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1.
Blood Coagul Fibrinolysis ; 31(6): 382-386, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32815913

RESUMEN

: The defect function of the von Willebrand factor (VWF) in carrying factor VIII (FVIII) leads to von Willebrand disease type 2N (VWD 2N) which could be easily misdiagnosed as hemophilia A. Differentiating of VWD 2N from hemophilia A is crucial for patient treatment and genetic counseling. As a retrospective study, we aimed to evaluate the current diagnostic work-up of Iranian patients with mild/moderate deficiency of FVIII levels and the possibility of misdiagnosis of VWD 2N as hemophilia A. All patients who referred to the reference coagulation laboratory at the Iranian Blood Transfusion Organization in a 10-months period for bleeding diathesis work-up with the request of FVIII activity level were included. Clinical and laboratory phenotypes including International Society on Thrombosis and Hemostasis - Bleeding Assessment Tool, FVIII activity, VWF antigen, VWF ristocetin cofactor, and FVIII binding capacity of VWF were assessed on suspected cases for VWD 2N. In total, the results of 896 patients for investigation of VWD 2N were evaluated and five new patients were identified within unrelated families with abnormal VWF:FVIIIB levels. Four were heterozygous for VWD 2N and one homozygous whom all were misdiagnosed as hemophilia A and underwent inappropriate treatments. The median bleeding score of the VWD 2N population was nine (4-13). In Iran, probably a significant number of VWD 2N patients are misdiagnosed as hemophilia A due to insufficient test panel for subtyping of von Willebrand disease. This study also emphasized the need for inclusion of the VWF:FVIIIB in suspected hemophilia A to achieve an optimal treatment strategy.


Asunto(s)
Enfermedad de von Willebrand Tipo 2/diagnóstico , Enfermedades de von Willebrand/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Diferencial , Manejo de la Enfermedad , Femenino , Hemofilia A , Hemorragia/sangre , Hemorragia/diagnóstico , Hemorragia/epidemiología , Hemorragia/terapia , Hemostasis , Humanos , Lactante , Irán/epidemiología , Masculino , Persona de Mediana Edad , Adulto Joven , Enfermedad de von Willebrand Tipo 2/sangre , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/terapia , Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/epidemiología , Enfermedades de von Willebrand/terapia
2.
Am J Hematol ; 95(1): 10-17, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31612544

RESUMEN

There are limited observational studies among children diagnosed with von Willebrand Disease (VWD). We analyzed differences in bleeding characteristics by sex and type of VWD using the largest reported surveillance database of children with VWD (n = 2712), ages 2 to 12 years old. We found that the mean ages of first bleed and diagnosis were lowest among children with type 3 VWD. It was even lower among boys than girls among all VWD types, with statistically significant difference among children with type 1 or type 3 VWD. Children with type 3 VWD also reported higher proportions of ever having a bleed compared to other VWD types, with statistically higher proportions of boys compared to girls reporting ever having a bleed with type 1 and type 2 VWD. A similar pattern was observed with the use of treatment product, showing higher usage among type 3 VWD, and among boys than girls with type 1 and type 2 VWD. While there were no differences in life quality or in well-being status by sex, children with type 3 VWD showed a greater need for mobility assistance compared to children with type 1 and type 2 VWD. In an adjusted analysis among children with type 1 VWD, boys showed a significant association of ever bleeding [hazard ratio 1.4; P-value <.001)] compared to girls. Understanding phenotypic bleeding characteristics, well-being status, treatment, and higher risk groups for bleeding among pre-adolescent children with VWD will aid physicians in efforts to educate families about bleeding symptoms.


