Electrocardiographic Findings Among Asymptomatic Adults With Haemophilia

Abstract Background: People with haemophilia (PwH) are living longer. Therefore, they can develop atherosclerotic cardiovascular disease (ASCVD). Electrocardiogram (ECG) alterations may be a sign of initial ASCVD before the occurrence of symptoms. Objective: To describe the prevalence of resting ECG alterations among PwH adults asymptomatic for ASCVD. Methods: PwH aged ≥ 30 years without previous ASCVD events were considered for the analysis. Resting ECG traces were analysed according to international reference values and the Brazilian Longitudinal Adult Health Study (ELSA-Brasil) results for asymptomatic Brazilian men. Based on the established normal values and using the QT index, we further described the altered ECGs as minor or major changes, according to the Minnesota Code. Differences between prevalences were evaluated by Pearson's χ2 test. Differences between medians were evaluated by the Mann-Whitney U test. A p-value < 0.05 was accepted as statistically significant. Results: A total of 64 PwH were included in the study. Median age was 44 years (interquartile range 35-52). Most patients had haemophilia A (81%) and 47% were severe. The prevalence of obesity, systemic arterial hypertension (SAH), diabetes mellitus (DM), and dyslipidaemia were 16%, 56%, 14%, and 72%, respectively. All the PwH had sinus rhythm, except for one, who had an implanted pacemaker due to idiopathic third-degree atrioventricular block. Altered ECGs were found in 25% and 30% of PwH, according to established criteria and ELSA-Brasil criteria, respectively. Major changes were found in eight (13%) PwH according to the Minnesota Code, including two ECGs with ischaemia-like wall inactivity. Conclusions: The prevalence of altered ECG varied from 25% to 30% among asymptomatic PwH.

Consenso de hemofilia en México / Mexican Consensus in Haemophilia

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Abstract 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 charachterized by acquired deficiency of FVIII secondary to neutralized antibodies named acquired hemophilia.

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.

Management of pseudo tumour in haemophilia patients

A hemophilic pseudotumor is one of the rare complications of hemophilia that results from repetitive bleeding, forming an expanding destructive encapsulated hematoma and necrosed tissue. It has a considerable amount of morbidity. These have become rare over the years with better treatment modalities like factor replacement. Presently, excision is the preferred treatment by many authors. There are instances where surgical excision is not feasible. In such situations, radiotherapy and arterial embolization should be considered either alone or as an adjunct to surgery. A 32 years old male patient, with severe hemophilia A diagnosed with an abdominal tumour 7 years ago during routine screening, that progressively grew to encompass the lower abdominal area. A 44 years old male patient with hemophilia A presented with slow growing swelling over the left gluteal region since, 10 years associated with ulceration and bleeding since, 3 days. The management of a patient with a haemophilic pseudo tumour is complex, with a high rate of potential complications. Surgical excision is the treatment of choice but can only be carried out by a multidisciplinary surgical team. The main postoperative complications are rebleed, infection, fistula and pathological fractures. Pelvic pseudo tumours can even become complicated by fistula formation to the large bowel and by obstruction of the ureters. Untreated pseudo tumours will ultimately destroy soft tissues, erode bone, and may produce neurovascular complications. The hemophilic pseudo tumour is a rare entity which is slow growing painless tumour, with few reports worldwide in the management of this rare complication.

Validación del ensayo FVIII: C cromogénico en una plataforma automatizada

El objetivo de este trabajo fue realizar la validación analítica del método cromogénico (FVIII:Ccro) en la plataforma ACL TOP y correlacionarlo con el método coagulable en una etapa (FVIII:Ccoag). El estudio de validación (EP5-A2, EP6-A2 y comparación de métodos por EP-9) se realizó para la curva de rango normal-bajo (CRNB): aproximadamente entre 10-150 UI/dL de FVIII y de rango muy bajo (CRMB): aproximadamente entre 0-10 UI/dL. Los resultados de repetitividad (CVr) y precisión intermedia (CVi) fueron menores del 6% y comparables a los informados por el fabricante para otras plataformas. El rango de medición analítica fue de 11-129 UI/dL con CRNB, y se extrapoló a 0,3 UI/dL al utilizar la CRMB. Para la CRNB FVIII:Ccro mostró buena correlación con FVIII:Ccoag: r: 0,98, pendiente: 0,982 (0,961-1,003), ordenada al origen: -0,3 (-1,1-0,5), sesgo: -2,0%. Para CRMB se obtuvo un r de 0,96, pendiente: 0,921 (0,855-0,988), ordenada al origen: -0,07 (-0,35-0,20), sesgo: -10,2%. Sólo 4 pacientes presentaron niveles discrepantes entre ambos métodos. La determinación de FVIII:C por el método cromogénico automatizado en la familia ACL TOP fue comparable con FVIII coagulable en una etapa en el rango analítico evaluado. El FVIII:Ccro automatizado puede utilizarse para el diagnóstico y seguimiento del tratamiento de los pacientes hemofílicos.

