Efectividad de inducción de tolerancia inmune en niños con hemofilia A y aloanticuerpos neutralizantes / Immunotolerance induction effectivity in hemophilia A children and neutralizing alloantibodies

Resumen: Introducción: El desarrollo de aloanticuerpos neutralizantes anti-factor VIII en hemofilia A es la complicación más seria relacionada al tratamiento. La inducción de tolerancia inmune (ITI) o inmunotolerancia es el único tratamiento que erradica inhibidores, permitiendo utilizar nuevamente factor VIII para el tratamiento o profilaxis de eventos hemorrágicos. Objetivo: reportar la experiencia en niños sometidos a inmunotolerancia en la red pública del país. Pacientes y Método: Análisis retrospectivo y descriptivo de 13 niños con Hemofilia A severa e inhibidores persistentes de alto título, que recibieron ITI y seguimiento completo. Se utilizó concentrado de FVIII plasmático en dosis de 70-180 UI/Kg/diarias, definiendo éxito como la negativización del inhibidor y recu peración de la vida media del FVIII. Resultados expresados en media (rango). Resultados: En 13 pacientes se identificó el inhibidor, a una edad de 17,6 meses (2-48), tras 35,2 días (9-112) de exposición a FVIII. Once pacientes (84,6%) recuperaron la vida media del FVIII, tras 49,6 meses (26-70) de tratamiento. En los pacientes que respondieron, el título del inhibidor se negativizó en 7,3 meses (1-20). Conclusiones: En niños con hemofilia A e inhibidores persistentes de alto título, la ITI tiene un elevado éxito. Dado que el tiempo de respuesta es variable, la inmunotolerancia debe ser personalizada.

Abstract: Introduction: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. Objective: To report the experience of pediatric patients who underwent ITI in the country's public health care network. Patients and Method: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). Results: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. Conclusions: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.

Hemofilia adquirida / Acquired hemophilia

Resumen La hemofilia adquirida (HA) es un trastorno hemostático autoinmune ocasionado por autoanticuerpos dirigidos contra el factor VIII: C. En 52 % de los casos, la causa se desconoce o no se asocia con otra entidad patológica; en el resto, existen factores concomitantes: lupus, artritis reumatoide, cáncer, embarazo y medicamentos. En México no existe registro ni conciencia de la enfermedad entre el personal de salud. Los grupos de mayor incidencia son las mujeres en edad reproductiva y los individuos mayores de 70 años. Se caracteriza por hemorragia grave, sobre todo posterior a traumatismos y parto o cesárea, y equimosis grandes en tronco y extremidades. La sospecha es simple, basta que concurran hemorragia súbita, grave y un TTPa prolongado que no se corrige con plasma. El tratamiento consiste en lograr la hemostasia y erradicar el anticuerpo; lo primero se logra con el factor VII activado recombinante o concentrado del complejo de protrombínico activado. La ciclofosfamida, prednisona o rituximab sirven para erradicar el anticuerpo. La mayoría de los casos no son diagnosticados y la mortalidad es alta. Ya que los médicos desconocen el problema, no se sospecha, no se diagnostica y no se trata. Este documento revisa los datos más recientes de la HA y abunda en el diagnóstico y tratamiento.

Abstract Acquired hemophilia (AH) is an autoimmune hemostatic disorder mediated by autoantibodies directed against factor VIII: C. In 52% of cases, the cause is unknown or is not associated with other pathological entities; in the rest, there are concomitant factors: lupus, rheumatoid arthritis, cancer, pregnancy, and medications. In Mexico, there is not a registry of AH, and awareness of the disease among health personnel is low. The groups with the highest incidence are women of childbearing age and individuals older than 70 years. It is characterized by severe bleeding, especially after trauma and normal childbirth or cesarean delivery, and large ecchymoses in the trunk and extremities. The suspicion is simple, it just takes for sudden, severe hemorrhage and a prolonged activated partial thromboplastin time that is not corrected with plasma to concur in an individual. Treatment involves achieving hemostasis and eradicating the antibody. The former is achieved with recombinant activated factor VII or activated prothrombin complex concentrate. Cyclophosphamide, prednisone or rituximab are used to eradicate the antibody. Most cases of AH are not diagnosed, which translates into a high mortality rate. Given that awareness about the disease among physicians is low, it is not suspected, neither diagnosed, and nor is it treated. This document reviews the most recent data on AH and expands on its diagnosis and treatment.

