Von Willebrand Factor and ADAMTS13 in Cardiovascular Disease

Von Willebrand Factor plays an important role in primary hemostasis by platelet adhesion and aggregation. High molecular weight VWF multimers are the most procoagulant forms and are cleaved by ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin motif repeats 13) into smaller, less coagulant, forms. Recent studies have shown an association between both high VWF levels, low ADAMTS13 levels and arterial thrombosis, including ischemic stroke and acute coronary syndrome. In this thesis several studies on VWF, ADAMTS13 and arterial thrombosis have been presented. We conclude that the extent of atherosclerosis is strongly associated with VWF levels. Furthermore, VWF might be a marker of an unfavorable outcome in coronary heart disease and ischemic stroke patients. Plaque characteristics, such as high risk lesions, do not seem to be associated with VWF levels. Lastly, low ADAMTS13 is strongly associated with an increased risk of arterial thrombosis, including ischemic stroke and coronary heart disease. Overall, the studies in this thesis provide a better understanding of the role of VWF and ADAMTS13 in arterial thrombosis

Von Willebrand factor and ADAMTS13 activity in relation to risk of dementia

Low ADAMTS13 activity is associated with an increased risk of cardiovascular disease, which is generally attributed to its proteolytic effects on Von Willebrand factor (VWF). Cardiovascular health is an important determinant of cognitive decline, but the association of either VWF or ADAMTS13 with risk of dementia is unknown. Between 1997-2002, we measured VWF antigen and ADAMTS13 activity in 6055 participants of the population-based Rotterdam Study (mean age 69.3 years, 57.2% women). At baseline, 85 participants had dementia, and during 15 years of follow-up 821 developed dementia. Higher VWF was associated with prevalence and risk of dementia, unaffected by concurrent ADAMTS13 activity, but estimates strongly attenuated over time and were no longer statistically significant at 4 years of follow-up (relative risks [95% CI] per standard deviation increase- cross-sectional: 1.37 [1.06-1.77], and longitudinal: 1.05 [0.97-1.14]). In contrast, low ADAMTS13 was associated with increased risk of dementia throughout follow-up (hazard ratio per SD decrease- 1.16 [1.06-1.28]), which alike for ischaemic stroke, was modified by the presence of diabetes (P-interaction = 0.003). In conclusion, higher VWF and low ADAMTS13 activity are associated with increased risk of dementia, but differences in time-course and lack of synergistic effects may indicate in part independent underlying mechanisms

von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study

Background Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ratio in relation to decline in kidney function. Study Design Prospective cohort study. Setting & Participants 2,479 individuals (mean age, 65.1 ± 5.9 [SD] years; 43% men) from the population-based Rotterdam Study. Predictors vWF, ADAMTS13, and vWF:ADAMTS13 ratio. Outcomes & Measurements Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR < 60 mL/min/1.73 m2 were assessed. Results During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR < 60 mL/min/1.73 m2 occurred. The population had a mean eGFR decline of 0.96 ± 0.92 mL/min/1.73 m2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, −0.06 [95% CI, −0.09 to −0.02] mL/min/1.73 m2 per year) and higher risk for new-onset eGFR < 60 mL/min/1.73 m2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same. Limitations No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13. Conclusions In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease