Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infectious hepatitis

Plasma concentrations of tissue-type plasminogen activator (t-PA), urokinase (u-PA), plasminogen activator inhibitor 1 (PAI-1) and PAI-2 were studied in 53 patients with liver deficiency caused by chronic alcoholism (n = 40), viral hepatitis (n = 10) or malignant disease of the liver (n = 3) and compared to that of a control group (n = 20) of healthy subjects. u-PA and PAI-1 levels were significantly increased in all patients with chronic alcoholism, whereas high t-PA was only observed in combination with disturbed liver function tests or with liver cirrhosis (two and six-fold above control values, respectively). A good correlation was observed between t-PA and gamma glutamyl transferase (r = 0.615; p less than 0.001). In patients with infectious hepatitis or with malignant disease of the liver t-PA was normal whereas u-PA and PAI-1 were increased. PAI-2 levels were close to or below the detection limit (15 ng/ml) in the control group and in most patients. However, in two patients with alcohol induced cirrhosis PAI-2 levels were approximately 45 ng/ml and in one patient with hepatocarcinoma even 66 ng/ml. Thus, in liver disease, marked elevations of t-PA, u-PA and PAI-1 levels may occur, with increased PAI-1 as an early marker of liver defects and t-PA a marker of severe liver defects.     

Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states

The 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 less than 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.     

Detection of both type 1 and type 2 plasminogen activator inhibitors in human monocytes

Increasing evidence suggests the involvement of leukocytes in the fibrinolytic system. Monocytes secrete pro-urokinase (Grau, Thromb Res 1989; 53: 145) and it has been shown that these cells have specific receptors for urokinase and plasminogen (Miles, Thromb Haemostas 1987; 58: 936). The aim of this study was to analyse the presence of plasminogen activator inhibitor(s) in platelet-free suspensions of human peripheral blood monocytes and polymorphonuclear leukocytes (PMN). SDS-PAGE and reverse fibrin autography showed an inhibitory band of 50 kDa in the monocyte extracts (Triton X-100) but not in the PMN extracts. Urokinase (u-PA) was mixed with increasing amounts of monocyte extract for 10 min and the mixtures were added to 125I-fibrin coated wells containing plasminogen. A dose-dependent decrease in the u-PA fibrinolytic activity was observed. The amount of inhibition increased when the monocyte releasates were preincubated with u-PA (40% inhibition after 5 min preincubation and 80% after 15 min), indicating a direct interaction between this activator and an inhibitor(s). After SDS-PAGE of monocyte extracts, immunoblotting and peroxidase staining identified both PAI1 and PAI2, with an apparent molecular weight of 47-50 kDa. Monocyte-associated PAI1 formed complexes with single chain t-PA with a molecular mass 50 kDa higher than the molecular mass of the free PAI1. However, a significant amount of PAI1 remained unbound to t-PA. This inactive PAI1 could have come from a rapid inactivation of the primary active PAI1. These PAI1 and PAI2 detected in human monocytes may be transcendent in the regulation of the fibrinolytic system.     

Plasminogen activator inhibitor-1 is the primary inhibitor of tissue-type plasminogen activator in pregnancy plasma

The aim of the present work was to clarify to what extent plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) contribute to the increase in plasma inhibition of tissue-type plasminogen activator (t-PA) observed during pregnancy. It was demonstrated that a monoclonal antibody against PAI-1 almost completely quenched inhibition of single-chain t-PA and most of the inhibition of two-chain t-PA in plasma during the third trimester of pregnancy. The remaining inhibition of two-chain t-PA was to a great extent abolished by a PAI-2 antibody. The second order rate constant (k1) for inhibition of single-chain t-PA by the inhibitor neutralized by the PAI-1 antibody was about 4.8.10(6) M-1.s-1. The conversion of single-chain t-PA to the two-chain form increased the reaction rate with the inhibitor about 3-fold. These kinetic data are comparable with those obtained with PAI-1 in non-pregnancy plasma or with purified PAI-1. From the above results it is concluded that PAI-1 is the primary inhibitor of both single-chain and two-chain t-PA and that PAI-2 is the secondary inhibitor of two-chain t-PA in pregnancy plasma. The concentration of reactive PAI-1 versus gestation age was assayed in plasma from 6 women by binding of PAI-1 to 125I-labelled single-chain t-PA followed by quantitation of the labelled t-PA-PAI-1 complex after separation by SDS-polyacrylamide gel electrophoresis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of plasminogen activator inhibitors type 1 and type 3 and urokinase plasminogen activator protein and mRNA in breast cancer

