RESUMEN
PATIENTS AND METHODS: A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate (AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. RESULTS: The median age at the beginning of the study was 10 years (IQR 7-12). The median clotting factor concentrate (CFC) usage was 662 IU kg-1 year-1 (IQ range: 280-1437). The median AJBR was 10 (IQ range: 5-17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses (P < 0.001); The median change in WFH clinical score and Pettersson radiological score over the 5 years was 0.4/year for each, while the FISH deteriorated at a rate of 0.2/year with poor correlation of these changes with CFC dose. WFH and FISH scores were significantly worse in those with an AJBR of >3 per year (P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year (P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. CONCLUSION: Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia.
Asunto(s)
Factores de Coagulación Sanguínea/farmacología , Hemorragia/prevención & control , Sistema Musculoesquelético/efectos de los fármacos , Adolescente , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Sistema Musculoesquelético/patología , Adulto JovenRESUMEN
Haemorrhagic disorders like Postpartum haemorrhage and Dengue haemorrhagic fever are life threatening and requires an active and efficient transfusion service that could provide the most appropriate blood product which could be effective in managing them. This would essentially require prompt identification of the coagulopathy so that the best available product can be given to the bleeding patient to correct the identified haemostatic defect which will help control the bleeding. This would only be possible if the transfusion service has a laboratory to correctly detect the haemostatic defect and that too with an accuracy and precision which is ensured by a good laboratory quality assurance practices. These same processes are necessary for the transfusion services to ensure the quality of the blood products manufactured by them and that it contains adequate amounts of haemostasis factors which will be good to be effective in the management of haemorrhagic disorders. These issues are discussed in detail individually in the management of postpartum haemorrhage and Dengue haemorrhagic fever including when these can help in the use of rFVIIa in Dengue haemorrhagic fever. The requirements to ensure good-quality blood products are made available for the management of these disorders and the same have also been described.
Asunto(s)
Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos Hemorrágicos/diagnóstico , Laboratorios/normas , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Manejo de la Enfermedad , Factor VIIa/uso terapéutico , Femenino , Trastornos Hemorrágicos/prevención & control , Humanos , Hemorragia Posparto/prevención & control , Embarazo , Proteínas Recombinantes/uso terapéutico , Dengue Grave/tratamiento farmacológicoRESUMEN
BACKGROUND: Haemophilia is a lifelong X-linked recessive inherited bleeding disorder. Since the haemophilia management in economically less-developed countries is inadequately provided, prevention of new cases of haemophilia is essentially required. SUBJECTS AND METHODS: A total of 42 pregnancies in 37 women at risk for severe and moderate haemophilia (A = 33, B = 4) were enrolled. The prenatal diagnostic (PND) procedure was performed in 32 women, while 10 women refused further PND procedure after knowing their foetuses were female (n = 8) and male (n = 2). The foetal specimen was obtained through chorionic villus sampling (n = 14), amniocentesis (n = 1) and cordocentesis (n = 17). The status of haemophilia was determined using informative RFLP markers and inversion of intron 22 of the F8 gene, and/or foetal FVIII:C or FIX:C. RESULTS: The final diagnosis revealed normal males (n = 18), haemophilia A males (n = 9), normal females (n = 3) and haemophilia A carrier females (n = 2). All women with affected haemophilia sons requested to terminate their pregnancies except one woman. One of 32 pregnancies (3.1%) had spontaneous abortion. At follow-up after birth, the PND was accurately confirmed in one haemophilia A male, three normal females and two carrier females by laboratory testing, and 18 unaffected normal males by history taking of no bleeding manifestations. However, 10 women who continued their pregnancies after knowing foetal sex turned out to have two haemophilia A males, one normal female, one haemophilia A carrier female and six normal or carrier females. CONCLUSION: The PND of haemophilia could be accurately determined but it was not well accepted by all couples at risk.
Asunto(s)
Hemofilia A/diagnóstico , Diagnóstico Prenatal/métodos , Adulto , Femenino , Humanos , Embarazo , Factores Sexuales , TailandiaRESUMEN
INTRODUCTION: A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. AIM: Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. METHODS: A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. RESULTS: In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 µg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 µg kg(-1) (divided as three doses). CONCLUSION: Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies.
