Hemofilia A adquirida: un diagnóstico de infarto / Acquired Hemophilia A: a heart attacking diagnosis

Resumen La hemofilia A adquirida es una entidad poco reportada y potencialmente fatal, que se asocia con la aparición de autoanticuerpos contra el factor VIII de la coagulación. Si bien puede estar subestimada, se calcula una incidencia aproximada de 1 a 1.5 casos por millón de habitantes con una mortalidad reportada entre el 9 y el 33%. Se manifiesta con equimosis extensas espontáneas y sangrado en mucosas, tracto gastrointestinal o en el periodo postparto. Se debe sospechar en adultos a partir de la cuarta década de la vida con sangrados espontáneos y un tiempo parcial de tromboplastina prolongado en ausencia de anticoagulante lúpico. Se reporta el caso de un adulto mayor con cardiopatía isquémica, en quien, en el contexto de un evento coronario agudo, se diagnosticó hemofilia A adquirida ante la presencia de sangrado subcutáneo extenso en cuello, con compresión de faringe y laringe que amenazó su vida representando un verdadero reto terapéutico.

Abstract Acquired hemophilia A is an underreported and potentially fatal entity that is associated with the formation of autoantibodies against coagulation factor VIII. Although it may be underestimated, the estimated incidence is between 1-1.5 cases per million people with a reported mortality between 9 and 33%2. It presents with extensive spontaneous ecchymosis, mucosal, gastrointestinal, or postpartum bleeding. It should be suspected in adults from the fourth decade of life with spontaneous bleeding and prolonged TPT in the absence of lupus anticoagulant. We report the case of an older adult with ischemic heart disease in the context of an acute coronary syndrome, who was diagnosed with acquired hemophilia A and presented with significant cervical subcutaneous bleeding with pharyngeal and laryngeal compression that threatened his life, constituting a real therapeutic challenge.

Consensus on hemophilia in Mexico.

Hemophilia is a hemorrhagic disorder with a sex-linked inherited pattern, characterized by an inability to amplify coagulation due to a deficiency in coagulation factor VIII (hemophilia A or classic) or factor IX (hemophilia B). Sequencing of the genes involved in hemophilia has provided a description and record of the main mutations, as well as a correlation with the various degrees of severity. Hemorrhagic manifestations are related to levels of circulating factor, mainly affecting the musculoskeletal system and specifically the large joints (knees, ankles, and elbows). This document is a review and consensus of the main genetic aspects of hemophilia, from the inheritance pattern to the concept of women carriers, physiopathology and classification of the disorder, the basic and confirmation studies when hemophilia is suspected, the various treatment regimens based on infusion of the deficient coagulation factor as well as innovative factor-free therapies and recommendations for the management of complications associated with treatment (development of inhibitors and/or transfusion-transmitted infections), or secondary to articular hemorrhagic events (hemophilic arthropathy). Finally, relevant reviews of clinical and treatment aspects of hemorrhagic pathology characterized by acquired deficiency of FVIII secondary to neutralized antibodies named acquired hemophilia.

La hemofilia es un trastorno hemorrágico con patrón de herencia ligado al sexo, caracterizado por una incapacidad en la amplificación de la coagulación ocasionada por la deficiencia del factor VIII (hemofilia A o clásica) o del factor IX (hemofilia B). La secuenciación de los genes involucrados en la hemofilia ha permitido la descripción y registro de las principales mutaciones, así como la correlación con los diversos grados de severidad. Las manifestaciones hemorrágicas se relacionan con los niveles de factor deficiente circulante, afectando principalmente al sistema musculoesquelético y en particular a las grandes articulaciones (rodillas, tobillos y codos). El presente documento hace una revisión y consenso de los principales aspectos genéticos de la hemofilia, desde el patrón de herencia y el concepto de mujeres portadoras, la fisiopatología y clasificación de la enfermedad, los estudios básicos y de confirmación ante la sospecha de hemofilia, y de los diversos esquemas de tratamiento basados en la infusión del factor de coagulación deficiente hasta las terapias innovadoras libres de factor, así como de las recomendaciones para el manejo de las complicaciones asociadas al tratamiento (desarrollo de inhibidores y/o infecciones transmitidas por transfusión) o secundarias a los eventos hemorrágicos a nivel articular (artropatía hemofílica). La parte final del documento revisa los aspectos clínicos y de tratamiento relevantes de una patología hemorragica caracterizada por la deficiencia adquirida del FVIII mediada por anticuerpos neutralizantes denominada hemofilia adquirida.

