Postoperative changes in plasma tissue-type plasminogen activator and type I plasminogen activator inhibitor

To clarify the changes which occur postoperatively in intravascular fibrinolysis, plasma levels of tissue-type plasminogen activator (t-PA) antigen, the total plasminogen activator inhibitor type-1 (PAI-1) antigen, and the t-PA-PAI-1 complexes were assayed in this study. Blood samples were taken the morning before surgery, then at 0, 12, 24, 36, 60, 108, and 156h postoperatively in ten patients who underwent radical surgery for thoracic esophageal cancer. The plasma levels of the t-PA and total PAI-1 antigens, and the t-PA-PAI-1 complexes were then measured by enzyme immunoassay. The plasma t-PA and total PAI-1 levels increased significantly in the immediate postoperative period, the percent increase of the latter being much greater than that of the former. Moreover, the calculated free t-PA antigen level was decreased throughout the postoperative period, suggesting postoperative hypofibrinolysis. The platelet count and neutrophil elastase level were significantly correlated with the free t-PA antigen level atr = 0.630,P < 0.001, andr = -0.447,P < 0.01, respectively. The results of this study indicated that postoperative hypofibrinolysis caused by the increased synthesis of PAI-1 may enhance postoperative hypercoagulability, and this may lead to the development of organ damage. Thus, the concentration of the PAI-1 antigen may be a potentially important index for the prediction of postoperative illness.     

Effect of dextran on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1(PAI-1) during surgery

Dextran is known to increase the plasminogen activation rate in vitro and to decrease the α₂-antiplasmin activity.
We decided to explore the effect of dextran on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1(PAI-1) during surgical trauma.
Thirty-one patients undergoing elective surgery were given 500 ml of 6% dextran 70. Another nine patients serving as controls were given 500 ml of a glucose-electrolyte solution. The activities of t-PA and PAI-1during surgery were determined, as was the concentration of t-PA antigen.
PAI-1activity was decreased by 19% after infusion of 250 ml of dextran. After 500 ml, the activity was reduced by 22% (both P <0.05). The activity of t-PA was increased by 43% and 29% (both P <0.05) and the antigenic amount of t-PA was increased by 18% and 15% (both P <0.05) after infusion of 250 ml and 500 ml of dextran, respectively. No changes in these variables were observed in the control patients.
It is concluded that infusion of dextran promotes fibrinolysis by enhancing plasminogen activation in patients subjected to trauma. Since elevated levels of PAI-1prior to surgery are known to predispose to deep vein thrombosis, which may form already during the operation, the effect of dextran on PAI-1described here may explain its clot preventing properties.     

Evaluation of chest tube administration of tissue plasminogen activator to treat retained hemothorax

Background

When retained hemothorax occurs, video-assisted thoracoscopy or thoracotomy is performed, but recently, tissue plasminogen activator (tPA) has been used. This study evaluated intrapleural tPA use for retained traumatic hemothoraces.

Methods

A retrospective review was conducted of trauma patients treated with intrapleural tPA for retained hemothorax. Data included demographics, past medical and surgical histories, injury details, treatment details, and outcomes.

Results

Seven patients (median age = 47 years, male = 6, blunt trauma = 6) met study criteria. All patients received a chest tube. Six patients later received computed tomography-guided drains for tPA infusion. Number of tPA treatments per patient varied from 1 to 5. Median total tPA dosage was 24 mg. Median time from injury to chest tube placement was 11 days and from chest tube placement to first tPA treatment was 4 days. No patients required a video-assisted thoracoscopy; however, 1 patient required thoracotomy. There were no deaths or bleeding complications attributed to intrapleural tPA.

Conclusion

Although future studies are needed to identify optimum treatment guidelines, intrapleural tPA appears to be a safe and efficacious treatment option.     

Time- and dose-related regional fluxes of tissue-type plasminogen activator in anesthetized endotoxemic pigs