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Coagulantes/uso terapéutico , Deficiencia del Factor VII/tratamiento farmacológico , Factor VIIa/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antifibrinolíticos/uso terapéutico , Niño , Preescolar , Estudios de Cohortes , Factor VII/análisis , Femenino , Hemorragia/epidemiología , Hemorragia/prevención & control , Humanos , Lactante , Masculino , Menorragia/epidemiología , Persona de Mediana Edad , Fenotipo , Modelos de Riesgos Proporcionales , Curva ROC , Proteínas Recombinantes/uso terapéutico , Sistema de Registros , Resultado del Tratamiento , Adulto JovenAsunto(s)
Factor IX/genética , Factor VIII/genética , Hemofilia A/metabolismo , Hemofilia B/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Interleucina-10/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adolescente , Niño , Preescolar , Factor IX/inmunología , Factor VIII/inmunología , Femenino , Hemofilia A/genética , Hemofilia A/inmunología , Hemofilia B/genética , Hemofilia B/inmunología , Humanos , Lactante , Recién Nacido , Masculino , Mutación , TailandiaAsunto(s)
Inhibidores de Factor de Coagulación Sanguínea/sangre , Factor VIII/antagonistas & inhibidores , Factor VIIa/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Exones , Factor VIII/genética , Factor VIII/inmunología , Eliminación de Gen , Humanos , Tolerancia Inmunológica , MasculinoRESUMEN
BACKGROUND: Nonsense mutations in coagulation factor (F) VII potentially cause a lethal hemorrhagic diathesis. Readthrough of nonsense mutations by aminoglycosides has been studied in a few human disease models with variable results. OBJECTIVES: We investigated the K316X and W364X FVII mutations, associated with intracranial hemorrhage, and their correction by aminoglycosides. The rare nonsense mutations in FVII represent favorite models to test this strategy, because even tiny increases in the amount of functional full-length protein in patients could ameliorate hemorrhagic phenotypes. RESULTS: A FVII-green fluorescent protein (GFP) chimaera provided us with a fluorescent model of FVII expression in living cells. Appreciable fluorescence in cells transfected with nonsense FVII-GFP mutants was detected upon geneticin treatment, thus demonstrating suppression of premature translation termination. To investigate the rescue of FVII function, nonsense variants of the native FVII without GFP (p316X-FVII and p364X-FVII) were transfected and found to secrete low amounts of FVII (approximately 1% of Wt-FVII activity), thus suggesting a spontaneous stop codon readthrough. Geneticin treatment of cells resulted in a significant and dose-dependent increase of secreted FVII molecules (p316X-FVII, 24 +/- 12 ng mL(-1), 3.6 +/- 0.8% of Wt-FVII activity; p364X-FVII, 26 +/- 10 ng mL(-1), 3.7+/-0.6%) characterized by reduced specific activity, thus indicating the synthesis of dysfunctional proteins. Similar results were observed with gentamicin, a commonly used aminoglycoside of potential interest for patient treatment. CONCLUSIONS: Our approach, extendable to other coagulation factors, represents an effective tool for a systematic study of the effects of aminoglycosides and neighboring sequences on nonsense codon readthrough. These results provide the rationale for a mutation-specific therapeutic approach in FVII deficiency.
