Co-inheritance of the 20210A Allele of the Prothrombin Gene Increases the Risk of Thrombosis in Subjects with Familial Thrombophilia

Summary

The presence of the 20210A allele of the prothrombin (PT) gene has recently been shown to be a risk factor for venous thromboembolism. This is probably mediated through increased plasma prothrombin levels. The aim of this study was to compare the prevalence of the prothrombin 20210A allele in control subjects and in subjects with recognised thrombophilia and to establish whether the additional inheritance of the PT 20210A allele is associated with an increased risk of venous thromboembolism. 101 subjects with a history of venous thromboembolism and diagnosed as having either factor V Leiden (R506Q) or heritable deficiencies of protein C, protein S or antithrombin were studied. The prevalence of the PT 20210A allele in this group was compared with the results obtained for 150 control subjects. In addition, the relationships were examined between genetic status and the number of documented thromboembolic episodes, and between plasma prothrombin levels and possession of the PT 20210A allele. 8 (7.9%) of the 101 patients were also heterozygous for the PT 20210A allele. This compares with 0.7% in the control subjects (p = 0.005). After exclusion of patients on warfarin, the mean plasma prothrombin of 113 subjects without 20210A was 1.09 U/ml, as compared with 1.32 U/ml in 8 with the allele (p = 0.0002). Among the 101 patients with either factor V Leiden, protein S deficiency, protein C deficiency or antithrombin deficiency, the age adjusted mean (SD) number of venous thromboembolic episodes at diagnosis was 3.7 (1.5) in those with the PT 20210A allele, as compared with 1.9 (1.1) in those without (p = 0.0001). We have demonstrated that the prevalence of the PT 20210A allele is significantly greater in subjects with venous thrombosis and characterised heritable thrombophilia than in normal control subjects and that the additional inheritance of PT 20210A is associated with an increased risk of venous thromboembolism. We have also confirmed that plasma prothrombin levels are significantly greater in subjects possessing the PT 20210A compared with those who do not.

• References

• 1 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjen-kov V, Chandy M, Dahlback B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia. part 1 Thromb Haemost 1996; 76: 651-662
• 2 Dahlbӓck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004
• 3 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der VeldenPA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64
• 4 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703
• 5 Woodhams B. The simultaneous measurement of total and free protein S by ELISA. Thrombosis Research 1988; 50: 213-220
• 6 Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston FE, Peake IR. High prevalence of a mutation in the factor V gene within the UK population: Relationship to activated protein C resistance and familial thrombosis. Br J Haematol 1994; 88: 219
• 7 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect on von Willebrand factor on occurrence of deep vein thrombosis. Lancet 1995; 345: 152-155
• 8 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477
• 9 Zoller B, Bemtsdotter A, Garcia de FrutosP, Dahlbӓck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-3523
• 10 Allaart CF, Poort SR, Rosendaal F, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-138
• 11 Koeleman BPC, Reitsma PH, Allart CF, Bertina RM. Activated protein c resistance as an additional risk factor for thrombosis in protein c deficient families. Blood 1994; 84: 1031
• 12 Preston FE, Rosendaal FR, Walker ID, Briët E, Bemtorp E, Conard J, Font-cuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der MeerFJM. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916