5,247 results on '"Factor Xa"'
Search Results
52. Reports from Taipei Tzu Chi Hospital Highlight Recent Findings in Deep Vein Thrombosis (The Comparative Efficacy and Safety of Factor Xa Inhibitors and Warfarin for Primary Thromboprophylaxis In Multiple Myeloma Patients Undergoing...).
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VENOUS thrombosis ,MULTIPLE myeloma ,WARFARIN ,SAFETY factor in engineering ,BLOOD protein disorders - Abstract
A recent study conducted at Taipei Tzu Chi Hospital in New Taipei, Taiwan compared the efficacy and safety of factor Xa inhibitors and warfarin for primary thromboprophylaxis in multiple myeloma (MM) patients undergoing immunomodulatory therapy. The study found that factor Xa inhibitors had similar risk of deep vein thrombosis and pulmonary embolism compared to warfarin. There were no differences in the risk of bleeding, but factor Xa inhibitor-treated patients had lower all-cause mortality compared to warfarin. These findings suggest that factor Xa inhibitors are a safe and effective alternative to warfarin for MM patients on immunomodulatory therapy. [Extracted from the article]
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- 2024
53. Research from Nanyang Technological University Has Provided New Data on Arthroplasty (Pharmacotherapy for Venous Thromboprophylaxis following Total Hip or Knee Arthroplasty: A Systematic Review and Network Meta-analysis).
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TOTAL knee replacement ,TOTAL hip replacement ,DRUG therapy ,ARTHROPLASTY ,BLOOD coagulation factors - Abstract
A recent study conducted by researchers at Nanyang Technological University in Singapore aimed to determine the most effective and safe pharmacological prophylaxis for venous thromboembolism (VTE) after hip or knee arthroplasty. The study analyzed 70 randomized clinical trials involving over 55,000 participants and compared the efficacy and safety of various medications. The findings suggest that factor Xa inhibitors, such as LMWH, are associated with reduced VTE without an increase in bleeding or mortality compared to other medications like warfarin and aspirin. This research provides valuable insights for healthcare professionals and patients in making informed decisions about VTE prevention after arthroplasty. [Extracted from the article]
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- 2024
54. Studies from University of Oklahoma Yield New Information about Factor Xa (Antithrombin Supplementation Attenuates Heparin Resistance In Plasma Spiked With Gla-domainless Factor Xa S195a In Vitro).
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A study conducted by researchers at the University of Oklahoma explores the use of antithrombin supplementation to attenuate heparin resistance induced by a mutant form of Factor Xa. The study found that maintaining high levels of heparin and supplementing with antithrombin effectively mitigated heparin resistance and compensated for the loss of tissue factor pathway inhibitor. The research provides valuable insights into the effectiveness and optimal dosage of antithrombin in this context. This study was supported by a Diversity and Inclusion Grant from the Society of Cardiovascular Anesthesiologists. [Extracted from the article]
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- 2024
55. "Unit Dose Formulation Of Antidotes For Factor Xa Inhibitors And Methods Of Using The Same" in Patent Application Approval Process (USPTO 20240189401).
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A patent application has been filed for a unit dose formulation of antidotes for factor Xa inhibitors, which are commonly used as anticoagulant therapies. The formulation includes a polypeptide that can neutralize the factor Xa inhibitor and a pharmaceutically acceptable carrier. The patent application also discusses methods of administering the formulation to selectively bind and inhibit the factor Xa inhibitor, as well as preventing or reducing bleeding in patients undergoing anticoagulant therapy. The invention also includes a kit comprising the factor Xa inhibitor and the antidote. The patent application provides specific dosage ranges and administration methods for the formulation. [Extracted from the article]
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- 2024
56. Joao de Barros Barreto University Hospital Researchers Publish New Data on Intracranial Hemorrhages [Andexanet Alfa versus Four-Factor Prothrombin Complex Concentrate for the Reversal of Factor Xa (FXa) Inhibitor-Associated Intracranial...].
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INTRACRANIAL hemorrhage ,PROTHROMBIN ,BLOOD coagulation factors ,UNIVERSITY hospitals ,RESEARCH personnel - Abstract
Researchers from Joao de Barros Barreto University Hospital in Belem, Brazil, have conducted a systematic literature review comparing the efficacy of Andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) for the reversal of factor Xa inhibitor-associated intracranial hemorrhage (ICH). The review included retrospective studies that evaluated both drugs in terms of bleeding control, complications, and mortality. The qualitative analysis suggests that AA may have a better efficacy profile compared to 4F-PCC, but further studies and a collaborative network are needed to monitor these patients. The research was funded by Propesp-ufpa and published in the Journal of Clinical Medicine. [Extracted from the article]
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- 2024
57. Researchers at Yale University School of Medicine Release New Data on Peripheral Artery Disease (Comparative Outcomes of Peripheral Vascular Interventions In Patients On Chronic Anticoagulation With Factor Xa Inhibitors and Vitamin K Antagonists).
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PERIPHERAL vascular diseases ,ANTICOAGULANTS ,ANKLE brachial index ,RESEARCH personnel ,BLOOD coagulation factors ,DATA release ,DABIGATRAN - Abstract
A recent study conducted by researchers at Yale University School of Medicine compared the outcomes of patients with peripheral artery disease (PAD) who underwent peripheral vascular intervention (PVI) and were on chronic anticoagulation with either Factor Xa inhibitors (FXaI) or vitamin K antagonists (VKA). The study found that patients on FXaI had improved limb and cardiovascular outcomes compared to those on VKA. Patients on VKA had higher rates of hematoma following PVI and were more likely to experience major amputation and mortality. The study suggests that FXaI should be the preferred agents for chronic anticoagulation in patients with PAD undergoing PVI. [Extracted from the article]
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- 2024
58. Kinetic analysis of prothrombinase assembly and substrate delivery mechanisms.
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Gantseva, A.R., Gantseva, E.R., Sveshnikova, A.N., Panteleev, M.A., and Kovalenko, T.A.
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BLOOD coagulation factors , *BLOOD coagulation , *PROTHROMBIN , *BLOOD coagulation factor X , *THROMBIN , *THROMBIN receptors , *ENZYMES - Abstract
• A mechanisms-driven model of prothrombin activation by prothrombinase was designed. • Pathways of FII or Xa binding to FVa depended on the reactants' concentrations. • Large FVa concentration had inhibitory effect due to the membrane occupation by FVa. Prothrombinase complex, composed of coagulation factors Xa (FXa) and Va (FVa) is a major enzyme of the blood coagulation network that produces thrombin via activation of its inactive precursor prothrombin (FII) on the surface of phospholipid membranes. However, pathways and mechanisms of prothrombinase formation and substrate delivery are still discussed. Here we designed a novel mathematical model that considered different potential pathways of FXa or FII binding (from the membrane or from solution) and analyzed the kinetics of thrombin formation in the presence of a wide range of reactants concentrations. We observed the inhibitory effect of large FVa concentrations and this effect was phospholipid concentration-dependent. We predicted that efficient FII activation occurred via formation of the ternary complex, in which FVa, FXa and FII were in the membrane-bound state. Prothrombin delivery was mostly membrane-dependent, but delivery from solution was predominant under conditions of phospholipid deficiency or FXa/FVa excess. Likewise, FXa delivery from solution was predominant in the case of FVa excess, but high FII did not switch the FXa delivery to the solution-dependent one. Additionally, the FXa delivery pathway did not depend on the phospholipid concentration, being the membrane-dependent one even in case of the phospholipid deficiency. These results suggest a flexible mechanism of prothrombinase functioning which utilizes different complex formation and even inhibitory mechanisms depending on conditions. [ABSTRACT FROM AUTHOR]
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- 2024
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59. A common protein C inhibitor exosite partially controls the heparin induced activation and inhibition of serine proteases.
