Factors VIII, IX, and XI are clotting proteins made primarily in the liver. Factor VIII circulates in an inactive form bound to von Willebrand factor (VWF) until blood vessel injury activates it and separates them. Free Factor VIII then interacts with factor IX to facilitate clotting.
Elevated factor VIII levels were first recognized to be a risk factor for venous thromboembolism (VTE) in the Leiden Thrombophilia Study, a case control study of patients with a first episode of VTE without cancer, and age- and sex-matched controls. Factor VIII activity > 150 IU/L was associated with a nearly 5-fold increased risk of VTE (1). Elevated factor VIII levels have also been identified as a risk factor for recurrent VTE (2).
Elevated factor IX and factor XI antigen levels are also associated with an increased risk of VTE (3, 4). However, the Longitudinal Investigation of Thromboembolism Etiology study also found that factor XI, but not factor IX, was associated with increased VTE risk when adjusted for age, sex, race, study, BMI (body mass index), and diabetes (5).
Elevated von Willebrand factor levels have also been associated with an increased risk of VTE (6).
General references
1. van der Meer FJ, Koster T, Vandenbroucke JP, Briët E, Rosendaal FR. The Leiden Thrombophilia Study (LETS). Thromb Haemost. 1997;78(1):631-635.
2. Kyrle PA, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000; 343(7):457-462. doi: 10.1056/NEJM200008173430702
3. van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood. 2000; 95(12):3678-3682.
4. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000; 342(10):696-701. doi: 10.1056/NEJM200003093421004
5. Cushman M, O'Meara ES, Folsom AR, et al. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood. 2009; 114(14):2878-2883. doi: 10.1182/blood-2009-05-219915
6. Edvardsen MS, Hindberg K, Hansen ES, et al. Plasma levels of von Willebrand factor and future risk of incident venous thromboembolism. Blood Adv. 2021;5(1):224-232. doi:10.1182/bloodadvances.2020003135
Diagnosis of Elevated Factor VIII, IX, and XI Levels
Measurement of factor VIII, IX, or XI
Levels of factor VIII, IX, and XI antigen and activity can be directly measured.
Factor VIII, IX and XI have been associated with an increased risk of venous thromboembolism (1, 2). When measuring factor activity levels, it is important to do testing in the absence of anticoagulants. Warfarin affects vitamin K dependent factors II, VII, IX and X activity and antigen levels. Direct oral anticoagulants can result in the underestimation of factor activity levels (). When measuring factor activity levels, it is important to do testing in the absence of anticoagulants. Warfarin affects vitamin K dependent factors II, VII, IX and X activity and antigen levels. Direct oral anticoagulants can result in the underestimation of factor activity levels (3). Factor antigen levels are not affected by direct oral anticoagulants.
Diagnosis references
1. Lowe G, Wu O, van Hylckama Vlieg A, Folsom A, Rosendaal F, Woodward M. Plasma levels of coagulation factors VIII and IX and risk of venous thromboembolism: Systematic review and meta-analysis. Thromb Res. 2023;229:31-39. doi:10.1016/j.thromres.2023.06.026
2. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000;342(10):696-701. doi:10.1056/NEJM200003093421004
3. Douxfils J, Ageno W, Samama CM, et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost. 2018;16(2):209-219. doi:10.1111/jth.13912
Treatment of Elevated Factor VIII, IX, and XI Levels
Anticoagulation
Direct oral anticoagulants and vitamin K antagonists are effective for treatment of patients with elevated factor VIII, IX and XI levels with a venous thromboembolism (1).
Treatment reference
1. Campello E, Spiezia L, Simion C, et al. Direct Oral Anticoagulants in Patients With Inherited Thrombophilia and Venous Thromboembolism: A Prospective Cohort Study. J Am Heart Assoc. 2020;9(23):e018917. doi:10.1161/JAHA.120.018917
