High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor

Unlabelled Box Essentials • Elevated procoagulant levels are associated with an increased risk of venous thrombosis (VT). • The dependency on concurrent increased factor levels and VT was analyzed in a large study. • Factor VIII (FVIII) and von Willebrand factor (VWF) were associated with the highest VT risk. • The risks for other procoagulant factor levels were largely explained by FVIII and VWF. Summary Background Coagulation factors are essential for robust clot formation. However, elevated levels of procoagulant factors are associated with an increased risk of venous thrombosis (VT). The precise contribution of these factors to the development of VT is not yet understood. Objectives We determined the thrombosis risk for the highest levels of eight selected coagulation factors. Furthermore, we analyzed which of these coagulation factors had the strongest impact on the supposed association. Methods We used data of 2377 patients with a first VT and 2940 control subjects in whom fibrinogen, von Willebrand factor (VWF), factor II, FVII, FVIII, FIX, FX and FXI levels were measured. Results The odds ratios (ORs) for the various coagulation factor levels (> 99th percentile versus ≤ 25th percentile) varied between 1.8 and 4, except for FVIII (OR 23.0; 95% confidence interval [CI] 14.7–36.0) and VWF (OR 24.0; 95% CI 15.3–37.3). Adjustment for FVIII and VWF in a mediation analysis reduced the risks of the other factors to unity, with the exception of FIX and FXI (remaining ORs between 1.7 and 1.9). Conversely, the ORs for FVIII and VWF levels remained high after adjustment for all other procoagulant factors (FVIII: 16.0; 95% CI 9.7–26.3; VWF: 17.6; 95% CI 10.7–28.8). Conclusions Our results imply that the observed relationship between VT and coagulation factor levels can be largely explained by FVIII and VWF. FVIII and VWF levels were also associated with the highest VT risk.