Exome Sequencing and Clot Lysis Experiments Demonstrate the R458C Mutation of the Alpha Chain of Fibrinogen to be Associated with Impaired Fibrinolysis in a Family with Thrombophilia

Israel Fernández-Cadenas; Anna Penalba; Cristina Boada; Caty Carrerra MsC; Santiago Rodriguez Bueno; Adoración Quiroga; Jasone Monasterio; Pilar Delgado; Eduardo Anglés-Cano; Joan Montaner

doi:10.5551/jat.30676

Original Article

Exome Sequencing and Clot Lysis Experiments Demonstrate the R458C Mutation of the Alpha Chain of Fibrinogen to be Associated with Impaired Fibrinolysis in a Family with Thrombophilia

Israel Fernández-Cadenas, Anna Penalba, Cristina Boada, Caty Carrerra MsC, Santiago Rodriguez Bueno, Adoración Quiroga, Jasone Monasterio, Pilar Delgado, Eduardo Anglés-Cano, Joan Montaner

Author information

Israel Fernández-Cadenas
Stroke pharmacogenomics and genetics laboratory, Fundació Docencia i Recerca MutuaTerrassa, Hospital Mutua de Terrassa,
Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital
Anna Penalba
Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital
Cristina Boada
Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital
Caty Carrerra MsC
Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital
Santiago Rodriguez Bueno
Servicio de Hematología. Hospitals “Vall d'Hebron”
Adoración Quiroga
Vascular Biology and Haemostasis Research Unit, Vall d'Hebrón Hospital
Jasone Monasterio
Vascular Biology and Haemostasis Research Unit, Vall d'Hebrón Hospital
Pilar Delgado
Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital
Eduardo Anglés-Cano
Inserm UMRS 1140, Therapeutic Innovations in Haemostasis, Université Paris Descartes
Joan Montaner
Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital

Keywords: Coagulation, Dysfibrinogenemia, Fibrinogen, Thrombosis, Genetics

JOURNAL OPEN ACCESS

2016 Volume 23 Issue 4 Pages 431-440

DOI https://doi.org/10.5551/jat.30676

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Abstract

Aim: We report the study of a familial rare disease with recurrent venous thromboembolic events that remained undiagnosed for many years using standard coagulation and hemostasis techniques.
Methods: Exome sequencing was performed in three familial cases with venous thromboembolic disease and one familial control using NimbleGen exome array. Clot lysis experiments were performed to analyze the reasons of the altered fibrinolytic activity caused by the mutation found.
Results: We found a mutation that consists of a R458C substitution on the fibrinogen alpha chain (FGA) gene confirmed in 13 new familial subjects that causes a rare subtype of dysfibrinogenemia characterized by venous thromboembolic events. The mutation was already reported to be associated with a fibrinogen variant called fibrinogen Bordeaux. Clot-lysis experiments showed a decreased and slower fibrinolytic activity in carriers of this mutation as compared to normal subjects, thus demonstrating an impaired fibrinolysis of fibrinogen Bordeaux.
Conclusions: The exome sequencing and clot-lysis experiments might be powerful tools to diagnose idiopathic thrombophilias after an unsuccessful set of biochemical laboratory tests. Fibrinogen Bordeaux is associated with impaired fibrinolysis in this family with idiopathic thrombophilia.

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