RESUMEN
We have identified a previously unreported mutation, V1499E, with a high penetrance in a family with type 2A von Willebrand disease. Affected family members were difficult to identify owing to variable von Willebrand factor (VWF) levels, variable expression of VWF multimers, and clinical symptoms. Recombinant V1499E-VWF was more readily cleaved by ADAMTS13 than the wild-type protein, suggesting that V1499E is the causative mutation. Surprisingly, this seemingly novel unique mutation was also found in other family members in 2 other hospitals displaying the same variable laboratory and clinical symptoms. The fact that this V1499E mutation was detected independently in 3 hospitals is strongly in favor of 1 central database, especially considering the variable laboratory and clinical picture.
Asunto(s)
Hemorragia/genética , Mutación Puntual , Factor de von Willebrand/genética , Proteínas ADAM/metabolismo , Proteínas ADAM/farmacología , Proteína ADAMTS13 , Niño , Preescolar , Bases de Datos Genéticas , Salud de la Familia , Femenino , Genotipo , Humanos , Lactante , Masculino , Penetrancia , Fenotipo , Factor de von Willebrand/metabolismoRESUMEN
The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies in plasma of patients. It has been published that antibeta2-glycoprotein I (beta2-GPI) antibodies, with lupus anticoagulant activity (LAC), highly correlate with thrombosis. Resistance related to antiphospholipid antibodies against activated protein C (APC) is one of the proposed mechanisms responsible for thrombosis. We investigated a possible correlation between a beta2-GPI-dependent LAC (titration of cardiolipin into an activated partial thromboplastin time-based assay) and increased APC resistance in a population of 22 plasma samples with LAC activity. Eleven plasma samples that displayed a beta2-GPI-dependent LAC also showed increased APC resistance. In contrast, only one of the 11 plasma samples with a beta2-GPI-independent LAC displayed increased APC resistance. In addition, a monoclonal antibeta2-GPI antibody and patient-purified immunoglobulin G (both with LAC activity) were diluted in plasma with/without protein C. Both antibodies only displayed a beta2-GPI-dependent LAC in plasma in the presence of protein C. This indicates that the principle of the beta2-GPI LAC-assay was based on increased resistance against protein C. Surface plasmon resonance analysis was used to investigate binding between APC and beta2-GPI. We observed that beta2-GPI was able to bind APC directly, especially in the presence of a monoclonal antibeta2-GPI antibody. In conclusion, our observations show a direct correlation between a major clinical symptom of antiphospholipid syndrome (thrombosis), a diagnostic assay (beta2-GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC resistance).