Background: Acute endotoxinemia elicits an early fibrinolytic response. This study analyzes the effects of the dose and duration of endotoxin infusion on arterial levels of tissue-type plasminogen activator (tPA) and pulmonary, mesenteric and hepatic plasma tPA fluxes.
Methods: Pigs were randomized to receive an acute, high-dose (for 6 h, n =13, high ETX) or a prolonged, low-dose (for 18 h, n =18, low ETX) infusion of endotoxin or saline vehicle alone (for 18 h, n =14, control). All animals were fluid resuscitated to maintain a normodynamic circulation. Systemic and regional blood flows were measured and arterial, pulmonary arterial, portal and hepatic venous blood samples were analyzed to calculate regional net fluxes of tPA. Plasma tumor necrosis factor (TNF-α) levels were analyzed.
Results: Mesenteric tPA release and hepatic uptake increased maximally at 1.5 h in ETX groups related to dose. Maximal mesenteric tPA release [high ETX 612 (138–1185) μg/min/kg, low ETX 72 (32–94) μg/min/kg, median±interquartile range] and hepatic tPA uptake [high ETX −1549 (−1134 to −2194) μg/min/kg, low ETX −153 (−105 to −307) μg/min/kg] correlated to TNF-α levels. Regional tPA fluxes returned to baseline levels at 6 h in both ETX groups and also remained low during sustained low ETX. No changes were observed in control animals.
Conclusions: Endotoxemia induces an early increase in mesenteric tPA release and hepatic tPA uptake related to the severity of endotoxemia. The time patterns of changes in mesenteric and hepatic tPA fluxes are similar in acute high-dose endotoxemia and sustained low-dose endotoxemia.     

血清t-PA和PAI-1水平在腹腔镜手术中的临床意义

目的:探讨腹腔镜与开腹手术中血浆纤维蛋白溶酶的变化。方法:在腹腔镜与开腹手术前、术后8h分别测量血浆中组织型纤溶酶原激活物(Tissue-type p lasm inogen activator,t-PA),纤溶酶原激活物抑制物-1(P lasm inogen activator inh ib itortype-1,PAI-1)浓度。结果:血浆t-PA浓度在腹腔镜手术和传统腹部手术两组病例术后均下降,但在传统腹部手术组下降更显著(P<0.05),而血浆PAI-1浓度在腹腔镜手术和传统腹部手术两组病例术后均升高,但在传统腹部手术组升高更显著(P<0.05)。结论:本次临床研究结果表明:腹腔镜手术组术前、术后血浆中t-PA、PAI-1浓度的变化小于传统腹部手术组,腹腔镜手术组引起腹腔粘连严重程度也低于传统腹部手术组。     

Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis

PURPOSE: Urokinase-type plasminogen activator (uPA) has an important role in tumor progression through the degradation of extracellular matrix. In addition, uPA receptor (uPAR) and plasminogen activator inhibitors (PAIs), composed of PAI-1 and 2, are also known to affect such activities. Tumor associated macrophage (TAM) is an important regulator of tumor progression that is associated with the uPA system in various cancers. However, to our knowledge the clinical significance of PAI-2 and the relationship between the uPA system and TAM in human renal cell carcinoma (RCC) tissues have not been investigated. We investigated and clarified these issues. MATERIALS AND METHODS: The subjects of the current study were 106 consecutive surgically resected specimens from patients with RCC. The expression of uPA, uPAR, PAI-1 and PAI-2 was determined by immunohistochemistry. We also examined the relationships among these molecules, survival and TAM. RESULTS: The mean immunoreactive scores (range 0 to 6) of uPA, uPAR, PAI-1 and PAI-2 were 3.09, 2.22, 1.99 and 0.56, respectively. These scores correlated with the grade and presence of metastasis. The expression of uPA, uPAR and PAI-1 but not PAI-2 correlated negatively with cause specific survival. Of uPA family members multivariate analysis showed that PAI-1 independently influenced cause specific survival. TAM counts correlated with PAI-1 only (p <0.001). CONCLUSIONS: Our results suggest that PAI-1 is an important regulator of tumor progression and survival, and PAI-1 may modulate them via TAM. On the other hand, PAI-2 has a minimum role in survival. Our results may help discussions of treatment strategy in patients with RCC.     

纤溶酶原激活物抑制物1与肝细胞癌

目的研究纤溶酶原激活物抑制物１（ＰＡＩ１）在肝细胞癌（ＨＣＣ）蛋白和ｍＲＮＡ水平的表达及其与ＨＣＣ生物学特性的关系。方法取ＨＣＣ石蜡标本４８例,肝良性肿瘤石蜡标本１２例（对照组）做免疫组化染色;液氮冻存ＨＣＣ标本２０例,肝血管瘤５例（对照组）做免疫印迹杂交。结果肝癌细胞与癌周细胞及对照组肝细胞相比,ＰＡＩ１抗原蛋白和ｍＲＮＡ表达显著升高,差异有显著意义,Ｐ值分别＜００１和＜０．０５。术后２年内死亡病例与生存病例相比,ＰＡＩ１阳性率有显著意义的升高,Ｐ＜００５。ＰＡＩ１和纤溶酶原激活物（ｕＰＡ）及其受体（ｕＰＡＲ）同时阳性患者与同时阴性患者相比,前者侵袭性病例较后者升高有显著性意义（Ｐ＜００５）。结论ＨＣＣ中ＰＡＩ１蛋白和ｍＲＮＡ表达明显增高。ＰＡＩ１与ＨＣＣ浸润转移和预后密切相关。     

