RESUMEN
Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.
Asunto(s)
Anticoagulantes , Interacciones Farmacológicas , Piridinas , Rivaroxabán , Humanos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Estudios Retrospectivos , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/farmacocinética , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anilidas/administración & dosificación , Anilidas/efectos adversos , Anilidas/farmacocinética , Hemorragia/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Trombosis/inducido químicamente , Trombosis/etiología , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Administración Oral , AncianoRESUMEN
SOURCE CITATION: Connolly SJ, Sharma M, Cohen AT, et al; ANNEXA-I Investigators. Andexanet for factor Xa inhibitor-associated acute intracerebral hemorrhage. N Engl J Med. 2024;390:1745-1755. 38749032.
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Inhibidores del Factor Xa , Trombosis , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Humanos , Trombosis/inducido químicamente , Hemorragia Cerebral/inducido químicamente , Masculino , Proteínas Recombinantes , Factor XaAsunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Anticuerpos Biespecíficos , Anticuerpos Monoclonales Humanizados , Factor VIII , Trombosis , Humanos , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Factor VIII/efectos adversos , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Hemofilia A/diagnóstico , Factores de Riesgo , Trombosis/prevención & control , Trombosis/inducido químicamente , Trombosis/epidemiología , Estados Unidos/epidemiología , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Titanium dioxide nanoparticles (TiO2NPs) are widely used in medical application. However, the relevant health risk has not been completely assessed, the potential of inducing arterial thrombosis (AT) in particular. METHODS: Alterations in platelet function and susceptibility to arterial thrombosis induced by TiO2NPs were examined using peripheral blood samples from healthy adult males and an in vivo mouse model, respectively. RESULTS: Here, using human platelets (hPLTs) freshly isolated from health volunteers, we demonstrated TiO2NP treatment triggered the procoagulant activity of hPLTs through phosphatidylserine exposure and microvesicles generation. In addition, TiO2NP treatment increased the levels of glycoprotein IIb/IIIa and P-selectin leading to aggregation and activation of hPLTs, which were exacerbated by providing physiology-mimicking conditions, including introduction of thrombin, collagen, and high shear stress. Interestingly, intracellular calcium levels in hPLTs were increased upon TiO2NP treatment, which were crucial in TiO2NP-induced hPLT procoagulant activity, activation and aggregation. Moreover, using mice in vivo models, we further confirmed that TiO2NP treatment a reduction in mouse platelet (mPLT) counts, disrupted blood flow, and exacerbated carotid arterial thrombosis with enhanced deposition of mPLT. CONCLUSIONS: Together, our study provides evidence for an ignored health risk caused by TiO2NPs, specifically TiO2NP treatment augments procoagulant activity, activation and aggregation of PLTs via calcium-dependent mechanism and thus increases the risk of AT.
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Plaquetas , Activación Plaquetaria , Agregación Plaquetaria , Trombosis , Titanio , Titanio/toxicidad , Animales , Humanos , Agregación Plaquetaria/efectos de los fármacos , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Masculino , Trombosis/inducido químicamente , Ratones , Activación Plaquetaria/efectos de los fármacos , Adulto , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Ratones Endogámicos C57BL , Selectina-P/metabolismo , Calcio/metabolismo , Calcio/sangre , Nanopartículas/toxicidad , Nanopartículas del Metal/toxicidadRESUMEN
BACKGROUND: Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease-relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined. METHODS: Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released. RESULTS: Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930-7300] versus 3.75 [3.35-3.87] µmol/L; P<0.0001) and exhibited acute enhancement of stimulus-dependent aggregation responses in all subjects, agonists, and doses examined. Erythritol ingestion also enhanced stimulus-dependent release of the platelet dense granule marker serotonin (P<0.0001 for TRAP6 [thrombin activator peptide 6] and P=0.004 for ADP) and the platelet α-granule marker CXCL4 (C-X-C motif ligand-4; P<0.0001 for TRAP6 and P=0.06 for ADP). In contrast, glucose ingestion triggered no significant increases in stimulus-dependent release of either serotonin or CXCL4. CONCLUSIONS: Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04731363.