BACKGROUND: The urokinase plasminogen activator (uPA) system has been involved in cancer cell invasion and in metastasis. uPA activity is controlled by its principal inhibitor, the PA inhibitor type-1 (PAI-1), but it can also be inhibited by PAI-3. Increased levels of uPA and PAI-1 are known to be associated with a poor prognosis in breast cancer. To our knowledge this is the first study of the expression and role of PAI-3 in human breast cancer tissue. MATERIALS AND METHODS: Protein and mRNA levels were evaluated for uPA, PAI-1 and PAI-3 in breast cancer tissues from 70 different patients. The localization of antigen and mRNA of these proteins was studied by immunohistochemistry and in situ hybridization, respectively. RESULTS: No significant differences were observed for PAI-3 mRNA or protein levels between the nodal status groups or the different post-surgical tumor-node-metastasis (pTNM) stages. However, uPA and PAI-1 mRNA and antigen levels significantly increased at the pTNM stage and in node-positive patients. PAI-3 antigen levels were significantly higher in early relapse-free patients, whereas PAI-1 antigen levels were significantly higher in patients who suffered a relapse. PAI-3 protein and mRNA were localized in stromal cells. PAI-1 and uPA protein were detected in cancer, endothelial and stromal cells and their mRNA mainly in stromal cells. CONCLUSIONS: Our results indicate that PAI-3 is expressed in human breast cancer tissues, and that elevated levels of PAI-3 could be a positive prognostic factor in this disease. A potential mechanism for the contribution of PAI-3 to a positive long-term outcome may involve suppression of tumor invasion through protease inhibition in stroma.     

Source of increased plasminogen activators during pregnancy and puerperium

We investigated the increase of plasminogen activators (tPA and uPA) in the plasma during pregnancy. Both tPA and uPA antigens were found to increase after the third trimester of pregnancy and high levels of PAs persisted through the first stage of labor. The tPA antigen levels rose further for the first few hours post-partum, while the level of uPA antigen returned to normal immediately following childbirth. To clarify whether the uterus and/or placenta are involved in the increased levels of plasma PAs, the levels were measured in uterine venous blood in cases of caesarean sections. During the ante-partum period, the level of uPA antigen in the uterine venous blood was higher than that in the peripheral venous blood, while there was no significant difference between the levels of tPA antigen in peripheral blood and uterine venous blood. The level of tPA antigen in the uterine venous blood rose after delivery. In contrast, the level of uPA antigen declined immediately after delivery. These results suggest that (1) the placenta is the major source of the increased uPA antigen during pregnancy, (2) entire vascular system is involved in the increased tPA antigen during pregnancy, (3) a further increase in tPA after delivery is due to the release of this enzyme from the involuting uterus.     

Plasminogen activator inhibitor type 2 inhibits cell surface associated tissue plasminogen activator in vitro: potential receptor interactions

Regulation of cellular plasminogen activation is necessary for maintenance of tissue homeostasis. Despite increasing evidence for co-expression of tissue type plasminogen activator (tPA) and plasminogen activator inhibitor type-2 (PAI-2; SERPINB2) under patho/physiological conditions, the inhibition of cell-bound tPA mediated plasminogen activation by PAI-2 has not been addressed. Here we show that PAI-2 can inhibit cell-bound tPA activity in vitro and thus prevent plasmin formation. We also examined the potential involvement in this inhibition of the annexin II heterotetramer (AIIt), one of the many well characterized cell-surface co/receptors for tPA and plasminogen that efficiently promotes plasminogen activation. This receptor was of interest because AIIt has also been shown to directly bind PAI-2. Characterization of these potential interactions using purified protein systems revealed that PAI-2 directly bound AIIt via the p11 (S100A10) subunit. However, PAI-2 prevented AIIt/tPA-mediated plasminogen activation by its classic serpin inhibitory activity rather than through competition with tPA/plasminogen for binding. Further analysis showed that PAI-2 inhibited cell bound tPA-induced plasmin activity in both an AIIt-dependent and -independent manner. These data open new possibilities for further investigations regarding the regulation of cellular plasmin generation in vivo, especially in tissues where PAI-2 and tPA may be co-expressed.     