The significance of tissue-type plasminogen activator for pretransplant assessment of liver graft viability: analysis of effluent from the graft in rats

We studied the significance of tissue-type plasminogen activator (tPA) on the pretransplant assessment of liver graft viability in rats. The liver grafts were excised from the rats and then divided into two groups. Group 1 consisted of grafts preserved for 4 h in chilled, lactated Ringer's solution (4°C) and group 2 consisted of grafts preserved for 6 h in the same solution. After preservation, the liver grafts were flushed out through the portal vein using 5 ml of chilled, lactated Ringer's solution (4°C). The entire effluent from the hepatic veins was then collected and analyzed for tPA, ammonia, lactate, pyruvate, glutamic oxaloacetic transaminase, and lactate dehydrogenase. The tPA concentration of effluent in group 2 was significantly higher than that in group 1 (0.80±0.23 ng/ml vs 0.42±0.08 ng/ml, P<0.05). The lactate, pyruvate, and ammonia levels in group 2 were also higher than those in group 1 (134±13 mg/dl vs 120±2 mg/dl, 0.34±0.40 mg/dl vs 0.09±0.01 mg/dl, and 183±79 g/dl vs 102±40 g/dl, respectively). However, the discriminative power of tPA was stronger than that of the other parameters. Histological findings revealed a higher number of trypan blue-stained sinusoidal lining cells that were detached and swollen in group 2. We conclude that the amount of tPA in the effluent flushed from the graft can serve as a sensitive and reliable indicator of cold-preserved liver grafts in rats.     

纤维蛋白对肾小球内皮细胞表达纤溶酶原激活物及纤溶酶原激活物抑制物的作用

目的：观察体外培养人肾小球内皮细胞（GEC）表面原位形成的纤维蛋白对GEC表达纤溶酶原激活物及纤溶酶原激活物抑制物（PA／PAI）的影响。方法：应用逆转录聚合酶链反应（RT－PCR）,酶谱分析法与反向酶谱法分别在基因转录水平与蛋白质活性水平上检测纤维蛋白对GEC表达tPA,uPA gn PAI-1r 作用,纤维蛋白平板法检测纤维蛋白对GEC PA／PAI系统的综合效应,结果：纤维蛋白能够明显促进tPA,uPA与PAI－1的mRNA表达上调,无血清RPMI 1640培养下的GEC几乎检测不到PAI知性,但可检测到PAI－1的活性。纤维蛋白能够浓度依赖性刺激GEC tPA与uPA活性增加以及PAI01的活性增加,呈浓度依赖性与时间依赖性,相同剂量的纤维蛋白原与纤维蛋白的作用相似,放线菌酮与放线菌素D均可抑制纤维蛋白上调GEC表达tPA,uPA与PAI的作用,纤维蛋白平板法显示,纤维蛋白对GEC PA／PAI系统的综合效应是以升高PA活性为主,其活性能够被抑肽酶完全阻断。结论：肾脏局部毛细血[管内沉积的纤维蛋白可能通过对GEC PA／PAI系统的调节发挥其病理作用。     

The effects of recombinant tissue-type plasminogen activator (rt-PA) on canine cadaver lung transplantation

The intrapulmonary thrombi that form after the cessation of circulation are thought to be one of the major causes of graft function failure. We evaluated the effect of recombinant tissue-type plasminogen activator (rt-PA) in a canine cadaver lung transplant model. Donor dogs were killed by the intravenous administration of pancuronium bromide without heparinization, and left for 2h at room temperature. The donor lungs were then flushed with low potassium dextran glucose (LPDG) solution, being subjected to a total ischemic time of 3h. Following left lung transplantation, the contralateral pulmonary artery of the recipient dogs was ligated. In group 1 (n=6), chloride solution was administered from the main pulmonary artery for 90 min, commencing 15 min prior to reperfusion. In group 2 (n=6), 2.5 μg/kg per min of rt-PA, and in group 3 (n=6), 5.0 μg/kg per min of rt-PA, were continuously infused in the same manner as in group 1. Lung function, including arterial blood gases and pulmonary hemodynamics, was measured for 3h. The side effects of rt-PA were evaluated by measuring the prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, alpha₂-plasmin inhibitor (α₂-PI), plasminogen, and fibrin/fibrinogen degradation product (FDP). All of the animals in the three groups survived throughout the observation period. The group 3 animals had significantly better gas exchange than the group 1 animals, and the pulmonary hemodynamics were significantly better in the group 2 and 3 animals than in the group 1 animals. The FDP levels in the group 2 and 3 animals were significantly higher than those in the group 1 animals, while the PT and APTT were significantly prolonged in the group 3 animals. These findings led us to conclude that rt-PA improves early lung function, particularly pulmonary hemodynamics.     