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Plaquetas , Eritritol , Glucosa , Voluntarios Sanos , Agregación Plaquetaria , Trombosis , Humanos , Eritritol/sangre , Eritritol/administración & dosificación , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Masculino , Trombosis/sangre , Trombosis/inducido químicamente , Trombosis/prevención & control , Estudios Prospectivos , Agregación Plaquetaria/efectos de los fármacos , Femenino , Adulto , Edulcorantes no Nutritivos/administración & dosificación , Edulcorantes no Nutritivos/efectos adversos , Adulto Joven , Factor Plaquetario 4/sangre , Espectrometría de Masas en Tándem , Persona de Mediana Edad , Serotonina/sangre , Edulcorantes/administración & dosificación , Pruebas de Función PlaquetariaAsunto(s)
Foramen Oval Permeable , Heparina , Trombocitopenia , Trombosis , Humanos , Trombocitopenia/inducido químicamente , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/diagnóstico por imagen , Heparina/efectos adversos , Trombosis/inducido químicamente , Trombosis/diagnóstico por imagen , Femenino , Anticoagulantes/efectos adversos , Masculino , Cardiopatías/inducido químicamente , Cardiopatías/diagnóstico por imagen , Cardiopatías/etiología , Persona de Mediana EdadRESUMEN
BACKGROUND: Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process. METHODS: The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined. RESULTS: In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG. CONCLUSIONS: High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.
Asunto(s)
Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos , Polifosfatos , Proteínas , Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Polifosfatos/toxicidad , Proteínas/metabolismo , Proteínas/genética , Supervivencia Celular/efectos de los fármacos , Ratones , Masculino , Fibrina/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Relación Dosis-Respuesta a Droga , Trombosis/prevención & control , Trombosis/inducido químicamente , Trombosis/metabolismo , Trombosis/genética , Trombosis/patología , Troponina I/metabolismo , Modelos Animales de Enfermedad , Cardiotoxicidad , Línea Celular , Electrocardiografía , Coagulación Sanguínea/efectos de los fármacosRESUMEN
The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of safe and effective measures against pollutant particles-induced vascular toxicity is warranted. Carnosol is a bioactive phenolic diterpene found in rosemary herb, with anti-inflammatory and antioxidant actions. However, its possible protective effect on the thrombotic and vascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed here the potential alleviating effect of carnosol (20 mg/kg) administered intraperitoneally 1 h before intratracheal (i.t.) instillation of DEP (20 µg/mouse). Twenty-four hours after the administration of DEP, various parameters were assessed. Carnosol administration prevented the increase in the plasma concentrations of C-reactive protein, fibrinogen, and tissue factor induced by DEP exposure. Carnosol inhibited DEP-induced prothrombotic effects in pial microvessels in vivo and platelet aggregation in vitro. The shortening of activated partial thromboplastin time and prothrombin time induced by DEP was abated by carnosol administration. Carnosol inhibited the increase in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin) in aortic tissue. Moreover, it averted the effects of DEP-induced increase of thiobarbituric acid reactive substances, depletion of antioxidants and DNA damage in the aortic tissue. Likewise, carnosol prevented the decrease in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) caused by DEP. We conclude that carnosol alleviates DEP-induced thrombogenicity and vascular inflammation, oxidative damage, and DNA injury through Nrf2 and HO-1 activation.
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Abietanos , Trombosis , Emisiones de Vehículos , Animales , Abietanos/farmacología , Ratones , Masculino , Emisiones de Vehículos/toxicidad , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , Trombosis/inducido químicamente , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Lesiones del Sistema Vascular/tratamiento farmacológico , Antioxidantes/farmacología , Material Particulado/toxicidad , Material Particulado/efectos adversos , Factor 2 Relacionado con NF-E2/metabolismo , Contaminantes Atmosféricos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacosRESUMEN
Non-activated four-factor prothrombin complex concentrate (4 F-PCC) has emerged as the preferred reversal strategy for patients on warfarin with life-threatening bleeding. Current dosing recommendations for 4 F-PCC require pre-treatment international normalized ratio (INR) and bodyweight values, resulting in ordering and administration delays. Studies have shown that alternative dosing regimens are safe and efficacious. This retrospective, single-center, pre- and post-protocol analysis was conducted to assess the efficacy of a pharmacist driven modified fixed-dose 4 F-PCC regimen versus package insert weight- and INR-based dosing regimen for warfarin reversal. The primary outcome was achievement of INR less than two. Secondary outcomes included dose and cost of 4 F-PCC, a time analysis, incidence of concomitant vitamin K administration, and incidence of thrombosis within seven days of 4 F-PCC. There were 195 patients included in the analysis, with 74 in the pre-cohort and 121 in the post-cohort. Baseline characteristics were similar between cohorts with the most common indication for warfarin use being atrial fibrillation (48.6% versus 47.1%) and reversal being intracerebral hemorrhage (68.9% versus 43.0%). Achievement of the primary endpoint occurred in 92% versus 95% (p = 0.097) of patients. A statistically significant difference was seen between cohorts regarding median dose and cost of 4 F-PCC administered (p < 0.001). Eleven thromboembolic events occurred with three events in the pre-cohort and eight events in the post-cohort (p = 0.453). A fixed-dose of 1500IU of 4 F-PCC was effective in reversing INR to less than two in most patients regardless of reversal indication with minimal thrombotic risks.
