RESUMEN
Essentials New VWF activity assays are increasingly used but information on their comparability is limited. This is an ISTH SSC-organized study (expert labs, 5 countries) to compare all available assays. VWF activity by six assays correlated well with each other. The new assays show improved characteristics - minor differences are noted. SUMMARY: Background Several new assays have become available to measure von Willebrand factor (VWF) activity. The new assays appear to have improved performance characteristics compared with the old reference standard, ristocetin cofactor activity (VWF:RCo), but information is limited about how they compare with VWF:RCo and each other. Methods The von Willebrand factor Subcommittee of the International Society for Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) designed a collaborative study involving expert laboratories from several countries to compare available tests with each other and with VWF:RCo. Eight laboratories from five countries were provided with blinded samples from normal healthy individuals and well-characterized clinical cases. Laboratories measured VWF activity using all tests available to them; data from six laboratories, not affected by thawing during transportation, are included in this study. Results All tests correlated well with VWF:RCo activity (r-values ranged from 0.963 to 0.989). Slightly steeper regression lines for VWF:Ab and VWF:GPIbM were clinically insignificant. The new assays showed improved performance characteristics. Of the commercially available assays, the VWF:GPIbR using the AcuStar system was the most sensitive and could reliably detect VWF activity below 1 IU dL-1 . The lower limit of the measuring interval for the VWF:GPIbM and the VWF:GPIbR assays was in the 3-4 and 3-6 IU dL-1 range, respectively. Inter-laboratory variation was also improved for most new assays. Conclusion All VWF activity assays correlated well with each other and the VWF:RCo assay. The slight differences in characteristics found in the COMPASS-VWF study will assist the VWF community in interpreting and comparing activity results.
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Carcinoma Papilar/patología , Proteína SMARCB1/genética , Neoplasias de la Médula Espinal/patología , Carcinoma Papilar/genética , Carcinoma Papilar/cirugía , Humanos , Laminectomía , Masculino , Persona de Mediana Edad , Neoplasias de la Médula Espinal/genética , Neoplasias de la Médula Espinal/cirugía , Vértebras Torácicas , Resultado del TratamientoRESUMEN
UNLABELLED: Essentials Von Willebrand disease IIC Miami features high von Willebrand factor (VWF) with reduced function. We aimed to identify and characterize the elusive underlying mutation in the original family. An inframe duplication of VWF exons 9-10 was identified and characterized. The mutation causes a defect in VWF multimerization and decreased VWF clearance from the circulation. SUMMARY: Background A variant of von Willebrand disease (VWD) type 2A, phenotype IIC (VWD2AIIC), is characterized by recessive inheritance, low von Willebrand factor antigen (VWF:Ag), lack of VWF high-molecular-weight multimers, absence of VWF proteolytic fragments and mutations in the VWF propeptide. A family with dominantly inherited VWD2AIIC but markedly elevated VWF:Ag of > 2 U L(-1) was described as VWD type IIC Miami (VWD2AIIC-Miami) in 1993; however, the molecular defect remained elusive. Objectives To identify the molecular mechanism underlying the phenotype of the original VWD2AIIC-Miami. Patients and Methods We studied the original family with VWD2AIIC-Miami phenotypically and by genotyping. The identified mutation was recombinantly expressed and characterized by standard techniques, confocal imaging and in a mouse model, respectively. Results By Multiplex ligation-dependent probe amplification we identified an in-frame duplication of VWF exons 9-10 (c.998_1156dup; p.Glu333_385dup) in all patients. Recombinant mutant (rm)VWF only presented as a dimer. Co-expressed with wild-type VWF, the multimer pattern was indistinguishable from patients' plasma VWF. Immunofluorescence studies indicated retention of rmVWF in unusually large intracellular granules in the endoplasmic reticulum. ADAMTS-13 proteolysis of rmVWF under denaturing conditions was normal; however, an aberrant proteolytic fragment was apparent. A decreased ratio of VWF propeptide to VWF:Ag and a 1-desamino-8-d-arginine vasopressin (DDAVP) test in one patient indicated delayed VWF clearance, which was supported by clearance data after infusion of rmVWF into VWF(-/-) mice. Conclusion The unique phenotype of VWD2 type IIC-Miami results from dominant impairment of multimer assembly, an aberrant structure of mutant mature VWF and reduced clearance in vivo.
