Another lesson from the factor V Leiden mouse: thrombin generation drives arterial disease.

The discovery of activated protein C (APC) resistance by Dahlbäck in 19931 was a milestone in thrombophilia research that led to major advances in our understanding of the biochemistry, genetics, and clinical manifestations of hypercoagulability. APC resistance was quickly demonstrated to be caused by a single point mutation (1691G3A) in the coding region of the factor V gene.2 This mutation, factor V Leiden, is now known to be the most prevalent risk factor for venous thromboembolism (VTE) in people of European descent, occurring in 3% to 15% of the general population in Europe and North America.3 These observations ushered in a new era in the clinical evaluation of thromboembolism. For the first time, it became possible to diagnose a genetic defect (with a defined biochemical mechanism) in a substantial fraction of patients with venous thrombosis. Before the discovery of factor V Leiden, hereditary risk factors could be identified in 5% of patients presenting with VTE, even when a strong family history of thrombosis was obtained. In the current era, with widespread availability of genetic testing for factor V Leiden and another common hereditary risk factor, prothrombin 20210G3A,4 it is now possible to identify a genetic thrombophilic factor in 10% to 20% of unselected patients with VTE and up to 50% of patients with familial thromboembolism.5