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Siddiqui, Urfi, Khan, Abdul Burhan, Ahmad, Tahif, Rehman, Ahmed Abdur, and Jairajpuri, Mohamad Aman
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THROMBIN receptors , *PROTEIN C , *BLOOD coagulation factor IX , *HEPARIN , *WESTERN immunoblotting , *THROMBIN - Abstract
Protein C inhibitor (PCI) maintains hemostasis by inhibiting both procoagulant and anticoagulant serine proteases, and plays important roles in coagulation, fibrinolysis, reproduction, and anti-angiogenesis. The reactive site loop of PCI traps and irreversibly inhibits the proteases like APC (activating protein C), thrombin (FIIa) and factor Xa (FXa). Previous studies on antithrombin (ATIII) had identified Tyr253 and Glu255 as functional exosites that interact and aid in the inhibition of factor IXa and FXa. Presence of exosite in PCI is not known, however a sequence comparison with the PCI from different vertebrate species and ATIII identified Glu239 to be absolutely conserved. PCI residues analogous to ATIII exosite residues were mutated to R238A and E239A. Purified variant PCI in the presence of heparin (10 μg/ml) showed a 2–4 fold decrease in the rate of inhibition of the proteases. However, the stoichiometry of inhibition of FIIa, APC, and FXa by native PCI, R238A and E239A variants were found to be close to 1.0, which also indicated the formation of stable complexes based on SDS-PAGE and western blot analysis with thrombin and APC. Our findings revealed the possible presence of an exosite in PCI that influences the protease inhibition rates. [ABSTRACT FROM AUTHOR]
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- 2024
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60. Anticoagulant profile of subcutaneous enoxaparin in healthy dogs.
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Frum, Julianna, Havill, Katie, Andrews, Caroline, Langston, Cory, Brooks, Marjory B., Archer, Todd, Mackin, Andrew, and Thomason, John
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ENOXAPARIN , *ANTICOAGULANTS , *DOGS , *BEAGLE (Dog breed) , *PHARMACOKINETICS , *HEPARIN , *DRUG dosage - Abstract
Our study objective was to identify a subcutaneous enoxaparin dosage that provided a consistent anticoagulant intensity in dogs. Our hypotheses were that a dose of 0.8 mg/kg would provide inconsistent anticoagulation, a higher dose would provide consistent anticoagulation over a greater duration of time, and viscoelastometry would effectively monitor the anticoagulant status. Six healthy dogs received two subcutaneous enoxaparin doses (0.8 and 2 mg/kg) for anti‐Xa activity determinations and pharmacokinetic modeling. Based on calculations derived from these results, 1.3 mg/kg, SC, q8 h was administered for seven doses. Target ranges for anticoagulant intensity were defined as anti‐Xa activity of 0.5–1 U/ml, and change from baseline of two viscoelastometric parameters: activated clotting time (ΔACT; ≥40 s), and clot rate (CRpost; ≤20 U/min). Following an initial injection at 1.3 mg/kg, anti‐Xa activity of 5/6 dogs reached or exceeded the target range. Following the final dose, anti‐Xa activity reached or exceeded the target range in all dogs, and ΔACT and CRpost values exceeded target for 2–6 and 4–12 h, respectively. At an enoxaparin dosage of 1.3 mg/kg, SC, q8 h, anti‐Xa activity was consistently above the minimum threshold of the target range; however, the safety of this dosage remains to be determined. [ABSTRACT FROM AUTHOR]
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- 2022
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61. Prediction of inhibition constants of (R)-3-amidinophenylalanine inhibitors toward factor Xa by 2D-QSAR model
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Thi Bich Van Pham and Minh Hao Hoang
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coagulation cascade ,descriptors ,factor Xa ,(R)-3-amidinophenylalanine inhibitors ,2D-QSAR ,Science - Abstract
A coagulation cascade forms through proteolytic reactions and involves different factors. There are two coagulation pathways, including intrinsic and extrinsic mechanisms, which converge by the formation of factor Xa. Factor Xa plays a crucial role in the formation of the complex with factor Va in the presence of calcium ions and phospholipids. This complex converts prothrombin to thrombin, which leads to the formation of a very strong fibrin clot. Much effort has been devoted to the efficient interference of this enzyme cascade by the inhibition of factor Xa due to its important effect. (R)-3-amidinophenylalanine inhibitors are known inhibitors of factor Xa reported so far. In the present work, a two-dimensional quantitative structure activity relationship (2D-QSAR) was performed on 50 (R)-3-amidinophenylalanine inhibitors (the training set) with respect to their pKi values toward factor Xa, where pKi=-logKi, and Ki is the inhibition constant, to develop a mathematical model that depends on the physicochemical properties of the inhibitors. Partial least squares regression (PLSR) was used to yield a QSAR model containing molecular descriptors that significantly contribute to pKi values. The statistically significant parameters of the model, such as squared correlation coefficient, R2=0.834, root mean square error, RMSE=0.210, cross-validated Q2cv=0.789, and cross-validated RMSEcv=0.237, were obtained for the training set. The developed 2D-QSAR model was applied to predict the pKi values of the 62 inhibitors. Furthermore, the reliability of the model was also confirmed via statistically significant parameters obtained from validation on an external set.
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- 2022
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62. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry
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Edward R Kastenhuber, Marisa Mercadante, Benjamin Nilsson-Payant, Jared L Johnson, Javier A Jaimes, Frauke Muecksch, Yiska Weisblum, Yaron Bram, Vasuretha Chandar, Gary R Whittaker, Benjamin R tenOever, Robert E Schwartz, and Lewis Cantley
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SARS-CoV-2 ,coronavirus ,coagulopathy ,factor Xa ,anticoagulants ,nafamostat ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases and coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.
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- 2022
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63. Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation
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Rahul H. Rayani, Jigar Y. Soni, Deepa R. Parmar, Rakesh V. Kusurkar, Ibrahim.H. Eissae, Ahmed M. Metwaly, Ahmed Khalil, Vishwanath Zunjar, Satyanarayana Battula, and Sarfaraj Niazi
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ADMET ,Anti-coagulation ,DFT study ,Factor Xa ,Molecular docking ,Pyrazolyl piperidine ,Chemistry ,QD1-999 - Abstract
Coagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this study, we reported the design and synthesis of pyrazolyl piperidine analogs 4(a–h) as a new class of anticoagulant drug candidates. Among the synthesized analogs 4(a–h), compound 4a consisting of the 4-chlorophenyl substitution displayed the highest in vitro FXa inhibition activity with an IC50 value of 13.4 nM. The PT and aPTT assay indicated that compound 4a showed good anticoagulation activity compared to Heparin. Furthermore, docking studies suggested that the synthesized analogs displayed binding modes similar to the cocrystallized Rivaroxaban ligand. In addition, in-silico ADMET and DFT studies were carried out for all the designed compounds. Together, our study suggests that the compound (4a) displayed anti-coagulant activity through the inhibition of FXa.
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- 2022
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64. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
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Connolly, Stuart J, Milling, Truman J, Eikelboom, John W, Gibson, C Michael, Curnutte, John T, Gold, Alex, Bronson, Michele D, Lu, Genmin, Conley, Pamela B, Verhamme, Peter, Schmidt, Jeannot, Middeldorp, Saskia, Cohen, Alexander T, Beyer-Westendorf, Jan, Albaladejo, Pierre, Lopez-Sendon, Jose, Goodman, Shelly, Leeds, Janet, Wiens, Brian L, Siegal, Deborah M, Zotova, Elena, Meeks, Brandi, Nakamya, Juliet, Lim, W Ting, and Crowther, Mark
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Hematology ,Clinical Research ,Cardiovascular ,Acute Disease ,Aged ,Aged ,80 and over ,Cardiovascular Diseases ,Enoxaparin ,Factor Xa ,Factor Xa Inhibitors ,Female ,Gastrointestinal Hemorrhage ,Hemorrhage ,Humans ,Infusions ,Intravenous ,Intracranial Hemorrhages ,Male ,Prospective Studies ,Pyrazoles ,Pyridones ,Recombinant Proteins ,Rivaroxaban ,Thrombosis ,ANNEXA-4 Investigators ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundAndexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.MethodsIn this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.ResultsThe mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.ConclusionsOn the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).