Asunto(s)
Monitoreo Epidemiológico , Hemorragia/etiología , Terapéutica/estadística & datos numéricos , Enfermedades de von Willebrand/patología , Enfermedades de von Willebrand/terapia , Niño , Preescolar , Femenino , Humanos , Masculino , Factores Sexuales , Enfermedad de von Willebrand Tipo 1/epidemiología , Enfermedad de von Willebrand Tipo 1/patología , Enfermedad de von Willebrand Tipo 1/terapia , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/patología , Enfermedad de von Willebrand Tipo 2/terapia , Enfermedad de von Willebrand Tipo 3/epidemiología , Enfermedad de von Willebrand Tipo 3/patología , Enfermedad de von Willebrand Tipo 3/terapia , Enfermedades de von Willebrand/clasificación , Enfermedades de von Willebrand/epidemiología
3.
Haemophilia ; 24(1): 134-140, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29115006

RESUMEN

INTRODUCTION: An abnormal factor VIII (FVIII) binding capacity of von Willebrand factor (VWF) identifies type 2N von Willebrand disease (VWD). Type 2N VWD patients are identified by means of the VWF FVIII binding (VWF:FVIIIB) assay, and especially their VWF:FVIIIB/VWF:Ag ratio (VWF:FVIIIB ratio). AIM: We report on our 15-year experience of diagnosing type 2N VWD. METHODS: We have performed 2178 VWF:FVIIIB assays in bleeders and normal subjects. RESULTS: von Willebrand factor (VWF):FVIIIB was reduced in 682, but only 60 had low VWF:FVIIIB ratios (<0.74). Among nine patients who had a VWF:FVIIIB ratio below 0.3, four had normal VWF levels and were homozygotes for the p.R854Q mutation; the other five had low VWF levels due to a quantitative VWF mutation combined with p.R854Q. The VWF:FVIIIB ratio ranged between 0.3 and 0.73 in 51 subjects; 34 of them were heterozygotes for the p.R854Q mutation, while one carried the p.R760C. The heterozygotes for type 2N included subjects with or without bleeding symptoms, the former with significantly lower mean VWF levels than the latter. Among the 116 normal subjects tested, six were heterozygotes for the p.R854Q mutation (all asymptomatic). CONCLUSIONS: The prevalence of type 2N in our VWD cohort was 2.5%, and 5.2% of the general population in Northeast Italy was found heterozygous for the p.R854Q mutation. It might be difficult to reveal a type 2N defect using routine tests alone, especially when it is combined with a quantitative VWF mutation. Accordingly, we always recommend VWF:FVIIIB assay in the diagnostic workup of VWD.


Asunto(s)
Enfermedad de von Willebrand Tipo 2/diagnóstico , Alelos , Diagnóstico Diferencial , Factor VIII/análisis , Factor VIII/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Polimorfismo de Nucleótido Simple , Prevalencia , Unión Proteica , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/genética , Factor de von Willebrand/análisis , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo
4.
Haemophilia ; 22(3): e145-55, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27029718

RESUMEN

INTRODUCTION: Appropriate diagnosis of von Willebrand disease (VWD), including differential identification of qualitative vs. quantitative von Willebrand factor (VWF) defects has important management implications, but remains problematic. AIM: The aim of the study was to assess whether 2M VWD, defining qualitative defects not associated with loss of high molecular weight (HMW) VWF, is often misidentified, given highly variable reported frequency ranging from 0 to ~60% of all type 2 VWD. METHODS: A comparative evaluation of laboratory ability to appropriately identify 2M VWD (n = 4) vs. HMW VWF reduction (n = 4), as sent to participants of an international external quality assessment programme. RESULTS: Laboratories had considerably greater difficulty identifying type 2M VWD, correctly identifying these on average only 29.4% of occasions, with the 70.6% error rate representing use of insufficient test panels (41.7%), misinterpretation of test results (10.0%) and analytical errors (13.3%). One type 2M case, giving a median of 49 U dL(-1) VWF:Ag, was more often misidentified as type 2A/2B VWD (46.7%) than 2M (34.8%). Another 2M case, giving a median of 189 U dL(-1) VWF:Ag, was instead often misidentified as being normal (non-VWD) (36.4%), with identifications of type 2A/2B VWD (13.6%) also represented. In comparison, errors in identification of HMW VWF reduced samples only averaged 11.5%, primarily driven by use of insufficient test panels (6.3%) or misinterpretation of results (4.2%) and infrequently analytical errors (1.0%). CONCLUSION: Type 2M VWD is more often misidentified (70.6%) than correctly identified as 2M VWD (29.4%), and potentially explaining the relative under-reported incidence of 2M VWD in the literature.


