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Elevated Factor VIII, IX, and XI Levels

By

Michael B. Streiff

, MD, Johns Hopkins University School of Medicine

Reviewed/Revised Aug 2023
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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 General references 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... read more ). Elevated factor VIII levels have also been identified as a risk factor for recurrent VTE (2 General references 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... read more ).

Elevated factor IX and XI antigen levels are also associated with an increased risk of VTE (3, 4 General references 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... read more ). 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 General references 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... read more ).

General references

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 Diagnosis reference 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... read more ).

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

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 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... read more ).

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

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