Plasminogen activators and plasminogen activator inhibitor 1 before and after venous occlusion of the upper limb in thromboangiitis obliterans (Buerger's disease).

Plasma levels of plasminogen activators (t-PA, u-PA) and their inhibitor (PAI-1) were studied in patients suffering from Buerger's disease and healthy volunteers before and after 15 minutes of venous occlusion test. The baseline levels of t-PA in group of patients did not differ from those of controls. On the contrary patients with Burger's disease showed a marked increase in u-PA antigen concentrations with concomitant decrease in PAI-1 antigen levels. During venous stasis t-PA antigen concentrations increased in all subjects, however it was much pronounced in controls. Venous occlusion resulted in significant decrease in free PAI-1 levels in the group of patients only. In conclusion, Buerger's disease is associated with the endothelial derangement with increased u-PA release and decreased PAI-1 release, which does not influence the function of fibrinolytic system. The fact that the reduced response of the endothelium to release t-PA after venous stasis goes in parallel with marked decrease in PAI-1 antigen levels seems to suggest that patients suffering from Buerger's disease are not at high risk of intravascular fibrin deposition.     

Secretion of tissue plasminogen activator and plasminogen activator inhibitor 1 during cardiopulmonary bypass

INTRODUCTION: Cardiopulmonary bypass (CPB) is associated with elevated tissue plasminogen activator (t-PA) levels during CPB and increased plasminogen activator inhibitor 1 (PAI-1) levels post-operatively. The goal of this study was to estimate the rate of t-PA and PAI-1 secretion in vivo, before, during and after CPB. MATERIALS AND METHODS: Estimated rates of t-PA and PAI-1 secretion were based on measured levels of active and total t-PA, and active and total PAI-1, obtained before, during and after CPB from nine males, combined with a computer model of each patient's vascular system that continuously accounted for secretion, clearance, hemodilution, blood loss and transfusion. RESULTS AND CONCLUSIONS: At baseline, the average t-PA and PAI-1 secretion rates were 0.74+/-0.33 and 1.28+/-0.74 pmol/s, respectively. Within 5 min of CPB initiation, t-PA secretion increased six-fold to 4.41+/-2.58 pmol/s, while PAI-1 secretion was unchanged, resulting in a six-fold increase in active t-PA levels. t-PA secretion remained elevated throughout CPB and into the early post-operative period. Average PAI-1 secretion did not start to increase until the end of CPB. By 2 h after surgery, average PAI-1 secretion had increased 15-fold to 19.60+/-17.10 pmol/s, resulting in reduced levels of active t-PA even though t-PA secretion was still elevated. We conclude that CPB induces an immediate sustained increase in t-PA secretion followed by a delayed progressive increase in PAI-1 production. Variations in the level of active t-PA are a function of the relative rates of t-PA versus PAI-1 secretion at different times during and after surgery.     

Plasminogen and tissue plasminogen activator interact with antithrombin III

Human antithrombin III was demonstrated to bind plasminogen specifically in a time and concentration-dependent manner. The above binding was also confirmed using ligand western blot assays. The interaction of plasminogen was significantly (>90%) inhibited by lysine, indicating the involvement of kringles in binding antithrombin III. Plasminogen also bound to heparin-antithrombin III complex. In converse experiments, antithrombin III also interacted with immobilized plasminogen. Using carboxypeptidase B digestion, the plasminogen-binding site of antithrombin III was localized to the carboxy-terminus lysine of the anticoagulant protein. Tissue plasminogen activator also interacted with antithrombin III in a time- and concentration-dependent manner and its binding was also significantly (>90%) inhibited by lysine. Moreover, the interaction of plasminogen and tissue plasminogen activator with antithrombin III was competitive. These results provide the first evidence for the interaction of antithrombin III with fibrinolytic factors and suggest that antithrombin III may serve to localize these factors at the site of clot formation.     

Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis

The role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis mediated by plasminogen activation was studied with the use of aorticVSMC derived from mice with deficiency of PAI-1 (PAI-1 (-/-) ), tissue-type (t-PA (-/-) ) or urokinase-type (u-PA (-/-) ) plasminogen activator or from wildtype (WT) mice with corresponding genetic background. Plasminogen incubated with confluent VSMC was activated in a concentration-dependent and saturable manner for all four cell types, with maximal activation rates that were comparable for WT, u-PA (-/-) and t-PA (-/-) cells, but about two-fold higher for PAI-1 (-/-) cells. Plasminogen activation was impaired by addition of the lysine analogue 6-aminohexanoic acid, and by addition of t-PA and u-PA neutralizing antibodies, suggesting that it depends on binding to cell surface COOH-terminal lysine residues, and on plasminogen activator activity. Morphological alterations consistent with apoptosis were observed much earlier in PAI-1 (-/-) than in WT VSMC. Without addition of plasminogen, the apoptotic index was similar for all four cell types, whereas after incubation with physiological plasminogen concentrations, it was greater in PAI-1 (-/-) VSMC, as compared to WT, t-PA (-/-) or u-PA (-/-) VSMC. Furthermore, the apoptotic rate paralleled the release of plasmin. Thus, plasmin-mediated apoptosis of VSMC occurs via plasminogen activation by either t-PA or u-PA and is impaired by PAI-1.     

Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease

We have studied the activation state of the fibrinolytic system in 39 patients with systemic meningococcal disease (SMD). Patients defined as having fulminant septicemia (n = 13) with high (greater than 700 ng/L) levels of endotoxin (LPS) in plasma and severe coagulopathy, had significantly lower functional levels of plasminogen (P less than 0.05) and alpha-2-antiplasmin (P less than 0.01) and higher antigen levels of plasminogen activator inhibitor 1 (PAI-1) (P less than 0.01), and fibrin degradation products (FDP) (P less than 0.01), but not of PAI-2 (P greater than 0.1) as compared with less severely ill patients (meningitis and meningococcemia) (n = 25). A positive correlation existed between the admission (maximum) levels of LPS and PAI-1 (r = 0.86, P less than 0.0001). Decreasing admission levels of platelets were associated with increasing levels of PAI-1 (r = -0.55, P less than 0.001). After initiation of treatment with antibiotics and fresh frozen plasma, the PAI-1 levels declined rapidly. PAI-1 levels greater than 360 micrograms/L on admission predicted the development of a severe septic shock combined with renal impairment correctly in 12 of 13 patients (92%). None of 25 patients without multiple organ failure had PAI-1 levels greater than 260 micrograms/L. PAI-1 levels greater than 1850 micrograms/L were associated with 100% fatality. The results suggest that in the early phase of fulminant meningococcal septicemia an extensive plasmin generation occurs. On admission, however, high levels of PAI-1 seem to inhibit the plasmin generation, and thereby promote DIC.     

The fast inhibitor of tissue plasminogen activator in plasma during pregnancy

The novel fast inhibitor to tissue plasminogen activator in plasma has been determined in 20 healthy non-pregnant women, 48 apparently healthy pregnant women and 136 women with risk pregnancies (preeclampsia, suspected fetal growth retardation, thrombosis or previous history of thrombosis, diabetes and others). In healthy fertile non-pregnant women, the inhibitor concentration was found to be 0.4 +/- 0.7 U/ml. In pregnant women the concentration stayed at this level until week 10, but then an almost linear increase was found, reaching about 6.5 U/ml at week 40. In plasma samples from the patients with risk pregnancies many with deviating concentrations were found. Thus, in the last trimester a range of 0-24.0 U/ml was found in these patients, as compared to 4.0-6.4 U/ml in healthy pregnant women. The pathophysiological impact of this finding is at present unclear.     

