Renate Beckmann

Concentration of Endogenous tPA Antigen in Coronary Artery Disease Relation to Thrombotic Events, Aspirin Treatment, Hyperlipidemia, and Multivessel Disease

Tissue plasminogen activator (tPA) is the major plasminogen activator responsible for dissolving blood clots found in blood vessels. However, elevated concentrations of tPA antigen were found to be related to adverse events in patients with coronary artery disease (CAD). Considerable controversy about the significance of these results exists. The goal of this cross-sectional study was to identify independent determinants for tPA antigen concentrations in patients with CAD, to possibly clarify the above paradoxical relationship. The baseline tPA antigen concentrations of 366 patients with angiographic evidence of coronary sclerosis were determined. Univariate analysis showed that age (P=0.013), angiographic extent of disease (P<0.001), presence of angina at rest (P<0.001), diabetes mellitus (P=0.004), hypercholesterolemia (P=0. 045), hypertriglyceridemia (P=0.015), and chronic intake of nitrates (P<0.001) were significantly and positively related to tPA antigen concentration, while the chronic intake of aspirin was inversely related to tPA antigen (P<0.001). In addition, plasminogen activator inhibitor type 1 (PAI-1) activity was found to be significantly and positively associated with tPA antigen concentration (P<0.001). A multivariate analysis identified chronic low-dose aspirin therapy (P<0.001), PAI-1 activity (P<0.001), hypertriglyceridemia (P=0.005), the type of angina (P=0.026), multivessel disease (P=0.041), and hypercholesterolemia (P=0.043) as significant and independent determinants of tPA antigen. While hypertriglyceridemia and hypercholesterolemia both are related to the underlying disease, the type of angina and the number of involved vessels are linked to the severity and extent of disease, and all of them are indicators of a prothrombotic state found during the progression of CAD. In contrary, low-dose aspirin rather would decrease the likelihood of thrombotic events. The relation of tPA antigen to PAI-1 activity furthermore underlines the relation between tPA antigen concentration and a prothrombotic state. Therefore, the positive or-in case of aspirin therapy-negative correlation of these parameters with tPA antigen concentration would indicate that thrombus formation and simultaneous endothelial cell activation might be major determinants for tPA antigen concentration in CAD.

Circadian fluctuations in plasma levels of tissue plasminogen activator antigen and plasminogen activator inhibitor activity

Abstract Daily fluctuations of t-PA antigen and PAM activity were measured in plasma samples of physically active young healthy volunteers (group 1, n = 11; age range 20–38 years) and compared to data obtained from resting patients (group 11, n = 23; age range 44–67 years) suffering from moderate valvular disease without evidence for inflammatory, neoplastic, or thrombosis-related diseases (e.g. deep vein thrombosis, coronary artery disease). t-PA antigen concentration showed a similar diurnal pattern in both study groups with the peak value at 06:00 but was significantly increased in the higher aged group at all collection times. PAM activity had its acrophase in both groups at or around 03:00 but no age-dependent differences could be demonstrated. t-PA antigen as well as PAI-1 activity fluctuations conserved their typical pattern despite differences in physical activity in the study groups.

Tissue-type plasminogen activator and Type-1 plasminogen activator inhibitor in patients with coronary artery disease — Relations to clinical variables and cardiovascular risk factors

Summary In this study we investigated associations of the fibrinolytic parameters t-PA antigen and PAI-1 activity in 317 patients with angiographically proven coronary artery disease with gender, age classes, angiographic extent of disease, symptom class and history of myocardial infarction as clinical parameters, as well as with the established cardiovascular risk factors: smoking, arterial hypertension, cholesterol levels, triglyceride levels, obesity and diabetes mellitus, by use of univariate and multifactorial analysis, respectively. While PAI-1 activity was only associated with unstable angina, t-PA antigen was significantly associated with hypertriglyceridemia, unstable angina, and angiographic extent of disease.

Modulation of heparin cofactor II activity by glycosaminoglycans and adhesive glycoproteins

Heparin cofactor II (HCII) is a specific thrombin inhibitor; its inhibitory activity is stimulated by heparin (Hep) and dermatan sulfate (DS). Vitronectin (VN), a heparin binding adhesive glycoprotein present in plasma and extracellular matrix, has been shown to decrease the stimulatory effect of Hep but not of DS on thrombin inhibition by HCII (Preissner and Sié, 1988). We analyzed the effect of glycosaminoglycans (GAGs) and GAG-binding proteins on the HCII/thrombin interaction in more detail. HCII was purified from the supernatant of barium citrate adsorbed normal human plasma by polyethylene glycol precipitation followed by affinity chromatography on heparin-Sepharose CL-6B and ion-exchange chromatography on a QAE-Sephadex A-50. Inhibition of thrombin by HCII was studied in the absence and presence of GAGs (hep 0.03-30 micrograms/ml, DS 0.05-50 micrograms/ml, heparan sulfate (HS) 0.05-50 micrograms/ml) in a chromogenic substrate assay using S-2366 as a thrombin substrate. The effects of VN and fibronectin (FN) on HCII stimulation by GAGs were determined. In addition to Hep and DS the inhibitory effect of HCII was stimulated by HS, however, to a lesser extent. Using 0.03U/ml thrombin and 1nM HCII the stimulatory effect of GAGs was completely inhibited when Hep (less than or equal to 0.3 micrograms/ml) was preincubated with VN (60 micrograms/ml) and decreased to less than 50% when HS (50 micrograms/ml) was preincubated with VN (60 micrograms/ml). VN had no effect on DS as already described previously.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative cross-over study of the effects of lisinopril and doxazosin on insulin, glucose and lipoprotein metabolism and the endogenous fibrinolytic system

Summary Objective: The present study was performed to compare the effects of the alpha-1-blocker doxazosin (4 mg/d) with the ACE-inhibitor lisinopril (10 mg/d) in a cross-over study on plasma levels of metabolic and fibrinolytic parameters. Patients, methods: In 10 male patients with upper body obesity, proven stable coronary artery disease and hypertension, measurements included baseline determination of lipoproteins and fibrinolytic parameters and determinations of glucose and insulin during intravenous glucose tolerance tests after two 12-week treatment periods. Results: Basal insulin levels were significantly decreased by both doxazosin and lisinopril (from 15.5±3.5 μU/ml to 11.6±2 μU/ml, P≤0.05 and from 16.5±2.8 μU/ml to 11.2±2.4 μU/ml, P≤0.001; respectively). Lisinopril decreased the area under the insulin-concentration time curve by 31.9% (P≤0.007) as compared to 23.6% (n.s.) after doxazosin treatment. HDL-cholesterol was increased by lisinopril from 38±3.5 to 43.5±4.4 mg/dl (P≤0.05), t-PA antigen was increased by doxazosin from 8.3±0.7 to 11.4±1.6 ng/ml (P≤0.05) and PAI-1 was not affected by either therapy. Conclusion: These potentially favorable effects on insulin and lipid metabolism and the endogenous fibrinolytic system might contribute to a higher efficacy of antihypertensive treatment in patients with coronary artery disease and accompanying metabolic cardiovascular risk factors.