Asunto(s)
Proteínas Sanguíneas/análisis , Errores Diagnósticos/estadística & datos numéricos , Enfermedad de von Willebrand Tipo 2/diagnóstico , Factor de von Willebrand/análisis , Australia , Coagulación Sanguínea/genética , Plaquetas/fisiología , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Técnicas de Laboratorio Clínico/normas , Diagnóstico Diferencial , Errores Diagnósticos/prevención & control , Humanos , Incidencia , Mutación/genética , Nueva Zelanda , Valores de Referencia , Enfermedad de von Willebrand Tipo 2/epidemiología , Factor de von Willebrand/química , Factor de von Willebrand/genética
5.
J Ayub Med Coll Abbottabad ; 26(4): 470-3, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25672167

RESUMEN

BACKGROUND: Von Willebrand's disease (VWD) is a common inherited bleeding disorder caused by quantitative deficiency (Type-1 & Type-3 VWD) or qualitative defect of Von Willebrand's Factor (Type-2 VWD). Regarding VWD limited studies are available in Pakistan. The current study was aimed to determine the clinical presentation and frequency of types of VWD. METHODS: A cross sectional study was carried out from 16th December 2012 to 15th December 2013 on fifty one patients of VWD. RESULTS: Patients were diagnosed on the basis of prolonged bleeding time, abnormal APTT, reduced level of VWF: Ag, FVIII, VWF: RCo and ratio of VWF: RCo/VWF Ag. Among them 26 (50.98%) were male and 25 (49.02%) were female. Type3 VWD (94.12%) was found to be the commonest type. Two (3.92%) cases of type-2 VWD and only one (1.96%) case of type-1 VWD were identified. Easy bruising was the most commonly observed clinical presentation, 21 (41.18%) patients, followed by epistaxis 7 (13.73%), gum bleed 4(7.84%) menorrhagia 5(9.80%), haemarthosis 2(3.92%), haematoma formation 5 (9.80%), bleeding after circumcision 2 (3.92%), bleeding after surgery 2 (3.92%) and umbilical cord bleeding 3 (5.88%). Consanguineous marriages were reported in parents of 42 (82.4%) patients. Family history of bleeding disorder was reported in 44 (86.27%) of cases. CONCLUSION: Type-3 VWD was found to be the commonest type which can be attributed to the fact that type-3 VWD is transmitted through autosomal recessive pattern of inheritance and consanguineous marriages are highly practiced in our society leading to high frequency of this form of VWD. Easy bruising and epistaxis were concluded to be the most common clinical presentation. Menorrhagia was found to be common in the females of child bearing age.


Asunto(s)
Hemorragia/etiología , Enfermedad de von Willebrand Tipo 1/sangre , Enfermedad de von Willebrand Tipo 2/sangre , Enfermedad de von Willebrand Tipo 3/sangre , Adolescente , Niño , Preescolar , Consanguinidad , Contusiones/etiología , Estudios Transversales , Epistaxis/etiología , Factor VIII/metabolismo , Femenino , Humanos , Lactante , Masculino , Menorragia/etiología , Pakistán/epidemiología , Tiempo de Tromboplastina Parcial , Recuento de Plaquetas , Enfermedad de von Willebrand Tipo 1/complicaciones , Enfermedad de von Willebrand Tipo 1/epidemiología , Enfermedad de von Willebrand Tipo 2/complicaciones , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 3/complicaciones , Enfermedad de von Willebrand Tipo 3/epidemiología , Factor de von Willebrand/metabolismo
6.
Am J Hematol ; 88(12): 1030-4, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23913812

