Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms

Abstract

Essentials von Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms.

Summary: Background The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (β = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (β = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (β = -0.15; 95% CI, -0.25, -0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly influenced by the presence of the other.

Keywords: ABO blood group system; aging; metabolic clearance rate; secretion; von Willebrand factor.

Figure 1. Distinct associations of aging with plasma VWF and FVIII levels

Aging was positively associated with both VWF (r²=0.18, p<0.0001) (A) and FVIII levels (r²=0.25, p<0.0001) (C). A distinct effect of aging on VWF and FVIII levels was observed between blood types. For VWF antigen levels, aging was more strongly associated in individuals with blood type non-O than with type O (r²= 0.24 vs. 0.12, p=0.008) (B). Likewise, aging was more strongly associated with FVIII antigen levels in individuals with blood type non-O versus type O (r²= 0.35 vs. 0.16, p=0.004) (D). Linear regression with 95% CI lines (dotted lines) are shown.

Figure 2. Combined effect of ABO blood type and aging on VWF and FVIII levels

In the young population, levels of VWF and FVIII were not significantly different. With aging, as the levels of VWF and FVIII increased in individuals with blood type non-O, the difference between blood type O and non-O became evident and more marked with advanced age (A,B). Mean values are depicted and error bars represent SEM. *p<0.05, **p<0.01, ***p<0.001. Exact p-values are described in the text.

Figure 3. Increases in VWFpp with aging and different blood types

No significant differences in VWFpp levels throughout aging were observed in individuals with blood type O, while VWFpp levels were significantly elevated in old individuals with blood type non-O. Mean values are depicted and error bars represent SEM. **p<0.01, ***p<0.001. Exact p-values are described in the text.

Figure 4. Distinct changes in VWF clearance with age and the effect of ABO blood type

A significant reduction in VWF clearance in individuals with blood type non-O was observed, as shown by a decrease in VWFpp/VWF:Ag ratio (A) and by an increase in the estimated VWF half-life (B). A small reduction in VWF clearance in later life was observed in individuals with blood type O, based on the VWFpp/VWF:Ag ratio (C) or in the estimated VWF half-life (D). Mean values are depicted and error bars represent SEM. **p<0.01, ***p<0.001. Exact p-values are described in the text.

Figure 5. Distinct changes in VWF clearance with age and blood types

The differences in VWFpp/VWF:Ag ratio with blood type were apparent only with advancing age, as no differences were observed in the young population (A). Similarly, no differences in the estimated VWF half-life were observed between blood types in young individuals, but were shown with increasing age (B). Mean values are depicted and error bars represent SEM. *p<0.05, ***p<0.001. Exact p-values are described in the text.

Figure 6. Relative A antigen content on VWF with aging and its association with VWF levels

Relative A-VWF levels were associated with advancing age (A), and were associated with VWF:Ag levels (B) and VWF clearance (D), but not with VWF secretion (C). Linear regression with 95% CI lines (dotted lines) are shown.