Thrombophilia as a multigenic disease

Background and Objective. Venous thrombosis is a common disease annually af fecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing gene tic and/or environmental risk factors in thrombosis patients. Most of the g enetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the pr otein C system. Information sources. Published results in articles covered by the Medline(R ) database have been integrated with our original studies in the field of t hrombophilia. State of the Art and Perspectives. The risk of venous thrombosis is increas ed when the hemostatic balance between pro- and anticoagulant forces is shi fted in favor of coagulation. When this is caused by an inherited defect, t he resulting hypercoagulable state is a lifelong risk factor for thrombosis . Resistance to activated protein C (APC resistance) is the most common inh erited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which p redicts the substitution of Arg506 with a Gin. Arg506 is one of three APC-c leavage sites and the mutation results in the loss of this APC-cleavage sit e. The mutation is only found in Caucasians but the prevalence of the mutan t FV allele (FV:Q506) varies between countries. It is found to be highly pr evalent (up to 15%) in Scandinavian populations, in areas with high inciden ce of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. Th e second most common inherited risk factor for thrombosis is a point mutati on (G20210A) in the 3' untranslated region of the prothrombin gene. This mu tation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or prote in S. Such defects are present in less than 1% of healthy individuals and t ogether they account for 5-10% of genetic defects found in patients with ve nous thrombosis. Owing to the high prevalence of inherited APC resistance ( FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals w ith multiple defects have a highly increased risk of thrombosis. As a conse quence, multiple defects are often found in patients with thrombosis. (C)19 99, Ferrata Storti Foundation.