RESUMEN
BACKGROUND: Since the approval of the oral factor Xa inhibitors, there have been concerns regarding the ability to neutralize their anticoagulant effects after intracranial hemorrhage (ICH). Multiple guidelines suggest using prothrombin complex concentrates (PCCs) in these patients on the basis of research that includes a limited number of patients with ICH. Given this, we aimed to evaluate the safety and efficacy of PCCs for factor Xa inhibitor-related ICH in a large, multicenter cohort of patients. METHODS: This was a multicenter, retrospective, observational cohort study of patients with apixaban- or rivaroxaban-related ICH who received PCCs between January 1, 2015, and March 1, 2019. The study had 2 primary analysis groups: safety and hemostatic efficacy. The safety analysis evaluated all patients meeting inclusion criteria for the occurrence of a thrombotic event, which were censored at hospital discharge or 30 days after PCC administration. Patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least 1 follow-up image within 24 hours of PCC administration were assessed for hemostatic efficacy. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis on the basis of the modified Sarode criteria. Secondary outcomes included an evaluation of in-hospital mortality, length of stay, infusion-related reactions, and thrombotic event occurrence during multiple predefined periods. RESULTS: A total of 663 patients were included and assessed for safety outcomes. Of these, 433 patients met criteria for hemostatic efficacy evaluation. We observed excellent or good hemostasis in 354 patients (81.8% [95% CI, 77.9-85.2]). Twenty-five (3.8%) patients had a total of 26 thrombotic events, of which 22 occurred in the first 14 days after PCC administration. One patient had documentation of an infusion-related reaction. For the full cohort of patients, in-hospital mortality was 19.0%, and the median intensive care unit and hospital lengths of stay were 2.0 and 6.0 days, respectively. CONCLUSIONS: Administration of PCCs after apixaban- and rivaroxaban-related ICH provided a high rate of excellent or good hemostasis (81.8%) coupled with a 3.8% thrombosis rate. Randomized, controlled trials evaluating the clinical efficacy of PCCs in patients with factor Xa inhibitor-related ICH are needed.
Asunto(s)
Factores de Coagulación Sanguínea/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Hematoma Subdural/tratamiento farmacológico , Hemostasis/efectos de los fármacos , Hemostáticos/uso terapéutico , Pirazoles/efectos adversos , Piridonas/efectos adversos , Rivaroxabán/efectos adversos , Hemorragia Subaracnoidea/tratamiento farmacológico , Anciano , Factores de Coagulación Sanguínea/efectos adversos , Femenino , Hematoma Subdural/inducido químicamente , Hematoma Subdural/diagnóstico por imagen , Hematoma Subdural/mortalidad , Hemostáticos/efectos adversos , Mortalidad Hospitalaria , Humanos , Trombosis Intracraneal/inducido químicamente , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Hemorragia Subaracnoidea/inducido químicamente , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosAsunto(s)
Circulación Colateral , Trombosis Intracraneal/inducido químicamente , Trombosis Intracraneal/fisiopatología , Fitoterapia/efectos adversos , Tribulus , Trombosis de la Vena/inducido químicamente , Trombosis de la Vena/fisiopatología , Adulto , Angiografía Cerebral , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Humanos , Trombosis Intracraneal/diagnóstico , Trombosis Intracraneal/patología , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Neovascularización Fisiológica , Flebografía , Extractos Vegetales/efectos adversos , Pronóstico , Tomografía Computarizada por Rayos X , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/patologíaAsunto(s)
Creatina/administración & dosificación , Creatina/efectos adversos , Trombosis Intracraneal/inducido químicamente , Trombolisis Mecánica/métodos , Tromboembolia Venosa/inducido químicamente , Adolescente , Adulto , Suplementos Dietéticos , Humanos , Trombosis Intracraneal/tratamiento farmacológico , Trombosis Intracraneal/patología , Masculino , Tromboembolia Venosa/terapiaRESUMEN
BACKGROUND: The accumulation of toxic free radicals plays a pivotal role in the early molecular cascades of blood-brain barrier (BBB) disruption mediated by matrix metalloproteinases (MMPs) activation in ischemic stroke. Theoretically, it is expected that early blockade of activation of MMPs may provide protective effects from secondary neural tissue damage. The present study was designed to determine the ability of melatonin to influence MMP-9 activity and BBB disruption, in a focal ischemia rat model induced by photothrombosis. METHODS: Adult, male, 8-week Sprague-Dawley rats weighing 230-300 g received focal cerebral ischemia by photothrombosis using Rose Bengal (RB). The injured animals were divided into two groups. One group received 50mg/kg of melatonin intraperitoneally, starting 1h after injury and at 12h intervals for 3 days. The control group received weight-adjusted doses of saline vehicle. In each group, MMP-9 expression and activity were assessed by Western blot and gelatin zymography, respectively, at various times. The effects of melatonin on BBB disruption and brain edema were also determined. RESULTS: MMP-9 activity and expression were significantly elevated at 24h in the ischemic cortex, which remained up-regulated at least until 72 h after injury. Melatonin treatment significantly attenuated MMP-9 activity and expression at 24, 48, and 72 h after ischemic injury. Relative to control group, BBB permeability was significantly reduced in the melatonin-treated group. The water content was decreased by melatonin treatment, although there was no statistically significant difference. CONCLUSIONS: Melatonin treatment starting 1h after injury attenuated BBB disruption during focal ischemia, which is at least partly due to inhibition of MMP-9 activity. Melatonin might have a potential role in clinical trials aimed to improve the outcome of patients suffering cerebral ischemia.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Isquemia Encefálica/prevención & control , Trombosis Intracraneal/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Melatonina/uso terapéutico , Animales , Agua Corporal , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/enzimología , Modelos Animales de Enfermedad , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inyecciones Intraperitoneales , Trombosis Intracraneal/inducido químicamente , Trombosis Intracraneal/enzimología , Masculino , Melatonina/farmacología , Fotoquímica , Prosencéfalo/enzimología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Rosa Bengala/efectos de la radiación , Rosa Bengala/toxicidadRESUMEN
In this study, we adapted the original rat photothrombosis model of Watson et al. (Ann Neurol 17 (1985) 497) for use in mice by refining the application route of the dye, illumination and stereotactic parameters. After intraperitoneal injection of the photosensitive dye Rose bengal, subsequent focal illumination of the brain with a cold light source through the intact skull led to focal cortical infarcts of reproducible size, location and geometry. Cresyl violet histology displayed well-demarcated infarcts that matured with time in a predictable manner. Microglial responses, as assessed by immunocytochemistry, against F4/80 and CD11b antigens were rapid and complete at the infarct site, but delayed and incomplete in degenerating fiber tracts and ipsilateral thalamic nuclei. In contrast to the rat, where the expression of CD4 and CD8 antigens discriminate distinct subpopulations of lesion-associated phagocytes, the expression of both markers was low to absent in the mouse model. In both rats and mice, cerebral photothrombosis shares essential inflammatory responses with focal ischemia induced by middle cerebral artery occlusion. It may provide a useful model to study functional aspects of lesion-associated and remote molecular responses in transgenic mice.