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- 2016
65. The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms.
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Chowdhury, Abhinandan, Lewin, Matthew R., Zdenek, Christina N., Carter, Rebecca, and Fry, Bryan G.
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VENOM ,COBRAS ,SPIDER venom ,SMALL molecules ,ANTIVENINS ,ANTICOAGULANTS - Abstract
African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A
2 (Group I PLA2 ) toxins whose activity contributes to the lethality of these species. This anticoagulant toxicity is particularly problematic as it is not neutralized by current antivenoms. Previous work demonstrated this trait for Naja mossambica, N. nigricincta , N. nigricollis , and N. pallida. The present work builds upon previous research by testing across the full taxonomical range of African spitting cobras, demonstrating that N. ashei , N. katiensis , and N. nubiae are also potently anticoagulant through the inhibition of Factor Xa, and therefore the amplification of potent anticoagulant activity occurred at the base of the African spitting cobra radiation. Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta , N. nigricollis , and N. pallida venoms. The current work demonstrates that varespladib was also able to neutralize N. ashei , N. katiensis , and N. nubiae. Thus varespladib is shown to have broad utility across the full range of African spitting cobras. In addition, we examined the cross-reactivity of the metalloprotease inhibitor prinomastat, which had been previously intriguingly indicated as being capable of neutralizing viperid venom PLA2 (Group II PLA2 ). In this study prinomastat inhibited the FXa-inhibiting PLA2 toxins of all the African spitting cobras at the same concentration at which it has been shown to inhibit metalloproteases, and thus was comparably effective in its cross-reactivity. In addition we showed that the metalloprotease-inhibitor marimastat was also able to cross-neutralize PLA2 but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized. [ABSTRACT FROM AUTHOR]- Published
- 2021
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66. Characterization of thrombin/factor Xa inhibitors in Rhizoma Chuanxiong through UPLC-MS-based multivariate statistical analysis
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Yi-Yao Yang, Zhao-Yu Wu, Fang-Bo Xia, Hao Zhang, Xu Wang, Jian-Li Gao, Feng-Qing Yang, and Jian-Bo Wan
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Chuanxiong ,Thrombin ,Factor Xa ,Enzyme inhibitor ,Multivariate statistical analysis ,Molecular docking ,Other systems of medicine ,RZ201-999 - Abstract
Abstract Background The dry root and rhizome of Ligusticum chuanxiong Hort., or Chuanxiong, has been used as a blood-activating and stasis-removing traditional Chinese medicine for 1000 years. Our previous studies have shown the inhibitory activity on platelet and thrombin (THR) of Chuanxiong. THR and factor Xa (FXa) play significant roles in the coagulation cascade and their inhibitors are of valuable in the treatment of thromboembolic diseases. The aim of the present study is to screen THR and FXa inhibitors from Chuanxiong. Methods Four extracts [ethyl acetate (EA), butanol (BA) and remained extract (RE) from 75% ethanol extract, and water extract (WE)] of Chuanxiong were prepared, and their THR/FXa inhibitory activities were assessed in vitro. Following silica-gel column chromatography (SC), the active EA extract and BA extract was further partitioned, respectively. Their active fractions (EA-SC1 to EA-SC5; BA-SC1 to BA-SC5) were obtained and analyzed by LC–MS. After modeling by the principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA), the specific marker compounds were predicted and identified. Their enzyme inhibitory was assessed in vitro and interactions with THR/FXa were investigated by molecular docking analysis. Results Chuanxiong EA extract showed strong activity against THR and BA extract was more effective in inhibiting FXa activity, and their fractions exhibited obvious difference in enzyme inhibitory activity. Furthermore, marker compounds a–h were predicted by PCA and OPLS-DA, and their chemical structures were identified. Among them, senkyunolide A, Z-ligustilide, ferulic acid and senkyunolide I (IC50 was determined as 0.77 mM) with potential THR inhibitory activity, as well as isochlorogenic acid A with FXa inhibitory activity were screened out. It was found that the four components could interact with the active site of THR, and the binding energy was lower than − 5 kcal/mol. Isochlorogenic acid A were bound to the active site of FXa, and the binding energy was − 9.39 kcal/mol. The IC50 was determined as 0.56 mM. Conclusions THR/FXa inhibitory components in different extracts of Chuanxiong were successfully characterized by the method of enzyme inhibition activity assays with ultra performance liquid chromatography-quadrupole time of flight mass spectrometry-based multivariate statistical analysis.
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- 2020
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67. LC–MS-based multivariate statistical analysis for the screening of potential thrombin/factor Xa inhibitors from Radix Salvia Miltiorrhiza
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Yi-Yao Yang, Zhao-Yu Wu, Hao Zhang, Shi-Jun Yin, Fang-Bo Xia, Qian Zhang, Jian-Bo Wan, Jian-Li Gao, and Feng-Qing Yang
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Radix Salvia Miltiorrhiza ,Thrombin ,Factor Xa ,Inhibitor screening ,Multivariate statistical analysis ,Molecular docking ,Other systems of medicine ,RZ201-999 - Abstract
Abstract Background The dry root and rhizome of Salvia miltiorrhiza Bunge, or Danshen, is a well-known traditional Chinese medicine with anticoagulant activity. Taking into account that thrombin (THR) and factor Xa (FXa) play crucial roles in the coagulation cascade, it is reasonable and meaningful to screening THR and/or FXa inhibitors from Danshen. Methods Four extracts [butanol (BA), ethyl acetate (EA) and remained extract (RE) from 75% ethanol extract, and water extract (WE)] of Danshen were prepared, and their THR/FXa inhibitory activities were assessed in vitro. Then, the active EA extract was further separated by silica-gel column chromatography (SC), and its fractions (SC1–SC5) were analyzed by LC–MS. The principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA) were employed for predicting the specific marker compounds. The chemical structures of targeted compounds were identified by LC–MS/MS and their interactions with THR/FXa were analyzed by the molecular docking analysis. Results Danshen EA extract showed strong activity against THR and FXa, and its fractions (SC1–SC5) exhibited obvious difference in inhibitory activity against these two enzymes. Furthermore, four marker compounds with potential THR/FXa inhibitory activity were screened by PCA and OPLS-DA, and were identified as cryptotanshinone, tanshinone I, dihydrotanshinone I and tanshinone IIA. The molecular docking study showed that all these four tanshinones can interact with some key amino acid residues of the THR/FXa active cavities, such as HIS57 and SER195, which were considered to be promising candidates targeting THR and/or FXa with low binding energy (
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- 2020
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68. Non-vitamin K oral antagonist failure and tailored treatment in patients with atrial fibrillation and stroke
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Hyung Jun Kim, Soyoun Choi, Hee-Jin Kim, and Oh Young Bang
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atrial fibrillation ,cerebral infarction ,edoxaban ,factor xa ,Medicine - Abstract
In case of any embolic event, treatment strategy should be established according to the pathomechanisms of failure of non-vitamin K oral anticoagulants (NOAC). A 72-year-old man was referred to our hospital with a sudden speech disturbance. Diffusion-weighted imaging revealed cerebral infarction in the left middle cerebral artery territory. The patient had been diagnosed with nonvalvular atrial fibrillation 3 years ago and was administered a dose of 60 mg edoxaban/day. Anti-Xa and factor Xa activity assay confirmed the effect of this drug. A detailed transthoracic and transesophageal echocardiography revealed fibroelastoma of mitral valve, atrial septal defect, and spontaneous echo contrast in the left atrial appendage. Although the drug was effective, cardioembolism occurred and hence we decided to perform surgery. As the etiology of NOAC failure varies, anti-Xa and factor Xa activity assays help to determine the cause modifying the treatment strategy accordingly.
