慢性心力衰竭患者血浆组织型纤溶酶原激活物和纤溶酶原激活物抑制物-1含量变化及其临床意义

目的　研究慢性心力衰竭 (CHF)患者血浆组织型纤溶酶原激活物 (t PA)和纤溶酶原激活物抑制物 1(PAI 1)含量的变化及其临床意义。方法　用酶联免疫吸附法 (ELISA)检测 6 0例CHF患者 (CHF组 )和 2 0例健康体检者 (正常对照组 )血浆t PA及PAI 1抗原含量。结果　CHF组血浆t PA和PAI 1平均含量都明显高于对照组 (P<0 .0 1)。CHF患者血浆PAI 1含量增高随心功能恶化而愈加明显。结论　CHF患者纤溶功能明显下降 ,可用血浆t PA、PAI 1含量作为判断病情的参考指标之一。     

组织型纤溶酶原激活物在急性肺血栓栓塞肺动脉组织中的表达

目的　探讨组织型纤溶酶原激活物 ( t PA)在急性肺血栓栓塞 ( PTE)肺动脉中的表达及意义。方法　 30只家兔随机分组。采用血栓阻塞法制备 PTE动物模型。取材栓塞 3、8和 2 4 h后动物栓塞部位的肺动脉和栓塞远端肺动脉 ;同时设实验对照组 ,取材正常肺动脉。应用免疫组化方法检测肺动脉组织内 t PA的抗原水平。结果　正常肺动脉极少见胞浆棕染的 t PA阳性细胞。栓塞 3h组的栓塞肺动脉和未栓塞肺动脉 t PA阳性细胞数与对照组比较差异没有显著性。栓塞 8h和 2 4 h组肺动脉残存的内皮细胞和平滑肌细胞内均可见明显的胞浆棕染的阳性细胞 ( P均 <0 .0 1)。结论　急性 PTE后可见到栓塞肺动脉 t PA表达增强 ,表明肺具有强大的纤溶潜力 ,这种内源性纤溶活性的增强有利于血栓的溶解     

卡维地洛及TNF-α对内皮细胞释放t-PA和PAI-1的影响

目的　研究卡维地洛及肿瘤坏死因子α(TNF α)对内皮细胞分泌组织纤溶酶原激活物 (t PA)和纤溶酶原激活物抑制剂 1(PAI 1)的影响。方法　培养内皮细胞株 (ECV3 0 4) ,分为TNF α刺激组 ,培养基中TNF α加至终浓度为 5、10、2 5、5 0、10 0ng/ml;卡维地洛干预组 ,培养基中加TNF α (5 0ng/ml)后加入卡维地洛 ,终浓度为 2 0、5 0、10 0、2 0 0nmol/L ,2 4h后测定上清中的组织纤溶酶原激活物 (t PA)和纤溶酶原激活物抑制剂 1(PAI 1)的含量。结果　内皮细胞在TNF α刺激 2 4h后 ,其分泌的PAI 1抗原含量与对照组比有明显升高 ,有显著性差异 (P <0 0 5 ) ,而两组间t PA含量无明显差异 (P >0 0 5 )。而卡维地洛干预组却显著降低PAI 1(P <0 0 5 ) ,对t PA含量无明显作用 (P >0 0 5 )。结论　TNF α对内皮细胞株分泌的PAI 1有显著的升高作用 ,而对t PA无显著影响 ;用卡维地洛干预后 ,PAI 1显著降低 ,t PA含量无明显改变。     

缬纱坦对急性冠状动脉综合征患者凝血及纤溶系统的影响

目的探讨血管紧张素受体拮抗剂对凝血及纤溶系统的影响。方法急性冠状动脉综合征患者60例,随机分为对照组（30例）和缬纱坦组（30例）,对照组按临床常规处理,缬纱坦组在此基础上加用缬纱坦80mg／d,分别于入院后即刻和第3天采血测激活的凝血时间（ACT）和血浆组织型纤溶酶原激活剂（t—PA）及其抑制物（PAI—I）。结果治疗前后及组间比较ACT均无显著变化,两组的t—PA活性治疗后均比治疗前明显增高,而PAI活性明显降低（均P〈0、05或〈0．01）,组间比较,缬纱坦组t—PA活性升高及PAI活性降低的幅度显著高于对照组（P〈0．01）。结论缬纱坦对急性冠状动脉综合征患者的凝血系统无明显影响,但可使t—PA活性增高而PAI—I活性降低。     

欣舒注射液对兔血管内膜剥脱术后血小板活化及纤溶活性的影响

目的观察欣舒注射液 (XSPS)对兔血管内膜剥脱术后血浆血小板α颗粒膜蛋白 (GMP 14 0 )及组织型纤溶酶原激活剂 (t PA)、Ⅰ型纤溶酶原激活物抑制因子 (PAI 1)含量变化的影响。方法选取日本雄性大耳白兔 2 0只 ,随机分为对照组和中药组 ,用球囊导管剥脱其腹主动脉内皮。分别于术前及术后 3天、7天耳缘静脉采血测定血浆GMP 14 0 ,t PA、PAI 1的含量。结果XSPS可显著降低血浆GMP 14 0水平 ,使t PA升高、PAI 1下降 ,与对照组相比有显著性差异 (P <0 0 5 )。结论XSPS可明显抑制兔动脉损伤后血小板的活化 ,促进纤溶活性 ,从而抑制动脉成形术后血栓的形成 ,可能达到防治再狭窄的作用。     

