Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. The PLAT Group.

Abstract

A case-control comparison within the framework of the prospective, multidisciplinary PLAT Study was performed to assess whether altered baseline fibrinolytic variables were associated with an elevated risk of ischemic thrombotic events in patients with documented coronary, cerebral, and/or peripheral atherosclerotic disease. Fibrinogen, D-dimer, tissue plasminogen activator (t-PA) antigen, and fibrinolytic activity before and after venous stasis (A=difference between the two values), t-PA inhibitor, and lipid levels in 60 atherosclerotic patients with a thrombotic event during the first year of follow-up were compared with those in 94 atherosclerotic patients without such events, who were matched for age, sex, and diagnosis at enrollment. Events were associated with a higher release of A t-PA antigen (P=.O47), higher D-dimer (P=.O24), and higher t-PA inhibitor (P=.001) levels. A Fibrinolytic activity was correlated inversely with t-PA inhibitor (P<.01) and triglycerides (J*<.05). D-Dimer was also correlated with systolic blood pressure (P<.01). Atherosclerotic patients at higher risk of thrombotic ischemic events are characterized by increased fibrin turnover and impaired fibrinolytic activity due to high t-PA inhibitor levels. This hemostatic disequilibrium may participate with conventional risk factors such as elevated triglyceride levels and systolic blood pressure in the multifactorial mechanism of ischemic sequelae in patients with preexisting vascular atherothrombotic disease. (ArUrioscler Thromb. 1993;13:1412-1417.) KEY WORDS • atherothrombosis • ischemic events • fibrinolytic variables • plasminogen activator inhibitor • D-dimerR ecent clinical studies have reported decreases in fibrinolytic activity in patients with coronary artery disease. 15 The major mechanisms involved in the type of fibrinolytic impairment seen in these patients are an increase in plasma tissue-type plasminogen activator (t-PA) inhibitor, particularly in subjects with hypertriglyceridemia, and a selective depression of t-PA activity in euglobulins. The t-PA inhibitor (PAI-1) has also been shown to be an independent risk factor for reinfarction in young survivors of myocardial infarction (MI). 6The prospective, multidisciplinary PLAT Study, which was performed to investigate the associations between hemostatic variables and ischemic events in 953 patients with documented atherosclerotic disease, 79 afforded the opportunity of carrying out a nested casecontrol study, with the aim of assessing whether altered baseline fibrinolytic variables characterize subjects at a higher risk of ischemic sequelae, and we now report the results. Fibrinogen, fibrinolytic activity, and t-PA anti-

Physical Activity Status and Adverse Age-Related Differences in Coagulation and Fibrinolytic Factors in Women

“…30 Both clinical and epidemiological data have suggested that reduced endogenous fibrinolytic activity, characterized by increased t-PA antigen, PAI-1 antigen, and PAI-1 activity and reduced t-PA activity, is a major contributor to both the development and severity of atherothrombosis. [31][32][33][34] Our finding of impaired fibrinolytic function with age in sedentary women is consistent with previous reports 22 and supports the hypothesis that hypofibrinolysis may contribute to the increased risk of atherothrombotic events with age in women. 33 In addition, the lower t-PA antigen and PAI-1 activity observed in the physically active postmenopausal women relative to the sedentary control subjects confirm our previous observations in middle-aged and older women.…”

“…In the sedentary postmenopausal women, the age-related increase in plasma fibrin D-dimer levels may reflect a prothrombotic state characterized by numerous small amounts of fibrin degradation products resulting from chronic extensive intravascular fibrin formation and degradation. 34 On the other hand, the elevated levels of plasma fibrin D-dimer found in our physically active postmenopausal group may reflect increased fibrin turnover resulting from elevated levels of circulating fibrin. 44 …”

Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity.

“…Using freshly collected tissues from severely obese patients, our results did not exhibit differences in PAI-1 expression between visceral and SC fats. Thus, the increase in PAI-1 levels observed in obese subjects does not reflect (14), who described in genetically obese mice, by comparison with their lean counterparts, an increase in PAI-1 expression in several tissues, the greatest of which was observed in adipose tissue without a strong difference between SC and epididymal fat (5). Whereas it is well established in mice that the PAI-1 adipose tissue content increases with the level of obesity, only one study has addressed this point in humans, showing that the SC adipose tissue secretion of PAI-1 correlated significantly with BMI and more strongly with the volume of adipocytes (17).…”

“…Prospective cohort studies conducted in atherosclerotic patients have indicated that elevated PAI-1 plasma concentrations are associated with increased risk for future coronary events (3)(4)(5).…”

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles

“…28 In the past, prospective cohort studies conducted in atherosclerotic patients have indicated that elevated PAI-1 plasma concentrations are associated with adverse cardiovascular outcome. [29][30][31] In dietinduced type 2 diabetic mice, both the intensity of macrophage infiltration and impaired fibrinolysis, as reflected by the measurement of the uPA/PAI-1 ratio, were found to be involved in impaired resolution of deep vein thrombosis. 32 In the present study, VLCD induces a 38% reduction in PAI-levels, a result in line with previously published data.…”