Genetic risk factors for venous thrombosis: key players or minor risk modifiers?

Abstract

Venous thrombosis is a common disease, which manifests itself mostly in the deep veins of the leg, with a reported incidence of 1-2 per 1000 individuals per year. Several genetic risk factors have been identified for venous thrombosis. It is, however, difficult to predict the risk of venous thrombosis for carriers of these defects, as venous thrombosis manifests itself as a multicausal disease, in which multiple genetic and environmental factors play a role and can interact in the onset of disease. In families with a clear tendency to develop venous thrombosis (thrombophilia) the presence of multiple genetic risk factors explains the higher risk in individuals from these families compared with individuals with the same defect without a family history of venous thrombosis. Large studies on the risk of venous thrombosis associated with familial thrombophilia are scarce, therefore we initiated a large European prospective cohort study including individuals with inherited thrombophilia: the EPCOT study. Data from this study showed that the risk of a first or second thrombotic event was increased in carriers of familial thrombophilic defects, but that the risk did not outweigh the risk of major bleeding from long-term anticoagulant treatment. In addition the EPCOT study showed that women with inherited thrombophilia have a slightly increased risk of fetal loss. However, the likelihood of a positive outcome remained high in women with familial thrombophilia. In addition, as the currently known genetic defects can explain only partly the increased risk of venous thrombosis in thrombophilic families, we performed a search for "new" genes that might regulate blood plasma levels of coagulation factors in a large thrombophilic French-Canadian family. We found high heritability (i.e. the amount of variation of levels explained by gene variation) for several coagulation factors and we identified gene locations that might harbour genes influencing protein C activity.