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- 2020
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69. Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients
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José A. Fernández, Hiroshi Deguchi, Darlene J. Elias, and John H. Griffin
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factor Xa ,prothrombinase ,serum amyloid A ,serum amyloid A4 ,venous thrombosis ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background Serum amyloid A4 (SAA4) is an apolipoprotein that is in the SAA family and it is constitutively translated. Previously, acute‐phase SAA1 and SAA2 levels were associated with venous thromboembolism (VTE). Objective We investigated the association of plasma SAA4 with VTE and the role of SAA4 in coagulation. Patients and Methods The association of SAA4 with VTE in a case‐control study of adult VTE subjects (N = 113 each group) and the effects of recombinant SAA4 on plasma blood coagulation assays and prothrombin activation initiated by factor Xa were evaluated. Results Plasma SAA4 levels in VTE subjects were higher vs. controls (48.1 vs. 38.4 µg/mL; P
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- 2020
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70. Factor Xa Inhibition, A New Strategy for Prevention of Adverse Cardiac Remodeling in Early Stages?∗
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Biykem Bozkurt, MD, PhD
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anticoagulation ,direct oral anticoagulant ,factor X ,factor Xa ,fibrosis ,heart failure ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2020
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71. Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
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Yanpeng Ma, Yong Zhang, Chuan Qiu, Chunhui He, Ting He, Shuang Shi, and Zhongwei Liu
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atherosclerosis ,macrophage ,vascular smooth muscle cell ,polarization ,phenotypic conversion ,factor Xa ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS.Methods: Rivaroxaban was administered to AS mice. Primary macrophages were exposed to FXa, treated with rivaroxaban, and transfected with siRNA silencing protease-activated receptor 2 (PAR2), hypoxia-inducible factor 1α (HIF1α), delta-like receptor 4 (Dll4), and Akt. Interaction between macrophages and VSMCs was assessed by co-culturing systems. Atherosclerotic lesions were evaluated by oil red O stain. Fluorescent staining was used to determine the cell phenotypes. Secretions of inflammatory cytokines and collagen were assessed by ELISA and Sircol assays. Western blotting was used to evaluate the protein expression and phosphorylation levels.Results: Rivaroxaban reduced lesion area, accumulation of M1 macrophages, and contractile-synthetic phenotypic conversion of VSMCs in atherosclerotic plaques. FXa exposure induced polarization of macrophages toward M1 and Dll4 high expression, which were inhibited by PAR2, Akt1, and HIF1α silencing. Rivaroxaban treatment inhibited PAR2/Akt/HIF1α signaling activation and Dll4 expression in FXa-exposed macrophages. By cell-to-cell contact, M1 macrophages induced Notch signaling activation in VSMCs which committed contractile-synthetic conversion. Rivaroxaban treatment and Dll4 silencing incapacitated macrophage in inducing phenotypic conversion of VSMCs upon cell-to-cell contact.Conclusion: Rivaroxaban suppresses AS by inhibiting FXa-induced PAR2/Akt/HIF1α signaling activation-mediated macrophage M1 polarization and high Dll4 expression. These macrophages facilitated VSMCs to perform contractile-synthetic phenotypic conversion upon macrophage-VSMCs cell-to-cell contact.
- Published
- 2021
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72. The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms
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Abhinandan Chowdhury, Matthew R. Lewin, Christina N. Zdenek, Rebecca Carter, and Bryan G. Fry
- Subjects
venom ,anticoagulant ,Factor Xa ,enzyme ,inhibitor ,Immunologic diseases. Allergy ,RC581-607 - Abstract
African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A2 (Group I PLA2) toxins whose activity contributes to the lethality of these species. This anticoagulant toxicity is particularly problematic as it is not neutralized by current antivenoms. Previous work demonstrated this trait for Naja mossambica, N. nigricincta, N. nigricollis, and N. pallida. The present work builds upon previous research by testing across the full taxonomical range of African spitting cobras, demonstrating that N. ashei, N. katiensis, and N. nubiae are also potently anticoagulant through the inhibition of Factor Xa, and therefore the amplification of potent anticoagulant activity occurred at the base of the African spitting cobra radiation. Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta, N. nigricollis, and N. pallida venoms. The current work demonstrates that varespladib was also able to neutralize N. ashei, N. katiensis, and N. nubiae. Thus varespladib is shown to have broad utility across the full range of African spitting cobras. In addition, we examined the cross-reactivity of the metalloprotease inhibitor prinomastat, which had been previously intriguingly indicated as being capable of neutralizing viperid venom PLA2 (Group II PLA2). In this study prinomastat inhibited the FXa-inhibiting PLA2 toxins of all the African spitting cobras at the same concentration at which it has been shown to inhibit metalloproteases, and thus was comparably effective in its cross-reactivity. In addition we showed that the metalloprotease-inhibitor marimastat was also able to cross-neutralize PLA2 but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized.
- Published
- 2021
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73. Thrombin and Factor Xa Hydrolysis of Chromogenic Substrates in the Presence of Sulfated Derivatives of Galactomannan and Galactoglucomannan Natural Gels
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Natalia N. Drozd, Svetlana A. Kuznetsova, Yuriy N. Malyar, Aleksandr S. Kazachenko, Valentina S. Borovkova, and Yarosvala D. Berezhnaya
- Subjects
galactomannan sulfate ,galactoglucomannan sulfate ,chromogenic substrate ,thrombin ,factor Xa ,platelet aggregation ,Pharmacy and materia medica ,RS1-441 - Abstract
Polysaccharides are important structural components of all plant species. Gel-like polysaccharides have found wide application in various fields, including medicine, construction, and the food industry. In the present work, galactomannan and galactoglucomannan gel-like polysaccharides were modified with sulfate groups and their anticoagulant activity was studied. Sulfation with chlorosulfonic acid in pyridine and with sulfamic acid in pyridine and a sulfamic acid–urea deep eutectic solvent were used as synthesis routes. The resulting gel-like polysaccharide sulfates were studied by elemental analysis, Fourier-transform infrared spectroscopy, and gel permeation chromatography. It was established that the anticoagulant effect of sulfated galactoglucomannan (SGGM) and galactomannan (SGM-1 and SGM-2) is related to an independent antithrombin-independent decrease in the amidolytic activity of thrombin and factor Xa. It is shown that the inhibitory activity of SGGM and SGM-2 against the collagen-induced platelet aggregation can be an additional factor in selecting compounds that are most promising for modifying polymer surfaces to ensure resistance to blood clotting.
- Published
- 2022
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74. Reversal or Repletion Treatment Strategies and Outcomes of Patients With Major Bleeding Events Managed in the Emergency Department: Large Real-Life Investigation in the Northwestern Healthcare District of Tuscany.