Thrombospondin-1 and transforming growth factor beta-1 upregulate plasminogen activator inhibitor type 1 in pancreatic cancer

Controlled degradation of the extracellular matrix by proteases is crucial in tumor cell invasion. We have shown that thrombospondin-1 (TSP-1), through activation of transforming growth factor beta-1 (TGF-β1), regulates the plasminogen/plasmin protease system in breast cancer. To determine whether this occurred in other epithelial neoplasms, we studied the role of TSP-1 and TGF-β1 in the regulation of the plasminogen/plasmin system in pancreatic cancer. ASPC-1 and COLO-3S7 pancreatic cancer cells were treated with TSP-1 or TGF-β1 at varying concentrations. The TSP-1 and TGF-β1-treated cells were also treated with either anti-TSP-1, anti-TSP-1 receptor, or anti-TGF-β1 antibodies. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression was determined by enzyme-linked immunosorbent assay. TSP-1 and TGF-β1 promoted a dose-dependent upregulation of ASPC-1 and COLO-3S7 PAI-1 expression. The TSP-1 effect could be blocked with anti-TSP-1 or anti-TGF-β1 antibodies. The TGF-β1 effect could be blocked only with anti-TGF-β1 antibody. Anti-TSP-1 receptor antibody blocked the TSP-1 effect on PAI-1 expression but had no effect on TGF-β1-mediated PAI-1 expression. Neither TSP-1 nor TGF-β1 had an effect on uPA production. We conclude that TSP-1, in a receptor-mediated process that involves the activation of TGF-β1, upregulates PAI-1 expression in pancreatic cancer without an effect on uPA production. Supported in part by National Institutes of Health grants CA65675 and CA69722 (Dr. Tuszysnki). Dr. Berger is the recipient of an American Cancer Society Clinical Career Development Award 96-09. Presented at the Thirty-Eighth Annual Meeting of The Society for Surgery of the Alimentary Tract, Washington, D.C., May 11–14,1997.     

Transforming growth factor beta1, urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in head and neck squamous carcinoma and normal adjacent mucosa

BACKGROUND: A balance between urokinase-type plasminogen activator (uPA) and its main inhibitor type-1 (PAI-1) appears to be important for cancer invasive behavior. Since uPA/PAI-1 system seems to be regulated by transforming growth factor beta1 (TGFbeta1) in different cell types, our aim was to investigate the relationship between the expression of the three genes and lymph node status in head and neck squamous cell carcinomas (HNSCC) at specific sites. MATERIALS AND METHODS: uPA, PAI-1, and TGFbeta1 mRNAs were determined by Northern analysis in tumor, and paired normal mucosa samples were obtained from 91 operable HNSCC patients. RESULTS: In oral cavity, excluding tongue, TGFbeta1, PAI-1, and uPA mRNAs values were consistently lower in the normal tissues than in tumors. In larynx tumors, TGFbeta1 expression was increased, but no statistically significant differences were found for uPA or PAI-1 mRNAs as compared with normal tissues. Tongue tumors overexpressed only uPA mRNA, and uPA levels showed significant parallel variations with TGFbeta1 and PAI-1 mRNAs mainly in pN+ tumors. In oral cavity tumors, an inverse correlation between TGFbeta1 and uPA was observed in pN0 subgroup, elevated uPA mRNA was counterbalanced by high PAI-1 mRNA TGFbeta1, and PAI-1 were not coordinately expressed. Correlations between the three markers were not found in larynx. Hypopharynx tumors, all staged as pN+, expressed the lowest TGFbeta1 mRNA mean values. CONCLUSIONS: Combined information about TGFbeta1, uPA, and PAI-1 mRNAs may add some clues to the understanding of the pathophysiological role of uPA system in head and neck squamous cell carcinoma.     

