ≤2.5 g/dl) and controls without proteinuria were evaluated for thyroid, haemostatic and nutritional parameters, including body composition. Results A total of 42 nephrotic and 40 non-proteinuric patients were enrolled. The NS group showed higher thyroid-stimulating hormone and lower free hormones, corresponding to a higher frequency of both euthyroid sick syndrome {ESS; 36% versus 5%; odds ratio [OR] 10.6 [95% confidence interval (CI) 2.2–50.0]} and hypothyroidism [31% versus 5%; OR 8.5 (95% CI 1.8–40.7)] compared with the control group. Levothyroxine supplementation was required for 11 NS patients (26% of the NS group). In addition, compared with control individuals, NS patients exhibited lower lean tissue mass and a trend towards hypercoagulability, which was evidenced by higher levels of most coagulation factors and fibrinolysis inhibitors, and reduced endogenous anticoagulants activities. Furthermore, NS patients with ESS presented with a 10.4 kg (95% CI −18.68 to −2.12) lower lean tissue mass. Those with hypothyroidism had significantly reduced activity of coagulation factor X [by −30% (95% CI −47 to −13)] and protein S [by −27% (95% CI −41 to −13)] compared with euthyroid NS individuals. Conclusions Thyroid dysfunction is common in severe NS, often necessitating levothyroxine supplementation, which supports routine thyroid workup. A potential link between thyroid, nutritional and coagulation disorders in NS requires further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Congenital factor V (FV) deficiency is a rare clotting disorder affecting ∼1 in 1,000,000, with bleeding severity that ranges broadly for poorly understood reasons. Aim: To help understand the molecular basis of the observed phenotype in FV deficient patients, the genetics and biochemistry causing a patient's FV deficiency were evaluated. Methods and Results: A 71‐year‐old female, who had serious life‐long bleeding upon provocation and profound menorrhagia that lead to hysterectomy, was found to have 3% of normal plasma FV antigen with normal electrophoretic mobility. Platelet FV was similarly low, although the banding pattern was less fragmented than normal. Plasma clotting activity was <1% of normal. Familial inheritance and DNA sequence analysis from peripheral blood leukocytes were consistent with novel compound heterozygosity with missense mutations in exon XVII, Leu1821 to Ser (L1821S) and exon XXV, Gly2192 to Cys (G2192C). The respective single‐mutation variants were expressed and purified. Explaining why the antigen level and activity were inequivalent, thrombin activation of recombinant (r) FV/L1821S was impaired, and rFV/G2192C was unable to bind to a procoagulant phospholipid membrane. Conclusion: These findings are consistent with the observed phenotype, highlighting the importance of understanding FV biochemical function to rationalize clinical bleeding severity when the circulating antigen level is discordant. [ABSTRACT FROM AUTHOR]

Introduction: Patients with von Willebrand disease (VWD) require administration of von Willebrand factor (VWF) concentrates peri‐operatively. Concerns about FVIII accumulation after repetitive injections of a 1:1 ratio VWF/FVIII clotting factor concentrate (CFC) led this study to explore the recovery and FVIII accumulation over time. Methods: This monocentre study examined patients with VWD receiving perioperative 1:1 ratio CFC infusions. CFC dosing was based on body weight and endogenous VWF/FVIII activity. FVIII and VWF activity was monitored at T0 (baseline), T1 (15 min postinfusion), and trough levels at T2‐T6 (24‐120 h). Results: We included 125 patients, undergoing 125 procedures (63 major surgeries, 62 minor), with a median of two CFC infusions (IQR 1–3). With a mean administered dose of 35.7 IU/kg CFC, recovery rates of FVIII and VWF were 2.6 IU/dL per IU/kg and 2.4 IU/dL per IU/kg, respectively. Mean FVIII levels at T0 were 62 (SD 51.9), T1: 164 (SD 80.4), T2: 155 (SD 62.8), T3: 162 (SD 59.8), T4: 124 (SD 78.4), and T5: 120 (SD 65.3) IU/dL. Mean VWF activity levels at T0 were 29 (SD 25.0), T1: 133 (SD 43.7), T2: 92 (SD 37.2), and T3: 86 (SD 37.5) IU/dL. Subgroup analysis in 47 patients with more than three infusions, showed no accumulation of mean FVIII levels. Conclusion: This perioperative study demonstrated excellent FVIII and VWF recovery of a 1:1 ratio VWF product in patients with VWD. Stable FVIII and VWF activity levels were observed after repeated infusions, without accumulation. Most major surgeries required only three CFC infusions. [ABSTRACT FROM AUTHOR]