Asunto(s)
Factores de Coagulación Sanguínea , Relación Normalizada Internacional , Warfarina , Humanos , Warfarina/efectos adversos , Warfarina/administración & dosificación , Factores de Coagulación Sanguínea/administración & dosificación , Factores de Coagulación Sanguínea/uso terapéutico , Estudios Retrospectivos , Anciano , Masculino , Femenino , Hemorragia/inducido químicamente , Persona de Mediana Edad , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Anciano de 80 o más Años , Fibrilación Atrial/tratamiento farmacológico , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Trombosis/inducido químicamenteRESUMEN
BACKGROUND: The direct oral anticoagulants (DOACs) are now commonly regarded as first line anticoagulants in most cases of venous thromboembolism (VTE). However, the optimal choice of subsequent anticoagulant in instances of first line DOAC failure is unclear. OBJECTIVES: To describe and compare outcomes with second line anticoagulants used after DOAC failure. METHODS: Patients seen at an urban hospital system for an episode of acute VTE initially treated with either apixaban or rivaroxaban who experienced a subsequent recurrent thrombosis while on anticoagulation (1st recurrent thrombosis) were included. RESULTS: In total, 166 patients after apixaban or rivaroxaban failure were included. Following DOAC failure (1st recurrent thrombosis), the subsequent anticoagulant was warfarin in 60 patients (36%), dabigatran in 42 patients (25%), and enoxaparin in 64 patients (39%). Enoxaparin was preferentially prescribed in patients with a malignancy-associated etiology for 1st recurrent thrombosis (p < 0.01). The median follow-up time in our cohort was 16 months. There was no difference in 2nd recurrent thrombosis-free survival (p = 0.72) or risk for major bleeding event (p = 0.30) among patients treated with dabigatran, warfarin, or enoxaparin. CONCLUSIONS: In this retrospective analysis of patients failing first line DOAC therapy, rates of 2nd recurrent thrombosis and bleeding did not differ among subsequently chosen anticoagulants. Our study provides evidence that the optimal 2nd anticoagulant is not clear, and the choice of 2nd anticoagulant should continue to balance patient preference, cost, and provider experience.
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Anticoagulantes , Dabigatrán , Enoxaparina , Tromboembolia Venosa , Warfarina , Humanos , Dabigatrán/efectos adversos , Dabigatrán/administración & dosificación , Dabigatrán/uso terapéutico , Enoxaparina/efectos adversos , Enoxaparina/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Masculino , Femenino , Warfarina/efectos adversos , Warfarina/administración & dosificación , Anciano , Persona de Mediana Edad , Tromboembolia Venosa/tratamiento farmacológico , Administración Oral , Hemorragia/inducido químicamente , Estudios Retrospectivos , Insuficiencia del Tratamiento , Trombosis/prevención & control , Trombosis/inducido químicamente , Trombosis/etiología , Trombosis/tratamiento farmacológico , Rivaroxabán/efectos adversos , Rivaroxabán/administración & dosificación , Rivaroxabán/uso terapéutico , Pirazoles , PiridonasRESUMEN
BACKGROUND: Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium. OBJECTIVES: To investigate the effects of CFZ on the endothelium. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with CFZ, and expression of relevant markers of ER stress, inflammation, and thrombosis was measured and functionally assessed. RESULTS: CFZ failed to induce ER stress in HUVECs but induced the expression of Kruppel-like factor 4, endothelial nitric oxide synthase, tissue plasminogen activator, and thrombomodulin and reduced tumor necrosis factor alpha (TNFα)-mediated intercellular adhesion molecule 1 and tissue factor expression, suggesting a potential protective effect on the endothelium. Consistent with these observations, CFZ reduced leukocyte adhesion under shear stress and reduced factor Xa generation and fibrin clot formation on the endothelium following TNFα treatment and inhibited von Willebrand factor (VWF) and angiopoietin-2 exocytosis from Weibel-Palade bodies. Subsequently, CFZ inhibited the formation of VWF-platelet strings, and moreover, media derived from myeloma cell lines induced VWF release, a process also inhibited by CFZ. CONCLUSION: These data demonstrate that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the prothrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.
