High coagulant factors & venous thrombosis

The annual incidence of venous thrombosis is 1 per 1000 persons and mortality among patients with pulmonary emboli is high. Patients may develop a postthrombotic syndrome and recurrent events occur frequently.²  Major risk factors for venous thrombosis consist of acquired and genetic factors. Hypofibrinolysis appears to be a risk factor, but the role of individual fibrinolytic proteins is still unclear.³  Hypercoagulability caused by an imbalance between anticoagulant and procoagulant systems increases the risk of venous thrombosis.⁴  Deficiencies of antithrombin, protein C, and protein S are strong but rare risk factors for venous thrombosis. Factor V Leiden and the prothrombin 20210A mutation are more prevalent with a moderate increase in risk. High levels of factor VIII clearly increase the risk of venous thrombosis, but the results of studies investigating the effects of prothrombin, factor V, factor VII, and fibrinogen are inconsistent.⁵  In studies in which associations between these latter factors and venous thrombosis were found, the effects were much less than those of elevated factor VIII.⁴ 

So far, the effects of coagulant factors IX through XIII have been investigated in only a few case-control studies, including the Leiden Thrombophilia Study (LETS)⁵  and, more recently, the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study.^6,7  Prospective cohort studies have been lacking so far.⁵ 

In this issue of Blood, an efficient nested case-control design has been used within LITE, a prospective cohort study in individuals aged 45 to 100 years, with a median follow-up period of more than 9 years.¹  Included in the analyses were 462 validated cases of venous thrombosis and 1047 controls. Coagulation measurements took place in blood samples collected mostly at baseline. Levels were therefore measured long before the event, as opposed to case-control studies, in which levels are measured after the event, thus ruling out the possibility of reverse causation. A disadvantage is that levels may not reflect the situation immediately before the event, which, from an etiological point of view, would be the ideal situation. However, this is difficult if not impossible to achieve in any study design.

Although one might be inclined to expect differences in results between case-control studies and this cohort study simply because different populations were included or different assays used, the results were quite similar. Levels of factor X, factor XII, and factor XIII were not associated with risk of venous thrombosis.^1,5,8  Elevated factor XI was associated with a nearly 2-fold increased risk for the top quintile or percentile, which is quite close to the risk of factor VIII.^1,5,7  High levels of factor IX were associated with an increased risk of venous thrombosis in all studies,^1,5,6,9  but after adjustment for body mass index (BMI), the risk in LITE attenuated to the null.¹  No adjustments for BMI were performed in the case-control studies.^5,6,9 

For some coagulation factors, the associated risk is stronger for deep vein thrombosis in the leg than for a pulmonary embolism. The opposite may be true for elevated factor XI in LITE, as the risk of pulmonary embolism combined with deep vein thrombosis appears to be larger than for deep vein thrombosis alone. However, the case classification in this study may not be reliable, preventing strong conclusions.

If these overall results are confirmed by other studies, further study into possible mechanisms for the increased risk of elevated levels of factor XI is warranted, which include increased fibrin formation and decreased fibrinolysis.¹⁰  Furthermore, this study raises the question whether elevated factor XI is also a risk factor for a recurrent venous thrombotic event, and if so, whether treatment prevents recurrent events. Until these results become available, measurement in clinical practice is not yet indicated.