Primera experiencia de tratamiento con emicizumab en un paciente con hemofilia A severa e inhibidor de alto título en Uruguay / First report of emicizumab use in a patient with severe haemophilia A and high-titer inhibitor in Uruguay / Primeira experiência de tratamento com emicizumab em paciente com hemofilia A grave e inibidor de alto título no Uruguai

La hemofilia A es una coagulopatía congénita causada por la deficiencia o el mal funcionamiento del factor VIII de la coagulación. Una de las complicaciones más graves del tratamiento de la hemofilia A es el desarrollo de inhibidores que hacen que la terapia de reemplazo con FVIII sea ineficaz, dificultando la prevención y el control de los sangrados. El emicizumab es un anticuerpo monoclonal humanizado biespecífico dirigido contra los factores FIXa y FX, que imita la función de cofactor del FVIII. El tratamiento profiláctico con emicizumab es seguro y eficaz para prevenir hemorragias en los pacientes con hemofilia A con y sin inhibidores. Se presenta el caso del primer paciente tratado con emicizumab en Uruguay.

Haemophilia A is a congenital coagulopathy caused by a deficiency or malfunction of coagulation factor VIII. One of the most serious complications of haemophilia A treatment is the development of inhibitors that render FVIII replacement therapy ineffective, making it difficult to prevent and control bleeding. Emicizumab is a humanized bispecific monoclonal antibody directed against factors FIXa and FX, which mimics the cofactor function of FVIII. Emicizumab has been shown to be safe and effective as prophylaxis to prevent bleeding in haemophilia A patients with or without inhibitors to FVIII. We report the first patient treated with emicizumab in Uruguay.

A hemofilia A é uma coagulopatia congênita que se caracteriza pela ausência ou mau funcionamento do factor VIII da coagulação. Uma das complicações mais sérias do tratamento da hemofilia A é o desenvolvimento de inibidores que tornam a terapia de reposição do FVIII ineficaz, dificultando a prevenção e o controle do sangramento. O emicizumab é um anticorpo monoclonal biespecífico humanizado dirigido contra os fatores FIXa e FX, que imita a função de cofator do FVIII. O tratamento profilático com emicizumab é seguro e eficaz na prevenção de sangramento em pacientes com hemofilia A com e sem inibidores. É apresentado o caso do primeiro paciente tratado com emicizumabe no Uruguai.

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.

Efecto del inhibidor lúpico o anti-factor VIII sobre la actividad del factor VIII-sustrato cromogénico / Lupus anticoagulant or anti-factor VIII effect on factor VIII activity-chromogenic substrate

El objetivo del trabajo fue analizar el efecto de inmunoglobulinas (IgG) purificadas con actividad anti-factor VIII neutralizante o inhibidor lúpico, sobre el factor VIII medido por sustrato cromogénico (factor VIII SC), con el propósito de validar el método para detectar anti-factor VIII en presencia de inhibidor lúpico. Se aisló la fracción IgG (cromatografía de afinidad) a partir de plasmas normales (IgG-N), con anti-factor VIII (IgG-aFVIII) o con inhibidor lúpico (IgG-IL), preparándose un pool normal como aporte de factor VIII en los ensayos de inhibición. Se analizaron las mezclas del pool normal con IgG-N, IgG-aFVIII, IgG-IL o la combinación de IgG-aFVIII+IgG-IL, inmediatamente y luego de 2 h a 37 ºC, determinándose la actividad del factor VIII SC y el índice de inhibición inmediato (Ii) o post-incubación (Ip). La inhibición y la potenciación producida por IgG-aFVIII+IgG-IL (Ii:30%±0,7; Ip:55%±2,7), fueron similares a las observadas con IgG-aFVIII sola (Ii:30%±0,6; Ip:55%±2,7). La IgG-IL no afectó la actividad de factor VIII SC. Semejante a lo observado en plasma, la IgG-IL no interfirió en la inhibición del factor VIII SC mediada por IgG-aFVIII. Se confirmó así la especificidad del método amidolítico, que permite detectar inhibidores anti-factor VIII independientemente de la coexistencia con el inhibidor lúpico, solucionando el problema diagnóstico planteado en hemofilia A.

