title: [Coagulation factor mutations and thrombosis].
abstract: The coagulation system is governed by a subtle balance between clotting activators and inhibitors. Many genes can contribute to the overall phenotype, and polymorphisms may act to up regulate or down regulate the generation of thrombin, the coagulation-key enzyme. An increase in coagulation factor (gain function) or/and a decrease in coagulation inhibitors (loss of function) may favor venous thromboembolism (VTE). It has been observed since a long time that VTE may be a familial disease, but it was only in 1965 that Egeberg published the first case of inherited antithrombin (AT) deficiency. This was followed by similar reports of protein C (PC) and protein S (PS) deficiencies. Hereditary thrombophilia was thus initially considered as a rare monogenic disorder with incomplete penetrance. AT, PC and PS deficiencies are due to multiple and mostly private mutations of the corresponding genes. Most patients are heterozygous and experience VTE at adult age. Homozygosity associated with severe thrombosis at birth has been observed in newborns with undetectable PC or PS concentrations. The discovery of factor (F) V Leiden and F2 g.20210 G>A, two gain of function mutations, challenged the view of thrombophilia as a rare monogenic disorder. FV Leiden and F2 g.20210 G>A are due to a founder effect and affect populations of European descent with frequencies at 5% and 3% respectively. These two mutations are moderate of risk factor for thrombosis and paved the way for gene-gene and gene-environment interactions. Patients carrying more than one genetic risk factor are at higher risk to develop VTE. The exposition to acquired risk factors such as estrogen based oral contraception may also have a synergistic effect favoring thrombosis in patients with FV Leiden or other genetic risk factors.
authors.affiliation: Service d'Hématologie Biologique, Hôpital Européen Georges Pompidou, 20, Rue Leblanc, 75908 Paris Cedex 15, France. martine.aiach@egp.aphp.fr
authors.forename: Martine
authors.initials: M
authors.lastname: Aiach
authors.forename: Martine
authors.initials: M
authors.lastname: Alhenc-Gelas
authors.forename: Delphine
authors.initials: D
authors.lastname: Borgel
authors.forename: Joseph
authors.initials: J
authors.lastname: Emmerich
authors.forename: Sophie
authors.initials: S
authors.lastname: Gandrille
authors.forename: Véronique
authors.initials: V
authors.lastname: Picard
mesh_terms: D001778:Blood Coagulation Disorders / Q000235:genetics*; D001779:Blood Coagulation Factors / Q000235:genetics*; D014644:Genetic Variation; D006487:Hemostasis; D006801:Humans; D009154:Mutation; D019851:Thrombophilia / Q000235:genetics; D013927:Thrombosis / Q000235:genetics*
chemical_list: D001779:Blood Coagulation Factors