Acquired hemophilia A and other autoimmune diseases after alemtuzumab therapy for multiple sclerosis: A report of two cases.

Alemtuzumab (ALZ) is an anti-CD52 monoclonal antibody used to treat recurrent remittent multiple sclerosis (RRMS). After ALZ infusion, there is a depletion of T and B cells expressing CD52, while the stem cells and innate immune cells are spared. Longitudinal studies with long periods of follow-ups have reported ALZ-associated autoimmune diseases, such as thrombocytopenic purpura and thyroiditis. We report two patients who developed autoimmune hemophilia A or acquired hemophilia (AHA) after ALZ infusion, one of whom developed severe vitiligo. To the best of our knowledge, these two cases of ALZ-associated AHA are the first two cases to be reported in Brazil, and the fourth and fifth AHA cases to be reported worldwide. AHA is a potential life-threatening disease if not diagnosed and treated in a timely manner. The development of AHA should be cited as a possible adverse event, and specific coagulation tests must be part of the official recommendations for patient follow-ups.

Manifestaciones orales de la hemofilia adquirida tipo A. Reporte de un caso clínico / Oral manifestations of acquired hemophilia A. A clinical case report

Resumen Introducción La hemofilia tipo A adquirida es un trastorno hemorrágico poco frecuente producido por la presencia de autoanticuerpos dirigidos contra el factor VIII (FVIII) circulante. El sangrado suele aparecer en la piel, músculo, área retroperitoneal y tracto gastrointestinal; sin embargo, no es común en la cavidad oral. Caso clínico Presentamos el caso de una paciente de la octava década de la vida con este padecimiento, caracterizado por la presencia de ampollas sangrantes y dolorosas en la cavidad oral. El diagnóstico se estableció con un tiempo elevado de tromboplastina parcial activada (TTPa), tiempo normal de protrombina y niveles elevados de inhibidores del FVIII. La paciente fue tratada con el factor VII recombinante activado y prednisona asociada con ciclofosfamida durante seis semanas. La medicación fue suspendida cuando se normalizó el TTPa. Discusión El diagnóstico de hemofilia adquirida tipo A es complicado debido a que no hay antecedentes familiares de sangrado y a su etiopatogenia de origen autoinmune. La forma de presentación es un sangrado espontáneo y severo asociado con un tiempo prolongado de tromboplastina. Conclusión Su identificación inicial expedita y la aplicación del tratamiento son fundamentales para disminuir la tasa de mortalidad de los pacientes afectados.

Abstract Introduction Acquired hemophilia A is a hemorrhagic disorder produced by autoantibodies directed against circulating factor VIII. Bleeding often appears in the skin, muscles, the retroperitoneal area, and the gastrointestinal tract; however, it is not frequent regarding occurrence in the oral cavity. Case report We report an unusual case of an elderly woman in the eighth decade of life with AHA characterized by painful blood blisters in the oral cavity. The diagnosis was established with a high activated partial thromboplastin time (aPTT), normal prothrombin time and elevated levels of factor VIII inhibitor (FVIII: C). The patient was treated with the activated recombinant factor VII and prednisone associated with cyclophosphamide during six weeks. Drugs were stopped when normalization of aPTT was identified. Discussion The diagnosis of HAA is complicated because there is no family history of bleeding and its autoimmune etiopathogenesis. Furthermore, the clinical presentation is due to spontaneous and severe bleeding associated with a prolonged time of thromboplastin. Conclusion The initial identification and the application of the treatment are essential to reduce the mortality rate of those patients affected.

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.

