The Effects of Aging on Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease
Authors: Seaman Craig D. , Ragni Margaret V. 
Published: October 2019

Introduction: Little is known about aging in von Willebrand disease (VWD). While it has been well established that von Willebrand factor (VWF) levels increase with age among healthy adults, it is uncertain if VWD patients experience an age related increase in VWF levels, although limited data suggests so. Furthermore, it is unknown if normalization of VWF levels with aging ameliorates bleeding risk. We aimed to determine the effects of aging on VWF levels and bleeding risk in patients with type 1 VWD.
Methods: This is a cross-sectional study of patients with type 1 VWD presenting to the Hemophilia Clinic of Western Pennsylvania for regularly scheduled clinical visits. Exclusion criteria included concomitant hereditary bleeding disorder. Blood samples were obtained to determine VWF antigen level, VWF ristocetin cofactor activity, and factor VIII activity. A bleeding score was obtained using the condensed MCMDM-1 VWD bleeding assessment tool (BAT); however, we calculated the bleeding score based on bleeding symptoms over the previous three years. The prophylactic use of DDAVP or VWF concentrate prior to surgery was not included in the determination of the bleeding score. Descriptive statistics for continuous variables included mean, median, range, and standard error. Frequencies and percentages were used for categorical variables. Simple linear regression was used to predict the association of age with VWF antigen level and bleeding score.
Results: The average age of participants was 43.5 ± 5.28 years (median 38, range 22 to 85). Twelve of 14 patients were female. The mean VWF antigen level was 0.97 ± 0.10 IU/mL (median 0.88, range 0.58 to 1.56). The mean bleeding score was 1.64 ± 0.52 (median 1, range 0 to 6). Four of 12 female patients reported use of estrogen containing oral contraceptives. None reported pregnancy. A simple linear regression was calculated to predict bleeding score based on age. Average bleeding score was inversely proportion to age, with a decrease of 0.057 (-0.107, 0.006) for each year of age, p =0.03. There was no significant correlation between VWF antigen level and age, with an increase in average VWF antigen level of 0.003 (-0.009, 0.014) for each year of age, p =0.60.
Discussion: To our knowledge, this is the first report showing age-related amelioration of bleeding symptoms in patients with type 1 VWD. Prior studies have reported contradictory findings, some reporting that bleeding symptoms do not lessen with aging in patients with type 1 VWD. Several studies may be confounded by study design, including the method of BAT administration. Determining the bleeding score using lifetime bleeding symptoms may not be reflective of present day bleeding risk (i.e. an older patient with a remote history of moderate to severe bleeding without bleeding symptoms for several years). We found no association between aging and VWF antigen levels, which may, in part, be related to the small sample size. Determining whether or not bleeding risk is reduced in elderly type 1 VWD patients is essential for optimal clinical management. If older type 1 VWD patients have experienced normalization of VWF levels, and no longer have an increased risk of bleeding, administration of DDAVP or VWF concentrate may be harmful. Thrombosis risk increases with aging, and providing DDAVP or VWF concentrate unnecessarily may increase thrombosis risk, especially among patients with underlying CVD, CVD-related risk factors, or concomitant hypercoagulable states. Moreover, VWF concentrate is costly, and unwarranted use represents a significant waste of healthcare dollars. For these reasons, we plan a multicenter, cross-sectional study (VWD Aging and Bleeding Correlation Study, VWD-ABC) to further investigate the effects of aging on VWF levels and bleeding risk in patients with type 1 VWD.

Disclosures
Ragni: OPKO: Research Funding; Tacere Benitec: Consultancy; Biogen: Consultancy, Research Funding; Novo Nordisk: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Baxalta: Research Funding; Genentech: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Shire: Consultancy; SPARK: Research Funding; Vascular Medicine Institute: Research Funding.