Activation of coagulation in amniotic fluid during normal human pregnancy

Introduction

Amniotic fluid (AF) is an important medium for fetal development which exhibits high procoagulant activities; however, the role of these procoagulants during pregnancy has not been elucidated and might be associated with pregnancy complications. The current study aimed to evaluate factor X (FX) activation and its association with tissue factor (TF), tissue factor pathway inhibitor (TFPI) and coagulation activation markers in AF during normal human pregnancy.

Methods

Activation of FX and concentration of TF, free TFPI, D-dimer and prothrombin fragments (F1 + 2) were evaluated in AF samples obtained for chromosome analysis from 91 women with normal pregnancy: 65 samples were taken from patients at 16-20 weeks of gestation, 9 samples were drawn at 21-30 weeks and 17 samples−after 30 weeks of gestation.

Results

Activation of FX in AF significantly increased during normal pregnancy (from 65 ± 41 to 205 ± 80 equivalent RVV ng/mg total protein, P < 0.0001). TF and TFPI levels in AF also rose with gestational age. In contrast, the AF concentration of D-dimer and F1 + 2, markers of coagulation activation significantly decreased when expressed per mg total protein. Levels of free TFPI correlated with TF (r = 0.5, P < 0.001), and were 8-fold higher than those of TF during pregnancy.

Conclusion

High levels of TFPI might be associated with the inhibition of procoagulant activity in amniotic fluid during normal pregnancy, which may account for the rarity of clinical amniotic fluid embolism.     

A plasminogen activator inhibitor (PAI-2) circulates in two molecular forms during pregnancy

During normal pregnancy maternal haemostasis alters to protect against bleeding with a rise in plasma clotting factor levels and increased inhibition of fibrinolysis. The latter is due in part to increased levels of the 48 kDa plasminogen activator inhibitor (PAI-1) present in the plasma of non-pregnant individuals. A second plasminogen activator inhibitor (PAI-2) occurs in placenta and in a cultured histiocytic lymphoma cell line. We report here the identification by SDS-PAGE and zymography of PAI-2 in plasma during normal pregnancy. PAI-2 was present in two molecular forms of about 75 and 130 kDa, which were detectable at 12 weeks gestation and which persisted in the maternal circulation for up to 7 days after delivery. These forms of PAI-2 appear to be distinct from purified PAI-2, which has a molecular mass of 47-60 kDa and which is not normally detectable in this zymographic system, since it is sensitive to denaturants. The novel forms of PAI-2 may represent complexes or aggregates that retain activity after SDS-PAGE.     

Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes.

Two plasminogen activators (PAs): tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as the type-1 plasminogen activator inhibitor (PAI-1) are synthesized and secreted by rat astrocytes. Preliminary studies suggest that PA activity plays a role in astrocyte development and differentiation. We have examined the regulation of the PA system by the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in purified rat astrocyte cultures. PKA activity was increased by exposing cultured astrocytes to forskolin or dibutyryl cyclic AMP, whereas PKC activity was stimulated with phorbol-12-myristate 13-acetate (PMA). Activation of both second-messenger pathways produced a time- and dose-dependent increase in the total PA activity. However, based on SDS-PAGE/zymography we found that forskolin increased t-PA activity and reduced u-PA activity, whereas PMA treatment caused a significant increase in u-PA activity without altering t-PA activity. Reverse zymography analysis revealed that astrocyte PAI-1 activity is decreased by forskolin and increased by PMA. Together, these results demonstrate that the components of the PA system in rat astrocytes are independently and reciprocally regulated by PKA and PKC. Our findings raise the possibility that the plasminogen activator system could be involved in some of the actions of growth factors and/or neuromodulators that modulate PKC or PKA in astrocytes.     

The effect of insulin treatment on the balance between tissue plasminogen activator and plasminogen activator inhibitor-1 in type 2 diabetic patients.

