Venous thrombosis is a multicausal disease, precipitated by the interaction between genetic and acquired risk factors. Recent evidence suggests that a high level of factor VIII coagulant activity (FVIII:C) is one of the risk factors associated with a significantly increased risk of venous thrombosis. This was most clearly demonstrated in a large case-control study (the Leiden Thrombophilia Study) in which 301 patients younger than 70 with a first episode of venous thrombosis were compared with 301 healthy controls matched for age and sex. The patients were seen at least 3 months after withdrawal of oral anticoagulant therapy, and testing included FVIII:C levels and von Willebrand factor antigen (VWF:Ag). Higher levels of FVIII:C and VWF:Ag were associated with an increased risk of thrombosis, however after correction for the influence of other risk factors, only FVIII:C levels remained as an independent risk factor. Patients with FVIII:C level of greater than 150% had a 5- to 6-fold increased risk of venous thrombosis compared to those with levels below 100%. The prevalence of this high FVIII:C level (>150%) was high, being present in 25% of the patients.
Since factor VIII is an acute phase reactant, it was not known whether these high FVIII:C levels are a cause of thrombosis, or the result of an inflammatory response associated with thrombosis. This was addressed by two studies, which evaluated FVIII:C as well as acute phase proteins (C-reactive protein and/or ESR and fibrinogen) at least three months following an episode of venous thrombosis. Both studies showed that there was no significant correlation between the acute phase markers and FVIII:C levels, supporting a causal role for elevated FVIII:C in venous thrombosis.
It is not clear whether high FVIII:C levels are genetically determined. In a recent study, portion of the factor VIII gene was analyzed for polymorphisms in 62 individuals with a personal or family history of venous thrombosis and high FVIII:C levels. No polymorphisms were identified, however this does not rule out the possibility of an as yet unidentified genetic mutation.
It is important to keep in mind that FVIII:C is an acute phase reactant. If a VIII:C assay is ordered as part of a hypercoagulability work-up, it is essential that this be done at a time remote from a thrombotic episode or other acute event. There is also limited information as yet about a clinically relevant “upper limit of normal” for this assay, or how this value should be utilized in patient management. For these reasons, the FVIII:C assay will not be added at this point to the standard “Hypercoagulability Panel”. The FVIII:C assay is available, however, and can be ordered separately in selected patients with recurrent or unexplained thrombosis, keeping in mind the above limitations.
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