老年高血压病患者血浆中VWF，t—PA及PAI变化的意义

目的 观察老年高血压病患者的血管内皮细胞损伤及纤溶活性的变化。方法 选择30例Ⅰ、Ⅱ期老年高血压病患者和30例老年正常对照者，测定其血浆Von Willebrand因子（VWF）含量及组织型纤溶酶原激活物（t－PA）、纤溶酶原激活物抑制物（PAI）的活化。结果 老年高血压病患者血浆VWF含量及PAI活性明显高于老年正常对照组（P＜0．001），而t-PA活性明显低于老年对照组（P＜0．001）。结论 提示Ⅰ、Ⅱ老年高血压患者存在明显的内皮细胞损伤和纤溶活性下降，有血栓形成倾向。     

川芎嗪对TNF-α诱导的人腹膜间皮细胞t-PA和PAI-1表达的影响

【目的】探讨川芎嗪对体外培养的人腹膜间皮细胞（HPMCs）在肿瘤坏死因子‐α（TNF‐α）诱导后组织型纤溶酶原激活物（t‐PA）和纤溶酶原激活物抑制因子‐1（PAI‐1）表达的影响。【方法】应用胰蛋白酶消化法分离HPMCs进行原代培养并传代,分为5组（每组设3个样本）：正常对照组（完全培养液）、单纯TNF‐α（1μg／L）诱导组和TNF‐α诱导加低、中、高剂量川芎嗪（10、20和40 mg／L）组。采用半定量反转录聚合酶链反应（RT‐PCR）法检测细胞内t‐PA和PAI‐1 mRNA表达;酶联免疫吸附法（ELISA）检测细胞上清液中t‐PA和PAI‐1的蛋白质水平。【结果】与正常组比较,TNF‐α诱导组上清液中 t‐PA的含量减少和PAI‐1含量显著升高,且两组相比较差异有显著性（ P ＜0．01）;与TNF‐α诱导组比较,低、中、高剂量川芎嗪组上清液中t‐PA的含量增加,PA I‐1的含量显著降低,且两组相比较差异有显著性（ P ＜0．05或 P ＜0．01）。与正常组比较,单纯TNF‐α诱导组 HPMCs t‐PA／β‐actin mRNA 下降（87±5）％和 PAI‐1／β‐actin mRNA 上升（3．63±0．12）倍（ P ＜0．01）;与TNF‐α诱导组相比,低、中、高剂量川芎嗪组t‐PA／β‐actin mRNA表达明显增加（ P＜0．05或 P ＜0．01）和PAI‐1／β‐actin mR‐NA表达明显减少（ P＜0．05,P＜0．01）,两者在蛋白质和基因水平均呈量效关系。【结论】川芎嗪干预后能促进 HPMCs在炎症状态下t‐PA生成增加并抑制PAI‐1的表达,从而减少纤维化的发生。     

肝硬化患者纤溶活性指标的检测及其临床意义

目的 探讨肝硬化患者纤溶活性指标的变化及意义。方法 将80例肝硬化患者根据Child-Pugh分级分为三组：A级组30例,B级组32例,C级组18例。均同时检测组织纤溶酶原激活物（tPA）,组织纤溶酶原激活物抑制物（PAD、纤维蛋白（原）降解产物（FDP）和D-聚体。结果 随病情的加重,肝硬化患者纤维蛋白原活性明显下降,D-聚体和t—PA显著升高,差异有统计学意义（P〈0．05）。PAI活性变化不大,差异无统计学意义（P〉0．05）。结论 t-PA随病情加重而显著性升高．PAI无显著性变化,t-PA与肝硬化程度密切相关,其检测有利于了解肝硬化的进程。     

急性脑梗死患者血浆组织型纤溶酶原激活物与抑制物活性的动态变化

目的观察急性脑梗死不同时期患者血浆纤溶活性的动态变化,探讨其变化在病情发展中的作用。方法采用发色底物显色法测定60例脑梗死患者急性期与恢复期和60例同期住院非心、脑血管疾病患者血浆组织型纤溶酶原激活物(tissue-plasminogenactivator,t-PA)、纤溶酶原激活抑制物(plasminogenactivatorinhibitor,PAI)活性。结果脑梗死急性期组与恢复期组和对照组相比,t-PA活性明显减低,PAI活性显著增高(P均<0.01)。恢复期组与对照组比较差异无显著性意义(P>0.05)。结论急性脑梗死患者纤溶平衡失调,故检测其血浆t-PA,PAI活性动态变化可作为脑梗死诊断与治疗的一个客观参考指标。     