阿托伐他汀对糖尿病肾病患者脂蛋白（a）和纤溶酶原激活抑制物-1的影响

目的探讨阿托伐他汀对糖尿病肾病（DN）患者脂蛋白（a）[Lp（a）]、组织纤溶酶原激活物（tPA）以及纤溶酶原激活抑制物-1（PAI-1）的影响。方法60例DN患者随机分为2组，治疗组患者给予阿托伐他汀20mg每日1次睡前服用，对照组给予安慰剂，共6周，治疗前后所有患者测定血糖、肾功能、总胆固醇（TC）、甘油三脂（TG）、高密度脂蛋白-C（HDL-C）、低密度脂蛋白-C（LDL-C）、PAI-1、tPA以及尿白蛋白排泄率（UAER）进行比较。结果6周后，治疗组与对照组相比，TC、TG、LDL-C、Lp（a）、PAI-1活性及UAER下降（P〈0．05或P〈0．01），而HDLC水平和tPA活性上升（P〈0．05）。对照组治疗前后各项指标无明显变化（P〉0．05），而治疗组治疗前后上述指标有显著改变（P〈0．05或P〈0．01）。结论阿托伐他汀在降低DN患者血脂的同时，通过降低Lp（a）改善纤溶系统功能，保护受损的肾脏功能。     

Effects of uPA on mesangial matrix changes in the kidney of diabetic rats

Objective: To investigate the effect of urokinase-type plasminogen activator (uPA) on mesangial matrix in the kidney of diabetic rats and its related mechanisms. Methods: Diabetic Sprague-Dawley (SD) rats induced by intraperitoneal injection of streptozotocin (STZ) were randomly and evenly divided into two groups: DM?+?vehicle, and DM?+?uPA (2500?U?kg^?1 uPA via tail vein once a day for four weeks). The normal SD rats without diabetes were considered as control group. Rats in the three groups were executed and the heart blood was sampled for determination of blood glucose and serum creatinine. Meanwhile, kidney tissues of rats were also harvest for measurement of glomerular area, volume, and mesangial area by periodic acid silver methenamine (PASA) staining. The expression of urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and collagen IV in renal tissues was tested with immunohistochemistry. Results: Compared with control, the DM rats had obvious albuminuria, significantly (p?<?0.01) increased glomerular volume and mesangial matrix area, and significantly (p?<?0.05) higher expression of uPAR, PAI-1 and collagen IV in mesangial matrix, significantly up-regulated (p?<?0.05) glomerular uPAR, PAI-1, and collagen IV expression. After treated with uPA, the diabetic rats had significantly (p?<?0.05) reduced albuminuria, significantly (p?<?0.01) improved glomerular volume and mesangial matrix, significantly (p?<?0.05) down-regulated PAI-1 and collagen IV expression in mesangial matrix. However, the uPAR expression in renal tissues were unchangeable (p?>?0.05) and PAI-1 and collagen IV expression were significantly (p?<?0.05) reduced when diabetic rats were treated with uPA. Conclusion: uPA can down-regulate glomerular PAI-1 expression in the DM rats but not significantly influence uPAR expression, suggesting that uPA might regulate the mesangial cell (MC) and its matrix expression and improve diseased diabetic mesangial matrix via its combination with uPAR to uptake PAI-1 and accelerate its degradation.     

Gene expression of plasminogen activator inhibitor 1 in transplant kidneys complicated by renal vein thrombosis: a combined study by in-situ hybridization and immunohistochemistry

In an attempt to understand the pathogenesis of renal vein thrombosisoccurring early after renal transplantation, gene expressionof plasminogen activator inhibitor-1 (PAI-1) was investigatedby an in-situ hybridization technique. The cases examined weresix transplant kidneys complicated by renal vein thrombosis,four ‘normal’ kidneys and five time-matched transplantkidneys not complicated by renal vein thrombosis but showingacute tubular necrosis, infection, or normal histology. Thecell types expressing PAI-1 mRNA were also studied by combinedin-situ hybridization and immunohistochemical double stainingtechniques. Our results showed that PAI-1 mRNA was expressedin transplant kidneys complicated by renal vein thrombosis butthere was no detectable expression in ‘normal’ kidneys,nor in time-matched transplant kidneys not complicated by thrombosis.Double staining showed that PAI-1 mRNA was predominantly expressedby capillary endothelial cells, particularly around large- ormedium-sized renal arteries and small nerves. Smooth-musclecells in the wall of major or medium-sized renal arteries alsoshowed positive expression of PAI-1 in three of six thrombosedtransplants. However, endothelium in the major renal vein showedrelatively little signal. The pattern was different from thatin rejection. The possible relevance of these findings is discussed.     

