Analysis of the effects of low/intermediate dose of coagulation factor Ⅷ on 30 adult patients with severe hemophilia A in a single center / 中华血液学杂志

Objective: To evaluate the clinical effects of low- and intermediate-dose factor Ⅷ (F Ⅷ) prophylaxis in Chinese adult patients with severe hemophilia A. Methods: Thirty adult patients with severe hemophilia A who received low- (n=20) /intermediate-dose (n=10) F Ⅷ prophylaxis at Nanjing Drum Tower Hospital affiliated with Nanjing University Medical College were included in the study. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), number of target joints, functional independence score of hemophilia (FISH), quality of life score, and health status score (SF-36) before and after preventive treatment were retrospectively analyzed and compared. Results: The median follow-up was 48 months. Compared with on-demand treatment, low- and intermediate-dose prophylaxis significantly reduced ABR, AJBR, and the number of target joints (P<0.05) ; the improvement in the intermediate-dose prophylaxis group was better than that in the low-dose prophylaxis group (P<0.05). Compared with on-demand treatment, the FISH score, quality of life score, and SF-36 score significantly improved in both groups (P<0.05), but there was no significant difference between the two groups (P>0.05) . Conclusion: In Chinese adults with severe hemophilia A, low- and intermediate-dose prophylaxis can significantly reduce bleeding frequency, delay the progression of joint lesions, and improve the quality of life of patients as compared with on-demand treatment. The improvement in clinical bleeding was better with intermediate-dose prophylaxis than low-dose prophylaxis.

Prediction of Coagulation Factor Ⅷ Level in Chinese Hemophilia A Patients by the Pharmacokinetic Management Tool myPKFiT / 中国医学科学院学报

Objective To evaluate the performance of myPKFiT,a tool guiding the dosing of antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM),in maintaining the coagulation factor Ⅷ (FⅧ) level above a target threshold at the steady state and estimating the pharmacokinetics (PK) parameters in hemophilia A patients in China. Methods The data of 9 patients with severe hemophilia A in a trial (CTR20140434) assessing the safety and efficacy of rAHF-PFM in the Chinese patients with hemophilia A were analyzed.The myPKFiT was used to predict the adequate dose to maintain a patient's FⅧ level above target threshold at the steady state.Furthermore,the performance of myPKFiT in estimating the pharmacokinetics parameters of individuals was evaluated. Results Twelve combinations of two dosing intervals and six sparse sampling schedules were investigated,and 57%-88% of the patients remained the FⅧ level above the target threshold of 1 U/dl (1%) for at least 80% of the dosing interval.The clearance and time to FⅧ level of 1% obtained from sparse sampling by myPKFiT were similar to those obtained from extensive sampling. Conclusions The myPKFiT can provide adequate dose estimates to maintain the FⅧ level above the target threshold at the steady state in Chinese patients with severe hemophilia A.Moreover,it demonstrates good performance for estimating key pharmacokinetics parameters,including clearance and time to FⅧ level of 1%.

Estudio de costo-efectividad de profilaxis con emicizumab versus agentes hemostáticos alternativos en pacientes con hemofilia A grave en Perú / Cost-effectiveness study of prophylaxis with emicizumab versus bypassing agents in patients with severe hemophilia A in Peru

Contexto La hemofilia es un trastorno hemorrágico de la coagulación que ocurre en uno de cada 5000 nacimientos masculinos. Los pacientes con hemofilia A grave no tratados tienen complicaciones hemorrágicas, incluyendo sangrados articulares y menor sobrevida. El emicizumab es un anticuerpo monoclonal aprobado por los Estados Unidos para la profilaxis rutinaria de pacientes pediátricos y adultos con hemofilia A grave con inhibidores del factor VIII de coagulación. Objetivos Realizar un estudio de costo-efectividad de la profilaxis con emicizumab para niños y adultos con hemofilia A grave, en comparación con el actual manejo de esos pacientes en el Ministerio de Salud y el Seguro Social de Salud de Perú. Metodología Se modeló la transición del paciente entre estados médicos con la metodología de Markov y se estimó a lo largo de su vida costos y efectos incrementales de emicizumab comparados con el actual manejo. Se estimó el impacto presupuestario de emicizumab proyectando costos netos anuales y su valor presente a cinco años. Resultados Emicizumab generaría ahorros en el Ministerio de Salud entre 14,6 y 16,0 por niño y 11,8 por adulto, en US$ millones actuales, y en el Seguro Social de Salud de 12,8 a 14,9 por niño y 40,1 por adulto. Además, se generan ganancias en efectividad, medidas en años de vida ajustados por calidad, de 0,36 por niño y 0,56 por adulto y de 0,25 por niño y 0,36 por adulto en esas respectivas instituciones. El impacto presupuestario sería un ahorro anual neto, en US$ millones, de 12,8 y 15,0 en esas entidades. Conclusión El actual manejo de la enfermedad es muy costoso y con resultados de salud inferiores a los posibles con emicizumab. Este fármaco produciría grandes ahorros y mejor salud. Ambas entidades debieran implementar protocolos para la profilaxis y tratamiento de la hemofilia y financiarla con presupuesto propio.

