Gene-Gene and Gene-Environment Interactions Determine Risk of Thrombosis in Families With Inherited Antithrombin Deficiency

Abstract

To analyze inherited antithrombin deficiency as a risk factor for venous thromboembolism 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 families with inherited antithrombin deficiency. The incidence of venous thromboembolism for antithrombin deficient individuals was 20 times higher than among nondeficient individuals (1.1% v 0.05% per year). At the age of 50 years, greater than 50% of antithrombin-deficient individuals had experienced thrombosis 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 onset of thrombosis. The incidence among those with exposure to antithrombin deficiency and an acquired risk factor was increased 20-fold (20.3% per year; 95% CI, 12.0% to 34.3%). In conclusion, in these thrombophilia families, the genetic and environmental factors interact to bring about venous thrombosis. Inherited antithrombin deficiency proves to be a prominent risk factor for venous thromboembolism. The increased risks among those with exposure to acquired risk factors should be considered and adequate prophylactic anticoagulant therapy in high-risk situations seems indicated in selected families with inherited antithrombin deficiency.

Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene

“…Inherited AT deficiency is a major genetic thrombosis risk factor, causing a 20 fold increased in the risk of venous thromboembolism (van Boven et al 1999). Inherited AT deficiency is found in about 5% of young patients (before 40) presenting with venous thrombosis (Hirsh et al 1989, Rosendaal 1999.…”

Management of inherited thrombophilia: guide for genetics professionals

“…Relatives with multiple thrombophilic disorders had a significantly higher incidence of VTE (72%) than those with protein C deficiency (31%) or protein S deficiency (19%) alone (15,16). Similar gene-gene interactions occur in families with inherited antithrombin deficiency (17). Individuals doubly heterozygous for factor V Leiden and prothrombin 20210G>A may have a 20-fold increased relative risk of VTE, although risk estimates vary (6).…”

Inherited thrombotic tendency in a pedigree with antithrombin La Rochelle (N405K) and factor V Leiden

“…It is increasingly appreciated, that a given individual's liability to thrombus formation reflects the cumulative influence of multiple alleles having an impact on coagulation and, in parallel, associated environmental risk factors. In a previous study (Van Boven et al, 1999), venous thromboses occurred at an incidence of almost 5% per year, in those with both antithrombin deficiency and factor V Leiden. A family with a marked thrombotic tendency due to the novel association of Antithrombin La Rochelle (N405K), a type II antithrombin deficiency, and factor V Leiden is here described.…”

“…Antithrombin deficiency is a well-established risk factor for venous thrombosis (Egeberg, 1965). It has an autosomal dominant pattern of transmission, a population prevalence of approximately one in 3000 and is associated with an incidence of venous thromboembolism of about 1% per year (Van Boven et al, 1999). This condition fulfils the conventional criteria for an inherited thrombotic disease as it is a monogenic disorder with variable penetrance.…”