RESUMEN
The current investigation focused on separating Cerastes cerastes venom to produce the first Kunitz-type peptide. Based on its anti-trypsin effect, Cerastokunin, a 7.75 kDa peptide, was purified until homogenity by three steps of chromatography. Cerastokunin was found to include 67 amino acid residues that were obtained by de novo sequencing using LC-MALDI-MSMS. Upon alignment with Kunitz-type peptides, there was a high degree of similarity. Cerastokunin's 3D structure had 12% α-helices and 21% ß-strands with pI 8.48. Cerastokunin showed a potent anticoagulant effect by inhibiting the protease activity of thrombin and trypsin as well as blocking the intrinsic and extrinsic coagulation pathways. In both PT and aPPT, Cerastokunin increased the blood clotting time in a dose-dependent way. Using Lys48 and Gln192 for direct binding, Cerastokunin inhibited thrombin, Factor Xa and trypsin as shown by molecular docking. Cerastokunin exhibited a dose-response blockade of PARs-dependent pathway platelet once stimulated by thrombin. An increased concentration of Cerastokunin resulted in a larger decrease of tail thrombus in the mice-carrageenan model in an in vivo investigation when compared to the effects of antithrombotic medications. At all Cerastokunin doses up to 6 mg/kg, no in vivo toxicity was seen in challenged mice over the trial's duration.
Asunto(s)
Plaquetas , Inhibidores del Factor Xa , Trombina , Animales , Trombina/química , Trombina/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/química , Simulación del Acoplamiento Molecular , Humanos , Ratones , Anticoagulantes/farmacología , Anticoagulantes/química , Factor Xa/química , Factor Xa/metabolismo , Secuencia de AminoácidosRESUMEN
BACKGROUND: Cholestatic liver diseases induce local and systemic hypercoagulation, with neutrophil extracellular traps (NETs) serving as major drivers. These NETs have been linked to decreased liver function in patients with obstructive jaundice. However, the impact of NETs on liver hypercoagulation in cholestatic liver disease remains unknown. METHODS: We utilized bile duct ligation to create experimental mice and analyzed NETs formation in the liver. Fibrin deposition, tissue factor expression, and inflammation in the liver were visualized through western blot and immunohistochemical techniques. LSECs were incubated with isolated NETs, and we detected endothelial procoagulant activity using coagulation protein production assays and measuring endothelial permeability. In both in vivo and in vitro settings, DNase I was applied to clarify the effect of NETs on intrahepatic hypercoagulability, hepatotoxicity, LSEC, and macrophage activation or injury. RESULTS: Bile duct ligation mice exhibited significantly increased levels of NETs in liver tissue, accompanied by neutrophil infiltration, tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. Notably, NETs resulted in phosphatidylserine and tissue factor exposure on LSEC, enhancing coagulation Factor Xa and thrombin production. The enhanced procoagulant activity could be reversed by degrading NETs with DNase I. Additionally, NETs-induced permeability changes in LSECs, characterized by increased VE-cadherin expression and F-actin retraction, which could be rescued by DNase I. Meanwhile, NET formation is associated with KC activation and the formation of inflammatory factors. CONCLUSIONS: NETs promote intrahepatic activation of coagulation and inflammation, leading to liver tissue injury. Strategies targeting NET formation may offer a potential therapeutic approach for treating cholestatic liver disease.