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.

Economic Burden of High-Responding Inhibitors in Patients with Hemophilia A in Taiwan

PURPOSE: Hemophilia A (HA) is the most common X-linked inherited bleeding disorder. In some patients with HA, particularly those with severe HA, replacement therapy results in the production of high-responding clotting factor VIII inhibitors. The economic burden of this complication is the highest reported for a chronic disease. Our aim was to investigate the direct medical expenditure burden of high-responding inhibitors in patients with HA. MATERIALS AND METHODS: A retrospective study was conducted using the National Health Insurance Research Database, utilizing data covering the period of 2004-2007. RESULTS: In total, 638 males with HA, including 37 patients with high-responding inhibitors were evaluated. Over 99% of the annual median medical expenditure was attributable to the cost of clotting factor concentrates (CFCs) in patients with high-responding inhibitors. The annual median expenditure related to CFCs of the total medical care and outpatient care were US$170611 and US$141982, respectively, and were 4.6- and 4.3-fold higher in these patients during the study period, respectively. In patients with high-responding inhibitors, the median hospitalization expenditure and daily hospitalization cost with or without surgical procedures were 3.0- and 2.4-fold higher, respectively, and 4.3 and 5.6-fold higher, respectively. CONCLUSION: Our data reveal higher medical expenditures burden for patients with HA and high-responding inhibitors in Taiwan. Future research is encouraged to evaluate the impact of this burden on patient quality of life.

Deficiencia adquirida del factor VIII. Un ejemplo cuando la cirugía puede ser perjudicial y no para salvar vidas / Deficiência adquirida do fator VIII. Um exemplo de quando a cirurgia pode ser prejudicial e nâo vinculada a salvar vidas / Acquired factor VIII deficiency. One instance when surgery may be harmful and not life-saving

La hemofilia adquirida A es una condición extremadamente rara que ocurre en una persona en un millón por año. Puede causar riesgo para la vida por causar episodios de sangrado durante la edad adulta, debido a la producción de auto-anticuerpos que inactivan el factor VIII. Su tratamiento suele incluir la inmunosupresión y la cirugía se debe evitar en lo posible. Presentamos dos casos que nos tocó tratar, y realizamos una recopilación somera de la bibliografia, a fin de enfatizar la necesidad de no realizar tratamiento quirúrgico en estos casos.

A hemofilia adquirida A é uma condição extremamente rara que pode ocorrer com a probabilidade de um caso em um milhão de pessoas por ano. Pode causar risco para a vida por causar episódios de sangramento durante a idade adulta, devido à produção de autoanticorpos que inativam o fator VIII. Seu tratamento geralmente inclui a imunosupressão, e a cirurgia deve, dentro do possível, ser evitada. Apresentamos dois casos por nós tratados, e realizamos um breve resumo da bibliografia, com a finalidade de enfatizar o propósito de não realizar tratamento cirúrgico nestes casos.

Acquired hemophilia A is an extremely rare disease with an incidence of 1 in 1,000,000 per year. It may be life threatening as it produces bleeding episodes in adult life, due to the production of antibodies which inactivate factor VIII. Treatment may include immunosuppression and surgery must be avoided as much as possible. We shall present two of our cases and then make a brief review of the literature, in order to underscore the need of not operating these cases.

The First Case of Postpartum Acquired Hemophilia A in Korea

Acquired hemophilia A (AHA) is a rare coagulopathy caused by autoantibodies to coagulation factor VIII (FVIII). Most patients with AHA have been previously healthy; however, a variety of morbidities have been associated with the condition including pregnancy. A 40-yr-old woman visited our institution with extensive hematoma on the right hip area. Her medical history revealed no personal or familial history of bleeding diathesis. Her coagulation tests showed markedly prolonged aPTT (117 sec), markedly decreased level of FVIII activity (0.4%) and high-titer FVIII inhibitor (77 BU). Collectively, she was diagnosed as having postpartum AHA and was treated with bypassing agents and corticosteroids. Her aPTT was normalized on the 174th postpartum day and FVIII inhibitor showed negative conversion on the 224th postpartum day. This is the first case of postpartum AHA with high-titer FVIII inhibitor in Korea. Timely diagnosis and management can reduce morbidity and mortality of this potentially life-threatening condition.