Settings Hemophilia is a coagulation disorder that occurs in one in 5000 male births. Patients with untreated severe hemophilia A have hemorrhagic complications, including joint bleeds and decreased survival. Emicizumab is a monoclonal antibody approved by the United States for routine prophylaxis of pediatric and adult patients with severe hemophilia A with factor VIII inhibitors. Objectives To perform a cost-effectiveness study of emicizumab prophylaxis for children and adults with severe hemophilia A compared with the current disease management in the Peruvian Ministry of Health and Social Security Health Insurance. Methods The patient transition between medical states was modeled with Markov methodology, and the lifetime costs and incremental effects of emicizumab compared to current management were estimated. The budgetary impact of emicizumab was estimated by projecting annual net costs and its five-year present value. Results In the Ministry of Health, emicizumab would generate savings between 14.6 and 16.0 per child and 11.8 per adult, in current US$ million. Social Security Health Insurance savings would be 12.8 to 14.9 per child and 40.1 per adult. In addition, this strategy would generate effectiveness gains, measured in quality-adjusted life-years, of 0.36 per child and 0.56 per adult and 0.25 per child, and 0.36 per adult in those respective institutions. The budgetary impact would be a net annual saving of 12.8 and 15.0 US$ million in those entities. Conclusions The current management of hemophilia A is very costly and has health outcomes inferior to those possible with emicizumab. This drug would produce significant savings and better patient health. The Ministry of Health and Social Health Insurance should implement hemophilia prophylaxis and treatment protocols and finance this drug.

Hemofilia adquirida como manifestación inicial de recidiva de adenocarcinoma colorrectal / Acquired hemophilia as the initial manifestation of colorectal cancer's recurrence

Resumen Presentamos el caso de un varón de 86 años con un hematoma espontáneo en el músculo ilíaco izquierdo y diagnóstico previo de cáncer de colon en 1998 (estadio pT3N0M0), tratado quirúrgicamente mediante colectomía transversal, considerado en remisión completa. Tras realización de estudios complementarios se demostró la presencia de autoanticuerpos inhibidores del Factor VIII que confirmaron el diagnóstico de hemofilia adquirida. Durante el ingreso el paciente presentó un sangrado digestivo bajo que conllevó al descubrimiento de recidiva del adenocarcinoma colorrectal tratado previamente. Respondió de forma favorable a la terapia inicial con corticoides sistémicos y el complejo coagulante anti inhibidor que incluye el Factor VII activado [FEIBA].

Abstract We report the case of an 86-year-old man presenting with a spontaneous hematoma in the left iliac muscle and previous diagnosis of colon cancer in 1998 (stage pT3N0M0) treated with transverse colectomy and considered in complete remission. After a complete study, it was possible to identify the presence of Factor VIII inhibitors antibodies that confirmed the presence of acquired hemophilia. During hospitalization the patient presented a lower gastrointestinal bleeding leading to the diagnosis of recurrence of a previously treated colorectal adenocarcinoma. He responded to initial therapy with systemic corticoids and anti-inhibitory coagulant complex which includes activated VII Factor [FEIBA].

O acesso global e nacional ao tratamento da hemofilia: reflexões da bioética crítica sobre exclusão em saúde / Global and national access to the treatment of hemophilia: reflections from critical bioethics on health exclusion / El acceso global y nacional al tratamiento de la hemofilia: reflexiones de la bioética crítica sobre exclusión en salud

A hemofilia é uma doença rara, hereditária e caracterizada pela falta de fatores de coagulação, o que provoca sangramentos espontâneos e artropatias incapacitantes. O componente mais dispendioso em seu tratamento é a reposição do fator de coagulação. O presente ensaio examina, a partir da perspectiva da Bioética Crítica, modelo teórico baseado na articulação da Teoria Crítica com os Estudos da Colonialidade, o panorama do acesso global ao tratamento e o programa brasileiro. Demonstrou-se um quadro marcado por extremas disparidades de acesso em nível tanto global quanto nacional, cujas causas estão diretamente relacionadas com a formação histórica de um sistema-mundo baseado na dominação dos meios materiais, ideias e instituições pelos países centrais. Para seu enfrentamento, concluiu-se pela necessidade de contínuas pressões sociais, estímulo a uma produção científica e regulação tecnológica verdadeiramente comprometida com o cumprimento do direito fundamental à saúde.(AU)

Hemophilia is a rare, hereditary disease characterized by a lack of clotting factors, which causes spontaneous bleeding and disabling arthropathy. The most expensive component in its treatment is clotting factor replacement therapy. This essay examines, based on the perspective of Critical Bioethics - a theoretical model based on the articulation between Critical Theory and Coloniality Studies -, the panorama related to the global access to that treatment and the Brazilian program. A scenario marked by extreme disparities of access was found, both in the global and in the national levels, whose causes are directly related to the historical formation of a world system based on the domination of material means, ideas and institutions by central countries. To face this situation, a continuous social pressure is needed, as well as incentive to scientific production and technological regulation truly committed to the enforcement of the fundamental right to health.(AU)

