RESUMEN
Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.
Asunto(s)
Enfermedad de von Willebrand Tipo 3 , Enfermedades de von Willebrand , Genotipo , Humanos , Irán/epidemiología , Estudios Prospectivos , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/epidemiología , Enfermedad de von Willebrand Tipo 3/genéticaRESUMEN
BACKGROUND: Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. AIMS: To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. METHODS: We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. RESULTS: In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels < 20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. CONCLUSIONS: In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.
Asunto(s)
Enfermedad de von Willebrand Tipo 1 , Enfermedad de von Willebrand Tipo 3 , Enfermedades de von Willebrand , Estudios Transversales , Femenino , Hemartrosis , Humanos , Enfermedad de von Willebrand Tipo 1/diagnóstico , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/epidemiología , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/epidemiología , Factor de von WillebrandRESUMEN
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/epidemiologíaRESUMEN
INTRODUCTION: Type 3 von Willebrand disease (VWD) is the rare and most severe form of VWD which results from a near-complete deficiency of the von Willebrand factor (VWF). This study evaluates in detail the molecular pathology of type-3 VWD in India. One hundred and two patients from 90 families were evaluated. PATIENTS AND METHODS: Phenotypic data, including bleeding scores (BS), were documented using structured questionnaires. Diagnosis of type 3 VWD was based on undetectable VWF antigen levels in the plasma. Genomic DNA from these patients was screened for mutations in VWF gene. Structural modeling and expression studies were carried out for missense mutations. RESULTS: Out of 102 patients, mutations could be identified in 91% (n = 93). Fifty-five different gene variants were identified. Thirty-four (61.8%) were novel. Mutations could be identified in both the alleles in 90 patients, while no causative mutation could be identified in 9 patients; twenty-four (23.5%) patients had mutations clustered in the propeptide region of VWF. Interestingly, five mutations accounted for the defects in 37/93 (39.8%) patients. Structural analysis and in vitro studies on missense mutations imply impaired processes associated with secretion of VWF. CONCLUSION: This study is one of the largest series to define the molecular basis of type-3 VWD.
Asunto(s)
Enfermedad de von Willebrand Tipo 3/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Genotipo , Células HEK293 , Humanos , India/epidemiología , Lactante , Masculino , Mutación , Fenotipo , Encuestas y Cuestionarios , Adulto Joven , Enfermedad de von Willebrand Tipo 3/epidemiologíaRESUMEN
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/metabolismoRESUMEN
Severe type 3 VWD (VWD3) is characterised by complete absence or presence of trace amounts of non-functional von Willebrand factor (VWF). The study was designed to evaluate the VWF mutations in VWD3 patients and characterise the breakpoints of two identified homozygous novel large deletions. Patients were diagnosed by conventional tests and VWF multimer analysis. Mutation screening was performed in 19 VWD3 patients by direct sequencing of VWF including flanking intronic sequence and multiplex ligation-dependent probe amplification (MLPA) analysis. Breakpoint characterisation of two identified novel large deletions was done using walking primers and long spanning PCR. A total of 21 different mutations including 15 (71.4%) novel ones were identified in 17 (89.5%) patients. Of these mutations, five (23.8%) were nonsense (p.R1659*, p.R1779*, p.R1853*, p.Q2470*, p.Q2520*), one was a putative splice site (p.M814I) and seven (33.3%) were deletions (p.L254fs*48, p.C849fs*60, p.L1871fs*6, p.E2720fs*24) including three novel large deletions of exon 14-15, 80,830bp (-41510_657+7928A*del) and 2,231bp [1534-2072T_c.1692G*del(p.512fs*terminus)] respectively. A patient carried gene conversion comprising of pseudogene harbouring mutations. The missense mutations (p.G19R, p.K355R, p.D437Y, p.C633R, p.M771V, p.G2044D, p.C2491R) appear to play a major role and were identified in seven (36.8%) patients. In conclusion, a high frequency of novel mutations suggests the high propensity of VWF for new mutations. Missense and deletion mutations found to be a common cause of VWD3 in cohort of Indian VWD3 patients. Breakpoints characterisation of two large deletions reveals the double strand break and non-homologous recombination as deletions mechanism.
Asunto(s)
Coagulación Sanguínea/genética , Mutación Missense , Eliminación de Secuencia , Enfermedad de von Willebrand Tipo 3/sangre , Enfermedad de von Willebrand Tipo 3/genética , Factor de von Willebrand/genética , Secuencia de Bases , Pruebas de Coagulación Sanguínea , Puntos de Rotura del Cromosoma , Simulación por Computador , Análisis Mutacional de ADN/métodos , Exones , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , India/epidemiología , Intrones , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa Multiplex , Fenotipo , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/epidemiologíaRESUMEN
BACKGROUND: Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion. OBJECTIVES: The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. PATIENTS AND METHODS: Thirty-four families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values and anti-VWF inhibitor status were included as well as sequence analysis. RESULTS: We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS = 22) than those with mutations elsewhere in VWF (BS = 13). Sixty-two out of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified. CONCLUSIONS: We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In approximately 50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.