The objective of this work was to perform the analytical validation of the chromogenic method (FVIII:Ccro) on the ACL TOP platform correlating with one stage assay (FVIII:Ccoag). The validation study (EP5-A2, EP6-A2 and comparison of methods by EP-9) was performed for the low-normal range curve (CRNB): approximately between 10-150 IU/dL of FVIII and very low range (CRMB): approximately between 0-10 IU/dL. The results of CVr (repeatability) and CVi (intermediate precision) were lower than 6% and comparable to those reported by the manufacturer for other platforms. The analytical measurement range was 11-129 IU/dL, extrapolated to 0.3 IU/dL using the CRMB. For CRNB FVIII:Ccro showed good correlation with FVIII:Ccoag: r: 0.98, slope: 0.982 (0.961-1.003), intercept: -0.3 (-1.1-0.5), bias: -2.0%. For CRMB: r: 0.96 was obtained, pending: 0.921 (0.855-0.988), intercept: -0.07 (-0.35-0.20), bias: -10.2%. Only 4 patients presented discrepant levels between both methods. The automated chromogenic FVIII assay in the ACL TOP family is comparable with one stage coagulable FVIII in the analytical range studied. The FVIII:Ccro automated can be used for the diagnosis and monitoring of the treatment of hemophilic patients.

O objetivo deste trabalho foi a validação analítica do método cromogênico (FVIII:Ccro) na plataforma ACL TOP correlacionando-se com o método coagulável numa etapa (FVIII:Ccoag). O estudo de validação (EP5-A2, EP6-A2 e comparação de métodos por EP-9) foi realizado para a curva de faixa normal-baixa (CRNB) aproximadamente entre 10 e 150 Ul/dL de FVIII e de faixa muito baixa (CRMB): aproximadamente entre 0 e 10 UI/dL. Os resultados de Repetitividade (CVr) e precisão intermediária (CVi) foram inferiores a 6% e comparáveis aos descritos pelo fabricante para outras plataformas. A faixa de medição analítica foi de 11-129 UI/dL com CRNB extrapolando-se para 0,3 UI/dL utilizando a CRMB. Para a CRNB FVIII:Ccro houve boa correlação com o FVIII: Ccoag: r: 0,98, inclinação: 0,982 (0,961-1,003), ordenada na origem: -0,3 (-1,1-0,5), Viés: -2,0%. Para CRMB: foi obtido um r: 0,96, pendente: 0,921 (0,855-0,988), ordenado na origem: -0,07 (-0,35-0,20), Viés: -10,2%. Apenas quatro pacientes apresentaram níveis discrepantes entre os dois métodos. A determinação de FVIII:C pelo método cromogênico automatizado na família ACL TOP foi comparável ao FVIII coagulável em um estágio na faixa analítica avaliada. FVIII: O FVIII:Ccro automatizado pode ser utilizado para o diagnóstico e seguimento do tratamento dos pacientes hemofílicos.

Epidemiology, spectrum of clinical manifestations and diagnostic issue of acquired haemophilia: A case series

@#Introduction: Acquired haemophilia A (AHA) is a rare acquired bleeding disorder caused by polyclonal immunoglobulin G autoantibodies against clotting factor VIII (FVIII). The incidence was reported to be rare occurring in 0.2- 4 cases/million/year. Patients may present with different clinical manifestations to various specialties. Early recognition of the disease contributes to favourable clinical outcome. Case Series: Here, we reported five cases of this disorder with different clinical presentations from two tertiary hospitals in Kelantan state, Malaysia within a two year-period. Most of them were elderly, except for one who presented at the age of 36 years old. No direct or secondary cause was identified except for one patient who had developed from pregnancy-related at 3 weeks postpartum. These patients presented with spontaneous bleeding typically into skin, muscles, and mucous membranes but also at rare site in the epidural space. All patients denied previous history of bleeding or family history of bleeding disorder. FVIII activities were recorded between <1% to 19%, while the inhibitor titre levels were between 3.9 BU to 340 BU. The treatment approaches especially at presentation were complicated by unfamiliarity of managing this rare condition but all these patients received appropriate medical attention. Discussion: Prompt diagnosis and management in the right hand are critical. Awareness of this disorder by medical personnel at all levels in the community and in various specialties is important.