RESUMEN

A reference genotyping laboratory was established in 2000 at Queen's University, Kingston, to provide genetic testing for Hemophilia A (HA) and B (HB) and create a Canadian mutation database. Canadian hemophilia treatment centers and genetics clinics provided DNA and clinical information from November 2000 to March 2011. The factor VIII (F8) gene was analyzed in 1,177 patients (47% of HA population) and 787 female family members and the factor IX (F9) gene in 267 patients (47% of HB population) and 123 female family members, using Southern Blot, PCR, conformation sensitive gel electrophoresis, and/or direct sequencing. The mutation detection rates for HA and HB were 91% and 94%, respectively. 380 different F8 mutations were identified: inversions of intron 22 and intron 1, 229 missense, 45 nonsense, eight deletions, 70 frameshifts, 25 splice site, and one compound mutation with a splice site and intron 1 inversion. Of these mutations, 228 were novel to the Hemophilia A Database (HADB, http://hadb.org.uk/). A total 125 different F9 mutations were identified: 80 missense, 12 frameshift, 12 splice site, nine nonsense and seven promoter mutations, three large deletions, and two compound mutations with both missense and nonsense changes. Of these mutations, 36 were novel to the International Haemophilia B Mutation database (http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html). The Canadian F8 and F9 mutation database reflects the allelic heterogeneity of HA and HB, and is similar to previously described populations. This report represents the largest and longest duration experience of a national hemophilia genotyping program documented, to date.


Asunto(s)
Bases de Datos Genéticas , Factor IX/genética , Factor VIII/genética , Hemofilia A/genética , Hemofilia B/genética , Mutación , Canadá/epidemiología , Análisis Mutacional de ADN , Exones/genética , Femenino , Frecuencia de los Genes , Tamización de Portadores Genéticos , Pruebas Genéticas , Hemofilia A/epidemiología , Hemofilia B/epidemiología , Humanos , Intrones/genética , Masculino , Fenotipo , Diagnóstico Prenatal , Sitios de Empalme de ARN , Estudios Retrospectivos , Análisis de Secuencia de ADN , Inversión de Secuencia , Terminología como Asunto , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/genética
7.
Haematologica ; 98(1): 147-52, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22875612

RESUMEN

The impaired capacity of von Willebrand factor to carry factor VIII is identified as type 2N von Willebrand's disease. R854Q is the most common type 2N mutation, and almost the only one identified in Italy. This aim of this study was to ascertain whether R854Q mutations in a cohort of Italian patients with type 2N von Willebrand's disease originated from a single event or recurrent events. Thirteen unrelated Italian families were investigated, analyzing the von Willebrand factor gene haplotype associated with the R854Q mutation. A common haplotype emerged in all the families, extending from single nucleotide polymorphisms rs2166902 to rs216293 over 48.2 kb and including five intragenic markers. This haplotype is infrequent in the healthy Italian population (17% versus 100%, P<0.0001) and each genetic marker within the said haplotype is similarly rare. These data strongly suggest a founder effect, with a single R854Q mutation event being the cause of the type 2N von Willebrand's disease in our cohort of patients. Using DMLE+ software and the mathematical model of Bengtsson and Thomson, it was estimated that the R854Q mutation occurred from 10,000 to 40,000 years ago, which is consistent with the short dimension of the haplotype shared by our patients. Together with the fact that the R854Q mutation seems to be limited to Caucasian populations, these findings suggest that a single mutational event took place after human populations moved from Africa towards Europe.