La hemofilia es una enfermedad rara, hereditaria, caracterizada por la falta de factores de coagulación, lo que provoca sangrados espontáneos y artropatías discapacitantes. El componente más caro de su tratamiento es la reposición del factor de coagulación. El presente ensayo examina, a partir de la perspectiva de la Bioética Crítica, un modelo teórico basado en la articulación de la Teoría Crítica con los Estudios de la Colonialidad, el panorama del acceso global al tratamiento y el programa brasileño. Demostró ser un cuadro marcado por disparidades extremas de acceso, tanto en nivel global como nacional, cuyas causas están directamente relacionadas con la formación histórica de un sistema de mundo basado en la dominación de los medios materiales, ideas e instituciones por los países centrales. La conclusión para enfrentarlo fue la necesidad de continuas presiones sociales y estímulo a una producción científica y regulación tecnológica verdaderamente comprometidas con el cumplimiento del derecho fundamental a la salud.(AU)

Clinical study on factor Ⅷ inhibitor in children with hemophilia A / 中华血液学杂志

Objective: To reveal the related factors of inhibitors and differences ofhemorrhage and joint disease before and after the production of inhibitors in children with hemophilia A (HA) . Methods: Retrospective analyses of the clinical data of 381 children with HA under the age of 16 registered in the Registration Management Center of Hemophilia in Henan Provincial from January 2015 to August 2018. Results: A total of the 381 children were enrolled with 116 (30.4%) mild, 196 (51.4%) moderate, and 69 (18.1%) severe cases; 54 patients (14.2%) had inhibitors, including 22 high and 32 low titer inhibitors. Positive family history was positively associated with inhibitors[P<0.001, OR=3.299 (95%CI 1.743-5.983) ], and high-intensity exposure was associated with inhibitors[P=0.002, OR=2.587 (95%CI 1.414-4.731) ]. High-intensity exposure was associated with high titer inhibitor production[P=0.001, OR=8.689 (95%CI 2.464-30.638) ], and high-intensity exposure increased the risk of high titer inhibitors in HA patients. After inhibitors occurred in 54 patients with HA, the rates of overall joint annual bleeding (z=-3.440, P=0.001) and traumatic annual bleeding (z=-2.232, P=0.026) increased, but the rates of the annual joint bleeding (z=-1.342, P=0.180) and spontaneous annual bleeding (z=-1.414, P=0.157) remained to be not statistically significant. The joint ultrasound score did not change significantly after the inhibitor information (z=-0.632, P=0.527) . Conclusions: Positive family history and high-intensity exposure could increase the risk of F Ⅷ inhibitors in HA patients, and high-intensity exposure increased the risk of high titer inhibitors. The rates of the overall joint annual bleeding and traumatic annual bleeding increased after the inhibitor information.

Impacto económico de los inhibidores en hemofilia tipo A pediátrica / Economic impact of inhibitors in pediatric hemophilia type A

Resumen Introducción: Pocos estudios han evaluado el impacto económico de los inhibidores en hemofilia tipo A en México, especialmente en población pediátrica. Objetivo: Determinar el impacto económico que conlleva el desarrollo de inhibidores en pacientes pediátricos con hemofilia tipo A. Método: Se evaluaron de forma retrospectiva los pacientes con hemofilia tipo A atendidos en un servicio de hematología pediátrica entre diciembre de 2015 y noviembre de 2017, y se determinaron los costos directos e indirectos a partir de la presencia o ausencia de inhibidores. Resultados: El análisis de costos de la población estudiada (n = 24) mostró que el diagnóstico, seguimiento, profilaxis, tratamiento y hospitalización de estos pacientes tuvo un costo de $6 883 187.4 anuales por paciente, de los cuales más de 95 % dependió del uso de factores hemostáticos. El costo anual por paciente en el grupo con inhibidores tuvo un costo de $5 548 765.0, en comparación con $1 334 422.4 del grupo sin inhibidores, 4.2 veces superior. Conclusiones: Se trata del primer estudio nacional que muestra que el desarrollo de inhibidores en pacientes pediátricos con hemofilia tipo A eleva más de cuatro veces la erogación económica derivada de esta enfermedad.

Abstract Introduction: Few studies have assessed the economic impact of inhibitors in hemophilia A in Mexico, especially in the pediatric population. Objective: To determine the economic impact entailed by the development of inhibitors in pediatric patients with hemophilia A. Method: Patients with hemophilia A under the care of a pediatric hematology department between December 2015 and November 2017 were retrospectively assessed. Direct and indirect costs were determined based on the presence or absence of inhibitors. Results: The cost analysis of the study population (n = 24) showed that diagnosis, follow-up, prophylaxis, treatment and hospitalization of these patients had an annual cost of $ 6 883 187.4 per patient, out of which more than 95 % depended on the use of hemostatic factors. Annual cost per patient in the group with inhibitors was $ 5 548 765.0 in comparison with $ 1 334 422.4 in the group without inhibitors, 4.2 times higher. Conclusions: This is the first national study to show that the presence of inhibitors in pediatric patients with hemophilia A increases the cost of the disease more than four times.