Asunto(s)
Coagulación Sanguínea/genética , Genes Dominantes , Mutación , Enfermedad de von Willebrand Tipo 3/genética , Factor de von Willebrand/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Canadá/epidemiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Herencia , Heterocigoto , Homocigoto , Humanos , Lactante , Isoanticuerpos/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Transfección , Adulto Joven , Enfermedad de von Willebrand Tipo 3/sangre , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/epidemiología , Factor de von Willebrand/inmunología , Factor de von Willebrand/metabolismoAsunto(s)
Anomalías Múltiples/diagnóstico , Consanguinidad , Enfermedad de von Willebrand Tipo 3/diagnóstico , Trastornos del Desarrollo Sexual 46, XX , Anomalías Múltiples/epidemiología , Adolescente , Amenorrea/diagnóstico , Anomalías Congénitas , Femenino , Hemorragia/diagnóstico , Humanos , Riñón/anomalías , Conductos Paramesonéfricos/anomalías , Quistes Ováricos/diagnóstico , Somitos/anomalías , Columna Vertebral/anomalías , Útero/anomalías , Vagina/anomalías , Enfermedad de von Willebrand Tipo 3/epidemiologíaRESUMEN
Type 3 von Willebrand disease (VWD) is a severe autosomal recessive inherited bleeding disorder. In affected individuals the underlying von Willebrand factor gene (VWF) mutations frequently remain uncharacterized. The aim of this study was to investigate the molecular basis of type 3 VWD in patients (11 Caucasians and 9 of Asian origin) attending the haemophilia centres at Central Manchester NHS Trust. A combination of DNA sequencing of VWF genomic and complementary DNA was performed to identify mutations in the patient cohort. Fifteen different VWF mutations were identified at the genomic DNA level: two gene conversion events, three nonsense, three frameshift, one missense, two splice site, one insertion-deletion and three deletion mutations. Homozygosity or compound heterozygosity for mutations was present in 15 of the 20 patients. In the remaining five individuals, heterozygosity for a single VWF mutation was identified in four cases and one patient had no detectable VWF mutation. Analysis of platelet-derived VWF RNA from these five individuals revealed heterozygosity for a deletion of exons 4 and 5 in four cases. The remaining patient was heterozygous for a three base deletion which had already been identified at the DNA level. Overall the observed VWF genotype explained the phenotype in 18 of the 20 patients investigated. In genetic studies in type 3 VWD, if VWF mutations are not detected at the DNA level, RNA analysis should be performed to search for intronic mutations, heterozygous deletions or aberrant splicing/post-transcriptional events. However, this may still not explain all cases of previously phenotypically diagnosed type 3 VWD.
Asunto(s)
Genes Recesivos/genética , Mutación/genética , Enfermedad de von Willebrand Tipo 3/genética , Estudios de Cohortes , Inglaterra/epidemiología , Genotipo , Humanos , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Enfermedad de von Willebrand Tipo 3/epidemiologíaRESUMEN
von Willebrand's disease (VWD) type 3 is a rare but severe autosomal-recessive inherited bleeding disorder with a prevalence higher in certain locations where consanguineous marriages are relatively frequent. The genetic defects causing recessive type 3 VWD in 10 unrelated families from Iran have been investigated and the genetic heterogeneity among these patients was evaluated. All exons and their flanking regions of von Willebrand factor gene were amplified by PCR and sequenced using specific primers. Eight patients were fully characterized at the molecular level. Six different gene alterations were identified. All the mutations caused null alleles, three being nonsense mutations (Q104X, Q793X and E1981X), two possible splice site mutations (2443-1G>C and 1110-1G>A) and one small deletion (3237delA). Three of them have not been described previously. Most patients were born from consanguineous marriages and all were homozygous for their mutations. The results confirm that molecular defects in type 3 VWD are heterogeneous with mutations arising randomly within the entire gene.
Asunto(s)
Codón sin Sentido/genética , Exones/genética , Genes Recesivos/genética , Enfermedad de von Willebrand Tipo 3/genética , Adulto , Femenino , Heterogeneidad Genética , Pruebas Genéticas , Genotipo , Humanos , Irán/epidemiología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Prevalencia , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad , Adulto Joven , Enfermedad de von Willebrand Tipo 3/epidemiologíaRESUMEN
UNLABELLED: Diagnostics and treatment of severe forms of haemorrhagic diatheses (HD), such as haemophilia A, B or type 3 von Willebrand disease (VWD) need high standards in haemophilia treatment centers (HTCs). Due to their generally low incidence, a close cooperation of haemophilia treaters is needed to optimize treatment strategies. For this purpose, the Kompetenznetz Hämorrhagische Diathesen Ost was founded. The first project was the conduction of a survey of epidemiological data of patients with HA, HB and type 3 VWD in all HTCs in the eastern part of Germany. METHOD: The study assessed the data regarding numbers of patients treated with HA, HB or type 3 VWD, disease severity, regime of coagulation factor replacement (CFR) and the frequency of factor VIII and IX inhibitors. RESULTS: Up to now, data of 838 patients from 27 HTCs were evaluated (5-151 per HTCs). Among the included patients, 201 were children or adolescents (<18 years). 81 children suffered from severe HA, 20 from severe HB and 10 from type 3 VWD. In 637 adults we found 246 with severe HA, 51 severe HB and 28 VWD of type 3. The most commonly used treatment of CFR in patients with severe disease was prophylactic modality. 90% of the children received prophylaxis, but also in 64% of the adults an intermittent or long-term secondary prophylaxis was the preferred treatment. At the time of survey conduction, a factor VIII or IX inhibitor was present in 1.9% of the children and in 1.6% of the adults with haemophilia. CONCLUSION: Our data allow an overview of the number of patients and treatment strategies in the eastern part of Germany.