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Título: | High levels of latent antithrombin in plasma from patients with antithrombin deficiency |
Fecha de publicación: | 2017 |
Editorial: | Thieme Gruppe European Society of Cardiology |
Cita bibliográfica: | Thrombosis and Haemostasis 2017; 117: 880–888 |
ISSN: | Print: 0340-6245 |
Palabras clave: | Antithrombin Thrombosis Gene mutations Latent |
Resumen: | Antithrombin is an anticoagulant serpin that efficiently inhibits multiple procoagulant proteases. The cost for the structural flexibility required for this function is the vulnerability to mutations that impact its folding pathway. Most conformational mutations identified in serpins cause polymerisation. Only three mutations in SERPINC1 affecting two residues have been found to favour transformation to the latent conformation of antithrombin, another hyperstable non-anticoagulant form with strong antiangiogenic activity that constitutes 3 % of plasma antithrombin in healthy subjects. The analysis of latent antithrombin in 141 unrelated patients with antithrombin deficiency carrying 89 different SERPINC1 mutations identified four cases with higher levels than that of controls: p.Pro439Thr, p.Pro461Ser, p.Met283Val, and p.His401Tyr, the last also with circulating polymers. Heating of plasma at 42ºC exacerbated the transformation to the latent conformation in p.Pro439Thr and p.Pro461Ser. The conformational effect of p.Met283Val, the mutation associated with the highest levels of latent antithrombin detected in four members of a family, was verified in a recombinant model. Antithrombin deficiency in these cases should be classified as pleiotropic based on the impaired reactivity and low heparin affinity of the variant. Despite high levels of latent antithrombin (up to 80 µg/ml in p.Met283Val carriers), no vascular defects were described in carriers of these mutations. In conclusion, our study identifies new residues involved in the structural stability of antithrombin (and potentially of all serpins). High levels of endogenous latent antithrombin seem to play a minor antiangiogenic effect. Finally, pleiotropic deficiencies may be caused by mutations inducing transformation to the latent conformation. |
Autor/es principal/es: | Morena-Barrio, María Eugenia de la Sandoval, Edna Llamas, Pilar Wypasek, Ewa Toderici, Mara Navarro-Fernández, José Rodríguez-Alen, Agustín Revilla, Nuria López-Gálvez, Raquel Miñano, Antoni Padilla, José Morena-Barrio, Belén de la Cuesta, Jorge Corral, Javier Vicente, Vicente |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Medicina |
URI: | http://hdl.handle.net/10201/139148 |
DOI: | https://doi.org/10.1160/TH16-11-0866 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 9 |
Derechos: | info:eu-repo/semantics/embargoedAccess |
Descripción: | © Schattauer 2017. This document is the Published version of a Published Work that appeared in final form in Thrombosis and Haemostasis. To access the final edited and published work see https://doi.org/10.1160/TH16-11-0866 |
Aparece en las colecciones: | Artículos: Medicina |
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