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.

Anticuerpos anti-FVIII: su evaluación por citometría de flujo / Anti FVIII antibodies: evaluation by flow cytometry

En este trabajo se describe un sistema para evaluar y caracterizar los anticuerpos anti-FVIII en pacientes con Hemofilia A Severa (HAS) que reciben el Factor como tratamiento de sustitución. Consiste en el empleo combinado de microesferas y Citometria de Flujo (CF). El rFVIII fue acoplado a microesferas de 2 µm de diámetro (m-FVIII) las cuales se incubaron con diluciones de plasma o suero de pacientes con (n=13) o sin (n=17) inhibidor, pacientes en Tratamiento Inmunotolerante (TIT)(n=5) y dadores normales (N) (n=12). Los anticuerpos se revelaron con anti-lgG humana, anti-lgG1, anti-lgG2, anti-IgG3 o anti-lgG4 biotiniladas, seguido por streptavidina-ficoeritrina. Se registraron los valores de Intensidad de Fluorescencia Media (IFM). Microesferas sin FVIII (m-Control) se utilizaron como control. El resultado se expresó como índice: (IFM de m-FVIII/IFM de m-Control) multiplicado por la inversa de la dilución de máxima respuesta. Se determinó el porcentaje de contribución de cada subclase de IgG. Los resultados presentaron un 86 por ciento de concordancia con la prueba de Bethesda y un 80 por ciento con ELISA. El método fue útil para el seguimiento de los pacientes durante el TIT. La IgG4 prevaleció en pacientes con alto título y al comienzo del TIT. La CF es fácil y rápida y requiere sólo 200 µl de muestra.

In this study, a Flow Cytometry (FC) system is described for detecting and characterizing antibodies (inhibitors) to Factor VIII (FVIII) in Severe Haemophilia A (SHA) patients following FVIII infusion. A combination of microspheres and Flow Cytometry (FC) was employed. First, rFVIII was coupled to microspheres of 2 µm of diameter (m-FVIII). Then, they were reacted with dilutions of plasma or serum of patients with (n=13) or without (n=17) inhibitors. Five patients receiving Immunotolerant Treatment (ITI) and 12 normal donors were included. Microspheres without rFVIII were used as control (m-Control). Captured anti-FVIII antibodies were detected using biotinylated anti-Human IgG, IgG1, IgG2, IgG3 or IgG4 followed by streptavidin-phycoerythrin. FC analysis was performed recording Mean Fluorescence Intensity (MFI). Results were given as an Index: the highest MFI ratio between m-FVIII and m-Control multiplied by the inverse of the corresponding plasma dilution. The contribution of each IgG subclass was expressed as percentage. FC results had 86 per cent and 80 per cent of coincidence with the Bethesda method and ELISA respectively. The test was useful to measure anti-FVIII antibodies during the ITI. IgG4 was the prevalent IgG subclass in patients with high level of inhibitors and previously to ITI. FC was easy, fast and requires only 200 µl of sample.

Desenvolvimento de inibidores do fator VIII na hemofilia A / Development of factor VIII inhibitors in hemophilia A

A hemofilia A é uma coagulopatia genética com herança recessiva ligada ao cromossomo X que afeta 1-2 a cada 10 mil indivíduos do sexo masculino nascidos vivos. Estes indivíduos têm baixas concentrações ou ausência do fator VIII (FVIII) da coagulação no plasma e apresentam quadros hemorrágicos leves, moderados e graves, dependendo da atividade de FVIII circulante. Estes pacientes necessitam de constante reposição proteica e aproximadamente 30 por cento deles desenvolvem aloanticorpos contra a proteína exógena. A síntese dos anticorpos anti-FVIII é iniciada quando o FVIII exógeno é endocitado por células apresentadoras de antígeno, degradado e apresentado às células T CD4+ na forma de peptídeos ligados a moléculas do complexo maior de histocompatibilidade (MHC) de classe II. Alguns fatores de risco (paciente/tratamento) podem ser relacionados ao desenvolvimento desta resposta imune. Neste contexto, as mutações no gene do FVIII e polimorfismos em genes envolvidos na resposta imune são candidatos moleculares como determinantes imunogenéticos na predisposição para o desenvolvimento de inibidores. Por não ser completamente entendido e controlado, o desenvolvimento desta resposta imune contra o FVIII constitui o maior problema decorrente do tratamento de indivíduos portadores de hemofilia A e faz-se necessária busca de opções que visem minimizar suas ações deletérias. Algumas alternativas de tratamento têm se mostrado eficazes no tratamento (anti-CD20, plasmaférese, concentrado de complexo protrombínico (PCCs), concentrado de complexo protrombínico ativado (APCCs), fator VII humano ativado), mas a retirada ou neutralização específica dos inibidores de FVIII ainda não foram alcançadas.