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Conti A, Leorin M, Bogazzi IC, Renzi N, Pepe G, Frosini F, Furesi L, Dalla Tomasina L, Pennati P, and Ghiadoni L
- Subjects
- Humans, Male, Female, Aged, Italy epidemiology, Recombinant Proteins therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Vitamin K antagonists & inhibitors, Middle Aged, Factor Xa Inhibitors therapeutic use, Factor Xa Inhibitors adverse effects, Aged, 80 and over, Hemorrhage chemically induced, Hemorrhage epidemiology, Retrospective Studies, Gastrointestinal Hemorrhage chemically induced, Gastrointestinal Hemorrhage epidemiology, Incidence, Cerebral Hemorrhage chemically induced, Cerebral Hemorrhage epidemiology, Cerebral Hemorrhage drug therapy, Cerebral Hemorrhage mortality, Treatment Outcome, Factor Xa, Emergency Service, Hospital, Blood Coagulation Factors therapeutic use, Anticoagulants therapeutic use, Anticoagulants adverse effects
- Abstract
Objective: To verify the incidence of bleeding events in patients on ongoing anticoagulant treatment in the real world and compare the results of different reversal or repletion strategies currently available for pharmacological treatment., Methods: Patients managed in the emergency department (ED) with major bleeding events, on ongoing anticoagulation were stratified according to bleeding site and reversal or repletion therapy with andexanet alfa (ADX), idarucizumab (IDA), prothrombin complex concentrate (PCC), and vitamin K (Vit-K)., Endpoint: Death at 30 days was compared in the subgroups with cerebral hemorrhage (CH) and gastrointestinal (GI) bleeding., Results: Of the 809,397 visits in the years 2022-2023 at 6 EDs in the northwestern health district of Tuscany, 5372 patients with bleeding events were considered; 3740 were excluded due to minor bleeding or propensity score matching. Of the remaining 1632 patients with major bleeding, 548 on ongoing anticoagulation were enrolled; 334 received reversal or repletion agents. Patients with CH (n = 176) and GI bleeding (n = 108) represented the primary analysis cohorts in the study's strategic treatment assessment. Overall, 30-day survival of patients on ongoing aFXa treatment receiving on-label ADX versus off-label PCC showed a relative increase of 71%, while 30-day survival of patients on ongoing aFII receiving on-label IDA versus off-label PCC showed a relative increase of 30%; no substantial difference was found when comparing on-label PCC combined with Vit-K versus off-label Vit-K alone. Indeed, patients undergoing on-label ADX or IDA showed a statistically significant difference over off-label PCC (ADX vs. PCC: n = 15, events = 4, mean ± SD 82.50 ± 18.9, vs. 49, 13, 98.82 ± 27, respectively; analysis of variance [ANOVA] variance 8627; P < 0.001; posthoc test diff 32, 95% confidence interval: 28-35; P < 001; IDA vs. PCC: 20, 5, 32.29 ± 15.0 vs. 2, 1, 28.00 ± 0.0, respectively; ANOVA 1484; P < 0.001; posthoc test -29, -29 -29, respectively; P = n.d.). On-label PCC combined with Vit-K showed overall a slight statistically significant difference versus off-label Vit-K alone (52, 16, 100.58 ± 22.6 vs. 53, 11, 154.62 ± 29.8, respectively; ANOVA 310; P < 0.02; posthoc test 4, 0.7-7.2, respectively; P < 0.02). Data were confirmed in the group of patients with CH (ADX vs. PCC: n = 13, events = 3, mean ± SD 91.55 ± 18.6 vs. 78, 21, 108.91 ± 20.9, respectively; ANOVA variance 10,091, F = 261; P < 0.001; posthoc difference test 36, 95% confidence interval: 30-41; P < 0.001; IDA vs. PCC: 10, 2, 4.50 ± 2.5 vs. 78, 21, 108.91 ± 20.9, respectively; ANOVA 16,876,303, respectively; P < 0.001; posthoc test 41, 34-47, respectively; P < 0.001). On-label PCC combined with Vit-K showed an overall slight statistically significant difference compared with off-label Vit-K alone (P < 0.01 and P < 0.001 in the subgroups of CH and GI bleeding)., Conclusions: Patients undergoing specific reversal therapy with on-label ADX or IDA, when treated with aFXa or aFII anticoagulants, respectively, showed statistically elevated differences in 30-day death compared with off-label repletion therapy with PCC. Overall, 30-day survival of patients on ongoing aFXa or aFII receiving on-label reversal therapy with ADX or IDA compared with off-label PCC repletion agents showed an increase of 71% and 30%, respectively., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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75. [Heparin Resistance After Administration of Andexanet Alfa:Report of a Case].
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Aratame A, Baba T, Minamimura H, Nishimoto Y, and Nangoya R
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- Humans, Aged, Male, Drug Resistance, Anticoagulants administration & dosage, Anticoagulants therapeutic use, Anticoagulants adverse effects, Factor Xa, Coronary Artery Bypass, Rivaroxaban administration & dosage, Rivaroxaban therapeutic use, Heparin administration & dosage, Recombinant Proteins administration & dosage
- Abstract
The management of patients on direct oral anticoagulants (DOACs) who require an emergency cardiac surgery has been disputed in Japan. Recently, the use of andexanet alfa as an antidote for apixaban and rivaroxaban, is approved in the setting of life-threating or uncontrollable major bleeding. However, the efficacy and safety of andexanet alfa have been investigated. We report a case of 72-year-old man taking rivaroxaban who required the emergency coronary artery bypass grafting. He received andexanet alfa prior to the operation. Heparin resistance was noted before starting cardiopulmonary bypass. Consideration should be given to the use of andexanet alfa before or during cardiopulmonary bypass.
- Published
- 2024
76. Trauma coagulopathy: Insights from the PROCOAG and CRYOSTAT-2 trials. Coagulation factors are not antibiotics.
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Gauss T and Bouzat P
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- Humans, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents adverse effects, Factor VIIa therapeutic use, Recombinant Proteins, Factor Xa, Blood Coagulation Disorders drug therapy, Blood Coagulation Disorders etiology, Wounds and Injuries complications, Wounds and Injuries blood, Blood Coagulation Factors therapeutic use
- Published
- 2024
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77. Reversing Oral Anticoagulation in Intracerebral Hemorrhage.
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Smith WS and Hemphill JC
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- Humans, Administration, Oral, Factor Xa, Factor Xa Inhibitors adverse effects, Randomized Controlled Trials as Topic, Anticoagulants administration & dosage, Anticoagulants adverse effects, Anticoagulants therapeutic use, Cerebral Hemorrhage chemically induced, Cerebral Hemorrhage drug therapy
- Published
- 2024
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78. Factor Xa inhibitors versus low-molecular-weight heparin for preventing coagulopathy following COVID-19: a systematic review and meta-analysis of randomized controlled trials.
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Amin L, Qayyum K, Uzair M, Khan F, Sethi P, Hanif L, Azhar A, Mazhar S, Ejaz U, and Jawad S
- Abstract
Background: Hospitalized patients with COVID-19 have shown a significant occurrence of thromboembolism and a heightened risk of death. It remains unclear whether factor Xa inhibitors are superior to enoxaparin in this context. Hence, there is a need for a direct comparison to assess the preventive effects and safety of factor Xa inhibitors versus enoxaparin in hospitalized COVID-19 patients., Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) or retrospective studies that compared the effectiveness or safety of factor Xa inhibitors and enoxaparin in preventing thromboembolism in hospitalized patients with COVID-19. Embolic incidence, incidence of bleeding, and all-cause mortality were among the outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95 percent CIs., Results: The analysis included six RCTs and two retrospective studies containing 4048 patients. Meta-analysis showed a statistically significant reduction among patients on factor Xa inhibitors compared with low-molecular-weight heparin (LMWH) in the embolic incidence [risk ratio (RR) 0.64 (95%, CI 0.42, 0.98); P =0.04, I
2 =12%]. Upon subgroup analysis by type of study design, no significant reductions were noted in patients on factor Xa inhibitors in RCTs (RR: 0.62; 95% CI: 0.33-1.17; P =0.14) or observational studies (RR: 0.53; 95% CI: 0.23-1.26; P =0.15) when compared with enoxaparin Factor Xa inhibitors were not significantly associated with incidence of bleeding [RR 0.76 (95% CI 0.36, 1.61); P =0.47, I2 =0%] or all-cause mortality (RR: 0.81; 95% CI: 0.48-1.36; P =0.43). Consistent results were obtained upon subgroup analysis by the type of study design., Conclusion: Factor Xa inhibitors are more effective than enoxaparin in preventing thromboembolism among patients with COVID-19 who are not acutely ill and are hospitalized. Additional rigorous RCTs comparing factor Xa inhibitors with enoxaparin are warranted., Competing Interests: The authors declare no conflict of interests.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)- Published
- 2024
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79. Effective application of a direct-acting oral anticoagulants reversal agent in acute type A aortic dissection repair: A case report.