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Trampas Extracelulares , Hígado , Trombosis , Trampas Extracelulares/metabolismo , Animales , Ratones , Hígado/patología , Hígado/metabolismo , Trombosis/etiología , Trombosis/patología , Colestasis/patología , Colestasis/complicaciones , Modelos Animales de Enfermedad , Masculino , Tromboplastina/metabolismo , Trombofilia/etiología , Trombofilia/sangre , Fibrina/metabolismo , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Humanos , Infiltración Neutrófila , Factor Xa/metabolismo , Trombina/metabolismoAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proyectos de Investigación , Rivaroxabán/efectos adversosAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Rivaroxabán/efectos adversos , Estudios Multicéntricos como Asunto , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Ensayos Clínicos Fase IV como Asunto , Proyectos de Investigación , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proyectos de Investigación , Rivaroxabán/efectos adversosAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Rivaroxabán/efectos adversos , Estudios Multicéntricos como Asunto , Proyectos de InvestigaciónRESUMEN
BACKGROUND: There is currently a lack of evidence for the comparative effectiveness of Andexanet alpha and four-factor prothrombin complex concentrate (4F-PCC) in anticoagulation reversal of direct oral anticoagulants (DOACs). The primary aim of our systematic review was to verify which drug is more effective in reducing short-term all-cause mortality. The secondary aim was to determine which of the two reverting strategies is less affected by thromboembolic events. METHODS: A systematic review and meta-analysis was performed. RESULTS: Twenty-two studies were analysed in the systematic review and quantitative synthesis. In all-cause short-term mortality, Andexanet alpha showed a risk ratio (RR) of 0.71(95% CI 0.37-1.34) in RCTs and PSMs, compared to 4F-PCC (I2 = 81%). Considering the retrospective studies, the pooled RR resulted in 0.84 (95% CI 0.69-1.01) for the common effects model and 0.82 (95% CI 0.63-1.07) for the random effects model (I2 = 34.2%). Regarding the incidence of thromboembolic events, for RCTs and PSMs, the common and the random effects model exhibited a RR of 1.74 (95% CI 1.09-2.77), and 1.71 (95% CI 1.01-2.89), respectively, for Andexanet alpha compared to 4F-PCC (I2 = 0%). Considering the retrospective studies, the pooled RR resulted in 1.21 (95% CI 0.87-1.69) for the common effects model and 1.18 (95% CI 0.86-1.62) for the random effects model (I2 = 0%). CONCLUSION: Considering a large group of both retrospective and controlled studies, Andexanet alpha did not show a statistically significant advantage over 4F-PCC in terms of mortality. In the analysis of the controlled studies alone, Andexanet alpha is associated with an increased risk of thromboembolic events. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2024, CRD42024548768.
Asunto(s)
Anticoagulantes , Factores de Coagulación Sanguínea , Humanos , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea/uso terapéutico , Factores de Coagulación Sanguínea/farmacología , Factor Xa/uso terapéutico , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Proteínas Recombinantes , Tromboembolia/prevención & controlRESUMEN
The hemostatic response to vascular injury entails a sequence of proteolytic events where several inactive zymogens of the trypsin family are converted to active proteases. The cascade starts with exposure of tissue factor from the damaged endothelium and culminates with conversion of prothrombin to thrombin in a reaction catalyzed by the prothrombinase complex composed of the enzyme factor Xa, cofactor Va, Ca2+, and phospholipids. This cofactor-dependent activation is paradigmatic of analogous reactions of the blood coagulation and complement cascades, which makes elucidation of its molecular mechanism of broad significance to the large class of trypsin-like zymogens to which prothrombin belongs. Because of its relevance as the most important reaction in the physiological response to vascular injury, as well as the main trigger of pathological thrombotic complications, the mechanism of prothrombin activation has been studied extensively. However, a molecular interpretation of this mechanism has become available only recently from important developments in structural biology. Here we review current knowledge on the prothrombin-prothrombinase interaction and outline future directions for the study of this key reaction of the coagulation cascade.
Asunto(s)
Coagulación Sanguínea , Protrombina , Tromboplastina , Humanos , Protrombina/metabolismo , Protrombina/química , Tromboplastina/metabolismo , Tromboplastina/química , Coagulación Sanguínea/fisiología , Animales , Unión Proteica , Factor Xa/metabolismo , Factor VRESUMEN
BACKGROUND: The high metastasis rate is one of the main reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC). Coagulation factor Xa (FXa) and its receptor proteinase-activated receptor-2 (PAR-2) proven to promote tumor metastasis in other forms of cancer. Here, we explore the role and mechanism of FXa in the regulation of resistance of anoikis and immune escape of HCC. METHODS: In vitro and in vivo experiments were conducted to explore the role of FXa in HCC metastasis and its potential mechanism. The effects of FXa inhibitor rivaroxaban on HCC immunotherapy were evaluated using intrahepatic metastasis animal models and clinical trial (No. ChiCTR20000040540). We investigated the potential of FXa inhibition as a treatment for HCC. RESULTS: FXa was highly expressed in HCC and promoted metastasis by activating PAR-2. Mechanistically, FXa-activated PAR-2 endows HCC cells with the ability of anoikis resistance to survive in the circulating blood by inhibiting the extrinsic apoptosis pathway. Furthermore, suspension stimulation-induced phosphorylation of STAT2, which promotes programmed death-ligand 1 (PD-L1) transcription and inhibits the antitumor effects of immune cells by inhibiting the infiltration of CD8+T cells in tumors and the levels of secreted cytokines. In vivo inhibition of FXa with rivaroxaban reduced HCC metastasis by decreasing PD-L1 expression and exhausting tumor-infiltrating lymphocytes. Notably, the combination of rivaroxaban and anti-programmed death-1 monoclonal antibody (anti-PD-1) programmed Death-1 monoclonal antibody (anti-PD-1) induced synergistic antitumor effects in animal models. Most importantly, rivaroxaban improved the objective response rate of patients with HCC to immune checkpoint inhibitors and prolonged overall survival time. CONCLUSIONS: FXa-activated PAR-2 promotes anoikis resistance and immune escape in HCC, suggesting the potential for combining coagulation inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance the therapeutic efficacy of HCC.
