Comparison of plasminogen activator inhibitor-1, tissue type plasminogen activator antigen, fibrinogen, and D-dimer levels in various age decades in patients with type 2 diabetes mellitus and stable coronary artery disease (from the BARI 2D trial)

Abstract

Advancing age is associated with downregulation of fibrinolysis in normal subjects. This is reflected by high concentrations of plasminogen activator inhibitor-1 (PAI-1) in the blood, which has been implicated in the increasing cardiovascular morbidity and mortality with age. We sought to delineate the relation of PAI-1 to several factors, including age, gender, and ethnicity in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. A total of 2,321 patients with DM and stable coronary artery disease in the BARI 2D trial were grouped by age (<50, 50 to 59, 60 to 69, and > or =70 years). Tissue-type plasminogen activator antigen, PAI-1 antigen and activity, fibrinogen, and D-dimer were quantified at baseline. The PAI-1 antigen (p <0.001) and its activity (p <0.001) and their ratios to tissue-type plasminogen activator (p <0.001) were all paradoxically lower with advancing age. In contrast, D-dimer (p <0.0001) was elevated. The fibrinogen level was greatest in the oldest age group (p = 0.01). The level of tissue-type plasminogen activator antigen did not vary with age. These age-related differences were observed primarily in men and non-Hispanic white and Asian/other participants. In conclusion, PAI-1 is inversely related to age in patients with DM and stable coronary artery disease and is associated with elevation of D-dimer, reflecting augmented fibrinolysis. The unexpected profibrinolytic state seen with advancing age and DM might reflect a protective phenomenon resulting from enhanced survival of some older patients with DM that endowed the older patients with longevity sufficient to enable them to participate in the BARI 2D trial. Targeting the factors that led to the downregulation of PAI-1 in older patients with type 2 DM might offer an attractive strategy for reducing cardiovascular risk.

Figure 1. The Distribution of Concentrations of baseline PAI-1 and t-PA

Each measure of the fibrinolytic system varied considerably across the BARI-2D cohort as a whole. The PAI-1 antigen (panel A) and activity (panel B) distributions were rightward shifted whereas the t-PA antigen content was distributed in a more Gaussian fashion (panel C).

Figure 2. Interquartile Range of Fibrinolytic System Variables by Age Quartiles

The PAI-1 antigen (panel A; p<0.001) and antigen content (panel B; p<0.001) were significantly lower in patients within the older quartiles compared with their younger counterparts. t-PA antigen content (panel C) did not vary by age. Data are presented as first quartile, median, and third quartile values.

Figure 3. Baseline distribution of Fibrinogen and Fibrin D-dimer

Fibrinogen was normally distributed. Fibrin D-dimer levels were very low in most of the participants.