A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Cerebral calcium embolism.

A new-onset neurological deficit after calcified aortic valve replacement and an hyperdense image on the computed tomography raised suspicion of an stroke of unusual etiology.

Emicizumab-induced photosensitivity.

Emicizumab constitutes a novel and effective prophylaxis for hemophilia A patients with and without inhibitors. In this case report, we describe an emicizumab-induced photosensitivity that forced permanent sun-exposure suppression. To the best of our knowledge, this side effect had not been communicated until present.

Monitoring coagulation factors during surgery. A systematic review.

OBJECTIVE: The management of surgeries in patients with hemophilia is  complex and requires adequate clotting factor adjustment to avoid bleeding  complications and excessive factor consumption. The aim of this systematic  review is to analyze the pharmacokinetic studies published on surgery in  hemophilic patients, the methodologies used, the main pharmacokinetic covariates applied, and the recommendations made by clinical guidelines. METHOD: A structured search was performed in Pubmed, the Cochrane Library,  and the Database of Abstracts of Reviews of Effects using the search terms  hemophilia (or haemophilia), surgery and pharmacokinetics (or PK). No date or  language limits were established. Results: The search yielded 186 results, from which 34 articles were selected.  Many of these analyzed the use of continuous infusions with the aim of  achieving stable factor VIII or IX levels and reducing overall factor  consumption. However, continuous infusions have fallen into disuse. For  decades, clinical guidelines have recommended the performance of comprehensive pharmacokinetic studies prior to surgery (9-11 samples). The clearance rate obtained is used to adjust the presurgical factor  dose (or the infusion rate in case of continuous perfusion). Another approach is the use of population pharmacokinetic models, which allow adjustments to  be made based on a more limited number of samples. However, the validity of  these presurgical pharmacokinetic estimates ceases as soon as the surgical  procedure is initiated, making it necessary to adjust the dose based on periodic  peak and trough levels. In addition, depending on the  type of  surgery, clinical guidelines recommend maintaining factor VIII and IX levels  above specific thresholds for certain periods of time, which makes it essential  to use pharmacokinetics during the pre- and post-surgical process. In recent  years, specific factor VIII and factor IX pharmacokinetic population models  have been developed for surgery. The main covariates of these population  pharmacokinetic models are age, blood type, and type of surgery for factor  VIII; and age and body weight for factor IX. CONCLUSIONS: Pharmacokinetic estimation could allow individual and standardized intraoperative dose adjustments to be conducted in patients with hemophilia. The development of specific population  pharmacokinetic models for surgery, including those based on extended half- life factors, will allow an optimization of current treatments, potentially  reducing factor consumption and hospital stays.

OBJETIVO: El manejo de las cirugías en pacientes hemofílicos es complejo y  requiere de un ajuste adecuado de los factores de coagulación para evitar  complicaciones hemorrágicas y un consumo elevado. El objetivo de esta  revisión sistemática es analizar los estudios farmacocinéticos publicados en  cirugía en pacientes con hemofilia, las metodologías empleadas, las principales  covariables farmacocinéticas y las recomendaciones de las guías  clínicas.Método: Se ha realizado una búsqueda estructurada sin restricciones de fecha  ni idioma en Pubmed, Cochrane y Database of Abstracts of Reviews of  Effects empleado los mismos términos de búsqueda: (hemophilia or  haemophilia), surgery y (pharmacokinetics or PK). Resultados: La búsqueda sistemática obtuvo 186 resultados, de los que seleccionamos 34 artículos. Muchos estudios analizaban el uso de  erfusiones continuas con el objetivo de lograr niveles estables de factor VIII o  IX y reducir el consumo global, aunque su empleo ha caído en desuso. Durante  décadas las guías clínicas recomendaban realizar estudios  farmacocinéticos completos previos a la cirugía (9-11 muestras), según los  cuales se ajusta la dosis prequirúrgica, así como la velocidad de infusión en caso de perfusión continua basándose en el aclaramiento calculado. Otra aproximación es el empleo de modelos poblacionales farmacocinéticos, ajustando con un número más limitado de muestras. Estas  estimaciones farmacocinéticas prequirúrgicas pierden validez tan pronto como  se inicia un procedimiento quirúrgico, y tienen que ajustarse con niveles pico y valle periódicos. Además, las guías clínicas recomiendan, en función del  populationtipo de cirugía, mantener los niveles de factores VIII y IX por  encima de los umbrales específicos durante periodos, por lo que resulta  fundamental emplear la farmacocinética durante el proceso pre y  postquirúrgico. En los últimos años se han desarrollado modelos poblacionales  farmacocinéticos de factores VIII y IX específicos para cirugía. Las principales  covariables de estos modelos son la edad, el grupo sanguíneo y el tipo de  cirugía para el factor VIII, y la edad y el peso corporal para el factor IX. CONCLUSIONES: La farmacocinética puede permitir ajustar de forma individual y  protocolizada las cirugías en pacientes hemofílicos. El desarrollo de modelos farmacocinéticos poblacionales específicos para cirugía, incluyendo los factores de vida media extendida, permitirá optimizar estos tratamientos, con potencial reducción del consumo y las  estancias hospitalarias.

Hidden myelodysplastic syndrome (MDS): A prospective study to confirm or exclude MDS in patients with anemia of uncertain etiology.

INTRODUCTION: Diagnosis of myelodysplastic syndromes (MDSs) when anemia is the only abnormality can be complicated. The aim of our study was to investigate the primary causes of anemia and/or macrocytosis of uncertain etiology. METHODS: We conducted a multicenter, prospective study over 4 months in three hematology laboratories. In step 1, we used an automated informatics system to screen 137 453 hemograms for cases of anemia and/or macrocytosis (n = 2702). In step 2, we excluded all patients whose anemia appeared to be due to a known cause. This left 290 patients had anemia of uncertain etiology. In step 3, we conducted further investigations, including a peripheral blood smear, and analysis of iron, vitamin B12, folate, and thyroid hormone levels. RESULTS: A differential diagnosis was obtained in 139 patients (48%). The primary causes of anemia were iron deficiency (n = 59) and megaloblastic anemia (n = 39). In total, 25 hematologic disorders were diagnosed, including 14 patients with MDS (56%). The median age of MDS patients was 80 years, 12 had anemia as an isolated cytopenia, and most (n = 10) had lower-risk disease (IPSS-R ≤ 3.5). SF3B1 mutations were most frequent (n = 6) and correlated with the presence of ring sideroblasts (100%) and associated with better prognosis (P = 0.001). CONCLUSIONS: Our prospective, four-step approach is an efficient and logical strategy to facilitate the diagnosis of MDS on the basis of unexplained anemia and/or macrocytosis, and may allow the early diagnosis of the most serious causes of anemia. Molecular analysis of genes related to MDS could be a promising diagnostic and prognostic approach.

[Cloning and stem cells]. / Clonación y células madre.

Applied cloning technologies have become a great scientific advance. Many of their biotechnological applications (stem cells, transplants, tissue therapy) are improving medical fields to extents that we could not imagine a few years ago. Thus, for example, we are now able to produce cellular and tisular spares via differentiating stem cells in vitro. Yet the scientific community maintains a vibrant debate over technical aspects and applications of cloning technologies, with most scientists positioned against reproductive cloning while agreeing on its therapeutic use. This article summarizes the foremost applications and problems related to cloning and stem cells technologies, from an academic and health professionals' point of view.