Hemophilia A, which affects 1-2:10,000 live-born male neonates, is a genetic coagulopathy with recessive inheritance linked to the X chromosome. These individuals have low concentrations or no coagulation factor VIII (FVIII) in the plasma and suffer from mild, moderate and severe bleeding depending on the circulating FVIII activity. These patients need frequent protein infusions and approximately 30 percent of them develop alloantibodies against the exogenous protein. Anti-FVIII antibody synthesis initiates when the exogenous FVIII is internalized by antigen presenter cells, degraded and presented to CD4+ T-cells as peptides associated to the class II major histocompatibility complex (MHC). Some risk factors (patient/treatment) may be related to the development of this immune response. Thus, FVIII gene mutations and polymorphisms of genes involved in immune response are molecular candidates of immunogenic determinants in the predisposition for inhibitor development. As it is not fully understood and controlled, the development of immune response against FVIII constitutes a major problem in the treatment of hemophilia A which aims at minimizing the deleterious consequences. Some therapeutic alternatives have been effective (anti-CD20, plasmapheresis, prothrombin complex concentrates, activated prothrombin complex concentrates, human activated factor VII), but removal or neutralization of specific anti-FVIII inhibitors has not been achieved yet.

Transient Acquired Hemophilia Associated with Mycoplasma Pneumoniae Pneumonia

Acquired hemophilia is a rare disorder caused by autoantibodies to factor VIII (FVIII) (also referred to as factor VIII inhibitors or anti-FVIII) and may be associated with pregnancy, underlying malignancy, or autoimmune disorders. A 33-month-old girl who presented with hematochezia and ecchymotic skin lesions was diagnosed with Mycoplasma pneumoniae pneumonia by serology and polymerase chain reaction. Hematologic studies showed a prolonged activated partial thromboplastin time (aPTT), partially corrected mixing test for aPTT, reduced levels of FVIII, and the presence of antibodies against FVIII. She was treated conservatively with prednisone and intravenous immunoglobulin (IVIG) without FVIII transfusion and recovered without sequelae. This report provides the first description of acquired hemophilia due to anti-FVIII in association with M. pneumoniae in Korea. We discuss this case in the context of the current literature on acquired hemophilia in children.

Evaluación de neoantígenos en concentrados de factor VIII analizados por enzimoinmunoensayo / Neoantigens evaluation on F VIII concentrates analyzed by enzymeimmunoassay (EIA)

El propósito de este estudio fue evaluar la inmunogenicidad de concentrados de factor VIII producidos en UNC-Hemoderivados antes y después del tratamiento térmico empleando un enzimoinmunoensayo (EIE) desarrollado en nuestro laboratorio. Materiales y método: Para ese propósito se obtuvieron anticuerpos contra factor VIII calentado y no-calentado por inmunización de conejos y la inmunoglobulina G específica fue aislada por afinidad a Proteína A-Sepharosa. El EIE fue realizado empleando como antígeno de captura el factor VIII con o sin tratamiento térmico (0.5 ug/pocillo), los sitios inespecíficos bloqueados con albúmina al 2 por ciento y el anticuerpo revelado con un anti-IgG de conejo conjugada a peroxidasa. La presencia de neoantígenos fue estudiada por incubar durante 2 hs a 37°C y luego a 4°C toda la noche, con cantidades crecientes de factor VIII antes y después del tratamiento térmico (0.03 a 600 ug de proteínas), con cantidades adecuadas de IgG anti-factor VIII calentado y no-calentado. Luego de centrifugar la muestra para la separación de los inmunocomplejos, se valoró la presencia de anticuerpos en el sobrenadante por EIE tanto para factor VIII calentado y no calentado. Resultados: Los resultados obtenidos permitieron observar que para ambos anticuerpos (calentado y no calentado) se neutralizaba la misma cantidad de factor VIII calentado y no calentado (0.30 ug) y además, se pudo comprobar que esta conducta se repetía cuando se empleaban en el EIE como antígeno de captura, factor VIII con y sin tratamiento térmico. Conclusiones: Los datos obtenidos de este estudio nos permiten concluir que el tratamiento térmico aplicado a los concentrados de factor VIII elaborados en la UNC-Hemoderivados no producen ninguna formación de neoantígenos. A juzgar por el sensible y específico EIE desarrollado en nuestro laboratorio.