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Antibacterianos/farmacología , Codón sin Sentido , Factor VII/genética , Regulación de la Expresión Génica/efectos de los fármacos , Gentamicinas/farmacología , Adolescente , Animales , Coagulación Sanguínea/efectos de los fármacos , Línea Celular , Preescolar , Cricetinae , Relación Dosis-Respuesta a Droga , Factor VII/metabolismo , Deficiencia del Factor VII/sangre , Deficiencia del Factor VII/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Masculino , Proteínas Recombinantes de Fusión/metabolismo , TransfecciónAsunto(s)
Hemofilia A/parasitología , Hemofilia B/parasitología , Hemorragia/prevención & control , Dengue Grave/complicaciones , Dengue Grave/terapia , Adolescente , Factores de Coagulación Sanguínea/uso terapéutico , Niño , Preescolar , Virus del Dengue/aislamiento & purificación , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Humanos , Resultado del TratamientoRESUMEN
Thalassemia-free survival after allogeneic stem cell transplantation (SCT) is about 80-90% with either matched-related or -unrelated donors. We explored the use of a mismatched-related ('haplo- ') donor. All patients received two courses of pretransplant immunosuppressive therapy (PTIS) with fludarabine (Flu) and dexamethasone (Dxm). After two courses of PTIS, a conditioning regimen of rabbit antithymocyte globulin, Flu and IV busulfan (Bu) was given followed by T-cell-replete peripheral blood progenitor cells. GvHD prophylaxis consisted of cyclophosphamide (Cy) on days SCT +3 and +4 (post-Cy), and on day SCT +5 tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Thirty-one patients underwent haplo-SCT. Their median age was 10 years (range, 2-20 years). Twenty-nine patients engrafted with 100% donor chimerism. Two patients suffered primary graft failure. Median time to neutrophil engraftment was 14 days (range, 11-18 days). Five patients developed mild to moderate, reversible veno-occlusive disease, while nine patients developed acute GvHD grade II. Only five patients developed limited-chronic GvHD. Projected overall and event-free survival rates at 2 years are 95% and 94%, respectively. The median follow up time is 12 months (range, 7-33 months).
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante Haploidéntico/métodos , Talasemia beta/terapia , Adolescente , Eliminación de Componentes Sanguíneos , Niño , Preescolar , Supervivencia sin Enfermedad , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/mortalidad , Hemoglobina E , Homocigoto , Humanos , Inmunosupresores/uso terapéutico , Lactante , Trasplante de Células Madre de Sangre Periférica/mortalidad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Haploidéntico/mortalidad , Adulto JovenRESUMEN
Patients with the haemophilia B Leyden phenotype show a distinct pattern of factor IX expression characterized by a post-pubertal increase in FIX levels and the remission of clinical symptoms in adult life. This phenotype has previously been linked to single base mutations within transcription factor binding sites in a region of approximately 40 bp around the major start point of transcription of the FIX gene. Here we report a novel mutation in this region within the transcription factor C/EBP binding site at +1 to +18. The mutation is a single base pair deletion from a triplet of thymine residues at +6 to +8. We show that the extent to which this mutation disrupts the binding of C/EBP to its binding site is less marked than the disruption caused by the +13 A-->G mutation of FIX Norwich (1). This correlates with age-matched phenotypic data we have available for the patient reported here and that of FIX Norwich.
Asunto(s)
Composición de Base/genética , Factor IX/genética , Eliminación de Gen , Hemofilia B/genética , Regiones Promotoras Genéticas , Secuencia de Bases , Sitios de Unión , Niño , Preescolar , Humanos , Datos de Secuencia Molecular , Fenotipo , Transcripción GenéticaRESUMEN
Bone marrow transplantation is the only therapeutic option that can eliminate thalassemic disease. Early results indicated that children in class 3 Lucarelli had a much worse outcome because of high nonrejection mortality and high rejection rate. We therefore tried to investigate a nonmyeloablative stem cell transplantation (NST) approach for such a disease in order to reduce mortality and rejection. We report here the case of successful NST in a 10-year-old girl who had class 3 Lucarelli beta-thalassemia major. The conditioning regimen consisted of busulfan, fludarabine, antilymphocyte globulin and total lymphoid irradiation. Her GVHD prophylaxis included mycophenolate mofetil and cyclosporin. The patient had full donor engraftment without acute and chronic GVHD. She is now alive and well and remains disease-free 1 year after transplant.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Quimera por Trasplante , Acondicionamiento Pretrasplante/métodos , Talasemia beta/terapia , Trasplante de Médula Ósea/métodos , Niño , Supervivencia sin Enfermedad , Humanos , Inmunosupresores/administración & dosificación , Masculino , Radioterapia AdyuvanteRESUMEN
SUMMARY: We conducted a study of unrelated donor bone marrow transplantation (BMT) in 11 children with severe thalassaemia. The conditioning regimen consisted of busulphan, cyclophosphamide and antilymphocyte globulin. All received T-cell nondepleted bone marrow. The median marrow-nucleated cell dose was 4.9 x 10(8) /kg (range; 3.5-8.0 x 10(8) /kg). Median time of granulocyte recovery was 16 days (range; 13-21 days), and of platelet recovery was 39 days (range; 14-196). Grade 2-4 acute graft-versus-host disease (GVHD) developed in six patients (54%), and grade 3-4 in one patient (9%). Three (27%) of 11 evaluable patients had chronic GVHD (limited stage). All 11 patients are alive without thalassaemia after a median follow-up time of 397 days (range; 171-814 days). This study lends support to consideration of unrelated donor BMT as an acceptable therapy to cure severe thalassaemia especially in patients who are young and do not yet show irreversible severe complications of iron overload.