Manejo quirúrgico de pseudotumor hemofílico retroperitoneal: Reporte de caso / Surgical management of a retroperitoneal hemophilic pseudotumor: Report of a case

El pseudotumor hemofílico es una complicación muy rara vista en pacientes con hemofilia severa, y que cuyo manejo aún no se encuentra estandarizado. Se presenta el caso de un paciente varón de 33 años de edad admitido en el servicio de cirugía del Hospital Nacional Dos de Mayo por presentar una tumoración localizada en fosa iliaca izquierda, dolorosa a la palpación, asociada a alteración de la marcha. Realizada la exéresis, se identificó un pseudotumor hemofílico gigante ubicado en retroperitoneo. Este caso expone el primer reporte de manejo de pseudotumor hemofílico en nuestro país, con resultados satisfactorios a los 12 meses del posoperatorio.

The hemophilic pseudotumor is a very rare complication occurring in patients with severe hemophilia, and its management has not been standardized yet. We present the case of a 33-year old male patient who was admitted to the surgery ward in Dos de Mayo Hospital in Lima, Peru, who presented with a tumoral mass located in the left iliac fossa, which was painful when palpated, and it was associated with gait alterations. When the mass was excised, a giant hemophilic pseudotumor located in the retroperitoneum was identified. This is the first case describing the management of a hemophilic pseudotumor in our country, with satisfactory results at 12 months after surgery.

Comparación de la conducta de enfermedad en pacientes colombianos con hemofilia A, en una muestra con dolor crónico y sin dolor crónico / Comparison of disease behavior in Colombian patients with hemophilia A, in a sample compared with chronic pain and without chronic pain

Objetivo. Identificar las variables de conducta de enfermedad en una muestra de pacientes colombianos con Hemofilia A y comparar los resultados de grupos (con dolor crónico y sin dolor crónico) para un análisis de relaciones entre variables. Método. El enfoque fue cuantitativo y su diseño transversal; la metodología empleada fue ex post facto de tipo retrospectiva. Para el análisis estadístico se hizo una comparación de grupos (sin dolor crónico y con dolor crónico). El factor de conducta de enfermedad se evaluó a través del Cuestionario de Conducta de Enfermedad de Ballester y Botella del año 1993. Los resultados obtenidos mediante la prueba T, la correlación de Spearman, la prueba U de Mann-Whitney y la Curva de ROC. Resultados. Se evaluaron veintisiete sujetos con diagnóstico de Hemofilia A con un rango de edad entre 19 y 55 años. Diecisiete sujetos conformaron el grupo con dolor crónico y diez sujetos el grupo sin dolor crónico. En conclusión se hallaron asociaciones significativas entre el dolor crónico y las variables relacionadas a inestabilidad emocional, así como correlaciones positivas con resultados de investigaciones previas sobre la caracterización de la población con hemofilia.

Objective. To Identify the variables of illness behavior in a sample of Colombian patients with hemophilia A and to compare the results of groups (with chronic pain and without chronic pain chronic) for an analysis of relationships between variables. Methods. The approach was quantitative and its cross-sectional design. The methodology used was ex post facto retrospective type. A comparison groups (without chronic pain and chronic pain) was done for the statistical analysis. The disease behavior factor was evaluated through the Ballester and Botella Disease Questionnaire Conduct of 1993. The results obtained by the T-test, the Spearman correlation, the Mann-Whitney U test and the ROC curve. Results. Twenty-seven subjects diagnosed with haemophilia A diagnosed with a age range between 19 and 55 years were evaluated. Seventeen subjects formed the group with chronic pain and ten subjects the group without chronic pain. In conclusion, we found significant associations between chronic pain and variables related to emotional instability, as well as positive correlations with results of previous research on the characterization of the population with hemophilia.