Beside hypercoagulation and hyperactivated platelets disturbances of the fibrinolytic system towards hypofibrinolysis have been reported to be associated with both glycemic and lipidemic derangement in diabetic patients. In the present prospective follow-up study the effect of 16 weeks insulin treatment and glycemic regulation on plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), the main regulators of fibrinolysis, was investigated in 19 type-2 diabetic patients with secondary failure to sulphonylureas. A similar glycemic regulation was obtained in a control group of 10 type 2 diabetic patients with sufficient metabolic response to strict dietary treatment and continuation of sulphonylurea treatment. Compared to 27 healthy subjects levels of tPA and PAI-1 were not significantly increased in type 2 diabetic patients before metabolic intervention. Although a hypofibrinolytic state due to an increase of PAI-1 levels was previously reported in obese hyperinsulinemic patients, no effect of insulin treatment on both tPA- and PAI-1 levels was observed in the present study including patients with only slightly increased body mass index (median 26.0 kg/m2). By correlation analysis PAI-1 levels were significantly related to serum cholesterol (R = 0.52) and glycemic control (glucose R = 0.41) in the whole group of diabetic patients at entry and in both subgroups after 16 weeks of treatment (insulin group: cholesterol R = 0.46, HbA1c R = 0.51; sulphonylurea group: cholesterol R = 0.59, HbA1c R = 0.58). In healthy subjects tPA and PAI-1 was correlated to serum insulin (R = 0.54, R = 0.56) and triglycerides (R = 0.46, R = 0.40).(ABSTRACT TRUNCATED AT 250 WORDS)     

Tissue-type plasminogen activator, type 1 plasminogen activator inhibitor and their complex in plasma with disseminated intravascular coagulation.

The levels of tissue-type plasminogen activator (t-PA), type 1 plasminogen activator inhibitor (PAI-1), and t-PA/PAI-1 complex antigens were analyzed in the plasma of disseminated intravascular coagulation (DIC) patients and healthy controls. Other fibrinolytic parameters such as the levels of plasminogen, alpha 2-antiplasmin (alpha 2-AP), plasmin/alpha 2-AP (PAP), and D-dimer were also estimated to clarify the fibrinolytic states in these plasmas. The antigens of t-PA, PAI-1, and t-PA/PAI-1 complex were found to increase from 8.5 +/- 4.3, 54.4 +/- 21.2, and 8.6 +/- 3.5 ng/ml in normal plasma to 36.4 +/- 25.1, 106.8 +/- 54.7, and 46.6 +/- 34.5 ng/ml in DIC plasma, respectively. The molar ratio of total t-PA to total PAI-1 was 1:6 and 1:3 in normal plasma and DIC plasma, respectively, indicating an enhanced fibrinolytic state in the DIC plasma. The DIC plasma revealed a significant consumption of plasminogen (62.1 +/- 27.8%), and alpha 2-AP (63.7 +/- 25.3%) and an increase in PAP (2.6 +/- 2.7 micrograms/ml) and D-dimer (3.9 +/- 10.7 micrograms/ml). These results suggest that the production and secretion of t-PA and PAI-1 from endothelial cells were enhanced in DIC, resulting in an increased t-PA/PAI-1 complex with dominant fibrinolytic activity.     

Plasminogen activators and their inhibitors in normal, hyperplastic and carcinomatous human endometrium

Plasminogen activators (PA) and inhibitors of urokinase were determined by a solid phase ¹²⁵I-fibrin assay in endometrial tissue homogenates from 87 patients. PA was also determined by a histochemical method. Patients were divided according to histopathological diagnosis into three groups; normal, hyperplastic and cancerous. The mean values and S.D. of PA in control endometria, in hyperplastic endometria and in endometrial cancer were 0.68 + 0.55 units per mg protein, 1.9 + 1.6 units per mg protein and 3.21 + 1.03 units per mg protein, respectively. The results of the Fistochemical assay of PA correlated with the results of ¹²⁵I-fibrin assay (R = 0.818, p<0.001). The relative PA activity of urokinase-type was the lowest in normal endometrium; it increased in hyperplastic and it was the highest in carcinomatous endometrium. The urokinase inhibitor activity was similar in control and carcinomatous groups; it was slightly but significantly higher in hyperplasia. The results support the contention that PA reflects malignant transformation of endometrial cells. We suggest that determination of PA may facilitate diagnosis and proper treatment of precancerous and cancerous states of endometrium.