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Antiinflamatorios , Estrés del Retículo Endoplásmico , Fibrinolíticos , Células Endoteliales de la Vena Umbilical Humana , Oligopéptidos , Inhibidores de Proteasoma , Humanos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Oligopéptidos/farmacología , Inhibidores de Proteasoma/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fibrinolíticos/farmacología , Antiinflamatorios/farmacología , Adhesión Celular/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Tromboplastina/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Trombosis/prevención & control , Trombosis/inducido químicamente , Trombosis/metabolismo , Células Cultivadas , Inflamación/metabolismo , TrombomodulinaRESUMEN
BACKGROUND AND AIMS: Uncertainty of the causality determinations for ambient ozone (O3) on cardiovascular events is heightened by the limited understanding of the mechanisms involved in humans. We aimed to examine the pro-atherothrombotic impacts of O3 exposure and to explore the potential mediating roles of dysfunctional neutrophils, focusing on neutrophil extracellular traps (NETs). METHODS: A longitudinal panel study of 152 healthy adults was conducted in the cool to cold months with relatively low levels of O3 between September 2019 and January 2020 in Beijing, China. Four repeated measurements of indicators reflecting atherothrombotic balance and NETs were performed for each participant. RESULTS: Daily average exposure levels of ambient O3 were 16.6 µg/m3 throughout the study period. Per interquartile range increase in average concentrations of O3 exposure at prior up to 7 days, we observed elevations of 200.1-276.3% in D-dimer, 27.2-36.8% in thrombin-antithrombin complex, 10.8-60.3% in plasminogen activator inhibitor 1, 13.9-21.8% in soluble P-selectin, 16.5-45.1% in matrix metalloproteinase-8, and 2.4-12.4% in lipoprotein-associated phospholipase A2. These pro-atherothrombotic changes were accompanied by endothelial activation, lung injury, and immune inflammation. O3 exposure was also positively associated with circulating NETs indicators, including citrullinated histone H3, neutrophil elastase, myeloperoxidase, and double-stranded DNA. Mediation analyses indicated that NETs could mediate O3-associated pro-atherothrombotic responses. The observational associations remained significant and robust after controlling for other pollutants, and were generally greater in participants with low levels of physical activity. CONCLUSIONS: Ambient O3 exposure was associated with significant increases in NETs and pro-atherothrombotic potential, even at exposure levels well below current air quality guidelines of the World Health Organization.
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Biomarcadores , Trampas Extracelulares , Ozono , Humanos , Ozono/toxicidad , Ozono/efectos adversos , Trampas Extracelulares/metabolismo , Masculino , Femenino , Biomarcadores/sangre , Adulto , Persona de Mediana Edad , Estudios Longitudinales , Neutrófilos/metabolismo , Voluntarios Sanos , Trombosis/sangre , Trombosis/inducido químicamente , Contaminantes Atmosféricos/efectos adversos , Beijing , Factores de Tiempo , Adulto Joven , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
A 59-year-old man presented to our hospital with a chief complaint of epigastric pain. Pertinent history included a distal gastrectomy for gastric cancer and alcohol dependence. He underwent contrast-enhanced computed tomography (CT) and esophagogastroduodenoscopy, which led to a diagnosis of esophageal cancer (cT2N2M1, stage IVb). Subsequently, he underwent chemotherapy using 5-fluorouracil and cis-diamminedichloroplatinum and radiotherapy. A total of 44 days after treatment initiation, the patient experienced nausea and hepatobiliary enzyme elevation. CT and abdominal ultrasonography were performed, and he was diagnosed with an abdominal aortic thrombus. Intravenous heparin was administered as an anticoagulant therapy. Twenty-two days after treatment initiation, the thrombus was no longer visible on abdominal ultrasonography. The patient was then treated with warfarin. It cannot be ruled out that the patient's hepatobiliary enzyme elevation was induced by the anticancer drugs. However, enzyme elevation improved with the disappearance of the abdominal aortic thrombus, suggesting that the aortic thrombus may have contributed to the hepatobiliary enzyme elevation. No thrombus recurrence was observed until the patient's death after an initial treatment with antithrombotic agents. This case indicates that malignant tumors and chemotherapy can cause aortic thrombi, and thus, care should be exercised in monitoring this potential complication.
