Mutations des protéines de la coagulation et thromboses

Abstract

Les anomalies génétiques à l’origine des maladies hémorragiques ont permis de découvrir la plupart des protéines de l’hémostase. Par analogie avec l’hémophilie, on a utilisé le terme de thrombophilie pour désigner un excès de coagulation responsable de thrombose. Les premiers cas de thrombophilie héréditaire décrits dans la littérature sont les déficits en antithrombine, protéine C et protéine S, trois inhibiteurs de la coagulation. Il s’agit d’anomalies à transmission autosomique dominante se manifestant chez l’adulte par des thromboses veineuses profondes récidivantes. Ces déficits sont rares, alors que les thromboses veineuses ne le sont pas. Avec la découverte de deux mutations fréquentes, le FV Leiden et la mutation g.20210 G → A du gène de la prothrombine (F2), apparaît la notion de facteur de prédisposition génétique dont l’impact est démontré par des études épidémiologiques, mais dont la traduction clinique en termes de thrombose est beaucoup plus complexe.

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 estrogene based oral contraception may also have a synergistic effect favoring thrombosis in patients with FV Leiden or other genetic risk factors.