The inherited basis of venous thrombosis

Abstract

Venous thrombosis represents a manifestation of disordered hemostatic balance. The classical presentation is of pain and swelling of the lower limb, although clinical history and examination are notoriously misleading in reaching a diagnosis. A number of acquired predispositions have been associated with a tendency to thrombosis, such as immobilisation, surgery, malignancy and certain types of oral contraception, but in at least half of the instances no predisposition can be identified. A variety of genetic risk factors have also been identified. Mutations within the genes for antithrombin, protein C and protein S are associated with a venous thromboembolic phenotype. The commonest thrombophilic predisposition however is a variant of coagulation factor V, factor V Leiden, which results from a single amino acid substitution rendering the factor V molecule resistant to activated protein C. Factor V Leiden is present in approximately 5% of individuals of European origin, and is found in up to 40% of those with confirmed venous thrombosis. Increasingly it is recognised that venous thrombosis should be considered a polygenic disorder, with interactions between the various single gene defects which predispose to thrombosis, as well as normal genetic variation between individuals in the levels of both procoagulant and anticoagulant proteins, all determining which individuals will express the phenotype of venous thrombosis.