Population pharmacokinetics of two recombinant human coagulation factor Ⅷ preparations in patients with hemophilia A / 中华血液学杂志

Objective: To compare the differences in population pharmacokinetic (PK) parameters between two recombinant coagulation factor Ⅷ (FⅧ) preparations, Kogenate FS and Advate, in patients with hemophilia A, and to provide the theoretical basis of precise individualized treatment for those patients. Methods: Patients with moderate or severe hemophilia A who had at least one injection of Kogenate FS or Advate at 41 international hemophilia centers were enrolled as subjects from the WAPPS-Hemo project since January 2015 to December 2017. The half-lives of the two drugs and the time of FⅧ activity reaching 2% (TAT 2%) were calculated, and the differences of PK between the two drugs among different age and dose subgroups were further analyzed. Results: ①The mean age of patients in the Kogenate FS (n=117) and Advate groups (n=120) were (27.6±17.7) and (23.4±16.2) years old, respectively. All patients in the two groups were males. ②The administration doses in the Kogenate FS and Advate groups were (31.5±13.1) IU/kg and (38.17±14.83) IU/kg, respectively; the half-lives of the two drugs were (12.3±3.5) h and (10.8±2.9) h, respectively; and the TAT 2% were (65.2±21.7) h and (57.0±17.9) h, respectively. ③In the Kogenate FS group, the drug half-lives in patients aged ≥12 and <12 years old were (12.7±3.7) h and (11.1±2.5) h, respectively; the TAT 2% were (68.6±22.9) h and (55.8±14.6) h, respectively. In the Advate group, the drug half-lives in patients aged ≥12 and <12 years old were (11.4±3.1) h and (9.4±1.8) h, respectively; and the TAT 2% were (61.1±18.0) h and (45.2±11.3) h, respectively. ④In the Kogenate FS group, the drug half-lives in <20 IU/kg, (20-29) IU/kg, (30-39) IU/kg and ≥40 IU/kg groups were (13.3±4.0) h, (12.3±3.6) h, (12.2±3.5) h and (11.6±2.6) h, respectively; and the TAT 2% were (61.5±21.4) h, (63.9±22.4) h, (67.0±24.3) h and (68.0±19.5) h, respectively. In the Advate group, the drug half-lives in <20 IU/kg, (20-29) IU/kg, (30-39) IU/kg and <40 IU/kg groups were (11.5±3.8) h, (11.4±3.7) h, (11.0±2.9) h and (10.4±2.3) h, respectively; and the TAT 2% were (50.8±19.2) h, (56.7±21.0) h, (58.2±18.8) h and (58.1±15.8) h, respectively. Conclusion: The PK parameters of Kogenate FS are superior to those of Advate among different age and dose subgroups.

Hemofilia A adquirida. A propósito de un caso / Acquired hemophilia A. A case report

La hemofilia A adquirida es un trastorno hemorrágico poco frecuente caracterizado por la presencia de autoanticuerpos contra el factor VIII (FVIII) circulante. Se ha observado en un grupo heterogéneo de entidades que incluyen, entre otros, enfermedades malignas; de ellas el 32 por ciento asociada a procesos urológicos, donde el cáncer de próstata tiene la mayor prevalencia. Se presenta un paciente que fue atendido en el servicio de Oncología del Hospital Universitario Celestino Hernández Robau con el diagnóstico de hemofilia A adquirida en la evolución de un adenocarcinoma prostático. Se realizó estudio de coagulación en el Instituto de Hematología e Inmunología donde se comprobó la presencia de inhibidor del factor VIII, lo que confirmó el diagnóstico. Se puso tratamiento inmunosupresor con prednisona 1 mg/kg de peso, con una evolución favorable(AU)

Acquired hemophilia A is a rare bleeding disorder characterized by the presence of autoantibodies against circulating factor VIII (FVIII). It has been observed in a heterogeneous group of entities that include, among others, malignant diseases; 32 percent associated with urological processes, where prostate cancer has the highest prevalence. We present a patient who was treated at the Oncology Service of the Celestino Hernández Robau University Hospital with the diagnosis of acquired hemophilia A in the course of a prostatic adenocarcinoma. A coagulation study was carried out at the Institute of Hematology and Immunology where the presence of factor VIII inhibitor was confirmed, confirming the diagnosis. Immunosuppressive treatment was given with prednisone 1 mg/kg of weight, with a favorable evolution(AU)

Seguridad y eficacia de facto VII recombinante activado para el tratamiento de pacientes con hemofilia a severa con presencia de inhibidores y alto riesgo de eventos agudos de sangrado o hemorragia que no responden al concentrado de complejo protrombínico activado / Safety and efficacy de facto Recombinant VII activated for the treatment of patients with hemophilia to severe with inhibitors and high risk of acute bleeding or bleeding events that do not respond to activated prothrombin complex concentrate