Hemofilia A adquirida / Acquired hemophilia A

La hemofilia A adquirida (HAA) es un trastorno hemorrágico poco frecuente caracterizado por la presencia de autoanticuerpos contra el factor VIII (FVIII) circulante. Aproximadamente en la mitad de los casos se ha observado un grupo heterogéneo de procesos patológicos que incluyen, entre otros, enfermedades autoinmunes y malignas y durante el embarazo, parto y puerperio. Las manifestaciones hemorrágicas son variables y fundamentalmente de tipo cutáneo mucoso. El diagnóstico se basa en el hallazgo en un paciente con manifestaciones hemorrágicas, prolongación del tiempo parcial de tromboplastina activado (TPTA), disminución de la actividad del FVIII y presencia de inhibidores del FVIII. El tratamiento de HAA incluye el control de las manifestaciones hemorrágicas y la supresión de la producción del anticuerpo. El concentrado de factor VIIa recombinante (FVIIar) y el concentrado de complejo protrombínico (CCPA) se consideran el tratamiento antihemorrágico de primera línea. Como terapéutica alternativa, en algunos casos puede utilizarse el concentrado de FVIII, la plasmaféresis y la inmunoadsorción extracorpórea. La prednisona sola o asociada con la ciclofosfamida, constituye el tratamiento inmunosupresor de primera línea. En pacientes refractarios puede administrarse como terapéutica de segunda línea, el rituximab (anti-CD20). Con la azatiopina, la ciclosporina, la vincristina y el micofenolato de mofetil, se han obtenido resultados variables

Acquired hemophilia A (AHA) is an uncommon hemorrhagic disorder characterized by presence of autoantibodies to circulating factor VIII. Approximately in half of cases it is noted a heterogeneous group of pathological processes including among others, autoimmune and malignant diseases and during pregnancy, labor and puerperium. Hemorrhagic manifestations are variable and mainly of mucous cutaneous type. Diagnosis is based on the finding of a patient presenting with hemorrhagic manifestations, extension of activated partial thromboplastin time (APTT), decrease of Factor VIII activity, and presence of Factor VIII inhibitors. AHA treatment includes the control of hemorrhagic manifestations and the suppression of antibody production. The recombinant factor VIIIa (rVIIIaF) concentration and the prothrombin-complex concentrations (PCC) are considered like the first-line antihemorrhagic treatment. As alternative therapy in some cases the FCIII concentration, the plasmapheresis and extracorporeal immuno-adsorption may be used. The prednisone alone or associated with cyclophosphamide is the firs-line immunosuppressive treatment. In refractory patients it may be administered as a second-line therapy, the Rituximab (anti-CD20). With the use of Azathioprine, Cyclosporine, Vincristine and the Mycophenolate mofetil variable results have been achieved

Acquired hemophilia associated with rheumatoid arthritis / Hemofilia A adquirida associada à artrite reumatoide

O aparecimento do anticorpo contra fator VIII é um fenômeno bem estabelecido na hemofilia A, ocorrendo em 5 a 15 por cento dos pacientes hemofílicos dos Estados Unidos, Inglaterra, Suécia e França. Nos pacientes não-hemofílicos o seu aparecimento é raro, podendo ocorrer em indivíduos saudáveis, principalmente idosos e mulheres no puerpério, pacientes com neoplasia maligna ou doenças autoimunes, como lúpus eritematoso sistêmico, artrite reumatoide e síndrome de Sjõgren. Descrevemos o caso de uma paciente de 64 anos de idade, portadora de artrite reumatoide soropositiva há 23 anos, que há 10 dias desenvolveu equimoses e hematomas progressivos cuja investigação foi compatível com a presença de anticorpo contra fator VIII. Foi instituída terapia com metilprednisolona, ciclofosfamida endovenosa, imunoglobulina e reposição de complexo protrombínico, com remissão do quadro hemorrágico e negativação do anticorpo contra o fator VIII. Concluímos com esse caso que, apesar de ser rara, a presença de inibidores adquiridos do fator VIII deve ser pesquisada quando pacientes portadores de doença autoimune desenvolvem manifestações hemorrágicas associadas ao prolongamento do TTPA com TAP e contagem plaquetária normais.

The occurrence of the antibody against factor VIII is a well-known phenomenon in hemophilia A, occuring in 5 to 15 percent of the hemophilic patients in the United States, England, Sweden and France. The development of factor VIII in non-hemophilic patients is rare and may occur in healthy individuals, mostly elderly and women in postpartum period, and in patients with malignant neoplasia or autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and Sjõgren's syndrome. We described the case of a 64-year-old female patient who has had seropositive rheumatoid arthritis for 23 years and presented with a ten-day history of progressive ecchymosis. Therapy with methylprednisolone, intravenous cyclophosphamide, immunoglobulin and factor VIII reposition was instituted, resulting in a remission of the bleeding and negativity for antibodies against factor VIII titers. We concluded that, despite its rarity, the presence of acquired factor VIII inhibitors should be investigated when patients with autoimmune diseases develop bleeding manifestations.