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Mutación , Enfermedad de von Willebrand Tipo 2/genética , Factor de von Willebrand/genética , Adulto , Anciano , Animales , Desamino Arginina Vasopresina/química , Retículo Endoplásmico/metabolismo , Femenino , Genes Dominantes , Genes Recesivos , Genotipo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Fenotipo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Enfermedad de von Willebrand Tipo 2/metabolismo , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: Primary haemostasis defects comprise von Willebrand disease (VWD) and platelet disorders (PD). Although presenting with mild to moderate bleeding tendency in most cases, severe bleeding and blood loss may occur unexpectedly in trauma and surgery. Diagnosis of VWD and PD often remains difficult owing to the wide spectrum of clinical and laboratory manifestations. Platelet-type von Willebrand disease (PT-VWD) is frequently misdiagnosed as type 2B VWD. Discrimination between type 2B VWD and PT-VWD is crucial as treatment differs. METHODS AND RESULTS: A literature review revealed difficulties in diagnostic work-up and choice of optimal treatment of PT-VWD. Guidelines favour the therapeutic use of platelet concentrates. A telephone survey of diagnostic practice with regard to type 2B VWD/PT-VWD was conducted. The prevalence and incidence of type 2B and PT-VWD remained unclear, but PT-VWD may be underestimated. DISCUSSION: An international study estimated that PT-VWD constitutes up to 15% of the total number of patients diagnosed with type 2B VWD. Our survey confirmed difficulties with diagnosis and showed that some centres did not exclude PT-VWD in type 2B patients. Some authors emphasize that genetic testing is the gold standard for diagnosis, but functional testing allows immediate diagnosis. Due to the important therapeutic implications we suggest that type 2B VWD be confirmed by genetic testing and that in case of a negative result PT-VWD should be excluded. CONCLUSION: PT-VWD should be excluded in all suspected cases of type 2B. PT-VWD should be treated with platelet concentrates.
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Enfermedades de von Willebrand/diagnóstico , Niño , Estudios Transversales , Diagnóstico Diferencial , Pruebas Genéticas , Adhesión a Directriz , Humanos , Transfusión de Plaquetas , Mejoramiento de la Calidad , Enfermedades de von Willebrand/epidemiología , Enfermedades de von Willebrand/genética , Enfermedades de von Willebrand/terapiaAsunto(s)
Diagnóstico Tardío , Enfermedades de von Willebrand/diagnóstico , Factores de Edad , Anciano , Carcinoma Basocelular/cirugía , Análisis Mutacional de ADN , Femenino , Humanos , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Transfusión de Plaquetas , Hemorragia Posoperatoria/prevención & control , Cuidados Preoperatorios , Neoplasias Cutáneas/cirugía , Enfermedades de von Willebrand/terapiaAsunto(s)
Plaquetas/química , Citometría de Flujo/normas , Inmunoensayo/normas , Terminología como Asunto , Factor de von Willebrand/análisis , Biomarcadores/sangre , Consenso , Citometría de Flujo/clasificación , Humanos , Inmunoensayo/clasificación , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
Immune tolerance induction (ITI) in patients with haemophilia B and inhibitors may be complicated by anaphylactic reactions and nephrotic syndrome with lower success rates than in haemophilia A (25% vs. 50-90%). According to case reports, immunosuppressive therapy in addition to high doses of factor IX (FIX) appears to be promising. We report an 18-year-old patient with severe haemophilia B and a FIX inhibitor with a maximum titre of 2.6 Bethesda units and allergic skin reactions to FIX infusions. At 5 years of age, this patient already had a FIX inhibitor with allergic reactions to FIX and activated prothrombin complex concentrate. ITI at 11 years of age with high-dose FIX, dexamethasone, rituximab, mycophenolate mofetil and intravenous immunoglobulins had induced a sustained response until the current presentation. The patient was restarted on the same ITI regimen with aforementioned immunosuppressants, which were initiated one week before high-dose FIX. No allergic reactions, nephrotic syndrome or serious infection occurred during ITI. The FIX inhibitor was undetectable after five weeks of treatment and remained so until 19 months of follow-up.
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Inhibidores de Factor de Coagulación Sanguínea/sangre , Factor IX/administración & dosificación , Hemofilia B/tratamiento farmacológico , Hemofilia B/inmunología , Tolerancia Inmunológica/inmunología , Inmunosupresores/administración & dosificación , Adolescente , Inhibidores de Factor de Coagulación Sanguínea/inmunología , Quimioterapia Combinada , Factor IX/inmunología , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Inmunosupresores/inmunología , Recurrencia , Resultado del TratamientoRESUMEN
Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.
