RESUMEN
Type 2N von Willebrand disease (VWD) is characterized by a markedly decreased affinity of von Willebrand factor (VWF) for factor VIII (FVIII). The FVIII binding site has been localized within the first 272 amino acid residues of mature VWF, encoded by exons 18-23. Two substitutions in exon 18 of VWF gene, inducing candidate mutations Y795C and C804F were identified in the heterozygous state in two French patients who also displayed the frequent R854Q mutation in exon 20. Expression studies in Cos-7 cells showed that these abnormalities, which implicate cysteine residues, induced secretion, multimerization and FVIII binding defects of corresponding recombinant VWF. Results from transfection experiments with R854Q, performed to reproduce the hybrid VWF present in patient plasma, were in agreement with those obtained for patient's plasma VWF. These findings confirm the importance of the VWF D' domain in FVIII binding. In addition, this work shows that exon 18 should preferentially be sequenced in type 2N VWD patients when the frequent R854Q mutation in exon 20 has been excluded or detected in the heterozygous state.
Asunto(s)
Mutación Missense , Enfermedades de von Willebrand/sangre , Factor de von Willebrand/genética , Adulto , Sitios de Unión , Exones , Factor VIII/metabolismo , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad , Análisis de Secuencia de ADN , Enfermedades de von Willebrand/metabolismoRESUMEN
Population-based case-control studies and cases previously published suggest that the prothrombin G20210A mutation is a weak risk factor for thrombosis, leading to clinical expression mainly in the presence of other risk factors. We report the results of plasma and genetic analyses performed in a 13-year-old symptomatic boy homozygous for the 20210A allele and in his family, which are in accordance with this suggestion. These analyses demonstrated the presence of several PROC (R-5W, R87H) and PROS (R60C, T103N) gene mutations in this family. These additional mutations have modulating effects on clinical expression of the G20210A mutation. The present family study illustrates the concept of 'mild' mutation and the hypothesis that familial thrombophilia is a multifactorial disease.
Asunto(s)
Proteína C/genética , Proteína S/genética , Protrombina/genética , Trombofilia/genética , Adolescente , Adulto , Anciano , Salud de la Familia , Femenino , Tamización de Portadores Genéticos , Homocigoto , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Mutación , Linaje , Proteína C/metabolismo , Deficiencia de Proteína C/sangre , Deficiencia de Proteína C/genética , Proteína S/metabolismo , Deficiencia de Proteína S/sangre , Deficiencia de Proteína S/genética , Trombofilia/sangre , Trombosis/epidemiología , Trombosis/genéticaRESUMEN
There is no consensus concerning thromboembolic prophylaxis in high-risk pregnant women with a previous history of heparin-induced thrombocytopenia. An alternative anticoagulant therapy is danaparoïd, whereas unfractioned and low-molecular-weight heparin therapy is contraindicated. We report a case of successful thrombosis prophylaxis using danaparoïd in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia during a previous pregnancy and Widal's disease.