To analyse the effect of purified immunoglobulins (IgG) with anti-factor VIII or lupus anticoagulant activity on factor VIII measured by chromogenic substrate (factor VIIICS), in order to validate the chromogenic substrate method for detection of anti-factor VIII activity in the presence of lupus anticoagulant. IgG fractions were purified (affinity chromatography) from normal plasmas (IgG-N) and plasmas with anti-factor VIII (IgG-aFVIII) or lupus anticoagulant (IgG-LA). A normal plasma pool was prepared as source of factor VIII in the inhibition tests. Mixtures of this pool with IgG-N, IgG-aFVIII, IgG-LA or IgG-aFVIII+IgG-LA were tested immediately or after 2 h at 37 °C by factor VIIICS method; inhibition index (Ii) and post-incubation index (Ip) were calculated. The inhibitory and progressive inhibitory effects produced by IgG-aFVIII+IgG-LA (Ii:30%±0.7; Ip:55%±2.7) were similar to those observed with IgG-aFVIII (Ii:30%±0.6; Ip:55%±2.7). The IgG-LA did not inhibit the factor VIIIcs activity. As was observed in plasma samples, IgG-aFVIII and the mixture of IgG-aFVIII+IgG-LA inhibited factor VIIICS, whereas IgG-LA did not. These results confirm the specificity of the amidolytic method in detecting anti-factor VIII inhibitors independently of the presence of lupus anticoagulant, thus solving the diagnostic problem in haemophilia A.

Effects of hyperglycemia and aging in angiogenesis and reepithelization of colonic anastomoses in rats

PURPOSE: To evaluate angiogenesis and reepithelization of colonic anastomoses in rats. METHODS: 82 Wistar rats, divided into: young normoglycemic, old normoglycemic and hyperglycemic. Diabetes was induced with streptozotocin. Glycemia was assessed before induction, at 24 hours and after 90 days, when a colotomy and an anastomosis were performed, assessed at days 3, 7, and 14. Samples were prepared by immuno-histochemistry (PCNA and antifactor VIII). RESULTS: Mean glycemia after 90 days streptozotocin induction was 244,95 mg/dl. Day 7, reepithelization was greater in the young group than in the old normoglycemic (p<0.0001) and old hyperglycemic (p<0.0001) groups. Day 14, the differences were significant between the young and old normoglycemic (p<0.0001) and old hyperglycemic (p<0.0001) groups. The two old groups were not significantly different. At the three periods angiogenesis was higher in the young group than in the old normoglycemic (p3=0.014; p7<0.0001; p14<0.0001) or the old hyperglycemic groups (p3=0.014, p7<0.0001; p14<0.0001). The old groups, day 3, were not different (p3=0.627), but days 7 and 14, angiogenesis was bigger in the normoglycemic group (p7=0.042; p14=0.005). CONCLUSION: Age is important in reepithelization and angiogenesis of colonic anastomoses. Hyperglycemia interferes mainly in angiogenesis.

OBJETIVO: Avaliar a angiogênese e a reepitelização de anastomoses colônicas em ratos. MÉTODOS: 82 ratos Wistar divididos em: jovens normoglicêmicos, velhos normoglicêmicos e hiperglicêmicos. Diabetes foi induzido com estreptozotocin. Glicemia foi medida antes da indução, após 24 horas e 90 dias, quando realizou-se colotomia seguida de anastomose, a qual foi estudada no 3.°, 7.° e 14.° dia.Peças foram preparadas por imunohistoquímica (PCNA e Antifator VIII). RESULTADOS: Glicemia média após 90 dias foi de 244,95 mg/dl. No 7.° dia, a reepitelização foi maior no grupo jovem que nos grupos velho normoglicêmico (p<0,0001) e velho hiperglicêmico (p<0,0001). Dia 14, mantiveram-se as diferenças entre os grupos jovem e velhos normoglicêmico (p<0,0001) e hiperglicêmico (p<0,0001). Os dois grupos velhos não diferiram entre si. Nos três períodos a angiogênese foi maior no grupo jovem do que nos velhos normoglicêmicos (p3=0.014, p7<0.0001; p14<0.0001) e que nos velhos hiperglicêmicos (p3=0.014, p7<0.0001; p14<0.0001). No 3.° dia, os grupos velhos não foram diferentes (p3=0.627), mas no 7.° e no 14.°, a angiogênese foi maior no grupo normoglicêmico (p7=0.042; p14=0.005). CONCLUSÃO: Idade é importante para a reepitelização e angiogênese das anastomoses colônicas. Hiperglicemia interfere principalmente na angiogênese.

