Presente y futuro del tratamiento anticoagulante oral

The alternative new oral anticoagulants open a new era in antithrombotic treatment. For more than half a century, vitamin K antagonists have defined oral anticoagulant therapy for the long-term management of thrombotic disorders. However, vitamin-K antagonists have multiple, well-known limitations, including numerous interactions with other drugs and the need for regular blood monitoring and dose adjustments. Novel anticoagulants are directed against either thrombin (Dabigatran) or factor Xa (Rivaroxaban and Apixaban), have a short half-life in patients with normal renal function and rapid onset of action. Thousands of patients in clinical trials in prophylaxis and treatment of venous and arterial thrombosis have been treated. Nowadays, they are approved for hip and knee replacement prophylaxis, non valvular atrial fibrillation, venous deep thrombosis and pulmonary embolism. Also, there are reports of their potential utility in recent coronary syndrome. Though open questions remains such as how to manage hemorrhage and invasive procedures and many aspects of their use will be unfamiliar to practicing clinicians, it seems that the paradigm of oral anticoagulation has completely changed. In the future, the question will probably be who should not receive a direct action oral anticoagulantLos nuevos anticoagulantes orales abren una nueva era en el tratamiento antitrombótico.Durante más de cincuenta años los antagonistas de la vitamina K han tenido el papel protagonista en el tratamiento anticoagulante oral. Sin embargo, los antagonistas de la vitamina K tienen multiples limitaciones, incluyendo numerosas interacciones con otros fármacos y la necesidad de control biologico frecuente. Los nuevos anticoagulantes orales dirigidos ya contra trombina (Dabigatrán) o factor Xa ((Rivaroxabán y Apixabán), tienen una vida media corta en pacientes con function renal normal y una acción rápida. Miles de pacientes ya han sido tratados en ensayos clínicos en profilaxis y tratamiento de trombosis venosa y arterial. Actualmente están aprobados en profilaxis de cirugía protésica de cadera y rodilla, fibrilación auricular no valvular, trombosis venosa profunda y embolismo pulmonar. Además, hay datos preliminares de su potencial utilidad en sindrome coronario. Aunque todavía hay aspectos de debate tales como la actitud ante una hemorragia o ante procedimientos invasivos y muchos aspectos de su utlización no son familiares en la práctica clínica, parece que el paradigma de la anticoagulación oral ha cambiado. En el futuro, la pregunta sera probablemente que paciente con indicación de anticoagulación no debe recibir un anticoagulante oral de acción directa

Enfermedad de Gaucher

La Enfermedad de Gaucher (EG) pertenece al grupo de las Enfermedades por Depósito Lisosomal (EDL), en las que existe un error en el metabolismo celular, de modo que hay déficit o se presenta un trastorno funcional de la enzima Glucocerebrosidasa.Como consecuencia, se producirá un acúmulo lisosomal de glucocerebrósidos, compuestos presentes en la membrana celular que en condiciones normales son degradados por esta enzima.Se presenta en 1 de cada 50-100,000 personas en la población general y 1 de cada 500 personas en la población judía asquenazí. Se han identificado 3 variantes, en función a la afectación del Sistema Nervioso Central (SNC) y al curso clínico, siendo la más frecuente la tipo 1 o no neuropática.La Terapia de Reemplazo Enzimático (TRE) ha revolucionado completamente el pronóstico de los pacientes con EG. Sin embargo, el diagnóstico de la EG suele ser infraestimado por la falta de sospecha clínica, demorándose la administración de tratamiento y empeorando considerablemente el pronóstico y la calidad de vida de los pacientes.En esta revisión se recogen los aspectos esenciales de la EG, así como algoritmos que nos permitirán realizar un diagnóstico precoz, previniendo así ciertas complicaciones y mejorando la expectativa y calidad de vida de los pacientes.Gaucher disease (GD) belongs to the group of Lysosomal Storage Diseases (LSD).There is an error in cell metabolism, with a lack or a functional disorder of the enzyme Glucocerebrosidase. Consequently, it accumulates Glucocerebrosides in the lysosomes, which are compounds of cell membranes that in normal conditions are degraded by this enzyme. It occurs in 1 of 50-100,000 people in general population and 1 in 500 people in the Ashkenazi Jewish population.Three variants have been identified, according to the Central Nervous System (CNS) involvement and the clinical course. GD type 1 or non neurophatic type is the most frequent.Enzyme Replacement Therapy (ERT) has completely revolutionized the prognosis of patients with EG. However, the diagnosis of GD is often underestimated due to the lack of clinical suspicion, delaying the treatment administration and producing consequently worse prognosis and quality of life of patients.In this review the essential aspects of the GD is collected, as well as algorithms that allow us to make an early diagnosis, thus preventing certain complications and improving life expectancy and quality of life of patients