Asunto(s)
Desequilibrio de Ligamiento/genética , Mutación/genética , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/genética , Humanos , Italia/epidemiología , Enfermedad de von Willebrand Tipo 2/diagnóstico
8.
Res Vet Sci ; 93(3): 1462-6, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22824509

RESUMEN

Type 2 Von Willebrand disease (VWD) is a severe coagulopathy occurring in the Deutsch-Drahthaar dog (or German Wirehaired Pointer, DD/GWP). Recently, a causative recessive mutation has been identified, and a DNA test is now available for individual screening. The genotype distribution (clear, carrier, and affected dogs) was investigated in 1855 DD/GWP dogs using data collected by the DD DNA-VWD-Databank in several European countries. 1704 (91.8%) DD/GWP dogs were genotypically clear of the VWD mutation, 144 (7.8%) were carriers, and seven (0.4%) were affected. The estimated disease allele frequency was highest in Germany and Sweden (almost 5%), and about 1% in Denmark, Finland and Norway. The Hardy-Weinberg equilibrium was tested in the German sample, and showed no evidence of deviation.


Asunto(s)
Enfermedades de los Perros/genética , Predisposición Genética a la Enfermedad , Enfermedad de von Willebrand Tipo 2/veterinaria , Animales , Enfermedades de los Perros/epidemiología , Perros , Europa (Continente)/epidemiología , Femenino , Masculino , Prevalencia , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/genética
9.
J Thromb Haemost ; 10(4): 632-8, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22329792

RESUMEN

BACKGROUND: Type 2A and 2M von Willebrand disease (VWD2A and VWD2M) are characterized by the presence of a dysfunctional von Willebrand factor (VWF) and a variable bleeding tendency. So far, a head-to-head comparison of the clinical history and bleeding risk between VWD2A and VWD2M has never been provided in a prospective manner. AIM OF THE STUDY: We assessed the bleeding incidence rate and clinical characteristics in two cohorts of 17 families (46 patients) with VWD2A and 15 families (61 patients) with VWD2M prospectively followed-up for 24 months. VWF gene mutations were characterized in all of them. RESULTS: Mean bleeding score (BS) and VWF antigen at enrollment were significantly higher in VWD2A patients (P = 0.007). No correlation between VWF activity or factor VIII levels and the severity of BS was observed. The incidence rate of spontaneous bleeding requiring treatment was 107/100 patient-years (95% CI, 88.3-131) in VWD2A compared with 40/100 patient-years (95% CI, 30-53) in VWD2M (P < 0.001). The risk of bleeding was significantly higher in patients with BS ≥ 10 at enrollment compared with those with BS 0-2. Furthermore, 54 episodes of gastrointestinal bleeding occurred in 17/46 (36.9%) VWD2A patients and seven in 2/61 (3.3%) VWD2M patients (P < 0.0001). CONCLUSION: Bleeding tendency in VWD2A is greater than that of VWD2M, is not explained by factor VIII or VWF levels and is mainly due to an increased incidence of gastrointestinal bleeding.


Asunto(s)
Hemorragia/etiología , Enfermedad de von Willebrand Tipo 2/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Factor VIII/análisis , Femenino , Hemorragia Gastrointestinal/etiología , Predisposición Genética a la Enfermedad , Hemorragia/epidemiología , Hemorragia/genética , Hemorragia/terapia , Técnicas Hemostáticas , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Fenotipo , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Adulto Joven , Enfermedad de von Willebrand Tipo 2/epidemiología , Enfermedad de von Willebrand Tipo 2/genética , Factor de von Willebrand/análisis , Factor de von Willebrand/genética
10.
Thromb Haemost ; 105(3): 501-8, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21301777

RESUMEN

Less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses.


Asunto(s)
Plaquetas/metabolismo , Enfermedad de von Willebrand Tipo 2/sangre , Factor de von Willebrand/biosíntesis , Trastornos de las Plaquetas Sanguíneas/genética , Plaquetas/citología , ADN/metabolismo , Exones , Femenino , Hemostasis , Humanos , Cooperación Internacional , Masculino , Glicoproteínas de Membrana/genética , Mutación , Recuento de Plaquetas , Complejo GPIb-IX de Glicoproteína Plaquetaria , Sistema de Registros , Enfermedad de von Willebrand Tipo 2/epidemiología
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