Epidemiology of Thrombosis in Aging
Authors: Tang Weihong , Bell Elizabeth J , Roetker Nicholas S , Folsom Aaron R , Cushman Mary 
Published: October 2019

Abstract
Aging is an important risk factor for venous thromboembolism (VTE). Data on age-specific incidence rates of VTE from population-based studies are limited. While it is well conceived that aging likely acts through Virchow's triad to increase VTE risk, the relative contribution of the components of Virchow's triad is not understood. The objectives of this study are three-fold. First, we calculated age-specific incidence of VTE (deep vein thrombosis and/or pulmonary embolism) using data from two large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study. Second, we evaluated the contribution of coagulation factors VII and VIII, VWF, and activated partial thromboplastin time (aPTT) to age prediction of VTE risk. Third, we evaluated how aging influenced the prediction of VTE risk by confirmed genetic risk factors. We followed participants aged 45-64 years in ARIC (n=14,185) and ≥65 in CHS (n=5,414) at baseline visits (1987-89 in ARIC, 1989-90 and 1992-93 in CHS) for incident VTE through 2011 in ARIC and through 2001 in CHS. We computed person-years of follow-up from the date of the baseline examination to a censoring date. Genotype for the F5 Leiden and activity of coagulation factors (FVII:C and FVIII:C), VWF antigen, and aPTT were measured at baseline in ARIC. We performed proportional hazards regression to estimate the hazard ratio (HR) of VTE for baseline risk factors including age, the four hemostasis variables, and the F5 Leiden after adjusting for race and gender. The genetic analysis was stratified by race and follow-up time in both race groups, and additionally adjusted for principal components of population stratification in African Americans. ARIC participants developed 728 VTE events over 288,535 person-years of follow-up, and CHS participants developed 172 VTE events over 54,207 person-years of follow-up. Incidence rates of VTE per 1,000 person-years were 0.5, 1.0, 1.8, 2.8, 3.8, 5.4, 7.9, and 7.1 for 45-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, and 85-89 years in ARIC, respectively, and 0.8, 2.7, 2.7, 3.8, 6.2, and 5.7 for 65-69, 70-74, 75-79, 80-84, 85-89, and 90-99 years in CHS, respectively. The four hemostasis variables at baseline were significantly associated with baseline age (Pearson correlation coefficients -0.09 to 0.19, p<0.05) and future risk of VTE (p<0.05). Compared to the first quartile of baseline age distribution, the HRs of VTE with increasing quartile of age were 1.13 (95% CI 0.89-1.42), 1.92 (1.55-2.39), and 2.34 (1.89-2.92) for quartiles 2 to 4; the strength of association decreased after additional adjustment for FVII:C, FVIII:C, VWF, and aPTT: HRs 1.06 (0.84-1.34), 1.69 (1.36-2.11), and 1.97 (1.58-2.46), respectively. F5 Leiden was significantly associated with VTE risk in both whites and African Americans (p<0.05). The HRs for F5 Leiden were stronger for earlier follow-up (when the cohort was younger) than later follow-up in both race groups: whites: HR=4.59 (2.91, 7.25), 2.77 (1.88, 4.09), and 1.47 (0.69, 3.13) for first 10 years, second 10 years, and remaining ~5 years of follow-up, respectively; African Americans: HR=9.09 (2.00, 41.30), 2.14 (0.52, 8.79), and 6.10 (1.40, 26.47) for the three follow-up periods. In conclusion, our data suggest that contribution of aging to VTE risk is partly mediated through the coagulation pathway, and that the increased risk of VTE with aging is pushed to younger age by the presence of strong genetic predisposition (e.g. F5 Leiden).

Disclosures
No relevant conflicts of interest to declare.