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación del Facto VII recombinante en el manejo de pacientes con diagnóstico de Hemofilia A severa, con presencia de inhibidores y que presentan o estén en riesgo de presentar evento agudo de sangrado o hemorragia, con el objetivo de prevenir muerte por sangrado no controlado. Aspectos Generales: La hemofilia es un desorden hematológico congénito ligado al cromossoma X. Se han identificado dos tipos principalmente, la Hemofilia A que es causado por deficiencia de factor de coagulación VIII (FVIII) y la Hemofilia B que es causado por deficiencia de factor de coagulación IX (FIX). La deficiencia de estos factoes es el resultado de mutaciones en los genes de los factores de coagulación respectivos. Tecnología Sanitaria de Interés: Factor VII Recombinante Activado-RFVIIA (Novoseven - Marca Registrada): El RFVIIA es un glicoproteina dependiente de la vitamina K que consiste em 406 residuos de aminoácidos (MW 50K Dalton). Es estructuramente similar al factor VIIa derivado de plasma hmano y actúa de manera semejante al factor VII en la cascada de coagulación. Debido a que el factor VII actúa directamente sobre el factor X independientemente del facto VIII y IX, este medicamento puede ser usado en pacientes con hemofilia que han desarrollado inhibidores a los factores VII oIX. METODOLOGIA: Estratégia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de Factor VII recombinante activado con diagnóstico de Hemofilia A severa, con presencia de inhibidores altos respondedores definido por presentar una alta respuesta (>= 5 unidades Bethesda UB), que presentan o estén en alto riesgo de presentar evento agudo de sangrado o hemorragia y que haya usado aPCC previamente. RESULTADOS: Se realizó la búsqueda bibliografica y de evidencia cientifica para el sustento del uso del Factor VII recombinante activado en pacientes con Hemofilia A severa con titulos elevados de inhibidores, que sean altos respondedores (>= 5 unidades Bethesda UB), que tengan o estén en alto riesgo de presentar evento agudo de sangrado y que hayan usado aPCC previamente. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se ha encontrado escasa evidencia que muestre que facto VII recombinante activado (rFVIIa) ofrezca beneficios para los pacientes con diagnóstico de hemofilia A severa con presencia de inhibidores y con alto riesgo de hemorragia de evento agudo de sangrado o hemorragia que hayan usado el concentrado de complejo protrombínico activado (aPCC). La evidencia que respalda esto uso de rFVIIa es aún muy limitada, se establece que el efecto de rFVIIa se evaluará con los datos de los pacientes que los hayan recibido por el periodo de vigencia de este Dictamen, para determinar el impacto de su usi en los desenlaces de interés de este Dictamen. Esta información será tomada en cuenta en la reevaluación de este medicamento para efectos de un nuevo dictamen al terminar la vigencia del presente Dictamen Preliminar.

Hemorragia intracraniana espontânea em pediatria: relato de paciente hemofílico que sobreviveu devido a cisto cerebral / Spontaneous intracranial hemorrhage in children: report of a hemophilia patient who survived due to a brain cyst

RESUMO Relatamos o caso de um uma criança de 2 anos de idade que sobreviveu após um episódio agudo de hemorragia intracraniana espontânea grave com sinais clínicos e radiológicos de hipertensão intracraniana e herniação transtentorial. O paciente foi para cirurgia de urgência para drenagem do hematoma, sendo inserido um cateter para monitorar a pressão intracraniana. Na análise da tomografia de crânio inicial, antes da drenagem do hematoma, constatou-se um cisto cerebral contralateral ao hematoma que, segundo análise do neurocirurgião e do neuroradiologista, possivelmente evitou um desfecho pior, visto que o cisto serviu de acomodação para o cérebro após a hemorragia maciça. Após investigação, constatou-se tratar de um caso de hemofilia tipo A sem diagnóstico prévio. O paciente foi tratado em terapia intensiva com controle da pressão intracraniana, reposição de fator VIII e obteve alta sem sequelas neurológicas evidentes.

ABSTRACT We report the case of a 2-year-old child who survived an acute episode of severe spontaneous intracranial hemorrhage with clinical and radiological signs of intracranial hypertension and transtentorial herniation. The patient underwent emergency surgery to drain the hematoma, and a catheter was inserted to monitor intracranial pressure. In the initial computed tomography analysis performed prior to hematoma drainage, a brain cyst was evident contralateral to the hematoma, which, based on the analysis by the care team, possibly helped to avoid a worse outcome because the cyst accommodated the brain after the massive hemorrhage. After the investigation, the patient was determined to have previously undiagnosed hemophilia A. The patient underwent treatment in intensive care, which included the control of intracranial pressure, factor VIII replacement and discharge without signs of neurological impairment.