Comparation of multiple imaging in detection of arthropathies in patients with haemophilia / 中华放射学杂志

ObjectiveTo compare the diagnostic value of magnetic resonance imaging (MRI),computed tomography (CT) and radiography in the early detection of arthropathies of haemophilia.Methods Prospective studies of 21 joints in 11 patients were studied with X-ray,CT and MR examination. The 21 joints with haemophilia arthropathies were divided into three groups according to Pettersson scoring system.0 point were the first group,＜4 points were the second group,≥4 points were the third group.Abnormal imaging findings of osteoporosis,enlarge epiphysis,erosion of cartilage,irregular subchondral surface,narrowing of joints space,joint deformity,subchondral cyst formation,effusion/haemarthrosis of joint,synovial hypertrophy with haemosiderin,deformity of joints were used for all imaging comparison.The results were analysis with Chi-square test.To compare the first group,irregular subchondral surface and the number of subchondral cyst formation of all symptomatic joints were detected by CT and MR,the results were analysis with pair-sample t test.ResultsModerate and severe hemophilic joints were found in 80.95％ (17/21)of twenty-one symptomatic joints,and mild hemophilic joints were found in 19.05％ (4/21).The detected results were the same in enlarge epiphysis,narrowing of joints space,joint deformity in all joints by radiography,CT and MR.Significant difference in detection of irregular subchondral surface,subchondral cyst formation,effusion/haemarthrosis of joint,were found between radiography with either CT (x2 value 19.06,16.70,4.84,P ＜0.05 ) or MRI (x2 value 19.06,16.70,7.76,P ＜0.05),Significant difference in detection of the first group joint irregular subchondral surface and the subchondral cyst formation total number were found between CT and MR ( x2 =3.29,P ＜ 0.05 ). Conclusions MR and CT were superior in detection of the early abnormal changes in evaluating hemophilic arthropathies,however CT could detect more smaller irregular subchondral surface and subchondral cyst formation than MR.

Identification of a shared F8 mutation in the Korean patients with acquired hemophilia A

Although uncommon, acquired hemophilia A (HA) is associated with a high rate of mortality due to severe bleeding. In spite of many hypotheses regarding the cause of acquired HA, there is as yet no established theory. In this study, we investigated the possibility that mutation(s) in the F8 gene may be correlated with the development of inhibitory autoantibodies. Direct sequencing analysis was performed on all 26 exons of the F8 gene of 2 patients exhibiting acquired HA. Both patients were found to share a common point mutation (c.8899G>A) in the 3'-untranslated region (3'-UTR) of exon 26. This is the first report on the genotyping of F8 in the context of acquired HA.

Polimorfismos intragénicos de los genes de los factores VIII y IX y su utilidad en el diagnóstico indirecto de portadoras de hemofilias A y B / Intragenic polymorphisms of factor VIII and IX genes and their utility in the indirect diagnosis of carriers of haemophilias A and B

Las Hemofilias A y B se consideran enfermedades hereditarias ligadas al sexo debidas a mutaciones en los genes que codifican para los factores VIII y IX respectivamente, ocasionando deficiencia en los niveles de la concentración plasmática de estas proteínas y cuyos roles son los de participar activamente en el mecanismo de la coagulación sanguínea. Se han reportado diversas mutaciones responsables de la alteración de estos genes; razón por la cual resulta poco práctico la aplicación de un método de diagnóstico molecular directo para la identificación de mujeres portadoras, por ello, una estrategia diagnóstica apropiada es el análisis indirecto de polimorfismos ligados al gen. El objetivo de este trabajo fue identificar mujeres portadoras en diversas familias con antecedentes de HA y HB residentes del estado Zulia, en Venezuela, caracterizando polimorfismos intragénicos de los genes del factor VIII y factor IX, los cuales permitieron asignar haplotipos y diagnosticar o descartar el estado portador al 95 por ciento de las mujeres que requerían el estudio para HA y al 100 por ciento para HB.

Haemophilia A and B are considered sex-linked inherited diseases caused by mutations in genes that encode factors VIII and IX, respectively. This results in the deficiency of these proteins plasma levels which are actively involved in the mechanism of blood coagulation. It has been reported that several mutations are responsible for the alteration of these genes, which is why the application of a molecular diagnostic method for the direct identification of female carriers is impractical. An appropriate diagnostic strategy is the indirect analysis of polymorphisms linked to the gene. The aim of this study was to identify female carriers in different families with history of HA and HB that live in Zulia State, Venezuela, characterizing intragenic gene polymorphisms of the clotting factors VIII and IX, which helped to identify and assign haplotypes, to diagnose or to exclude the carrying condition, to 95 percent of women who were needing the study for HA and to 100 percent for HB.