Introduction: with the purpose of improving viral security, plasma-derived products are generally subjects of solvent/detergent and heating (100°C for 30 minutes) treatment which are introduced during the manufacturing process. The formation of neoantigens in factor VIII concentrates produced after the heat treatment could trigger an immune response against the modified protein and the native protein. Objetives: the purpose of this study was to evaluate the immunogenicity of factor VIII concentrates produced in UNC-Hemoderivados before and after heat treatment, using an EIA developed in our laboratory. Materials and methods: antibodies against factor VIII with and without heating treatment were obtained by rabbit immunization. The specific IgG was isolated by protein-A-Sepharose affinity chromatograpy. Two EIA plates were coated (0.5 ug/well) one with factor VIII heated (H) and the other one with factor VIII no-heat (no-H) and the antibodies detection were performed using rabbit anti-lgG peroxidase conjugated. The neoantigens were studied by incubation of increasing concentrations of factor VIII (0.03-600 ug of proteins) before and after heating treatment during 2 hours at 37 °C and overnight at 4 °C with adequate concentrations of anti-factor VIII IgG (with and without treatment). The immunocomplexes were removed by centrifugation and the free antibodies in the supernatant were measured by EIA in plates H and no-H. Results: the EIA showed a linear behavior between antibodies dilution ranged from 1/8000 to 1/512000. With these results we can conclude that the same concentration of factor VIII heated and unheated (0.30 ug) were neutralized with either antibodies (heated and unheated). These results were similar in both EIA plates coated with factor VIII H and no-H...

Spontaneously developing autoantibody to factor VIII in an elderly woman: diagnostic and therapeutic challenges.

An elderly woman with a continuously bleeding small wound was investigated for the presence of antibodies to FVIII using activated partial time-based screening and confirmatory tests. A late acting coagulation factor inhibitor was detected. The same was characterised to be a low titre antibody against FVIII (5.2 Bethesda units). Cryoprecipitate infusions, corticosteroids and topical desmopressin were unsuccessful in controlling the bleeding. Addition of cyclophosphamide brought about stoppage of bleeding and disappearance of the autoantibody.

Hemostasis in acquired hemophilia--role of intracavitary instillation of EACA.

An 82 year old man developed antibodies against coagulation factor VIII:C without any apparent cause. Bleeding from the soft tissue cavity could not be controlled by factor VIII:C concentrates, immunosuppression with steroids and intravenous immunoglobulin therapy in the standard dosages. However, a single injection of Epsilon Aminocaproic Acid (EACA) instilled into the cavity under aseptic precautions achieved lasting hemostasis with resultant wound healing.

Inhibidor neutralizante e inhibidor lúpico en hemofilia: un nuevo problema diagnóstico / Anti-factor VIII inhibitors and lupus anticoagulants in hemophilia: a diagnostic problem