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Antiarrítmicos/uso terapéutico , Trastornos de las Plaquetas Sanguíneas/congénito , Trastornos de las Plaquetas Sanguíneas/terapia , Desamino Arginina Vasopresina/uso terapéutico , Factor VIIa/uso terapéutico , Hemorragia/terapia , Transfusión de Plaquetas/normas , Antiarrítmicos/normas , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Niño , Preescolar , Femenino , Alemania , Hematología/normas , Hemorragia/congénito , Hemorragia/diagnóstico , Hemostáticos/uso terapéutico , Humanos , Lactante , Recién Nacido , Masculino , Pediatría/normas , Guías de Práctica Clínica como AsuntoRESUMEN
The function of von Willebrand factor (VWF), a huge multimeric protein and a key factor in platelet dependent primary haemostasis, is regulated by its specific protease ADAMTS13. The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so-called triplet structure of individual VWF oligomers by multimer analysis. Lack of VWF high molecular weight multimers (VWF-HMWM) or their pathologically enhanced degradation underlies a particular type of von Willebrand disease, VWD type 2A with a significant bleeding tendency, and may also be observed in acquired von Willebrand syndrome due to cardiovascular disease. In these conditions multimer analysis is an obligatory and powerful tool for diagnosis of VWD. The opposite condition, the persistence of ultralarge VWF (UL-VWF) multimers may cause the microangiopathic life-threatening disorder thrombotic thrombocytopenic purpura (TTP). During the course of active TTP, UL-VWF is consumed in the hyaline thrombi formed in the microvasculature which will ultimately result in the loss of UL-VWF and VWF-HMWM. Therefore, VWF multimer analysis is not a valid tool to diagnose TTP in the active phase of disease but may be helpful for the diagnosis of TTP patients in remission.
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Proteínas ADAM/sangre , Modelos Cardiovasculares , Mapeo de Interacción de Proteínas , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/diagnóstico , Enfermedades de von Willebrand/sangre , Factor de von Willebrand/metabolismo , Proteínas ADAM/química , Proteína ADAMTS13 , Animales , Biomarcadores/sangre , Coagulación Sanguínea , Dimerización , Humanos , Unión Proteica , Enfermedades de von Willebrand/diagnóstico , Factor de von Willebrand/químicaRESUMEN
Linkage analysis in autosomal inherited von Willebrand disease (VWD) is important to diagnose the carriers and reduce the burden of severe type VWD. The study was designed to identify the carriers and estimate the frequency of variable number of tandem repeats (VNTR) instability in VWD families. Carrier detection was performed in eight recessive type 3 VWD (VWD3) families using VNTRs VWF1 and VWF2, RsaI (789Thr/Ala) linkage markers, multimer analysis and DNA sequencing. Moreover, five dominant VWD families were studied through DNA sequencing and multimer analysis. Frequency of VWF VNTR instability was investigated in 20 VWD families. In VWD3 families, a total of 22 (81.5%) carriers were identified using VWF1 and VWF2 markers. However, only 13(48.1%) carriers were identified through RsaI markers. Mutation screening revealed 22(81.5%) carriers in VWD3 and 4 (33.3%) carriers in VWD2 families. In comparison to DNA sequencing, the accuracy of VWF1 and VWF2 markers in VWD3 was 85.7% while RsaI could identify 68.2% carriers accurately. Mutations p.R1205H and p.C1272R were identified as de novo in families. Multimer analysis confirmed the identified carriers in VWD2 families. Three VWD families were found to be carrying VNTR instability for VWF1 and VWF2 locus. VNTRs could be an effective linkage markers for carrier detection in VWD3 families. However, in the event of germline de novo mutations and VNTR instability, it may confound risk of misdiagnosis of carriers. Multimer analysis could be an alternative way of carrier detection in dominant type 2A and type 2B VWD families.
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Portador Sano/diagnóstico , Análisis Mutacional de ADN , Ligamiento Genético/genética , Marcadores Genéticos/genética , Mutación de Línea Germinal/genética , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética , Femenino , Sitios Genéticos/genética , Inestabilidad Genómica/genética , Humanos , Masculino , Linaje , Secuencias Repetidas en Tándem/genéticaRESUMEN
Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.