Proyecto de planificación estratégica para la "Real Academia de Medicina y Cirugía de Valladolid”

Estrategia significa un medio que una organización elige para moverse desde un presente a un estado deseado en el futuro.Un plan estrategico es un establecimiento de procesos organizativos para la identificación de un futuro deseable de la organización y desarrollo de guías de decisión.Es una herramienta válida y util para guiar todo tipo de organización, incluyendo la organización académica. El nivel organizativo al cual el proceso de plan estrategico es relevante depende de su tamaño, complejidad y los diferentes servicios que se ofrecen.Nuestra Academia puede estar en un apropiado nivel con tal que el plan sea alineado con otros planes de más alto niveles.Los puntos relevantes para el éxito son: definir una misión y valores, desarrollo de visión, identificar y comunicar planificación de objetivos estrategicos, un liderazgo que se haga valer, definir papeles y responsabilidades, reunir información relevante histórica, repasar pasadas estrategias e identificar exitos y fracasos, establecer un limitado número de metas y objetivos en un periodo de tres a cinco años, planificar programas, ejecución, evaluación de indicadores de aplicación de medidas, monitorización y actualización.El proceso de programación estrategica es programable y holistico e integra diferentes etapas, permitiendo la organización de la Academia para pretender relevantes transformaciones en el futuro.A strategy is a mean an organization chooses to move from where it is today to a desired state in the future. Strategic planning is the set of organizational processes for identifying the desired future of the organization and developing decisions guidelines. It is a valid and useful tool for guiding all types of organizations, including academic organizations. The organizational level at which the strategic planning process is relevant depends on the size, complexity and the differentiation of service provided. Our Academy can be an appropriate level as long as the plan is aligned with other plans at higher levels. Relevant points for success are:define mission and values, vision development, identify and communicate strategic planning objectives, assert leadership, define roles and responsibilities, assemble relevant historical data, review past strategies and identify successes and failures, analyzing the environment, competitive advantages and disadvantages, establish a limited number of goals and objectives for a three to five year horizon, planning schedule, implementation, evaluation applying measurement indicators, monitoring and updating. The process of strategic planning is programmable and holistic and integrates different periods of time, allowing the Academy organization to aim on relevant transformations for the future.Key words: Strategic planning, communicate, vision, leadership, goals, quality indicators, update

Esplenomegalia como signo de enfermedad lisosomal

La estructura sana del bazo funciona como función hematopoyética para el período fetal; después, se convierte en un gran órgano linfoide, y también, es del sistema de filtro de células sanguíneas. La enfermedad de Gaucher es un extraño trastorno de almacenamiento lisosomal, muchos de ellos son hereditarios y multisistémicos. Hoy en día, setenta LSD han sido adoptados

