Increased levels of factors VIII, IX, and XI are risk factors for venous thromboembolism (VTE). While these levels are genetically determined, elevated levels of factor VIII can occur in chronic inflammation and other systemic disorders. Treatment is with anticoagulation for VTE and, in the case of elevated factor VIII, specific treatment for underlying disorders.
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 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. PMID: 10845896
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, Heckbert SR. 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 VIII, IX, and XI antigen and activity can be directly measured.
Since factor VIII activity is affected by anticoagulation and it is an acute phase response protein, it is important to measure factor VIII activity when the patient is not taking anticoagulants and is unaffected by an infection or inflammatory conditions (1).
Factor VIII levels are also increased by pregnancy, estrogen-containing hormonal therapy, cancer, liver disease, kidney disease, hyperthyroidism, intravascular hemolysis, and exercise.
Measurement of factor VIII activity in a patient taking anticoagulants will result in falsely reduced factor VIII activity. Factor VIII antigen is not affected by anticoagulation. In contrast, Factor VIII antigen and activity levels increase with systemic inflammation and many other conditions (see above) so measurement of factor VIII is ideally done in the absence of these disorders.
Factor IX antigen can be reduced by vitamin K antagonists but not direct oral anticoagulants. Factor XI antigen is not affected by anticoagulation. Factor IX and XI activity levels are reduced by anticoagulation.
Diagnosis reference
1. O'Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77(5):825-828. PMID: 9184386
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