Bases genéticas de la hemofilia A / Genetic basis of haemophilia A

La Hemofilia A es un trastorno heredado de la coagulación sanguínea, que se caracteriza por presentar niveles reducidos de Factor VIII. En pacientes con enfermedad severa, alrededor del 50 por ciento presenta la inversión del intron 22 del gen del FVIII, y en el 5 por ciento ocurre la inversión del intron 1. Además, es posible encontrar otro tipo de mutaciones, tales como, inserciones, deleciones y mutaciones missense y nonsense. Las mutaciones en el gen del FVIII se asocian a riesgo de desarrollar inhibidores del FVIII, los que provocan refractariedad a la infusión de concentrados de factor. Gracias al conocimiento genético de la hemofilia A, se ha mejorado el diagnóstico tanto de pacientes como de portadoras, así como también la producción de concentrados de factor empleados en el tratamiento.

Relation of factor VIII and IX inhibitors with ABO blood groups in 150 patients with haemophilia A and B

Many investigations have proved relations between ABO blood groups with some diseases and factor VIII and von willebrand level in plasma. In this study we investigated a relation between ABO blood groups and factor VIII and IX inhibitors in 102 patients with haemophilia A and 48 patients with haemophilia B. The assay of inhibitor was done by Bethesda method. There were no relation between ABO blood groups and factor VIII and IX inhibitors

Blood coagulation factor VIII: An overview.

Factor VIII (FVIII) functions as a co-factor in the blood coagulation cascade for the proteolytic activation of factor X by factor IXa. Deficiency of FVIII causes hemophilia A, the most commonly inherited bleeding disorder. This review highlights current knowledge on selected aspects of FVIII in which both the scientist and the clinician should be interested.

Clinicohaematological profile of two cases of inhibitors to factor VIII.

Bleeding is a common manifestation of inherited and acquired disorders of haemostasis. Acquired disorders of haemostasis can be of varied etiology like liver disease, DIC, haemorrhagic disease of newborn and inhibitors to coagulation factors. Inhibitors to coagulation factors are an unusual cause of bleeding which can be superimposed on inherited factor deficiencies or sometimes resembles them. The clinical and haematological profile to two cases of factor VIII inhibitors are being presented here, one of which was a known haemophiliac receiving factor VIII therapy and another was a elderly lady with no other apparent underlying disorder. Hence any case of factor VIII deficiency who becomes refractory to factor VIII replacement therapy or those who are detected to have factor deficiency late in life should be investigated for inhibitors.

Treatment of patients with hemophilia A and inhibitors to factor FVIII with cimetidine

In this study, cimetidine was used to treat patients with hemophilia A and inhibitors to factor VIII who presented with acute hemorrhages (Group A) and those without hemorrahges (Group B). The dose of cimetidine was 15 mg/kg/day. Group A consisted of five patients with inhibitors between 156 and > 10,000 Bethesda Units (BU), all with serious hemorrhagic problems. The control of hemorrhaging was effective in 100 per cent of these patients, although inhibitor levels remained high (25-380 BU). Group B consisted of seven patients who did not have hemorrhages, whose inhibitor levels were 41-358 BU. Five of these patients no longer had anamnestic responses to Factor VIII after several months of treatment with cimetidine. No difference in the response to cimetidine was seen between HIV positive and HIV negative patients. The results suggest that cimetidine is useful to suppress inhibitores to Factor VIII in patients with hemophilia A

Experience with factor VIII: C inhibitors and acquired von Willebrand's disease in an adult at Ramathibodi Hospital.

Eleven cases of acquired inhibitors against factor VIII: C and von Willebrand's factor (vWF) seen at the Department of Medicine, Ramathibodi Hospital from 1979 to 1991 were reviewed. Factor VIII: C inhibitor was found in 6 of 36 patients (17%) with hemophilia A (median age 18 years). Three patients each were weak (titer < 10 Bethesda units/ml), and strong antibody producers. Two cases of weak antibody producers had spontaneous disappearance of inhibitor, while all 3 strong antibody producers required specific treatment (corticosteroids, immunosuppressive drugs, and plasmapheresis). The inhibitor level temporarily declined in 2 patients, and disappeared in one. Spontaneous acquired inhibitor to factor VIII: C was seen in 3 patients. One each respectively had pemphigus vulgaris and bullous pemphigoid, autoimmune disease, and NIDDM. They were characterized by older age (median age 54 years), frequent skin and soft-tissue hematoma, but less hemarthroses. Inhibitor titer ranged from 15-280 Bethesda units/ml. Disappearance of the inhibitor after treatment with corticosteroids and immunosuppressive drugs were observed in all patients. Acquired von Willebrand's disease developed in 2 previously healthy patients. One patient was in the postpartum period, while the other had simultaneous acute viral hepatitis A infection. Both presented with the recent onset of spontaneous severe gingival bleeding, and demonstrated a prolonged bleeding time, reduced vWF:Ag (F VIIIR:Ag), and ristocetin cofactor (F VIIIR:vWF). Treatment with cryoprecipitate and corticosteroid resulted in remission of bleeding symptoms. Despite the rarity of these disorders, the recognition and proper management are of importance.

