SummaryThe association of increased PA-inhibitor (PAI) activity and of PAI-1 and PAI-2 antigen levels with different pathological conditions was studied in a collective of over 300 patients. PAI-1 and PAI-2 levels were measured by specific radioimmunoassays. A good correlation was observed of PAI activity with PAI-1 antigen (r = 0.718; p <0.0001) but not with PAI-2 (r = 0.070; n.s.). Both in the controls and in the patients, PAI activity and PAI-1 antigen showed an extremely large range of values. PAI activity ranged from 0.5 to 68 U/ml and PAI-1 antigen from 6 to 600 ng/ml. Increased PAI activity and PAI-1 antigen was observed in patients with malignant tumors, cardiovascular or thromboembolic disease, in the postoperative phase, with hepatic insufficiency, after trauma and after extracorporeal circulation. The large spectrum of disease states with increased PAI activity and PAI-1 antigen reinforces previous suggestions that PAI-1 is an acute phase reactant. After extracorporeal circulation, PAI activity and PAI-1 concentrations strongly increased within one hour, remained elevated for at least one week and returned to preoperation values within 7 days.PAI-2 values ranged from below detection limit (15 ng/ml), observed in half of the plasmas, to 485 ng/ml in a pregnant woman. High values of PAI-2 were only observed in pregnancy.

During pregnancy the plasma concentration of two different inhibitors of plasminogen activators (PAIs) increases. The only one found in the plasma of nonpregnant women (PAI1) is immunologically related to a PAI of endothelial cells; its plasma activity, as deduced from the inhibition of single-chain tissue-type plasminogen activator (t-PA), increased from 3.4 +/- 2.3 U/mL (mean +/- 95% confidence limits) in the plasma of nonpregnant women to 29 +/- 7 U/mL at term, and its antigen level, measured by a radioimmunoassay, increased from 54 +/- 17 ng/mL to 144 +/- 25 ng/mL. In pregnancy plasma a second PAI (PAI 2) related to a PAI found in placenta extracts was observed. Its level, quantified with a radioimmunoassay, increased from below the detection limit (approximately 10 ng/mL) in normal plasma to 260 ng/mL at term. One hour after delivery, PAI 1 activities and antigen decreased sharply, but the PAI 2 antigen levels remained constant. Three days later, the PAI 1 antigen levels had fallen to normal levels, but the PAI 2 antigen levels were still at least eightfold above the nonpregnant values. During pregnancy, the t-PA and prourokinase (u-PA) antigen concentrations increased 50% and 200%, respectively, whereas the plasminogen and alpha 2-antiplasmin levels remained constant. Despite the large variations in the levels of PAs and PAIs, the overall fibrinolytic activity as measured in diluted plasma by a radioiodinated fibrin plate assay did not change significantly. Just after delivery, a great increase in the t-PA antigen levels was observed. Three to five days after delivery most parameters of the fibrinolytic system were normal again. Our results demonstrate that during pregnancy and in the puerperium profound alterations of the fibrinolytic system occur that are characterized by increases in PAs and their inhibitors, but these alterations do not affect the overall fibrinolytic activity.

The activity of plasminogen activators (PA) is regulated in part by PA-inhibitors. Two distinct PAIs have been identified: PAI-1 and PAI-2. To be able to measure these proteins specifically we have purified PAI-1 and PAI-2, raised antisera and developed specific radioimmunoassays (RIAs), with detection limits in plasma of 10 and 15 ng/ml, respectively.In a population of over 350 individuals, PAI activity correlated well with PAI-1 :Ag (r=0.699), but not with PAI-2:Ag (r=0.070). In healthy individuals PAI-1 concentrations varied considerably (between 10 and 85 ng/ml, median 29 ng/ml). During venous occlusion (VO) applied in 40 healthy individuals, average PAI-1 in plasma increased fran 27 before, to 43 and 59 ng/ml after 10 and 20 min VO (p <0.001, Wilcoxon test). Overall fibrinolytic activity increased 15 fold, and t-PA:Ag levels eightfold. Increased PAI activity and PAI-1 antigen levels with respect to controls were found in patients with cardiovascular or thromboembolic disease, malignancies, hepatic insufficiency, after major trauma and in the postoperative period. This wide spectrum of pathologies with increased PAI-1 levels supports previous suggestions that PAI-1 behaves as an acute phase reactant. In patients undergoing extracorporeal circulation PAI activity and PAI-1 antigen were measured before and 1 h, 1 d and 7 d after the operation. Highest values of activity and antigen were observed 1 h postoperatively. These values remained elevated the day after the operation, but returned to preoperative levels within 7 days.PAI-2 antigen concentrations were at or below the detection limit in all controls and the majority of patients. Very high levels of PAI-2 (above 30 ng/ml) were only observed in pregnant women and in patients with hepatocellular carcinoma.The specific measurement of PAIs thus show increased levels in a variety of clinical conditions. The availability of specific RIAs permits to conduct prospective studies and to evaluate to what degree elevated PAI-1 and PAI-2 concentrations are correlated with the stage of the disease, its prognosis and the risk to develop thromboembolic complications.