Coagulation factor VII (FVII) has a pivotal role in the initiation of blood coagulation. Severe coagulation FVII deficiency is a rare autosomal disorder in which premature death may occur from severe bleeding. Differently from the extensively investigated Hemophilia A and B, X linked and thus relatively frequent, the relationships between the FVII coagulation deficiency and the clinical phenotype are poorly defined. Recently we had the opportunity to collect information and to recruit a large number of patients in the frame of a world-wide co-operation (International Registry of FVII deficiency, IRF7) thus making feasible informative genotype-phenotype studies. Since findings in humans and in a mouse model indicate that a complete absence of FVII function is not compatible with life, a main goal of the project is to determine, with improved experimental tools, the residual FVII function. To characterize the genetic and biochemical components which modulate the individual risk of bleeding we propose, a) the detection of molecular lesions and the characterization through fluorogenic substrates of the residual ability of mutant FVII to activate factor X, in plasma or after "in vitro" expression; b) to characterize intragenic functional polymorphisms, able to modify the expression of the altered FVII gene, and frequent polymorphisms in other genes of the hemostatic system which could further modulate FVII deficiency; c) to characterize level variations of protein and lipids cofactors and particularly of specific FVII inhibitors in plasma and "in vitro" models. A proteomic approach will be also used. The comparison of patients characterized by identical FVII mutations will favour detection of the most relevant modifiers of the bleeding phenotype. This integrated knowledge will favour treatment of FVII deficiency on an individual basis and will improve the understanding of the molecular events of the beginning of the coagulation.

Progetto TELETHON: Genetic and Biochemical Components which Modulate the Individual Risk of Bleeding in Coagulation Factor VII Deficiency

BERNARDI, Francesco
2002

Abstract

Coagulation factor VII (FVII) has a pivotal role in the initiation of blood coagulation. Severe coagulation FVII deficiency is a rare autosomal disorder in which premature death may occur from severe bleeding. Differently from the extensively investigated Hemophilia A and B, X linked and thus relatively frequent, the relationships between the FVII coagulation deficiency and the clinical phenotype are poorly defined. Recently we had the opportunity to collect information and to recruit a large number of patients in the frame of a world-wide co-operation (International Registry of FVII deficiency, IRF7) thus making feasible informative genotype-phenotype studies. Since findings in humans and in a mouse model indicate that a complete absence of FVII function is not compatible with life, a main goal of the project is to determine, with improved experimental tools, the residual FVII function. To characterize the genetic and biochemical components which modulate the individual risk of bleeding we propose, a) the detection of molecular lesions and the characterization through fluorogenic substrates of the residual ability of mutant FVII to activate factor X, in plasma or after "in vitro" expression; b) to characterize intragenic functional polymorphisms, able to modify the expression of the altered FVII gene, and frequent polymorphisms in other genes of the hemostatic system which could further modulate FVII deficiency; c) to characterize level variations of protein and lipids cofactors and particularly of specific FVII inhibitors in plasma and "in vitro" models. A proteomic approach will be also used. The comparison of patients characterized by identical FVII mutations will favour detection of the most relevant modifiers of the bleeding phenotype. This integrated knowledge will favour treatment of FVII deficiency on an individual basis and will improve the understanding of the molecular events of the beginning of the coagulation.
2002
Bernardi, Francesco
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1683359
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