Inhibitors of factor VIII: detection and treatment.

Alloantibodies occurring in hemophiliacs is a side effect or repeated treatment and represents a severe complication. The induction of immune tolerance using one of the lower dose regimens should be attempted as soon as it is feasible as regimens started soon after the inhibitor appears may have greater success in inducing tolerance. If the hemophiliac with inhibitor hemorrhages, PCC for aPCC should be the first line of therapy since these concentrates can be given in the home setting. If the hemorrhage is severe and the anti-porcine inhibitor titer is low, the patient should be infused in a clinic or hospital setting with porcine factor VIII using increasing doses to achieve a circulating factor VIII level. Entry into clinical trials, such as those using rFVIIa should be encouraged.

Hemophilia with factor VIII and factor IX inhibitors, incidence, bleeding problems and management.

Among 117 cases of hemophilia, there were 7 hemophilia A and 2 hemophilia B with factor VIII and factor IX inhibitors diagnosed at the Department of Pediatrics, Siriraj Hospital, Bangkok, Thailand. The overall incidence of hemophilia with inhibitors was 7.7%. Eight cases (6 hemophilia A. 2 hemophilia B) were severe hemophilia and 1 moderate hemophilia A. The average age of the inhibitor detection was about 5 years. Of the 9 cases, 7 had high inhibitor titers and 2 had low inhibitor titers. The frequency of bleeding problems before and after inhibitor detection were not different. The bleedings included hemarthrosis, mucosal bleed, hematoma, oozing from wound, hematuria and intracranial hemorrhage. The treatment of hemarthrosis in hemophilia A with low inhibitor titers was the combination of short course of prednisolone and single large dose factor VIII. In high inhibitor titer patients with acute hemarthrosis (both hemophilia A and hemophilia B), the treatment consisted of prednisolone short course and single high dose of PCC. For bleeding control in both high and low inhibitor titer with mucosal bleeds, oozing from wounds, central nervous system bleeding and hematuria, the combination was used of high dose factor VIII or factor IX for 2 days, and tranexamic acid, prednisolone, cyclophosphamide were required. In life-threatening hemorrhage and surgical operation, plasmapheresis and large dosage factor VIII or factor IX were the treatment of choice. All supportive measures were also important in every case of mucosal bleeds, wounds and surgical operations. The result of treatment revealed one death from massive intracranial hemorrhage and 8 survivals, with joint contracture in 2 cases. All still have inhibitor detected, but in low titer.

Poliartrite crônica e inibidores adquiridos do fator VIII / Chronic polyarthritis and inhibitors acquired of fator VIII

Os autores relatam dois casos de poliartrite que durante a evoluçäo apresentaram sangramentos cutâneo-mucosos. A investigaçäo, foi constatada a reduçäo do fator VIII da coagulaçäo, decorrente da presença de inibidores. Fazem uma revisäo da literatura sobre a ocorrência de inibidores do fator VIII e analisam o diagnóstico do acometimento articular, perante complicaçöes hemorrágicas associadas, com o intuito de correlacioná-las

Historia natural de los inhibidores del factor VIII en pacientes con hemofilia A / Natural history of factor Viii inhibitors in patients with hemophilia A

Durante 3 años se estudiaron las características epidemiológicas, clínicas y de laboratorio de los inhibidores de factor VIII: C (F VIII:C) en 88 hemofílicos A. Al inicio del estudio, la incidencia fue del 13,6 %. En algunos pacientes se detectó el inhibidor en una sola ocasión a pesar del tratamiento ulterior con factor VIII. La incidencia de los inhibidores que aparecieron durante el estudio fue del 10.6 %. Se desarrollaron fundamentalmente en hemofílicos seriamente afectados; el nivel de F VIII:C no estuvo relacionado con la tasa alcanzada por el inhibidor y en más de la mitad de los pacientes aparecieron antes de los 10 años de edad. La conversión de un bajo respondedor a un altorespondedor por el uso de terapéuticas sustitutiva con factor VIII. Se demostró en un paciente. La desaparición del inhibidor fue de 12 meses como promedio, y no ocurrió en la mayoría de los enfermos alto respondedores. No se observó un mayor número de episodios hemorrágicos después de la aparición del inhibidor y éste estuvo presente en el 75 % de los pacientes fallecidos durante el estudio