Esplenomegalia como signo de enfermedad lisosomal

Healthy spleen structure works as hematopoietic function for the fetal period; after, it becomes a big lymphoid organ, and also, it´s from the blood cells filter System. Gaucher illness is a strange lysosomal storage disorder, most of them are inherited and multisystemic. Nowadays, seventy LSDs have been embracedLa estructura sana del bazo funciona como función hematopoyética para el período fetal; después, se convierte en un gran órgano linfoide, y también, es del sistema de filtro de células sanguíneas. La enfermedad de Gaucher es un extraño trastorno de almacenamiento lisosomal, muchos de ellos son hereditarios y multisistémicos. Hoy en día, setenta LSD han sido adoptados

Situación actual de los nuevos anticoagulantes orales

For more than half a century, vitamin K antagonists have defined oral anticoagulant therapy for the long-term management of thrombotic disorders. Despite its clinical efficacy, vitamin-antagonists have multiple, well-known limitations, including numerous interactions with other drugs and the need for regular blood monitoring and dose adjustments. The alterna- tive new oral anticoagulants that are at least equally efficacious, safer and easier to administer, open a new era in antithrombotic treatment. These agents are directed against either thrombin (Dabigatran) or factor Xa (Rivaroxabán and Apixabán), have a half-life around 12 hours in patients with normal renal function and a time to peak anticoagulant activity of two or three hours. Though thousands of patients have been treated in clinical trials in venous and arterial thrombosis, more experience is needed in ordinary practice. Open questions remain such as how to manage hemorrhage, invasive procedures particularly on emergency, resumption following procedures, need of bridging with heparin, treatment of overdoses and the present absence of antidote.En los últimos cincuenta años los antagonistas de la vitamina K han permitido el tratamiento crónico de los procesos trombóticos. A pesar de su eficacia clínica, los antagonistas de la vitamina K tienen múltiples limitaciones, incluyendo numerosas interacciones con fármacos y la necesidad de monitorizaciòn regular y ajuste de dosis. La alternativa de los nuevos anti- coagulantes orales, al menos tan eficaces, más seguros y más fáciles de administrar, abre una nueva era en el tratamiento antitrombótico. Estos agentes están dirigidos contra la trombina (Dabigatrán) o contra el factor Xa (Rivaroxabán y Apixabán), tienen una vida media de unas 12 horas en pacientes con función renal normal y un tiempo para alcanzar su máxima actividad de dos a tres horas. Aunque se han tratado miles de pacientes en ensayos clínicos en preven- ción y tratamiento de trombosis venosa y arterial, se necesita más experiencia en la práctica diaria. Son temas a debate cómo actuar ante una hemorragia, ante procedimientos invasivos, necesidad de terapia puente, el tratamiento de sobredosis y la presente ausencia de antídoto

The Unfolded Protein Response and the Phosphorylations of Activating Transcription Factor 2 in the trans-Activation of il23a Promoter Produced by β-Glucans

Producción CientíficaCurrent views on the control of IL-23 production focus on theregulation ofil23a, the gene encoding IL-23 p19, by NF- Bincombination with other transcription factors. C/EBP homolo-gous protein (CHOP), X2-Box-binding protein 1 (XBP1), acti-vator protein 1 (AP1), SMAD, CCAAT/enhancer-binding pro-tein (C/EBP ), and cAMP-response element-binding protein(CREB) have been involved in response to LPS, but no data areavailable regarding the mechanism triggered by the fungalmimic and -glucan-containing stimulus zymosan, which pro-duces IL-23 and to a low extent the related cytokine IL-12 p70.Zymosan induced the mobilization of CHOP from the nuclearfractions to phagocytic vesicles. Hypha-formingCandidaalsoinduced the nuclear disappearance of CHOP. Assay of tran-scription factor binding to theil23apromoter showed anincrease of Thr(P)-71–Thr(P)-69-activating transcription fac-tor 2 (ATF2) binding in response to zymosan. PKC and PKA/mitogen- and stress-activated kinase inhibitors down-regulatedThr(P)-71–ATF2 binding to theil23apromoter andil23amRNA expression. Consistent with the current concept ofcomplementary phosphorylations on N-terminal Thr-71 andThr-69 of ATF2 by ERK and p38 MAPK, MEK, and p38 MAPKinhibitors blunted Thr(P)-69–ATF2 binding. Knockdown ofatf2mRNA with siRNA correlated with inhibition ofil23amRNA, but it did not affect the expression ofil12/23bandil10mRNA. These data indicate the following: (i) zymosan decreasesnuclear proapoptotic CHOP, most likely by promoting its accu-mulation in phagocytic vesicles; (ii) zymosan-inducedil23amRNA expression is best explained through coordinated B-and ATF2-dependent transcription; and (iii)il23aexpressionrelies on complementary phosphorylation of ATF2 on Thr-69and Thr-71 dependent on PKC and MAPK activities