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Trasplante de Médula Ósea/métodos , Histocompatibilidad , Talasemia/terapia , Factores de Edad , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/inmunología , Niño , Preescolar , Supervivencia de Injerto , Enfermedad Injerto contra Huésped , Humanos , Lactante , Sobrecarga de Hierro/etiología , Cinética , Masculino , Talasemia/complicaciones , Talasemia/mortalidad , Donantes de Tejidos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/inmunología , Resultado del TratamientoRESUMEN
Recombinant activated factor VII (rFVIIa) was given to three children with acute bleeding resulting from liver failure and disseminated intravascular coagulation. Cases I and II (girls aged 3 years and 6 years, respectively) were diagnosed with Dengue hemorrhagic fever and prolonged shock. Case III, a boy aged 9 months, underwent left lobe hepatectomy for a hepatoblastoma, during which 60% of his liver was removed. This case was complicated by myoglobinuria, liver and renal impairment and early disseminated intravascular coagulation. All three patients exhibited active bleeding. Cases I and II received rFVIIa combined with other blood component replacement, while Case III received rFVIIa as the only hemostatic agent. A bolus of 40-180 microg/kg b.w. was administered followed by 16.5-33 microg/kg b.w. per h continuous infusion. As a result, bleeding was controlled, the prothrombin time was shortened and FVII clotting activity was significantly increased. In conclusion, rFVIIa has shown some efficacy in controlling acute bleeding in children with liver failure and disseminated intravascular coagulation.
Asunto(s)
Coagulación Intravascular Diseminada/complicaciones , Factor VIIa/administración & dosificación , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Fallo Hepático/complicaciones , Enfermedad Aguda , Coagulación Sanguínea/efectos de los fármacos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteínas Recombinantes/administración & dosificaciónRESUMEN
The frequency of five factor VIII gene intragenic and linked DNA polymorphisms and five factor IX gene intragenic polymorphisms was studied in Thai females. The polymorphisms in the FVIII gene were detected by restriction enzymes BclI, XbaI, BglI and at linked loci DX13 (DXS15) and St14 (DXS52) by BglII and TaqI, respectively, and in the FIX gene by MseI, DdeI, XmnI, TaqI and HhaI. With the exception of the BglI restriction fragment length polymorphism (RFLP), which is absent in Thais, factor VIII polymorphism frequencies were similar in Thais and Caucasians. Combined use of XbaI and TaqI/St14 resulted in a heterozygosity rate of greater than 90% in Thai females. For FIX, the recently described MseI RFLP in the 5' flanking region was the most informative polymorphism in Thais, 43% of females being heterozygous. The other four polymorphisms added little to the overall heterozygosity rate. The appropriate polymorphisms were used to track defective factor VIII and IX genes through 22 Thai pedigrees with haemophilia to enable carrier status to be assigned to female family members. The information obtained during this study will form the basis for carrier detection and prenatal diagnosis of haemophilia A and B by DNA polymorphism analysis in Thailand.