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Neoplasias Esofágicas , Neoplasias Gástricas , Trombosis , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/uso terapéutico , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Gástricas/tratamiento farmacológico , Trombosis/inducido químicamente , Trombosis/diagnóstico por imagenRESUMEN
BACKGROUND: Relatively little is known about thrombotic adverse events (AEs) of emicizumab in postmarketing real-world settings, particularly in comparison with factor VIII (FVIII) products. A recent European study reported a potentially greater thrombotic risk of emicizumab compared with FVIII products. OBJECTIVES: This drug safety study aims to investigate whether thrombotic AEs are more frequently reported for emicizumab than for FVIII products and if so, whether it is independent of bypassing agents as coreporting drugs using the United States Food and Drug Administration Adverse Event Reporting System data. METHODS: Disproportionality analyses for thrombotic AEs of emicizumab vs FVIII products were conducted. Three signal detection indicators were used: proportional reporting ratio (PRR), reporting odds ratio (ROR), and informational component (IC). RESULTS: During 2018-2022, the proportions of thrombotic AEs among all AEs were 4.07% (97 out of 2383) and 1.44% (134 out of 9324) for emicizumab and FVIII products, respectively: PRR = 2.83 (2.19-3.66), ROR = 2.91 (2.23-3.79), and IC = 1.04 (0.70-1.28). Bypassing agents as coreporting drugs were identified in 36% and 15% of the total thrombotic AE reports associated with emicizumab and FVIII products, respectively. Even after thrombotic AE reports with bypassing agents were excluded, the reporting proportion of thrombotic AEs was still greater for emicizumab than for FVIII products: PRR = 2.19 (1.60-2.99). CONCLUSION: Thrombotic AEs in the United States Food and Drug Administration Adverse Event Reporting System data were about 3 times more frequently reported for emicizumab than for FVIII products. More research and efforts in the future are warranted for monitoring, elucidating, and preventing the potential risk of thrombotic AEs in hemophilia therapy, including emicizumab.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Anticuerpos Biespecíficos , Anticuerpos Monoclonales Humanizados , Factor VIII , Trombosis , United States Food and Drug Administration , Humanos , Estados Unidos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trombosis/inducido químicamente , Trombosis/epidemiología , Anticuerpos Biespecíficos/efectos adversos , Factor VIII/efectos adversos , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Factores de Riesgo , Coagulantes/efectos adversos , Coagulantes/uso terapéutico , Medición de Riesgo , Bases de Datos FactualesRESUMEN
ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.
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Fibrilación Atrial , Trombosis , Humanos , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Estudios Prospectivos , Trombosis/inducido químicamente , Resultado del TratamientoRESUMEN
BACKGROUND: Germans hesitated to get vaccinated with AstraZeneca in the COVID-19 pandemic after reports of blood clots. METHODS: In two preregistered online experiments with stratified randomization (Study 1 N = 824, Study 2: N = 1,056), we tested whether providing evidence-based benefit-risk information reduces the perceived risk of the AstraZeneca vaccine and the perceived probability of blood clots due to the AstraZeneca vaccine and increases the vaccination intention. In Study 1, participants saw no infographic (control) or one of two infographics (low vs. high exposure risk varied by the underlying incidence rates). Study 2 additionally varied the infographic design displaying the risk information (presented as table, circle icons, or manikin-like icons). RESULTS: The infographic decreased the risk perception of the vaccine compared to no infographic (Study 1: Cohens d = 0.31, 95% CI [0.14, 0.48]; Study 2: Cohens d = 0.34, 95% CI [0.06, 0.62]), but it did not influence the perceived probability of blood clots due to the AstraZeneca vaccine (Study 2: Cohens d = 0.05, 95% CI [-0.23, 0.33]). Also, the infographic design did not affect the perceived probability of blood clots (Study 2). The vaccination intention was not affected by viewing the infographic (Study 1: Cohens d = 0.04, 95% CI [-0.13, 0.21]; Study 2: Cohens d = 0.04, 95% CI [-0.24, 0.32]) nor the presented infection rate (Study 1: Cohens d = 0.07, 95% CI [-0.09, 0.24], Study 2: Cohens d = 0.01, 95% CI [-0.12, 0.15]) but by risk perceptions, sociodemographic characteristics, confidence in the AstraZeneca vaccine, and preference for alternative vaccines. CONCLUSIONS: The evidence-based benefit-risk information helped putting the risk of vaccinations into perspective. Nevertheless, objective risk information alone did not affect vaccination intention that was low due to the preexisting lacking vaccine confidence.