Activación de la vía alternativa del sistema complemento en la hemofilia A / Activation of alternative pathway of the complement system in hemophilia A

Se realizó un estudio de la actividad hemolítica del sistema complemento por la vía clásica, la vía alternativa, la actividad funcional del factor B, solubilización de inmunocomplejos, inhibición de la precipitación de inmunocomplejos, C3, C4, así como la determinación de inmunocomplejos circulantes (ICC), mediante la prueba de desviación del Clq y el método de precipitación con polietilenglicol 6 000 al 3,75 %, en 59 pacientes con hemofilia A agrupados en 9 graves con inhibidores del factor VIII: C (F-VIII:C) y 50 sin inhibidores del F-VIII:C, 40 clasificados como graves y 10 como moderados. En el grupo de graves con inhibidores del F-VIII:C se obtuvo una disminución significativa de la actividad de la via alternativa, factor B, C3, solubilización de inmunocomplejos y niveles elevados de ICC. En el resto de los hemofílicos no hubo diferencia estadística con respecto a los controles normales en niguna de las variables estudiadas

Exchange transfusion and pulse steroid therapy in a hemophiliac with inhibitor.

In Thailand, the management of bleeding in hemophiliacs with inhibitor is still a challenging aspect. The source of Factor VIII is locally prepared fresh frozen plasma and cryoprecipitate. The Factor VIII concentrate and other commercial blood products are not available because of the remarkably high price. Successful management of bleeding in a 3-year-old hemophiliac boy with moderate inhibitor level (11.82 BU) was reported. He had active bleeding from a 1 cm size cut wound at upper gingivo-buccal fold and did not respond to local measures and supportive treatment. He received exchange transfusion, intravenous cyclophosphamide and high dosage of cryoprecipitate. The bleeding stopped and the inhibitor declined to 2.6 BU. A week later, the bleeding recurred with an anamnestic response of inhibitor to 5 BU. The second exchange transfusion and methylprednisolone as pulse steroid therapy were given daily for 3 days. No cryoprecipitate was infused. The bleeding gradually stopped within 48 hours and the inhibitor level declined to 3.2 BU which was still at low level for at least 2 months. Exchange transfusion and methylprednisolone as pulse steroid therapy may be an alternative treatment for controlling bleeding in a hemophiliac with moderate inhibitor level in countries where a high concentrate of Factor VIII or other blood products are not available. It is practical, simple, effective and of low cost.

Inhibidor contra la fracción coagulante del factor VII en el puerperio / Inhibitor against factor VIII coagulant fraction in puerperium

Una paciente femenina, tres semanas después de su tercer parto desarrolló hemorragia sistémica grave, habiéndose demostrado la presencia de un inhibidor adquirido contra la fracción coagulante del Factor VIII de la coagulación. Después del tratamiento con dosis altas de corticoesteroides la hemorragia desapareció y el inhibidor tambiém. Se desconoce la etiología de inhibidores de la coagulación en mujeres duranrte el puerperio. Sin embargo, el diagnóstico debe establecerse lo más rápido posible con el fin de evitar complciaciones que podrían ser mortales

La exsanguinotransfusión en el tratamiento del niño hemofílico con inhibidores del factor VIII / Exchange transfusión in the treatment of hemophiliac child with factor VIII inhibitors

Se presenta el caso de un niño de siete años de edad con hemofilia clásica severa quien presentó epistaxis bilateral profusa y sangrado en herida de venodiseccación que no respondió a la transfusión de crioprecipitados en dosis crecientes hasta de 100U/kg cada 6 horas. Debido a que la determinacación de los niveles de inhibidores del factor VIII mostró valor de 6.75 U Bethesda/ml, se practicaron dos exsanguinotransfusiones, lo que permitió controlar el sangrado. Se concluye que la exsanguinotransfusión es un procedimiento útil para reducir transitoriamente los niveles de anticuerpos circulantes contra el factor VIII en niños hemofílicos con esta complicación y en quienes es imperativo controlar las manifestaciones de sangrado