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Alelos , Proteínas Bacterianas , Factor IX/genética , Factor VIII/genética , Frecuencia de los Genes , Polimorfismo de Longitud del Fragmento de Restricción , Desoxirribonucleasas de Localización Especificada Tipo II , Europa (Continente) , Femenino , Tamización de Portadores Genéticos , Hemofilia A/genética , Hemofilia B/genética , Humanos , Masculino , TailandiaRESUMEN
A simple, rapid and cheap method for the analysis of variable dinucleotide tandem polymorphisms in introns 13 and 22 of the factor VIII gene has been established. The protocol uses blood spots stored on filter paper (Guthrie spots) and other DNA containing materials as sources of DNA. Following DNA amplification using a thermostable DNA polymerase, products are size fractionated on native polyacrylamide gels and visualized by silver staining. This simplified protocol obviates the use of DNA extraction, reducing time and costs and in addition, reduces the requirement for gel documentation equipment (i.e., photography), as silver staining can be visualized readily without additional equipment and the gels themselves can be stored. These alterations to the analysis enhance the universal applicability of these polymorphisms, as was demonstrated by a comparative study in Caucasian and Thai females.
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Repeticiones de Dinucleótido , Factor VIII/genética , Reacción en Cadena de la Polimerasa/economía , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético , Análisis Costo-Beneficio , Factor VIII/análisis , Factor VIII/economía , Hemofilia A/economía , Hemofilia A/genética , Humanos , LinajeRESUMEN
Developing of the hemophilia program in Thailand during 1978-1990 has been achieved step by step as follow: 1. In 1978, organizing a series of scientific conferences to motivate and recruit expert teams and to have support from the health authority. 2. In 1978, a national survey of hemophilia which showed an incidence of 1:13,000 of population. 3. Training medical and paramedical personnel during 1973-1992. 4. In 1980, establishment of the National Hemophilia Society. 5. Improvement of blood bank and blood product supported by National Blood Center, Red Cross Society during 1960-1992. 6. In 1981, submitting hemophilia program to the 5th National Health Developmental Plan for 1982-1986. 7. Establishment of a nationwide hemophilia care program by integration with the national health care system. 8. In 1979, starting a home care program and initiation of comprehensive hemophilia care. 9. In 1982, promotion of comprehensive hemophilia care surgical orthopedic correction. 10. Promotion of local manufacture of equipment, reagents, therapeutic material and modification of technology. 11. In 1987, carrier detection. 12. In 1990, laboratory set up for prenatal diagnosis. The future plan is described for the years 1992-2000.
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Atención Integral de Salud/organización & administración , Hemofilia A/terapia , Bancos de Sangre/organización & administración , Hemofilia A/diagnóstico , Hemofilia A/epidemiología , Humanos , Programas Nacionales de Salud/organización & administración , Desarrollo de Programa , Tailandia/epidemiologíaRESUMEN
A retrospective study of acquired aplastic anemia in 100 Thai children treated with testosterone and prednisolone during 1969 to 1987 is reported. The age ranged from 3-14.5 years (mean 10.3 years). The male to female ratio was 2.3:1. The duration of follow up ranged from 1-17 year (mean 5 years). Prior exposure to possible etiologic agents was found in 36% : antipyretics, Ya-chood, insecticides, benzene, chloramphenicol and paint. The presenting symptoms were bleeding and anemia 72%, fever with either bleeding or anemia 28%. The common sites of bleeding were purpura, epistaxis, gum and teeth, and the gastrointestinal tract. All patients received appropriate supportive treatment and testosterone combined with prednisolone. The results of treatment were evaluated in 80 cases who were followed up until death or at least one year after the diagnosis. Two-thirds of the patients presented with laboratory findings similar to severe aplastic anemia; the fatality rate was 50% (40/80). Most of them succumbed to infection or bleeding in the first 6 months after diagnosis. The recovery rate was 50% with complete, partial and initial responses in 28%, 17% and 5% respectively. The late malignancy rate was 2%. For severe aplastic anemia or for patients who have poor prognostic factors, early approaches of bone marrow transplantation or antilymphocyte globulin administration should be considered.