Los hemofílicos pueden desarrollar inhibidores neutralizantes (a-ŸVIII) y/o inhibidores lúpicos (IL). Durante 1993-1994, evaluamos 170 hemofílicos. Aquellos cuyo tiempo de tromboplastina parcial activado (TTPA) no corregía con plasma normal fueron reestudiados. En 43 pacientes (25 por ciento) se confirmó el inhibidor, realizándose a continuación: TTPA de la mezcla (1:1) luego de 1 h de incubación a 37§C; prueba con veneno de víbora Russell diluido (dRVVT), corrección (1:1) con normal y neutralización con plaquetas. El IL fue asignado en base a los resultados del dRVVT y el a-ŸVIII al detectarse efecto neutralizante contra ŸVIII e IL negativo. Siete (16 por ciento) pacientes presentaron a-ŸVIII e IL (-) (A). Los 36 (84 por ciento) restantes fueron IL (+); el efecto inhibitorio potenció con la incubación en 12 (B), fue leve en 6 (C) y negativo en 18 (D). Los antecedentes de a-ŸVIII fueron positivos en A:6/6, B:9/11, C:1/6 y D:9/17. La prevalencia de a-ŸVIII fue bajo (4 por ciento) y alto (50 por ciento) el porcentaje de IL tiempo dependiente. Estos resultados sugieren la coexistencia de a-ŸVIII con IL, o su desaparición. Se hace pues necesario el desarrollo de pruebas específicas que permitan identificar a-ŸVIII en presencia de IL.

Informe de dos casos con enfermedad de von Willebrand adquirida y uno con hemofilia A adquirida / Report of two cases of acquired von wiellebrand disease and one of acquired hemophilia a

Se informan tres mujeres con inhibidores adquiridos de la coagulación contra el complejo F VIII:C/F vW:Ag que se diagnosticaron como enfermedad de von Willebrand adquidida (vWA) en los casos 1 y 2, y como hemofilia A adquirida en el caso 3. Las edades son de 19, 40, y 38 años para los casos 1, 2 y 3, respectivamente. No tenían historia familiar de padecimientos hemorrágicos, pero sí de enfermedad autoinmune asociada (enfermedad de Graves, lupus eritematosos sistémico y artritis reumatoide + postparto, respectivamente); las tres pacientes presentaban manifestaciones hemorrágicas. En las pruebas de hemostais, el nivel del FVII:C fue menor de 8 U/dL en los tres casos y el F vW:Ag, F vW:RiCof y la agregración plaquetaria con ristocetina estuvieron disminuidos en los dos casos de vWA; la búsqueda del anticoagulante lúpico (Exner) fue positiva en un caso, pero no se confirmó ya que la prueba de neutralización con fosfolípidos plaquetarios fue negativa. La dosificación de los inhibidores contra el F VIII:C, con el método de unidades Bethesda, fue de 50, 38 y 20 para los casos 1 a 3 respectivamente. Al administrar crioprecipitados y DDAVP (desmopresina), las pacientes tuvieron respusta clínica con respuesta parcial en sus parámetros de laboratorio. Con el tratamiento de córticosteroides se obtuvo respuesta; en la paciente con hemofilia adquirida fue necesario un tratamiento inmunosupresor

Antígeno vinculado al factor VIII en sarcoma de Kaposi / Antigen related to the factor VIII of Kaposi's sarcoma

Se reportan los hallazgos histológicos e inmunológicos para antígeno vinculado al factor VIII en 10 pacientes con Sarcoma de Kaposi:4 de ellos con la forma clásica y 6 afectados con SIDA. En el estadio I el Factor VIII pudo demostrarse en los vasos centrales de las lesiones glomerulares mientras que la red vascular inmediata contiene vasos con tinción variable. En los estudios I y II los canales vasculares disecantes del colágeno situados en periferia fueron negativos en su inmunomarcación. Las lesiones nodulares del estadio III muestran inmunotinción irregularmente positiva en las células fusiformes. Asimismo, las estructuras angiomatoides del estadio II muestran células fusiformes sugiriendo el origen de las mismas a expensas del endotelio vascular. Los resultados histológicos e inmunohistoquímicos son similares en ambos grupos de pacientes

Acquired haemophilia.

Two cases of acquired haemophilia A are described. Neither had history of excessive bleeding in the past following operative procedures and both presented with spontaneous bruising as a result of F. VIII:C deficiency due to production of anti-F. VIII:C antibodies. The antibody titre of one case remained unchanged after 4 weeks of therapy with prednisolone and cyclophosphamide. No attempt was made to treat the second case as the antibody titre was very high.

Detection of haemophilia A traits in carriers.

Obligate carriers of haemophilia A and normal women matched for age were studied in order to find a suitable parameter for detection of carriers of haemophilia A. The ratio of factor VIII coagulant activities (F VIIIC) to factor VIII related antigen (F VIII R : Ag) was 0.55 in obligate carriers and 1.0 in non-carrier females.