The molecular genetics of familial venous thrombosis

In the past few years, important advances have been made in the identification of factors predisposing to familial thrombophilia. Particular attention has been paid to the characterization of known inherited defects and their genotype-phenotype relationship, and to studying the interaction between single or multiple inherited conditions and acquired risk factors for venous thrombosis. The recent discovery of 'new' and very common genetic lesions predisposing to thrombosis has greatly expanded the interest in this field. Hereditary predisposition to venous thrombosis may be related to lesions in one or more of 10-15 genes encoding antithrombin, Protein C, Protein S, Factor V, prothrombin, enzymes of the homocysteine metabolic pathway, fibrinogen, heparin cofactor II, plasminogen and thrombomodulin. About 500 different gene lesions (substitutions, deletions, insertions) have so far been reported to affect these genes in patients with thrombotic disease. Because there are potentially multiple interactions between genetic and environmental factors, familial thrombophilia is now considered to be a multifactorial disease. The aim of this chapter is to review aspects of the molecular genetics of familial thrombophilia. In particular, those gene/protein defects for which there is convincing evidence of an association with familial thrombosis will be examined in detail.