The molecular mechanisms of inherited thrombophilia

Abstract

Venous thromboembolism is a common acute cardiovascular disease. Thrombotic events develop as the result of multiple interactions between circumstantial and inborn risk factors shifting the delicate balance between pro- and anticoagulant processes towards coagulation. The most important circumstantial risk factors are age, tissue damage, oral contraception, pregnancy, obesity, and sedentary life style. Inborn factors predisposing to thrombosis are present in the majority of patients. These include three groups of defects affecting components of the anticoagulant pathways of blood coagulation, namely antithrombin III, protein C, and protein S. Together these defects are found in 15–20% of families with thrombophilia. They are extremely heterogeneous at the molecular level which largely precludes their diagnosis by current molecular biology techniques. The relatively rare defects of antithrombin III, protein C, and protein S can be distinguished from two common genetic polymorphisms of procoagulant molecules, factor V-Leiden, the most frequent cause of resistance to activated protein C, and the prothrombin 20210 A allele. Together, these anomalies are detected in almost two thirds of the thrombophilia families. The identification of factor FV-Leiden and prothrombin 20210 A has afforded the scrutinization of interactions between multiple components of genomic matrix and circumstantial factors. 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 a monogenetic 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.