Haplotipo del gen del factor VIII en el diagnóstico molecular de la hemofilia A: estudio de una familia / Factor VIII gene haplotype in the haemophilia a molecular dagnosis: a family study

La hemofilia A se caracteriza por ser una enfermedad congénita del trastorno de la coagulación y constituye un desorden recesivo ligado al cromosoma X. El estudio molecular se realiza por estudio indirecto, por ser causada por mutaciones heterogéneas en el gen del factor VIII. Se estudió una familia afectada, para la detección de portadora de la gestante y posteriormente se realizó el diagnóstico prenatal. La extracción de ADN se hizo por el método de precipitación salina Salting Out a tres muestras de sangre y una de líquido amniótico. Se efectuó el análisis de los polimorfismos St14, Bcl I y Hind III. Para la determinación de sexo fetal, se estudió el gen AMXY. La técnica empleada fue la reacción en cadena de la polimerasa. El análisis del marcador Bcl I arrojó que la gestante era portadora de hemofilia A, pero al ser homocigótica no era informativa; el polimorfismo St14 por sí solo no brindaba la información de la condición de la gestante, pero al ser heterocigótica para el mismo y conociendo de antemano la información de ser portadora, se pudo realizar diagnóstico prenatal, gracias al análisis conjunto de los marcadores. El polimorfismo Hind III no fue informativo. El feto resultó ser varón sano (AU)

Hemophilia A is a coagulation disorder congenital disease which consist in a recessive disorder linked to X chromosome. HA is cause by heterogeneous mutations in factor VIII gen, that's why, the study was carry out by indirect studies. We studied one family afected; we were determinated of carrier status of pregnancy woman and later we relizated of prenatal diagnosis. The DNA extraction from the three blood samples and one amniotic fluid was obtained by the saline precipitation procedure (Salting Out). We studied the polymorphisms St14, Hind III and Bcl1. The determination of fetal sex was studied of AMXY gen. The technique used was Polymerase Chain Reaction. The Bcl I marker analysis showed that the mother was a carrier of haemophilia A but being homozygous was not informative, ST14 polymorphism alone did not provide information on the condition of the mother but to be heterozygous for it and knowing beforehand information of being a carrier prenatal diagnosis was possible thanks to joint analysis of the markers. Hind III polymorphism was not informative. The male fetus was found to be healthy (AU)

Genetic polymorphisms of four short tandem repeat loci within factor Ⅷ gene and their application in gene diagnosis for haemophilia A / 中华检验医学杂志

Objective To study the polymorphisms of short tandem repeat (STR) loci in intron 1, 24, 13 and 22 (STR 1,24, 13, 22) of factor Ⅷ (FⅧ) gene in Chinese population, and establish single tube multiple fluorescent PCR method for rapid diagnosis of haemophilina A(HA). Methods Four STRs from genomie DNA of 220 females without blood relationship were amplified in a single tube using quadri-fluorescence PCR. Capillary electrophoresis was analyzed in ABI PRISM 310 Genetic Analyzer. DNA sequencing was used to assay the number of dinueleotide repeats. Gene diagnosis were performed in 96 HA families. Results It was observed that 7, 9, 10 and 7 different alleles were found in STR1, 24, 13 and 22, respectively. The PIC (polymorphism information contents) were 0. 3789, 0. 4055, 0. 5239 and 0. 4713 in STR1,24, 13 and 22, respectively, and the HR (heterozygesity rate) were 34. 55% (76/220), 38. 18% (84/220), 49. 55% (109/220) and 43.64% (96/220). In 96 HA families, the diagnosis rate of STR1, 24, 13 and 22 were 38. 54% (37/96), 38. 54% (37/96), 54. 17% (52/96), 42. 71% (41/96), respectively. Whereas it achieved 79. 17% (76/96) when combining the four STR markers. Conciusion The single tube multiple fluorescent PCR of four STR loci is an effective, simple, quick method for linkage analysis and gene diagnosis of haemophilia A.

Research on the BCL I Polymorphism of Haemophilia A in Han Chinese Population in Wenzhou / 中国慢性病预防与控制

Objective In order to find the polymorphism site applicable to efficient genetic diagnosis on Haemophilia A in Han Chinese Population in Wenzhou.Methods With the method of polymerase chain reaction(PCR) and polyacrylamide gel electrophoresis(PAGE),288 of X chromosomes from 96 men and 96 women were detected on the polymorphism of BCL I in the intron 18 of FV Ⅲ gene.Results The gene frequency of the polymorphic site BCL I was 34.38% in Han Chinese population in Wenzhou.43.75% women were heterozygous and the polymorphism information content(PIC) was 0.4512.Conclusion For Han Chinese population in Wenzhou,the BCL I genetic site has enough information,being one of the genetic markers with high polymorphism,applicable to the screening for carrier and prenatal diagnosis of Haemophilia A in Wenzhou.