Hemofilia adquirida (inhibidor adquirido del factor VIII) / Acquired haemophilia (acquired factor VIII inhibitor)

La hemofilia adquirida es una enfermedad de muy poco frecuente presentación. El paciente habitualmente consulta con equimosis y hematomas extensos en la piel y tejido celular subcutáneo, anemia y en algunas oportunidades un sangrado grave, que si no se controla puede ser fatal hasta en el 20% de los casos. Se produce por un autoanticuerpo dirigido contra el factor VIII de la coagulación y suele ocurrir en pacientes añosos sin historia de sangrados, pero también puede presentarse asociado a neoplasias, enfermedades autoinmunes, medicamentos y en mujeres jóvenes asociado al embarazo. Tiene un perfil de laboratorio característico con un tiempo de tromboplastina parcial activada (aPTT) prolongado, que no corrige con plasma normal, y niveles de factor VIII disminuidos. El tratamiento recomendado es muy específico, ya que para controlar el sangrado se utilizan agentes de puenteo (productos que sortean el efecto del inhibidor), factor VII recombinante activado o concentrado de complejo de protrombina activada, y medicación inmunosupresora para erradicar el autoanticuerpo.

Acquired haemophilia is a rare disorder. The clinical picture ranges from mild ecchymosis and anaemia to life threatening bleeding in up to 20% of patients. The disease is produced by an antibody against Factor VIII and it usually occurs in the elderly, with no previous history of a bleeding disorder. It can be associated to an underlying condition such as cancer, autoimmune disorders, drugs or pregnancy. It has a typical laboratory pattern with isolated prolonged activated partial thromboplastin time (aPTT) that fails to correct upon mixing tests with normal plasma and low levels of factor VIII. Treatment recommendations are based on controlling the acute bleeding episodes with either bypassing agent, recombinant activated factor VII or activated prothrombin complex concentrate, and eradication of the antibody with immunosuppressive therapy.

Dilataciones endoscópicas del tracto gastrointestinal / Endoscopic dilation of the gastrointestinal tract

Las dilataciones en el tracto gastrointestinal se llevan a cabo para aliviar la obstrucción sintomática, ya sea funcional u orgánica, secundarias a una variedad de patologías tanto benignas como malignas. Con el advenimiento de las nuevas tecnologías, virtualmente toda estenosis digestiva puede ser manejada en forma mínimamente invasiva. Pese a su amplia difusión en la práctica actual, existen pocos estudios controlados que comparen las diferentes modalidades de dilatación. En el presente artículo realizamos una revisión de esta técnica, así como de la evidencia disponible para su aplicación en los diferentes segmentos del tracto gastrointestinal. El futuro de la dilatación incluye el desarrollo de dilatadores que permitan evaluar la dilatación durante su realización. Estos advenimientos, así como la ejecución de estudios controlados prospectivos van a mejorar las indicaciones, beneficios y riesgos para cada uno de los sistemas de dilatación existentes.

The endoscopic dilation of the gastrointestinal tract is carried out to relieve either functional or organic disorders, secondary to a variety of both benign and malignant diseases. With the advent of new technologies, virtually all digestive stenosis can be managed in a minimally invasive way. Despite its wide dissemination in actual practice, there are few controlled studies comparing the different forms of endoscopic dilation. In this article, we review this technique and the evidence available for application in different segments of the gastrointestinal tract. The future of the dilations includes the development of dilators to assess dilation during the procedure. These advents and the implementation of prospective controlled studies will improve the indications, benefits and risks for each of the existing systems of dilations.

Violence against metropolitan bus drivers and fare collectors in Brazil / Violência a motoristas e cobradores de ônibus metropolitanos, Brasil

OBJECTIVE To analyze the correlation between sociodemographic factors and working conditions of bus workers in a metropolitan area and violence against them. METHODS This cross-sectional study used a nonprobabilistic sample estimated according to the number of workers employed in bus companies located in three cities in the Belo Horizonte metropolitan region in 2012 (N = 17,470). Face-to-face interviews were conducted using a digital questionnaire. The factors associated with violence were analyzed in two stages using Poisson regression, according to each level. The magnitude of the association was evaluated using prevalence ratios with robust variance and a statistical significance of 5%, and 95% confidence intervals were obtained. RESULTS The study sample comprised 782 drivers and 691 fare collectors; 45.0% participants reported at least one act of violence in the workplace in the last 12 months, with passengers being predominantly responsible. The age of the bus workers was inversely associated with violence. Chronic diseases, sickness absenteeism, and working conditions were also associated with violence. CONCLUSIONS The findings on the correlation between violence and working conditions are essential for implementing prevention strategies by transportation service managers. .