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Wakami T, Fukunaga N, Shimoji A, and Tamura N
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- Humans, Male, Aged, Treatment Outcome, Administration, Oral, Recombinant Proteins administration & dosage, Aortic Aneurysm, Thoracic surgery, Aortic Aneurysm, Thoracic diagnostic imaging, Cardiopulmonary Bypass, Blood Loss, Surgical prevention & control, Acute Disease, Factor Xa, Aortic Aneurysm surgery, Aortic Aneurysm diagnostic imaging, Aortic Dissection surgery, Aortic Dissection diagnostic imaging, Factor Xa Inhibitors administration & dosage, Factor Xa Inhibitors adverse effects, Blood Vessel Prosthesis Implantation adverse effects
- Abstract
There are insufficient reports on the use of andexanet alfa in cardiac surgery. A 67-year-old man was diagnosed with type A aortic dissection and performed emergent surgery. His medical history included atrial fibrillation treated with Edoxaban. We performed total arch replacement. Despite administration of enough protamine, fresh frozen plasma, and platelet administration, controlling bleeding was difficult. Thus, Andexanet Alfa was initiated after CPB withdrawal. Surgical bleeding was dramatically controlled after its administration. There were no findings suggestive of an embolic event. In conclusion, administration of Andexanet Alfa is safe after cardiopulmonary bypass withdrawal., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
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80. Total intracranial hemorrhage volume measurement summating all compartments best in traumatic and nontraumatic intracranial bleeding.
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Horn M, Banerjee A, Kasickova L, Volny O, Choi HS, Letteri F, Ohara T, Tanaka K, Connolly S, Ladenvall P, Crowther M, Beyer-Westendorf J, Shoamanesh A, Demchuk AM, and Al Sultan AS
- Subjects
- Humans, Male, Female, Middle Aged, Recombinant Proteins administration & dosage, Factor Xa Inhibitors administration & dosage, Factor Xa Inhibitors therapeutic use, Aged, Reproducibility of Results, Adult, Brain diagnostic imaging, Intracranial Hemorrhages, Factor Xa
- Abstract
Background and Purpose: The ANNEXA-4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume., Methods: Thirty patients were randomly selected from the ANNEXA-4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty-eight different ANNEXA-4 subjects were also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4., Results: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader., Conclusion: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)
- Published
- 2024
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81. Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants?
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Gendron N, Billoir P, Siguret V, Le Cam-Duchez V, Proulle V, Macchi L, Boissier E, Mouton C, De Maistre E, Gouin-Thibault I, and Jourdi G
- Subjects
- Humans, Administration, Oral, Factor Xa Inhibitors therapeutic use, Drug Monitoring methods, Antidotes therapeutic use, Anticoagulants therapeutic use, Recombinant Proteins, Factor Xa, Antibodies, Monoclonal, Humanized
- Abstract
Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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82. [Is monitoring of anti-factor Xa levels required for low molecular weight heparin prophylaxis of venous thromboembolism in critically ill patients?]
- Author
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Ding M, Ning Y, Song L, Li P, Xie F, Li S, and Wang C
- Subjects
- Humans, Anticoagulants therapeutic use, Anticoagulants administration & dosage, Factor Xa Inhibitors therapeutic use, Factor Xa Inhibitors administration & dosage, Factor Xa, Venous Thromboembolism prevention & control, Venous Thromboembolism etiology, Heparin, Low-Molecular-Weight therapeutic use, Heparin, Low-Molecular-Weight administration & dosage, Critical Illness
- Abstract
The incidence and mortality of venous thromboembolism (VTE) are high in critically ill patients, and there is still a risk of VTE and bleeding after the use of fixed-dose low molecular weight heparin (LMWH) for prophylaxis. The level of anti-factor Xa is not up to standard after LMWH prophylaxis in patients with surgery or trauma. The condition of critically ill patients is complicated, and the proportion of patients with low antithrombin III is high, which can affect the prophylactic efficacy of LMWH and contribute to VTE occurrence. There is currently no consensus on whether adjusting LMWH dose according to anti-factor Xa levels can reduce VTE occurrence in critically ill patients. High-quality multicenter randomized controlled studies are needed in the future to establish new approaches for precise prevention of VTE in critically ill patients.
- Published
- 2024
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83. Factor Xa inhibitors vs. warfarin in patients with Hughes syndrome: a systematic review and meta-analysis of randomized controlled trials.
- Author
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Mohtashim A, Azhar A, Mazhar S, Devi D, Danial M, Patel D, Khan O, Andani A, Khan MM, Samad S, Qureshi A, Ali H, Ejaz U, and Jawad S
- Abstract
Background: The optimal treatment regimen for patients with Hughes syndrome remains unclear. Therefore, the authors sought to compare the outcomes of warfarin vs. factor Xa inhibitors in patients with Hughes syndrome., Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) comparing 8 efficacy and safety of warfarin and factor Xa inhibitors in patients with Hughes syndrome. Recurrent thrombosis, all-cause mortality, stroke, adverse reactions, and bleeding were among 10 outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate 11 relative risks (RRs) with 95% CIs., Results: The analysis included 625 patients from four RCTs and one post-hoc analysis. Meta-analysis showed a statistically non-significant difference between factor Xa inhibitors and warfarin in the recurrent thrombosis risk (arterial or venous) [RR 2.77 (95%, CI 0.79, 9.65); P =0.11, I
2 =50%]. Consistent results were revealed among patients with a previous history of arterial thrombosis [RR 2.76 (95% CI 0.93, 8.16); P =0.75, I2 =0%], venous thrombosis [RR 1.71 (95% CI 0.60, 4.84); P =0.31, I2 =15%] and patients who were triple antiphospholipid antibodies (aPL) positive [RR 4.12 (95% CI 0.46, 37.10); 21 P =0.21, I2 =58%]. Factor Xa inhibitors were significantly associated with an increased risk of stroke [RR 8.51 (95% CI 2.35, 13.82); P =0.47, I2 =0%]., Conclusion: Factor Xa inhibitors exhibited an increased risk of stroke among patients with Hughes syndrome. In addition, although not significant, the higher RRs among patients on factor Xa inhibitors may indicate a higher risk of thrombotic events associated with factor Xa inhibitors., Competing Interests: Not applicable.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)- Published
- 2024
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84. Dysregulated platelet function in patients with postacute sequelae of COVID-19.
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Aggarwal A, Singh TK, Pham M, Godwin M, Chen R, McIntyre TM, Scalise A, Chung MK, Jennings C, Ali M, Park H, Englund K, Khorana AA, Svensson LG, Kapadia S, McCrae KR, and Cameron SJ
- Subjects
- Humans, SARS-CoV-2, Factor Xa, Blood Coagulation, Disease Progression, COVID-19 complications, Thrombosis etiology
- Abstract
Background: Postacute sequelae of COVID-19 (PASC), also referred to as "Long COVID", sometimes follows COVID-19, a disease caused by SARS-CoV-2. Although SARS-CoV-2 is well known to promote a prothrombotic state, less is known about the thrombosis risk in PASC. Our objective was to evaluate platelet function and thrombotic potential in patients following recovery from SARS-CoV-2, but with clear symptoms of patients with PASC., Methods: patients with PASC and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by light transmission aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions., Results: A mild increase in platelet aggregation in patients with PASC through the thromboxane receptor was observed, and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in patients with PASC compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in patients with PASC. Plasma from patients with PASC was an extremely potent activator of washed, healthy platelets - a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals., Conclusions: patients with PASC show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exist in patients with PASC to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
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85. The use of andexanet alfa vs. 4-factor prothrombin complex concentrates in the setting of life-threatening intracranial hemorrhage.