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COVID-19 , ChAdOx1 nCoV-19 , Visualización de Datos , Pueblo Europeo , Vacunación , Humanos , COVID-19/prevención & control , Intención , Pandemias , Trombosis/inducido químicamente , Vacunación/psicología , ChAdOx1 nCoV-19/administración & dosificaciónRESUMEN
Objective: This study explored whether anticoagulation is safe for frail and non-frail elderly patients who have nonvalvular atrial fibrillation (NVAF). Methods: At hospital discharge, the anticoagulant regimen and frailty status were recorded for 361 elderly patients (aged ≥75 y) with NVAF. The patients were followed for 12 months. The endpoints included occurrence of thrombosis; bleeding; all-cause death; and cardiovascular events. Results: At hospital discharge, frailty affected 50.42% of the population and the anticoagulation rate was 44.04%. At discharge, age (OR 0.948, P = 0.006), paroxysmal NVAF (OR 0.384, P < 0.001), and bleeding history (OR 0.396, P = 0.001) were associated with a decrease in rate of receiving anticoagulation, while thrombotic events during hospitalization (OR 2.281, P = 0.021) were associated with an increase. Relative to non-frail patients, those with frailty showed a higher rate of ischemic stroke (5.33% cf. 3.01%), bleeding (P = 0.006) events, and all-cause mortality (P = 0.001). Relative to the group without anticoagulation, in those with anticoagulation the rate of thrombotic events was lower (6.99 cf. 10.98%) and bleeding events were higher (20.98 cf. 12.72%), but the risk of major bleeding was comparable. Conclusion: In the elderly patients with NVAF, the decision toward anticoagulation therapy at hospital discharge was influenced by age, bleeding history, paroxysmal atrial fibrillation diagnosis, and absence of thrombosis. Frail patients were at greater risk of bleeding and all-cause mortality. Anticoagulation tended to reduce the risk of thrombotic events.
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Fibrilación Atrial , Fragilidad , Accidente Cerebrovascular , Trombosis , Anciano , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Fragilidad/complicaciones , Anticoagulantes/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Trombosis/inducido químicamente , Factores de RiesgoRESUMEN
In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0-3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0-3.0 or 3.0-4.0 is recommended by recent guidelines, considering the individual's bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75-100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment-refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.
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Síndrome Antifosfolípido , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Trombosis , Humanos , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Trombosis/inducido químicamente , HemorragiaRESUMEN
INTRODUCTION: Left ventricular thrombus (LVT) is associated with significant morbidity and mortality. Conventional treatment comprises warfarin-mediated anticoagulation; it is unclear whether non-vitamin K oral anticoagulants (NOACs) exhibit comparable efficacy and safety. Limited data are available for Asian patients. This study compared NOACs with warfarin in terms of clinical efficacy and safety for managing LVT. METHODS: Clinical and echocardiographic records were retrieved for all adult patients with echocardiography-confirmed LVT at a major regional centre in Hong Kong from January 2011 to January 2020. Discontinuation of anticoagulation by 1 year was recorded. Outcomes were compared between patients receiving NOACs and those receiving warfarin. Primary outcomes were cumulative mortality and net adverse clinical events (NACEs). Secondary outcomes were complete LVT resolution and percentage reduction in LVT size at 3 months. RESULTS: Forty-three patients were included; 28 received warfarin and 15 received NOACs, with follow-up periods (mean ± standard deviation) of 20 ± 12 months and 22 ± 9 months, respectively (P=0.522). Use of NOACs was associated with significantly lower NACE risk (hazard ratio [HR]=0.111, 95% confidence interval [CI]=0.012-0.994; P=0.049) and a tendency towards lower cumulative mortality (HR=0.184, 95% CI=0.032-1.059; P=0.058). There were no significant differences in secondary outcomes. Considering LVT resolution, discontinuation of anticoagulation by 1 year was not significantly associated with different outcomes. CONCLUSION: Non-vitamin K oral anticoagulants may be an efficacious and safe alternative to warfarin for LVT management. Future studies should explore the safety and efficacy of anticoagulation discontinuation by 1 year as an overall strategy.