OBJETIVO Analisar associação entre fatores sociodemográficos e de condições de trabalho e violência contra profissionais de ônibus de região metropolitana. MÉTODOS Estudo transversal com amostra não probabilística, estimada segundo quotas do efetivo distribuído nas empresas de ônibus localizadas em três cidades da região metropolitana de Belo Horizonte, em 2012 (n = 17.470). Foram realizadas entrevistas face a face com questionário digital. A análise dos fatores associados à violência foi realizada em duas etapas, pela regressão de Poisson, de acordo com cada nível. A magnitude da associação foi aferida pelas razões de prevalência com variância robusta e significância estatística de 5%. Foram obtidos intervalos de confiança de 95%. RESULTADOS Participaram da pesquisa 782 motoristas e 691 cobradores. Quase metade (45,0%) dos participantes relatou pelo menos um episódio de violência no trabalho nos últimos 12 meses, predominantemente praticado pelos passageiros. A idade do trabalhador rodoviário foi inversamente associada à violência. Doenças crônicas, absenteísmo-doença e condições de trabalho foram associados à violência. CONCLUSÕES As informações trazidas sobre a associação da violência com as condições de trabalho são fundamentais para guiar estratégias de prevenção indicadas aos gestores da produção dos serviços de transporte. .

Efficacy, Safety, and Pharmacokinetics of Beroctocog Alfa in Patients Previously Treated for Hemophilia A

PURPOSE: Beroctocog alfa is a second generation recombinant factor VIII manufactured by removing the B-domain from factor VIII. This prospective clinical trial was conducted to evaluate the efficacy, safety, and pharmacokinetics of beroctocog alfa in patients of ages > or =12 years previously treated for severe hemophilia A. MATERIALS AND METHODS: Seventy subjects received beroctocog alfa as an on-demand treatment for acute hemorrhage. RESULTS: The final hemostatic effect was excellent in 35 subjects (50%) and good in 26 subjects (37.1%). The drug showed an overall efficacy rate of 87.1%. The majority of acute hemorrhages was treated by administering the study drug once (86.2%) or twice (10.0%), and the mean dose administered per single infusion was 28.55+/-6.53 IU/kg. Ten subjects underwent 12 surgical procedures, and hemostatic efficacy was excellent in seven cases (58.3%) and good in five cases (41.7%), showing a 100% efficacy rate. A total of 52 of 88 subjects (59.0%) experienced 168 adverse events. There were 18 serious adverse events (10.7%) in 11 subjects, and two (mild dyspnea and facial edema) in one subject were related to the study drug. Only one subject formed a de novo factor VIII inhibitor, for an occurrence rate of 1.4% (one-sided 95% upper confidence limit: 3.85%). The final elimination half-life was 13.3 h and 12.6 h at baseline and 6 months after administration, respectively. CONCLUSION: Our results suggest that beroctocog alfa is safe and efficacious as either an on-demand treatment for acute hemorrhage or a surgical prophylaxis in patients with hemophilia A.

Prevalence, Incidence, and Factor Concentrate Usage Trends of Hemophiliacs in Taiwan

PURPOSE: Hemophilia A and B (HA, HB) are the most common X-linked inherited bleeding disorders. The introduction of factor concentrates has allowed for control of the lifelong chronic disease. However, no studies have been published regarding the epidemiology of hemophilia in Taiwan. Our aim was to determine the prevalence, incidence, and mortality rate, as well as trends in the use of factor concentrates, in individuals with hemophilia in Taiwan. MATERIALS AND METHODS: A retrospective study was conducted using the National Health Insurance Research Database between 1997 and 2007. RESULTS: We identified 988 males with hemophilia (HA : HB ratio=5.4 : 1). The mean prevalence per 100000 males was 6.7+/-0.1 for HA and 1.2+/-0.1 for HB. The estimated mean annual incidence per live male birth was 1 in 10752 for HA and 1 in 47619 for HB. Standardized mortality ratios for males with hemophilia (all severities) or severe hemophilia were 1.3- and 2.1-fold higher than that of the general male population, respectively. Mean factor VIII (FVIII) and factor IX (FIX) usage was 1.5003+/-0.4029 and 0.3126+/-0.0904 international units (IUs) per capita, respectively. Mean FVIII and FIX usage per patient with hemophilia (all severities) or severe hemophilia was 44027+/-11532 and 72341+/-17298, respectively, and 49407+/-13015 and 74369+/-18411 IUs per person with HA or HB, respectively. CONCLUSION: Our data revealed epidemiologic and factor concentrate usage trends in males with hemophilia in Taiwan, highlighting a need for improvements in the mandatory National Health Insurance registry. A better-designed, patient-centered registry system would enable more detailed patient information collection and analysis, improving subsequent care.

Hemofilia adquirida tratada con anti CD20, un anticuerpo anti linfocito B / Acquired hemophilia a treated with rituximab. Report of one case

We report a 54-year-old male presenting with a history or recurrent nose bleeds and ecchymoses. The coagulation study showed a prolongedpartial thromboplastin time, a factor VIII of 8 percent and a high inhibitor titer (193 Bethesda units). A diagnosis of acquired hemophilia A was reached. The patient was initially treated with cyclophosphamide for seven months without response. Therefore rituximab in doses of 375 mglm²Iweek for four weeks was started. After starting treatment, the patient had a hematoma in the psoas muscle with a concomitantfactor VIII ofless than 5 percent, thatwas treated with local measures. Thereafter, aprogressive reduction in inhibitor titers was observed, until its disappearance atfive months of treatment. Factor VIII levéis normalized and the patient has not experienced abnormal bleeding episodes. The patient remains in remission after 67 months offollow up. Rituximab, a chimeric monoclonal antibody against theprotein CD 20 is an effective treatment in acquired hemophilia A.