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Sistema de Registros , Tumor Rabdoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/efectos adversos , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Estudios de Factibilidad , Alemania , Humanos , Lactante , Recién Nacido , Infusiones Intraventriculares , Comunicación Interdisciplinaria , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Dosificación Radioterapéutica , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/mortalidad , Tasa de SupervivenciaRESUMEN
The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand factor (VWF), a multimeric glycoprotein essential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mutation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investigated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic approaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct characteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns. Using microfluidic assays we further determined shear flow-dependent characteristics in polymer-platelet-aggregate formation, platelet binding and string formation for all mutants. The phenotypes observed under flow conditions were not related to the mutated VWF domain. By MD simulations we further investigated how VWD 2A/IID mutations might alter the ability of VWF to form carboxy-terminal dimers. In conclusion, our study offers a comprehensive picture of shear-dependent and shear-independent dysfunction of VWD type 2A mutants. Furthermore, our microfluidic assay might open new possibilities for diagnosis of new VWD phenotypes and treatment choice for VWD patients with shear-dependent VWF dysfunctions that are currently not detectable by static tests.
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Plaquetas/fisiología , Enfermedad de von Willebrand Tipo 2/genética , Factor de von Willebrand/metabolismo , Dimerización , Células HEK293 , Humanos , Microfluídica , Simulación de Dinámica Molecular , Mutación/genética , Fenotipo , Estructura Terciaria de Proteína/genética , Resistencia al Corte/fisiología , Enfermedad de von Willebrand Tipo 2/clasificación , Factor de von Willebrand/genéticaRESUMEN
A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.
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Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/terapia , Tumor Rabdoide/terapia , Trasplante de Células Madre , Teratoma/terapia , Biopsia , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/cirugía , Preescolar , Terapia Combinada , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Metástasis de la Neoplasia , Sistema de Registros , Estudios Retrospectivos , Tumor Rabdoide/tratamiento farmacológico , Tumor Rabdoide/cirugía , Teratoma/tratamiento farmacológico , Teratoma/cirugíaRESUMEN
BACKGROUND: Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T-ALL, but its impact on prognosis remains unclear. PROCEDURE: We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC-BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long-term outcome. RESULTS: Overall, 101 out of 165 (61.2%) T-ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations. Eight T-ALL samples (4.8%) exclusively revealed FBXW7 mutations. Fifty-six T-ALL (33.9%) exhibited a wild-type configuration of either gene. Four novel NOTCH1 mutations were identified localized in the C-terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain. Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss-of-function mutation. CONCLUSIONS: Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T-ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy (P = 0.009). Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications.
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Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligasas/genética , Niño , Estudios de Cohortes , ADN de Neoplasias/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Genotipo , Humanos , Recurrencia Local de Neoplasia/terapia , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Tasa de SupervivenciaRESUMEN
Severe von Willebrand's disease (VWD) type 3 is a rare autosomal-recessively inherited bleeding disorder, showing considerable genotypic heterogeneity. We investigated the phenotype in correlation with the genotype in Finnish type 3 VWD patients. Ten patients previously diagnosed with VWD type 3 treated at the Coagulation Disorder Unit in Helsinki University Hospital were re-evaluated for bleeding tendency and treatment. Phenotypic characterization included coagulation and platelet function testing confirming the diagnosis. The genotype was assessed by initial screening for the common c.2435delC mutation and subsequently if needed, by analysing all 51 coding exons of the von Willebrand factor gene. Our result confirmed the diagnosis of type 3 VWD for all 10 patients. We discovered two common mutations: nine of the 20 alleles (45%) were found to carry the c.2435delC frameshift mutation, previously described to be frequent in countries surrounding the Baltic Sea. The nonsense mutation c.4975C>T (p.R1659X) was found on 8/20 (40%) of the alleles. In addition, three novel mutations, a potential splice site mutation (c.874+2T>C) and two frameshift mutations (c.1668delC and c.2072delCCinsG) were found. Seven patients were homozygous and three compound heterozygous for the reported mutations. This study indicates that mainly two mutations (c.2435delC and p.R1659X) cause the majority of type 3 VWD in Finland. This result sets future standards for the genetic testing among the Finnish type 3 VWD population.
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Enfermedad de von Willebrand Tipo 3/genética , Factor de von Willebrand/genética , Adulto , Anciano , Alelos , Codón sin Sentido , Femenino , Finlandia , Mutación del Sistema de Lectura , Genotipo , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Enfermedad de von Willebrand Tipo 3/diagnósticoRESUMEN
Hereditary thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome, ADAMTS13 Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed. In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.
