The molecular mechanisms of inherited thrombophilia

Venous Thromboembolism develops as the result of multiple interactions between non-genetic and genetic risk factors. The most important non-genetic risk factors are age, tissue damage, oral contraception, pregnancy, obesity and lack of physical activity. Inborn factors predisposing to thrombosis are present in the majority of patients. These comprise defects affecting the anticoagulant pathways of blood coagulation like antithrombin III, protein C and protein S. Together these defects are found in 15-20% of thrombophilia families. The relatively rare defects of antithrombin III, protein C and protein S stand in contrast to two common genetic polymorphisms of procoagulant molecules, factor V-Leiden, the most frequent cause for resistance to activated protein C, and the prothrombin 20210 A allele. Together, these anomalies are found in almost two third of the thrombophilia families. The identification of factor FV-Leiden and prothrombin 20210 A has allowed to examine in detail interactions between genetic and non-genetic risk factors of thromboembolism. The results of these studies indicate that many symptomatic individuals are endowed with more than one (genetic and/or environmental) risk factor. Thrombophilia thus represents an oligogenetic rather than monogenetic clinical phenotype, the expression of which is amplified by circumstantial risk factors. As a consequence of the "multiple hit" concept, the laboratory screening of thrombosis patients needs to include all of the known genetic risk factors even if the "clinical" situation seemingly provides sufficient "explanation" for a thrombotic event.