Asunto(s)
Anoicis , Antígeno B7-H1 , Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Receptor PAR-2 , Escape del Tumor , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Humanos , Receptor PAR-2/metabolismo , Animales , Ratones , Inmunoterapia/métodos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Factor Xa/metabolismo , Factor Xa/farmacología , Factor Xa/uso terapéutico , Masculino , Femenino , Línea Celular Tumoral , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéuticoRESUMEN
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.
Asunto(s)
Heparina , Proteínas Recombinantes , Humanos , Anciano , Masculino , Heparina/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Resistencia a Medicamentos , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversos , Factor Xa , Puente de Arteria Coronaria , Rivaroxabán/administración & dosificación , Rivaroxabán/uso terapéuticoAsunto(s)
Arginina , Benzamidinas , Guanidinas , Heparina , Ácidos Pipecólicos , Sulfonamidas , Humanos , Ácidos Pipecólicos/uso terapéutico , Arginina/análogos & derivados , Guanidinas/uso terapéutico , Heparina/efectos adversos , Resistencia a Medicamentos/efectos de los fármacos , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Anticoagulantes , Factor Xa/uso terapéuticoRESUMEN
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.
Asunto(s)
Disección Aórtica , Implantación de Prótesis Vascular , Inhibidores del Factor Xa , Humanos , Masculino , Anciano , Disección Aórtica/cirugía , Disección Aórtica/diagnóstico por imagen , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/efectos adversos , Resultado del Tratamiento , Implantación de Prótesis Vascular/efectos adversos , Administración Oral , Proteínas Recombinantes/administración & dosificación , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Puente Cardiopulmonar , Pérdida de Sangre Quirúrgica/prevención & control , Enfermedad Aguda , Factor Xa , Aneurisma de la Aorta/cirugía , Aneurisma de la Aorta/diagnóstico por imagenRESUMEN
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.
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Enfermedad Crítica , Heparina de Bajo-Peso-Molecular , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/etiología , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina de Bajo-Peso-Molecular/administración & dosificación , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/administración & dosificación , Factor XaAsunto(s)
Anticoagulantes , Antitrombinas , Resistencia a Medicamentos , Heparina , Proteínas Recombinantes , Humanos , Heparina/efectos adversos , Heparina/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Antitrombinas/uso terapéutico , Antitrombinas/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Resistencia a Medicamentos/fisiología , Factor Xa , Masculino , Inhibidores del Factor Xa/efectos adversos , Femenino , AncianoRESUMEN
The advantageous optical properties of quantum dots (QDs) motivate their use in a wide variety of applications related to imaging and bioanalysis, including the detection of proteases and their activity. Recent studies have shown that surface chemistry on QDs is able to modulate protease activity, but only nonspecifically. Here, we present a strategy to selectively accelerate the activity of a particular target protease by as much as two orders of magnitude. Exosite-binding "bait" peptides were derived from proteins that span a range of biological rolesâsubstrate, receptor, and inhibitorâand were used to increase the affinity of the QD-peptide conjugates for either thrombin or factor Xa, resulting in increased rates of proteolysis for coconjugated substrates. Unlike effects from QD surface chemistry, the acceleration was specific to the target protease with negligible acceleration of other proteases. Benefits of this "bait and cleave" sensing approach included detection limits that improved by more than an order of magnitude, reenabled detection of target protease against an overwhelming background of nontarget proteolysis, and mitigation of the action of inhibitors. The cumulative results point to a generalizable strategy, where the mechanism of acceleration, considerations for the design of bait peptides and conjugates, and routes to expanding the scope of this approach are discussed. Overall, this research represents a major step forward in the rational design of nanoparticle-based enzyme sensors that enhance sensitivity and selectivity.