Evaluation of the two FVIII assay types [clotting and chromogenic] for measuring FVIII activity in cryoprecipitate

In Iran, cryoprecipitate is an important plasma product for coagulation factors such as factor VIII [FVIII] to be ensured. As risk of bleeding is associated with FVIII activity, it is important to choose a suitable method for its measurement. In the present study we compared clotting and chromogenic assays on FVIII activity in cryoprecipitate. FVIII activity of cryoprecipitate from 48 donors with different blood groups was measured by clotting and chromogenic assays. Then the two assay types were compared with each other. Although the absolute values showed a significant difference, a good correlation was seen between one-stage clot-based and chromogenic assays for measuring FVIII activity in cryo. Although the one-stage clotting assay is a suitable method for measuring FVIII activity, the chromogenic assay has a good correlation with clotting based assay. Also a significant difference was seen between the two methods

Inmunogenicidad de los concentrados de Factor VIII doblemente inactivados producidos en UNC-Hemoderivados / Immunogenecity of double inactivation FVIII concentrates manufactures by UNC-Hemoderivados

El tratamiento de elección en la hemofilia A es la administración de concentrados de factor VIII y hasta un 33 % de estos pacientes pueden desarrollar inhibidores dirigidos contra el factor infundido. Varias causas pueden estar involucradas en este proceso inmune siendo la intensidad de la terapia y tipo de concentrados empleados uno de los más estudiados. Por lo tanto, el análisis cuali / cuantitativo de diferentes proteínas que hacen a un concentrado más inmunogénico que otros cobra vital importancia. En este trabajo se evaluaron los niveles de factor VIII antígeno (FVIII:Ag), factor von Willebrand (FvW) funcional e inmunológico, factor de crecimiento transformador ß1 (TGF-ß1), fibrinógeno e inmunoglobulinas G, A y M en diferentes lotes de concentrados de factor VIII manufacturados en UNC-Hemoderivados y fueron comparados con otros productos comerciales de similares características. Se estudiaron 6 lotes de 250 UI y 2 de 500 UI producidos en UNC-Hemoderivados, dos lotes de 250 UI producidos por las firmas A y B y un lote de 500 UI comercializado por la firma C. Para las determinaciones de factor VIII/factor de von Willebrand, funcional y antigénico, se emplearon métodos estándares y para el TGF-ß1 se utilizó un ELlSA comercial. Los resultados obtenidos mostraron que las relaciones entre FVIII:C/FVIII:Ag y FVIII:C/FvW funcional fueron en promedio 0.60 y 0.52 para el producto de UNC-Hemoderivados y 0.50 y 0.38 para los productos de origen comercial. Los valores TGF­ß1 y la actividad específica arrojaron mejores resultados en el producto de UNC-Hemoderivados que los productos A, B y C y en las otras proteínas analizadas no hubo diferencias. Por lo tanto podemos concluir que los concentrados de FVIII producidos en UNC-­Hemoderivados presentan propiedades que potencialmente indicarían una menor respuesta inmune contra el FVIII infundido.

Replacement therapy using plasma factor VIII (FVIII) concentrates is currently the major mean of preventing and controlling bleeding in hemophilia A patients. However. approximately a 33% of these patients may develop inhibitors to the substituted FVIII. Several causes may be involved in the immune process being the intensity of therapy and type of concentrate used one of the most studied. Therefore. the study quali/quantitative analysis of different proteins which make a concentrated more immunogenic than other takes a vital importance. In this study we evaluated FVIII antigen (FVIII: Ag), von Willebrand factor (vWF) functional and immunological, TGF-Beta1, fibrinogen and immunoglobulins G, A and M levels in FVIII concentrates manufactured in UNC-Hemoderivados and compared with other commercial products of similar characteristics. We studied 6 lots of 250 IU and 2 lots of 500 IU manufactured in UNC-Hemoderivados, 2 lots of 250 IU produced by two pharmaceutical companies named A and B and 1 batch of 500 IU marketed by C. For the determinations of F VIII/FvW functional and antigenic we used standards methods and the TGF-ß1 was assayed by ELlSA test. The results show that the relationship between FVIII/FVIII:Ag and FVIII/vWF functional were in average 0.6 and 0.52 for the product of UNC-Hemoderivados and 0.5 and 0.38 for products from commercial sources. TGF-ß1 levels and the specific activity showed upper values in UNC-Hemoderivados compared to commercial products and none difference was observed in the other proteins assayed. Therefore we can conclude that FVIII concentrates produced at UNC-Hemoderivados have properties that indicate a potentially lower immune response against the infused FVIII.