多囊卵巢综合征患者血纤溶能力的研究

目的了解多囊卵巢综合征(PCOS)患者的血纤溶能力及服用二甲双胍后血纤溶能力的变化。方法(1)对照组20例、PCOS患者30例,分别取血检测组织纤溶酶原激活物(t-PA)、纤溶酶原激活抑制物(PAI-1)的活性;(2)PCOS高胰岛素血症者10例,分别给予二甲双胍750~1 500 mg/d治疗,比较治疗前、后t-PA、PAI-1活性。结果PCOS组的血胰岛素(INS)、游离睾酮(F-T)t、-PA、PAI-1分别为(24.42±12.30)mU/L(、2.70±1.50)ng/L、(0.17±0.06)KU/L(、0.88±0.05)AU/ml,对照组分别为(10.04±6.12)mU/L(、1.70±1.00)ng/L(、0.28±0.04)KU/L、(0.70±0.09)AU/ml。10例PCOS患者经二甲双胍治疗后INS、F-Tt、-PA、PAI-1分别为(12.20±7.78)mU/L、(1.70±1.00)ng/L、(0.26±0.08)KU/L、(0.70±0.35)AU/ml。结论PCOS患者的血纤溶能力低于正常者,而服用二甲双胍后血纤溶能力明显改善。     

Increased levels of urokinase plasminogen activator receptor in prostate cancer cells derived from repeated metastasis

To understand alterations to the urokinase system that may occur in progressively metastatic prostate cancer cells, we assessed urokinase plasminogen activator receptor (uPAR) expression, in vitro motility towards vitronectin, urokinase plasminogen activator (uPA)-induced growth and growth factor regulation of uPAR expression in three cell lines—PC-3 and two derivatives from secondary metastases, PC-3M and PC-3MM2. DU-145 and Tsu-Pr1 cells were included for comparative purposes. uPAR expression increases with metastatic passage in these cell lines and accompanies increased growth and motility responses in the presence of uPA. Growth factors TGF1 and IGF-1 induce uPAR in all three prostate cancer lines; however, PC-3M and PC-3MM2 cells also respond to bFGF. Of the cell lines tested, PC-3MM2 most uniformly respond to added TGF1, IGF-1 and bFGF. These results show that in two progressive derivatives from repeated metastasis of PC-3 cells, constitutive and growth factor-induced uPAR expression is enhanced. This increased uPAR facilitates the properties of growth and motility.     

Enhanced expression of plasminogen activator inhibitor 1 in patients with nephrotic syndrome

Hypercoagulability is present in patients with nephrotic syndrome. However, alterations in coagulation and fibrinolysis reflected in the glomeruli and urine are not fully understood. We examined plasma and urine concentrations of tissue-type plasminogen activator (tPA) and type 1 plasminogen activator inhibitor (PAI-1) in 33 patients with nephrotic syndrome (nephrotic group). We compared these concentrations with the concentrations in 30 nonnephrotic patients with chronic glomerulonephritis (nonnephrotic group) and with the concentrations in 30 healthy volunteers (control group). We also examined fibrin/fibrinogen degradation products in serum and urine and plasma D-dimers. The expression of tPA and PAI-1 was examined in isolated glomeruli using RT-PCR methods. Deposition of fibrinogen/fibrin-related antigen was observed by direct immunofluorescence. The incidence of fibrinogen/fibrin-related antigen deposition in the nephrotic group was significantly higher than that in the nonnephrotic group. The concentrations of fibrin/fibrinogen degradation products in serum and urine and of plasma D-dimers were significantly elevated in the nephrotic group as compared with the nonnephrotic and control groups. The plasma concentrations of tPA in the nephrotic group were significantly higher than those in the control group. The urinary excretion of tPA in the nephrotic group was also significantly higher than in the nonnephrotic and control groups. The urinary excretion of PAI-1 in the nephrotic group was higher than that in the control group. The ratio of PAI-1 mRNA to tPA mRNA in glomeruli was increased in the nephrotic group as compared with the nonnephrotic group. These results indicate that the fibrinolytic activity is increased in patients with nephrotic syndrome despite urinary losses of tPA. However, a relatively enhanced expression of PAI-1 may be involved in the intraglomerular fibrinogen/fibrin-related antigen deposition seen in nephrotic syndrome.