Polymorphisms in receptors involved in opsonic and nonopsonic phagocytosis, and correlation with risk of infection in oncohematology patients

Producción CientíficaHigh-risk hematological malignancies are a privileged setting for infection by opportunistic microbes, with invasive mycosis being one of the most serious complications. Recently, genetic background has emerged as an unanticipated risk factor. For this reason, polymorphisms for genes encoding archetypal receptors involved in the opsonic and nonopsonic clearance of microbes, pentraxin-3 (PTX3) and Dectin-1, respectively, were studied and correlated with the risk of infection. Fungal, bacterial, and viral infections were registered for a group of 198 patients with highrisk hematological malignancies. Polymorphisms for the pentraxin-3 gene (PTX3) showed a significant association with the risk of fungal infection by Candida spp. and, especially, by Aspergillus spp. This link remained even for patients undergoing antifungal prophylaxis, thus demonstrating the clinical relevance of PTX3 in the defense against fungi. CLEC7A polymorphisms did not show any definite correlation with the risk of invasive mycosis, nor did they influence the expression of Dectin-1 isoforms generated by alternative splicing. The PTX3 mRNA expression level was significantly lower in samples from healthy volunteers who showed these polymorphisms, although no differences were observed in the extents of induction elicited by bacterial lipopolysaccharide and heat-killed Candida albicans, thus suggesting that the expression of PTX3 at the start of infection may influence the clinical outcome. PTX3 mRNA expression can be a good biomarker to establish proper antifungal prophylaxis in immunodepressed patients

Serum amyloid a1/toll-like receptor-4 Axis, an important link between inflammation and outcome of TBI patients

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability world-wide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patientsThis work was supported by grants from Fundación Mutua Madrileña and Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet CP14/00008; CPII19/00005; PI16/00735; PI19/00082) to JE, RYC2019-026870-I to JMR and PI18/01387 to A

Use of eltrombopag for patients 65 years old or older with immune thrombocytopenia

Background Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary and secondary ITP in our ≥65‐year‐old population. Methods A total of 106 primary ITP patients (16 with newly diagnosed ITP, 16 with persistent ITP, and 74 with chronic ITP) and 39 secondary ITP patients (20 with ITP secondary to immune disorders, 7 with ITP secondary to infectious diseases, and 12 with ITP secondary to lymphoproliferative disorders [LPD]) were retrospectively evaluated. Results Median age of our cohort was 76 (interquartile range, IQR, 70‐81) years. 75.9% of patients yielded a platelet response including 66.2% complete responders. Median time to platelet response was 14 (IQR, 8‐21) days. Median time on response was 320 (IQR, 147‐526) days. Sixty‐three adverse events (AEs), mainly grade 1‐2, occurred. The most common were hepatobiliary laboratory abnormalities (HBLAs) and headaches. One transient ischemic attack in a newly diagnosed ITP and two self‐limited pulmonary embolisms in secondary ITP were the only thrombotic events observed. Conclusion Eltrombopag showed efficacy and safety in ITP patients aged ≥65 years with primary and secondary ITP. However, efficacy results in LPD‐ITP were poor. A relatively high number of deaths were observed