Markers of fibrinolysis may predict development of lower extremity arterial disease in patients with diabetes: A longitudinal prospective cohort study with 10 years of follow-up

Background: A previous cross-sectional study suggested that tissue plasminogen activator-activity might be an early marker of asymptomatic lower extremity arterial disease, but the long-term relationship is unknown. Subjects and methods: This study included 96 diabetic (48 type 1/48 type 2) and 62 non-diabetic subjects aged 30-70 years without previously known lower extremity arterial disease (age: 50.3 +/- 9.3 years, gender: M/W 47.5/52.5% and body mass index: 26.6 +/- 4.5 kg/m(2)). The relationships between asymptomatic lower extremity arterial disease and fibrinolytic markers (tissue plasminogen activator-activity, tissue plasminogen activator-mass, plasminogen activator inhibitor-1 activity) at baseline and after 10 years were assessed by logistic regression analysis adjusting for age, hypertension, statin treatment, HbA1c, triglycerides and low-density lipoprotein cholesterol as fixed covariates. Results: The tissue plasminogen activator-activity at baseline and at the 10-year follow-up significantly predicted the presence of sign(s) of lower extremity arterial disease (odds ratio = 1.78, 95% confidence interval: 1.02-3.10, p = 0.043 and odds ratio = 1.78, 95% confidence interval: 1.12-2.23, p = 0.014, respectively). In addition, tissue plasminogen activator-mass at the 10-year follow-up was associated with signs of lower extremity arterial disease (odds ratio = 1.07, 95% confidence interval: 1.00-1.15, p = 0.046). Baseline age, hypertension and HbA1c were independently associated with sign(s) of lower extremity arterial disease at 10 years (odds ratio = 1.09, 95% confidence interval: 1.04-1.14, p=<0.001; odds ratio = 3.68, 95% confidence interval: 1.67-8.12, p = 0.001 and odds ratio = 1.54, 95% confidence interval: 1.21-1.95, p=<0.001, respectively). Conclusion: This long-term study supports previous findings of a significant association between asymptomatic lower extremity arterial disease and tissue plasminogen activator-activity. Thus, tissue plasminogen activator-activity may be an early marker of lower extremity arterial disease although the mechanism of this relationship remains unclear.