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Chronic Elevated Levels of Factor VIII and Other Coagulation Factors
Chronic elevation of some coagulation factor levels is associated with an increased risk of venous thrombosis (factors VIII, IX, XI, II). Some of these show level dependence; the risk increases linearly with the plasma factor level (factors VIII, IX, II). For other coagulation factors, elevated levels were either not confirmed as a venous thrombotic risk factor or the risk association was not independent; it disappeared when the risk was adjusted for other known risk factors. The utility of routine thrombophilia testing in patients with venous thromboembolism has been questioned in multiple studies, including the Choose Wisely campaign. Many studies are now showing that mild thrombophilic risk factors, particularly in the setting of provoked thrombosis, have no effect on therapy or risk of recurrence and should be abandoned.
Elevated Factor VIII
Factor VIII is an acute-phase factor that rises two- to fourfold during an inflammatory response to infection, cancer, surgery, trauma, and other stimuli. Factor VIII levels increase with age. Some individuals show a persistent elevation of factor VIII activity in the absence of an acute-phase response. Chronically elevated factor VIII is a level-related independent risk factor for venous thromboembolism with an odds ratio (OR) of two- to sixfold for factor VIII activities above 150–200 IU/dL after adjustment of other known risk factors. The risk of venous thrombosis associated with high factor VIII is present in children and the elderly. Children are also at greater risk of catheter-associated thrombosis if they have chronically elevated factor VIII activity. There is a fourfold increased risk of recurrent venous thrombosis in patients with chronic elevated factor VIII and unprovoked initial thrombosis, but no increase in recurrence in patients with provoked thrombosis. Risk associated with chronic factor VIII elevation is synergistic with acquired risk factors such as oral contraceptive use. It is recommended that evaluation for persistent factor VIII elevation be performed 3–6 months after the last episode of thrombosis, when the patient is otherwise well with no evidence of acute-phase response and off antithrombotic therapy. That being said, it is not clear that knowing the factor VIII status of a patient with venous thrombosis has any effect on either initial antithrombotic therapy or therapy during recurrence, and therefore routine evaluation of factor VIII in patients with venous thrombosis is not recommended.
Factor VIII levels are related to von Willebrand factor levels and blood group, but these are not independent predictors of thrombosis, their association appears to be mediated through elevated factor VIII levels. The genetic basis for persistent elevation of factor VIII is currently unknown; no polymorphisms have been detected in the factor VIII gene.
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