- Author
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Irizarry-Gatell VM, Bacchus MW, De Leo EK, Zhang Y, Lagasse CA, Khanna AY, Harris NS, and Zumberg MS
- Subjects
- Humans, Factor IX therapeutic use, Hemorrhage drug therapy, Retrospective Studies, Anticoagulants therapeutic use, Blood Coagulation Factors, Factor Xa, Intracranial Hemorrhages drug therapy, Recombinant Proteins
- Abstract
Objective: Andexanet alfa is a targeted reversal agent for life threatening hemorrhage associated with direct acting oral anticoagulants (DOACs), but there is uncertainty regarding the benefit when compared to 4-factor prothrombin complex concentrate (4F-PCC) for this indication. We investigated the clinical outcomes and cost associated with reversal of DOACs in the setting of life-threatening intracranial hemorrhage (ICH)., Methods: A retrospective evaluation was conducted to evaluate patients with ICH in the setting of anticoagulation with DOAC from 9/1/2013 to 4/30/2020. Patients were included in the study if they received reversal with either andexanet alfa or 4F-PCC., Results: Eighty-nine patients were included in the study. There was no statistically significant difference in 30-day mortality between patients who received andexanet alfa or 4F-PCC (52% vs. 35%, P = 0.14). Radiographic stability of bleed was identified in 57% of patients receiving andexanet alfa vs. 58% of patients receiving 4F-PCC ( P = 0.93). Median length of stay was not different between the andexanet alfa and 4F-PCC populations (7 days [IQR 6 - 12] vs. 6 days [IQR 3-12], P = 0.66). Median cost of reversal agent was higher in patients receiving andexanet alfa compared to 4F-PCC ($15 000 [IQR 15 000-$27 000] vs. $11 650 [IQR $8567-$14 149])., Conclusion: Among patients with life-threatening intracranial hemorrhage in the setting of DOAC therapy, no clinical differences were observed with respect to selection of reversal agent. Prothrombin complex concentrates remain a viable alternative to reversal of DOAC therapy though multicenter, randomized, prospective studies are needed to further evaluate the role of 4F-PCC in the reversal of DOAC therapy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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86. Factor Xa and thrombin induce endothelial progenitor cell activation. The effect of direct oral anticoagulants.
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Papadaki, Styliani, Sidiropoulou, Sofia, Moschonas, Iraklis C., and Tselepis, Alexandros D.
- Subjects
- *
THROMBIN receptors , *PROGENITOR cells , *ENDOTHELIAL cells , *THROMBIN , *PROTEASE-activated receptors , *ANTICOAGULANTS - Abstract
Factor Xa (FXa) and thrombin exert non-hemostatic cellular actions primarily mediated through protease-activated receptors (PARs). We investigated the effect of FXa and thrombin on human late-outgrowth endothelial cells (OECs), a type of endothelial progenitor cells (EPCs), and on human umbilical vein endothelial cells (HUVECs). The effect of direct oral anticoagulants (DOACs), rivaroxaban and dabigatran, was also studied. The membrane expression of intercellular adhesion molecule-1 (ICAM-1) and the secretion of monocyte chemoattractant protein-1 (MCP-1) were used as cell activation markers. FXa and thrombin increase the ICAM-1 expression and the MCP-1 secretion on both cells, being higher on OECs. Vorapaxar, a specific PAR-1 antagonist, completely inhibits FXa-induced activation of both cells and thrombin-induced HUVEC activation, but only partially thrombin-induced OEC activation. Furthermore, thrombin-receptor activating peptide; TRAP-6, only partially activates OECs. OECs do not membrane-express PAR-4, therefore it may not be involved on thrombin-induced OEC activation. Rivaroxaban and dabigatran inhibit OEC and HUVEC activation by FXa and thrombin, respectively. Rivaroxaban enhances thrombin-induced OEC and HUVEC activation, which is completely inhibited by vorapaxar. The inhibition of OEC and HUVEC activation by vorapaxar and DOACs may represent a new pleiotropic effect of these drugs. The pathophysiological and clinical significance of our findings need to be established. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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87. Coagulation, Protease-Activated Receptors, and Diabetic Kidney Disease: Lessons from eNOS-Deficient Mice.
- Author
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Yuji Oe, Mariko Miyazaki, and Nobuyuki Takahashi
- Abstract
Endothelial nitric oxide synthase (eNOS) dysfunction is known to exacerbate the progression and prognosis of diabetic kidney disease (DKD). One of the mechanisms through which this is achieved is that low eNOS levels are associated with hypercoagulability, which promotes kidney injury. In the extrinsic coagulation cascade, the tissue factor (factor III) and downstream coagulation factors, such as active factor X (FXa), exacerbate inflammation through activation of the protease-activated receptors (PARs). Recently, it has been shown that the lack of or reduced eNOS expression in diabetic mice, as a model of advanced DKD, increases renal tissue factor levels and PAR1 and 2 expression in their kidneys. Furthermore, pharmaceutical inhibition or genetic deletion of coagulation factors or PARs ameliorated inflammation in DKD in mice lacking eNOS. In this review, we summarize the relationship between eNOS, coagulation, and PARs and propose a novel therapeutic option for the management of patients with DKD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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88. Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment.
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Cate, Hugo ten, Guzik, Tomasz J, Eikelboom, John, and Spronk, Henri M H
- Subjects
- *
PERIPHERAL vascular diseases , *THROMBIN receptors , *CARDIOVASCULAR system , *ENDOTHELIUM diseases , *CARDIOLOGICAL manifestations of general diseases , *BLOOD coagulation - Abstract
Atherosclerosis is a chronic inflammatory disease in which atherothrombotic complications lead to cardiovascular morbidity and mortality. At advanced stages, myocardial infarction, ischaemic stroke, and peripheral artery disease, including major adverse limb events, are caused either by acute occlusive atherothrombosis or by thromboembolism. Endothelial dysfunction, vascular smooth muscle cell activation, and vascular inflammation are essential in the development of acute cardiovascular events. Effects of the coagulation system on vascular biology extend beyond thrombosis. Under physiological conditions, coagulation proteases in blood are pivotal in maintaining haemostasis and vascular integrity. Under pathological conditions, including atherosclerosis, the same coagulation proteases (including factor Xa, factor VIIa, and thrombin) become drivers of atherothrombosis, working in concert with platelets and vessel wall components. While initially atherothrombosis was attributed primarily to platelets, recent advances indicate the critical role of fibrin clot and plasma coagulation factors. Mechanisms of atherothrombosis and hypercoagulability vary depending on plaque erosion or plaque rupture. In addition to contributing to thrombus formation, factor Xa and thrombin can affect endothelial dysfunction, oxidative stress, vascular smooth muscle cell function as well as immune cell activation and vascular inflammation. By these mechanisms, they promote atherosclerosis and contribute to plaque instability. In this review, we first discuss the postulated vasoprotective mechanisms of protease-activated receptor signalling induced by coagulation enzymes under physiological conditions. Next, we discuss preclinical studies linking coagulation with endothelial cell dysfunction, thromboinflammation, and atherogenesis. Understanding these mechanisms is pivotal for the introduction of novel strategies in cardiovascular prevention and therapy. We therefore translate these findings to clinical studies of direct oral anticoagulant drugs and discuss the potential relevance of dual pathway inhibition for atherothrombosis prevention and vascular protection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
89. Blood coagulation factor X: molecular biology, inherited disease, and engineered therapeutics.
- Author
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Camire, Rodney M.
- Abstract
Blood coagulation factor X/Xa sits at a pivotal point in the coagulation cascade and has a role in each of the three major pathways (intrinsic, extrinsic and the common pathway). Due to this central position, it is an attractive therapeutic target to either enhance or dampen thrombin generation. In this brief review, I will summarize key developments in the molecular understanding of this critical clotting factor and discuss the molecular basis of FX deficiency, highlight difficulties in expressing recombinant factor X, and detail two factor X variants evaluated clinically. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
90. Prothrombinase: the paradigm for membrane bound enzyme complexes; a memoir.
- Author
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Mann, Kenneth G.