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Péptidos , Puntos Cuánticos , Trombina , Puntos Cuánticos/química , Péptidos/química , Péptidos/metabolismo , Trombina/metabolismo , Trombina/análisis , Trombina/química , Factor Xa/metabolismo , Factor Xa/química , Proteolisis , Humanos , Propiedades de Superficie , Péptido Hidrolasas/metabolismo , Péptido Hidrolasas/químicaRESUMEN
Cell-cell fusion mediated by most paramyxovirus requires fusion protein (F) and attachment protein (H, HN, or G). The F protein is proteolytic cleaved to be fusogenically active. J paramyxovirus (JPV) has a unique feature in the family Paramyxoviridae: It encodes an integral membrane protein, syncytial protein (SP, formerly known as transmembrane protein, TM), which is essential in JPV-promoted cell-cell fusion (i.e., syncytial). In this study, we report that cleavage of SP is essential for its syncytial-promoting activity. We have identified the cleavage site of SP at amino acid residues 172 to 175, LKTG, and deletion of the "LKTG" residues abolished SP protein cleavage and its ability to promote cell-cell fusion. Replacing the cleavage site LKTG with a factor Xa protease cleavage site allows cleavage of the SP with factor Xa protease and restores its ability to promote cell-cell fusion. Furthermore, results from a hemifusion assay indicate that cleavage of SP plays an important role in the progression from the intermediate hemifusion state to a complete fusion. This work indicates that SP has many characteristics of a fusion protein. We propose that SP is likely a cell-cell fusion-promoting protein.
Asunto(s)
Fusión Celular , Proteínas Virales de Fusión , Animales , Proteínas Virales de Fusión/metabolismo , Chlorocebus aethiops , Proteolisis , Células Vero , Internalización del Virus , Factor Xa/metabolismo , Humanos , Línea CelularRESUMEN
BACKGROUND: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. OBJECTIVES: The ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. METHODS: Human FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. RESULTS: F174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. CONCLUSION: These human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.
Asunto(s)
Coagulación Sanguínea , Factor X , Inhibidores del Factor Xa , Pirazoles , Piridonas , Rivaroxabán , Humanos , Inhibidores del Factor Xa/farmacología , Coagulación Sanguínea/efectos de los fármacos , Pirazoles/farmacología , Células HEK293 , Factor X/metabolismo , Piridonas/farmacología , Factor Xa/metabolismo , Piridinas/uso terapéutico , Piridinas/farmacología , Simulación de Dinámica Molecular , Tiazoles/farmacología , Trombina/metabolismo , Trombina/química , Hemorragia , Unión ProteicaRESUMEN
BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).
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Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Hematoma , Proteínas Recombinantes , Humanos , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Anciano , Masculino , Femenino , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/efectos adversos , Factor Xa/uso terapéutico , Factor Xa/efectos adversos , Hematoma/inducido químicamente , Hematoma/tratamiento farmacológico , Anciano de 80 o más Años , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/complicaciones , Enfermedad AgudaAsunto(s)
Anticoagulantes , Hemorragia Cerebral , Humanos , Administración Oral , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Factor Xa , Inhibidores del Factor Xa/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) is associated with complex hemostatic changes. Systemic anticoagulation is initiated to prevent clotting in the ECMO system, but this comes with an increased risk of bleeding. Evidence on the use of anti-Xa-guided monitoring to prevent bleeding during ECMO support is limited. Therefore, we aimed to analyze the association between anti-factor Xa-guided anticoagulation and hemorrhage during ECMO. METHODS: A systematic review and meta-analysis was performed (up to August 2023). PROSPERO: CRD42023448888. RESULTS: Twenty-six studies comprising 2293 patients were included in the analysis, with six works being part of the meta-analysis. The mean anti-Xa values did not show a significant difference between patients with and without hemorrhage (standardized mean difference -0.05; 95% confidence interval [CI]: -0.19; 0.28, p = .69). We found a positive correlation between anti-Xa levels and unfractionated heparin dose (UFH; pooled estimate of correlation coefficients 0.44; 95% CI: 0.33; 0.55, p < .001). The most frequent complications were any type of hemorrhage (pooled 36%) and thrombosis (33%). Nearly half of the critically ill patients did not survive to hospital discharge (47%). CONCLUSIONS: The most appropriate tool for anticoagulation monitoring in ECMO patients is uncertain. Our analysis did not reveal a significant difference in anti-Xa levels in patients with and without hemorrhagic events. However, we found a moderate correlation between anti-Xa and the UFH dose, supporting its utilization in monitoring UFH anticoagulation. Given the limitations of time-guided monitoring methods, the role of anti-Xa is promising and further research is warranted.