Several case-control studies have reported elevated plasma von Willebrand factor (VWF) levels in patients with venous thromboembolism (VTE) compared with controls. However, because few studies have investigated the association in a prospective design, it is unclear whether elevated plasma VWF is a risk factor or a consequence of the VTE event. Therefore, we aimed to investigate the prospective association between plasma VWF levels and risk of VTE, as well as to perform subgroup analyses of deep vein thrombosis (DVT) and pulmonary embolism. We established a population-based nested case-control study of 414 VTE cases and 843 age- and sex-matched controls based on the Tromsø study cohort (1994-2007). Blood samples were collected at cohort baseline (1994-1995). Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across quartiles of VWF levels. We found that the risk of VTE increased linearly across quartiles of VWF levels (P for trend = .023). Participants with VWF in the highest quartile had an OR of 1.45 (95% CI, 1.03-2.03) for VTE compared with those in the lowest quartile. The association was strongest for unprovoked VTE (OR, 2.74; 95% CI, 1.66-4.54) and unprovoked DVT in particular (OR, 6.73; 95% CI, 3.07-14.76). Further adjustment for body mass index, C-reactive protein, hypertension, estrogen use, and smoking had a modest effect on the risk estimates. To conclude, we found a dose-dependent relationship between plasma VWF levels and future risk of incident VTE, and unprovoked events in particular. Our findings suggest that VWF may represent a promising biomarker for future risk of incident VTE.
Plasma von Willebrand factor (VWF) and platelet reactivity are both risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (<8.5, 8.5-9.5, ≥9.5 fL) and platelet count (<230, 230-299, ≥300·109 L-1) strata. Here, participants with VWF levels in the highest tertile and MPV ≥9.5 fL had an OR of 1.98 (95% CI 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV <8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI 15% to 96%) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300·109 L-1 had an OR of 2.91 (95% CI 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count <230, and 39% (95% CI -2% to 97%) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that both platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk of incident VTE.
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