- Abstract
This review is a brief summary of the history of the development of the Prothrombinase complex paradigm and its incorporation into the "extrinsic pathway". It summarizes my laboratory's research from 1968 to 2012 and identifies many of the key players in these efforts. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
91. New Findings from University of Connecticut Describe Advances in Factor Xa (Andexanet Alfa Versus Pcc Products for Factor Xa Inhibitor Bleeding: a Systematic Review With Meta-analysis).
- Abstract
A recent study conducted by researchers at the University of Connecticut examined the effectiveness of andexanet alfa (AA) versus prothrombin complex concentrate (PCC) products for the treatment of major bleeding associated with Factor Xa inhibitors (FXaI). The study included a systematic review and meta-analysis of comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. The findings suggest that AA may be superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. However, the difference in thrombotic events between AA and PCC was not statistically significant. This research was supported by AstraZeneca and has been peer-reviewed. [Extracted from the article]
- Published
- 2024
92. Prospective Observational Association Between SLCO1B1 Gene Polymorphism and the Anti-factor Xa Activity of Edoxaban in Patients With Moderate to Severe Renal Insufficiency.
- Abstract
A clinical trial, NCT06431789, has been launched to study the association between the SLCO1B1 gene polymorphism and the anti-factor Xa activity of edoxaban in patients with moderate to severe renal insufficiency. The trial aims to provide reference for the rational use of edoxaban and optimize its individualized dosing regimen. The study will evaluate the safety of edoxaban in patients with different genotypes by measuring anti-XA factor activity and SLCO1B1 genotyping. The trial is currently recruiting participants in China and is expected to be completed by April 2026. [Extracted from the article]
- Published
- 2024
93. Reports from University of Cologne Provide New Insights into Thrombosis (Factor Xa Inhibitors for Patients After Mechanical Heart Valve Replacement?).
- Abstract
A recent report from the University of Cologne in Germany discusses the use of factor Xa inhibitors as a potential alternative to vitamin K antagonists (VKA) for patients with mechanical heart valves. VKAs are currently the only approved oral anticoagulants, but they have limitations and side effects. Direct oral anticoagulants (DOACs), such as factor Xa inhibitors, have shown promising results in preventing thrombosis and thrombo-embolic events in small-scale studies. However, further research is needed to evaluate their clinical safety. The report suggests that ongoing trials with factor Xa inhibitors could be promising for patients with mechanical heart valves. [Extracted from the article]
- Published
- 2024
94. Researchers' Work from Department of Pharmacy Focuses on Factor Xa (Comparison of Fixed Versus Weight-Based Prothrombin Complex Concentrate Dosing Strategies for Factor Xa Inhibitor Reversal).
- Subjects
PROTHROMBIN ,BLOOD coagulation factors ,ZYMOGENS ,RESEARCH personnel ,BLOOD proteins - Abstract
A recent study conducted by the Department of Pharmacy compared fixed-dose and weight-based dosing strategies for the reversal of Factor Xa Inhibitor (FXaI) effects. The study found that there was no significant difference in the time to medication administration, achievement of hemostasis, mortality rate, or adverse drug events between the two dosing methods. These findings suggest that the fixed-dosing method is a viable option for the reversal of FXaI effects. Further research and exploration of this topic may be beneficial for healthcare professionals and researchers in the field of hematology. [Extracted from the article]
- Published
- 2024
95. A Randomized Clinical Trial Comparing Three Anti-Thrombotic Strategies For Patients With Atrial Fibrillation And Severe Chronic Kidney Dysfunction.
- Subjects
ATRIAL fibrillation ,CLINICAL trials ,MYOCARDIAL infarction ,BLOOD coagulation factors ,BLOOD diseases ,KIDNEYS - Abstract
The article discusses a clinical trial called the VISIONAIRE trial, which aims to compare three anti-thrombotic strategies for patients with atrial fibrillation and severe chronic kidney dysfunction. The trial will include 1500 patients and will evaluate the effectiveness of warfarin, edoxaban, and no oral anticoagulant treatment. The primary outcome measures include stroke or systemic embolism, as well as major or clinically relevant non-major bleeding. The trial is set to start in July 2024 and is expected to be completed by December 2026. [Extracted from the article]
- Published
- 2024
96. Researchers' from Medical University of South Carolina Report Details of New Studies and Findings in the Area of Hematologic Agents (Changes in Internal Structure and Dynamics upon Binding Stabilise the Nematode Anticoagulant NAPc2).
- Subjects
HEMATOLOGIC agents ,RESEARCH personnel ,ANTICOAGULANTS ,BLOOD coagulation factors ,BLOOD proteins - Abstract
Researchers from the Medical University of South Carolina have conducted studies on hematologic agents, specifically focusing on the nematode anticoagulant NAPc2. NAPc2 is a potent inhibitor of coagulation that requires coagulation factor Xa but does not inhibit it. Molecular dynamics simulations revealed that NAPc2 becomes more rigid upon binding factor Xa, and two conserved residues form an internal salt bridge that stabilizes the bound conformation. The research suggests that this salt bridge mechanism is a conserved way of stabilizing the bound conformation of secondary structure-poor protease inhibitors. [Extracted from the article]
- Published
- 2024
97. Data on Morbid Obesity Detailed by Researchers at Department of Pharmacy (Factor Xa Inhibitors Versus Warfarin In Patients With Morbid Obesity and Atrial Fibrillation).
- Abstract
A new report presents data on the use of Factor Xa Inhibitors versus warfarin in patients with morbid obesity and atrial fibrillation. The study aimed to evaluate the safety and effectiveness of Factor Xa Inhibitors in this population. The analysis of real-world data found no difference in bleeding or thrombotic outcomes between Factor Xa Inhibitors and warfarin for severely obese patients with atrial fibrillation. This study adds further support for the use of Factor Xa Inhibitors as an alternative to warfarin in severely obese patients with atrial fibrillation. [Extracted from the article]
- Published
- 2024
98. New Traumatic Intracranial Hemorrhage Findings Reported from Wake Forest University School of Medicine (The Effect of 4-factor Prothrombin Complex Concentrate To Reverse Factor Xa Inhibitors In Patients With Traumatic Intracranial Hemorrhage).
- Subjects
INTRACRANIAL hemorrhage ,PROTHROMBIN ,BLOOD coagulation factors ,CENTRAL nervous system diseases ,ZYMOGENS - Abstract
A study conducted at Wake Forest University School of Medicine in Winston-Salem, North Carolina, examined the use of 4-factor prothrombin complex concentrate (4F-PCC) in patients with mild traumatic brain injury (mTBI) who were on factor Xa inhibitors (XaI). The study found that there was no significant difference in neurologic decline, need for neurosurgical intervention, or intracranial hemorrhage (ICH) progression between patients who received 4F-PCC and those who did not. The researchers concluded that further studies are needed to determine the necessity of 4F-PCC in mTBI cases. This research has been peer-reviewed. [Extracted from the article]
- Published
- 2024
99. New Factor Xa Study Results Reported from Western Michigan University (Prophylactic Enoxaparin Dosing Using Anti-factor Xa Levels In Hepatic Surgery Patients: a Pilot Study).
- Published
- 2024
100. Inpatient Monitoring of Unfractionated Heparin.
- Subjects
BLOOD coagulation factors ,HEPARIN ,BLOOD proteins ,THROMBOPLASTIN - Abstract
A clinical trial is being conducted at Vanderbilt University Medical Center to compare two methods of monitoring unfractionated heparin (UFH), an intravenous anticoagulant used to treat blood clots. The trial aims to determine whether the activated partial thromboplastin time (PTT) or the chromogenic anti-factor Xa assay (anti-Xa) method helps patients reach a therapeutic anticoagulation range faster. The trial will enroll 2000 patients and is expected to be completed by May 2026. The study is open to all genders, and the data collected will be shared after de-identification. [Extracted from the article]
- Published
- 2024
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