Effect of PAI-1 levels on the molar concentrations of active tissue plasminogen activator (t-PA) and t-PA/PAI-1 complex in plasma

Abstract

We determined the in vivo molar concentrations of active tissue plasminogen activator (t-PA), active plasminogen activator inhibitor type 1 (PAI-1), and t-PA/PAI-1 complex. t-PA activity was measured in plasma stabilized by immediate acidification. PAI-1 activity and t- PA/PAI-1 complex antigen were measured in citrated plasma; these measurements were corrected for the loss in PAI-1 activity and increase in complex that occurs in unacidified plasma samples due to the continued reaction between t-PA and PAI-1 after the sample was drawn. To convert t-PA and PAI-1 activity measurements into molar concentrations we determined the specific molar activity of t-PA and PAI-1 in vivo: 4.48 x 10(13) IU/mol. Of 72 subjects studied, 13 had less than 150 pmol/L active PAI-1; in these individuals 33% +/- 21% of their t-PA was active and the molar ratio of active t-PA to active PAI- 1 was 0.20 +/- 0.13. In the 11 subjects with greater than 500 pmol/L active PAI-1, 1.5% = 1.1% of the t-PA was active and the molar ratio of active t-PA to active PAI-1 was 0.0043 +/- 0.0036. Overall, the fraction of active t-PA declined exponentially as a function of the active PAI-1 concentration. During the day, the percentage of total t- PA that was active increased from 12% at 8:00 AM to 31% at 8:00 PM, while the molar ratio of active t-PA to active PAI-1 increased from 0.05 to 0.22 from morning to evening (n = 12).

Plasma Levels of Total Plasminogen Activator Inhibitor-I (PAI-I) and tPA/PAI-1 Complex in Patients With Disseminated Intravascular Coagulation and Thrombotic Thrombocytopenic Purpura

“…plasma, PAI-1 forms stable stoichiometric complexes with tPA (6). As PAI-I levels rise in plasma, jthe fraction of tPA in the active form falls while the 'issue-type activator/plasminogen activator inhibitor-I (tPA/PAI-1) complex levels rise (7,8). The increase in tPA/PAI-I complex levels correlates with the increase in the levels of PAI-I. Disseminated intravascular coagulation (DIC) is characterized by generation and deposition of fibrin in the microvasculature of various organs, which is believed to be an important contributing factor for the development of multiple organ failure (MOF) (9).…”

Intracellular signaling mechanisms of sex hormones in acute myocardial inflammation and injury

“…After one month, eight women had lower PAI-1 activity and seven had marginally greater t-PA activity. The ratio of t-PA to PAI-1 activity, as a measure of fibrinolytic potential (298), increased six to 650 percent in all nine women, whereas no significant change for the group was seen in coagulation activation markers prothrombin fragments 1 and 2 levels or in levels of thrombinantithrombin. This study, although small, suggests that coagulation activation by estrogen is not necessary for the increased potentiation of fibrinolysis (278).…”

Plasminogen Activator Inhibitor Type 1: Biochemistry and Evidence for Modulation of Fibrinolysis In Vivo

“…t-PA activity has a diurnal variation with highest levels detected in the afternoon, which may be due to decreased secretion of PAI-1. 116,119,120 PAI-1 activity is higher in men than in women 44,113,120 and increases with age. 113,118 PAI-1 activity is correlated with triglycerides [121][122][123] and obesity 124 as well as exer cise status 125 and is inversely correlated with levels of high density lipoprotein and with t-PA activity.…”

“…15,112 The venous occlusion test, in which the forearm is occluded for 10 or 20 minutes with the blood pressure cuff midway between the systolic and diastolic blood pressure is one way by which to determine if the t-PA can be released normally from the endothelium. 114,115 Venous occlusion does not cause a significant increase in PAI-1 antigen, 116,117 but induces a 10-to 20-fold in crease in t-PA antigen and activity. 118 Although PAI-1 antigen, which includes the level of active PAI-1 and PAI-1 complexed to t-PA, remains unchanged, the active PAI-1 may be neutralized by the increased t-PA. 116 Multiple factors influence the levels of t-PA and PAI-1 in plasma.…”

“…114,115 Venous occlusion does not cause a significant increase in PAI-1 antigen, 116,117 but induces a 10-to 20-fold in crease in t-PA antigen and activity. 118 Although PAI-1 antigen, which includes the level of active PAI-1 and PAI-1 complexed to t-PA, remains unchanged, the active PAI-1 may be neutralized by the increased t-PA. 116 Multiple factors influence the levels of t-PA and PAI-1 in plasma. t-PA activity has a diurnal variation with highest levels detected in the afternoon, which may be due to decreased secretion of PAI-1.…”