Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency

To analyze inherited antithrombin deficiency as a risk factor for venous th romboembolism in various conditions with regard to the presence or absence of additional genetic or acquired risk factors, we compared 48 antithrombin -deficient individuals with 44 nondeficient individuals of 14 selected fami lies with inherited antithrombin deficiency The incidence of venous thrombo embolism for antithrombin deficient individuals was 20 times higher than am ong nondeficient individuals (1.1% v 0.05% per year). At the age of 50 year s, greater than 50% of antithrombin-deficient individuals had experienced t hrombosis compared with 5% of nondeficient individuals. Additional genetic risk factors, Factor V Leiden and PT20210A, were found in more than half of these selected families. The effect of exposure to 2 genetic defects was a 5-fold increased incidence (4.6% per year; 95% confidence interval [CI], 1 .9% to 11.1%). Acquired risk factors were often present, determining the on set of thrombosis. The incidence among those with exposure to antithrombin deficiency and an acquired risk factor was increased 20-fold (20.3% per yea r; 95% CI, 12.0% to 34.3%), In conclusion, in these thrombophilia families, the genetic and environmental factors interact to bring about venous throm bosis. Inherited antithrombin deficiency proves to be a prominent risk fact or for venous thromboembolism, The increased risks among those with exposur e to acquired risk factors should be considered and adequate prophylactic a nticoagulant therapy in high-risk situations seems indicated in selected fa milies with inherited antithrombin deficiency. (C) 1999 by The American Soc iety of Hematology.