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Bases de Datos Genéticas , Púrpura Trombocitopénica Trombótica/genética , Sistema de Registros/estadística & datos numéricos , Adulto , Femenino , Humanos , Internacionalidad , Masculino , Prevalencia , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/epidemiología , Púrpura Trombocitopénica Trombótica/terapia , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
The Upshaw Schulman syndrome (MIM #274150) is a hereditary deficiency of the von Willebrand factor cleaving protease (ADAMTS13) due to homozygous or compound heterozygous mutations in the ADAMTS13 gene. Patients are prone to bouts of thrombotic thrombocytopenic purpura. However, disease manifestation needs a second trigger event. Pregnancy is a known risk factor for TTP. Patients with USS may manifest during pregnancy and the postpartum period or relapse with a TTP bout. Before plasma therapy mortality for both the mother and the fetus was high, but even nowadays when plasma is delivered, therapy is challenging, still bearing a high risk for miscarriage or long term sequelae for the mother. In this report on pregnancies in three mothers with USS, plasma therapy was increased in frequency and amount given with regard to platelet count or ADAMTS13 activity, thus leading to a successful outcome.
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Intercambio Plasmático/métodos , Complicaciones Hematológicas del Embarazo/diagnóstico , Complicaciones Hematológicas del Embarazo/terapia , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/terapia , Adolescente , Adulto , Femenino , Humanos , Embarazo , Complicaciones Hematológicas del Embarazo/genética , Resultado del Embarazo , Púrpura Trombocitopénica Trombótica/genética , Resultado del Tratamiento , Adulto JovenAsunto(s)
Sustitución de Aminoácidos/genética , Mutación/genética , Enfermedad de von Willebrand Tipo 2/genética , Factor de von Willebrand/química , Factor de von Willebrand/genética , Niño , Exones/genética , Factor VIII/genética , Femenino , Células HEK293 , Homocigoto , Humanos , Irán , Masculino , Proteínas Mutantes/metabolismo , Linaje , Fenotipo , Estructura Terciaria de Proteína , Proteínas Recombinantes/metabolismo , Enfermedad de von Willebrand Tipo 2/sangreRESUMEN
BACKGROUND: von Willebrand disease (VWD) is caused by mutations in von Willebrand factor (VWF) that have different pathophysiologic effect in causing low plasma VWF levels. Type 1 VWD includes quantitative plasma VWF deficiency with normal VWF structure and function. OBJECTIVES: We report three novel type 1 VWF mutations (A1716P, C2190Y and R2663C) located in different VWF domains that are associated with reduced secretion and reduced formation of elongated Weibel-Palade body (WPB)-like granules. METHODS: Transient expression of recombinant mutant full-length VWF in 293 EBNA cells was performed and secretion, collagen binding and GpIb binding assessed in comparison with wild-type VWF. Expression was also examined in HEK293 cells that form WPB-like granules when transfected with wild-type VWF. RESULTS: Laboratory results and multimer analysis of plasma VWF was compatible with type 1 VWD. Expression experiments demonstrated slightly reduced VWF synthesis and drastically impaired secretion upon homozygous expression. In HEK293 cells, homozygous expression of A1716P and C2190Y VWF variants failed to form elongated WPB-like granules, while R2663C was capable of WPB-like granules. Heterozygous expression of VWF variants had a negative impact on wild-type VWF with a reduction in elongated WPB-like granules in co-transfected cells. CONCLUSIONS: Our results demonstrate that homozygous and heterozygous quantitative VWF deficiency caused by missense VWF mutations in different VWF domains can be associated with inability to form endothelial WPB-like granules.
Asunto(s)
Cuerpos de Weibel-Palade/metabolismo , Cuerpos de Weibel-Palade/patología , Enfermedad de von Willebrand Tipo 1/patología , Factor de von Willebrand/metabolismo , Colágeno/metabolismo , Regulación hacia Abajo , Técnica del Anticuerpo Fluorescente , Predisposición Genética a la Enfermedad , Células HEK293 , Heterocigoto , Homocigoto , Humanos , Microscopía Confocal , Mutación Missense , Fenotipo , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Unión Proteica , Multimerización de Proteína , Transfección , Enfermedad de von Willebrand Tipo 1/sangre , Enfermedad de von Willebrand Tipo 1/genética , Factor de von Willebrand/genéticaRESUMEN
von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is characterised by a prolonged bleeding time due to quantitative and/or functional deficits of von Willebrand factor (VWF), a huge multimeric protein. Given the large size and complexity of the protein, the many functions of VWF, for example, binding to collagen, to platelet GPIb, and to FVIII, the localisation of these binding sites in different VWF domains, as well as the dependence on a high molecular weight multimer structure for proper function, VWF is prone to quantitative and very heterogeneous structural and functional defects. Comprehensive clinical and laboratory phenotypic description of patients with VWD in correlation to the genotype has considerably increased our knowledge on this disorder and the physiology and pathophysiology of VWF. This article focuses on the phenotype/genotype relationship in VWD and the context of VWD types and subtypes with particular VWF domains.