Background: Fresh frozen plasma (FFP) transfusions have been the mainstay of hemostatic intervention for the treatment of bleeding and coagulation abnormalities arising during liver transplantation (LT) for decades. However, numerous clinical studies showed that FFP has many side effects, including the risk of pathogen transmission, transfusion-associated circulatory overload (TACO), transfusion-related immunomodulation (TRIM), and transfusion-related acute lung injury (TRALI). These adverse events are particularly challenging in patients undergoing LT, who often suffer from severe portal hypertension, poor renal function and coexisting cardiac disease.The aims of this review are to summarize the pharmacological properties of currently available PCCs, to represent the theoretical benefits and the possible risks related to the use of these drugs in patients undergoing LT, and, finally, to review the current literature on the topic in order to highlight the evidence that currently supports PCC use in LT patients. Methods: The current literature on the topic was reviewed in order to highlight the evidence that currently supports PCC use in LT patients. Results: Prothrombin complex concentrates (PCCs) may offer several advantages when compared to FFP. Indeed, PCCs have been shown to reduce the risk of TACO, which during liver transplantation may deteriorate portal hypertension, increase intraoperative bleeding, and possibly reduce survival rates. One of the major concerns for PCC use is thrombogenicity. However, currently available PCCs are much safer as they contain inactivated forms of the vitamin K-dependent coagulation factors and protein C, protein S, antithrombin and/or heparin. Nowadays, the use of PCCs to correct coagulation abnormalities that occur during LT is an increasingly widespread practice. However, it is not yet clear what level of evidence supports this practice, and what the risks associated with it are. Conclusions: Administration of PCC in LT patients to correct haemostatic abnormalities seems to be well-tolerated, but the relationship between PCC use and thromboembolic events in the postoperative period remains unclear. Adequately powered, methodologically sound trials are urgently required for more definitive conclusions about the efficacy and safety of PCCs in a broad phenotype of LT recipients. [ABSTRACT FROM AUTHOR]

Background: Consumption coagulopathy and hemorrhagic syndrome are the typical features of Bothrops sp. snake envenoming. In contrast, B. lanceolatus envenoming can induce thrombotic complications. Our aim was to test whether crude B. lanceolatus and B. atrox venoms would display procoagulant activity and induce thrombus formation under flow conditions. Methods and Principal Findings: Fibrin formation in human plasma was observed for B. lanceolatus venom at 250–1000 ng/mL concentrations, which also induced clot formation in purified human fibrinogen, indicating thrombin-like activity. The degradation of fibrinogen confirmed the fibrinogenolytic activity of B. lanceolatus venom. B. lanceolatus venom displayed consistent thrombin-like and kallikrein-like activity increases in plasma conditions. The well-known procoagulant B. atrox venom activated plasmatic coagulation factors in vitro and induced firm thrombus formation under high shear rate conditions. In contrast, B. lanceolatus venom induced the formation of fragile thrombi that could not resist shear stress. Conclusions: Our results suggest that crude B. lanceolatus venom displays amidolytic activity and can activate the coagulation cascade, leading to prothrombin activation. B. lanceolatus venom induces the formation of an unstable thrombus under flow conditions, which can be prevented by the specific monovalent antivenom Bothrofav®. [ABSTRACT FROM AUTHOR]

Significant advancements have shaped the landscape of anticoagulant therapy in the past two decades, including the introduction of direct oral anticoagulants (DOACs), characterized by favorable safety and efficacy profiles and reduced drug-to-drug or food interaction resulting in excellent patient compliance. However, residual concerns still exist with standard-of-care anticoagulant therapy, including the inability to use DOACs in several clinical settings and the need to further reduce the risk of bleeding. Recent improvements in the understanding of the mechanisms behind thrombus formation have led to the awareness that the intrinsic pathway of the coagulation cascade may play an important role in pathological thrombosis, but not in hemostasis. This has represented the rationale for targeting this pathway with factor XI (FXI) inhibitors, with the aim of uncoupling hemostasis and thrombosis. Clinical evidence from patients with FXI deficiency further supports this concept. A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). To date, the majority of available trials have not gone beyond completion of phase 2 and results are conflictive making it difficult to appraise the clinical benefit of these compounds in the different clinical settings where they have been tested (i.e., atrial fibrillation, acute ischemic stroke, acute myocardial infarction, end-stage renal disease, total knee arthroplasty). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs. [ABSTRACT FROM AUTHOR]