脑卒中患者治疗前后纤溶系统指标动态观察

目的　探讨脑卒中患者纤溶系统相关指标的改变及临床意义。方法　检测 19例脑梗死患者和 10例脑出血患者的纤维蛋白原 (Fib)、组织纤溶酶原激活物 (t PA)、纤溶酶原激活物抑制剂 (PAI)、D 二聚体 (D D)、α2 抗纤溶酶 (α2 AP)、纤溶酶原 (PLG)的含量并进行动态观察。结果　除脑梗死组的Fib和脑出血组的D D在治疗前后有显著差异 (P <0 .0 1)外 ,其余指标均无差异 (P >0 .0 5 )。结论　脑梗死、脑出血患者在治疗后体内纤溶激活状态仍持续存在     

Plasminogen activators and plasminogen activator inhibitor in malignant and non-malignant ascitic fluid

Ascitic fluid from tumour patients (hepatoma, gastric cancer, gallbladder cancer, colorectal cancer, ovarian cancer) and from non-malignant diseases (liver cirrhosis, congestive heart failure) were compared with respect to their content of determinants of the fibrinolytic system, tissue-type plasminogen activator antigen (t-PAag) and activity (t-PAact), urokinase-type plasminogen activator antigen (u-PA) and plasminogen activator inhibitor activity (PAI). Furthermore, SDS-polyacrylamide slab-gel electrophoresis (SDS-PAGE) was performed to evaluate molecular weight distribution of the detectable fibrinolytic parameters. In malignant ascites, PAI activity was three to four times higher, and increased complex formation of PAI with t-PA could be demonstrated, compared with non-malignant ascitic fluid. Tissue-type plasminogen activator antigen and activity showed a similar concentration in ascites of both study groups. Urokinase-type plasminogen activator antigen was detectable neither in ascites of malignant nor in ascites of non-malignant origin. It is concluded that t-PA is the physiological plasminogen activator in ascites and that increased PAI levels followed by increased complex formation between t-PA and PAI might reflect a reaction of the peritoneum.     

The regulation by fibrinogen and fibrin of tissue plasminogen activator kinetics and inhibition by plasminogen activator inhibitor 1

BACKGROUND: Tissue plasminogen activator (tPA) is unusual in the coagulation and fibrinolysis cascades in that it is produced as an active single-chain enzyme (sctPA) rather than a zymogen. Two chain tPA (tctPA) is produced by plasmin but there are conflicting reports in the literature on the behaviour of sc- and tctPA and little work on inhibition by the specific inhibitor plasminogen activator inhibitor-1 (PAI-1) under physiological conditions. OBJECTIVES: To perform a systematic study on the kinetics of sctPA and tctPA as plasminogen activators and targets for PAI-1. METHODS: Detailed kinetic studies were performed in solution and in the presence of template stimulators, fibrinogen and fibrin, including native fibrin and partially digested fibrin. Numerical simulation techniques were utilized to cope with the challenges of investigating kinetics of activation and inhibition in the presence of fibrin(ogen). RESULTS: Enzyme efficiency (k(cat)/K(m)) was higher for tctPA than sctPA in solution with chromogenic substrate (3-fold) and plasminogen (7-fold) but in the presence of templates, such as fibrinogen and native or cleaved fibrin, the difference disappeared. sctPA was more susceptible to PAI-1 in buffer solution and in the presence of fibrinogen; however, in the presence of fibrin, PAI-1 inhibited more slowly and there was no difference between sc and tctPA. CONCLUSIONS: Fibrinogen and fibrin modulate the activity of tPA differently in regard to their activation of plasminogen and inhibition by PAI-1. Fibrinogen and fibrin stimulate tPA activity against plasminogen but fibrin protects tPA from PAI-1 to promote fibrinolysis.     

Regulation of local availability of active tissue-type plasminogen activator in vivo in man.

Free, biologically active tissue-type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI-1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused-forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6- and 12-fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r = 0.102, ns to r = 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI-1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI-1 or tPA. Despite a molar excess of PAI-1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.     

脑梗死患者血浆组织型纤溶酶原激活物和纤溶酶原激活物抑制物活性的变化与神经功能缺损的相关性

INTRODUCTIONItwasreportedthatlow-fibrinolysisstatecharacterizedwithdecreaseoftissue-typeplasminogenactivator(t-PA)activityandincreaseoftype1plasminogenactivatorinhibitor(PAI-1)activityexistedinthepathologicalprocessofarterioscleroticcerebralinfarction犤1犦.Butre-centanimalexperimentshowedthatmRNAoft-PAandu-PAex-pressedincreasinglyinischemiccerebraltissue犤2犦.Sofurtherobser-vationwasindispensable.Wetestedtheactivityofplasmat-PAandPAI-1of91patientswitharterioscleroticcerebralinfarct…     

冠心病发病与血浆纤溶酶原激活物抑制剂-1及其基因4G/5G多态性的关系

目的 探讨冠心病患者血浆纤溶酶原激活物抑制剂-1（PAI-1）水平和活性（PAI：A）的升高与PAI-1基因4G/5G多态性的关系及其对发病的影响。方法 122例冠心病患者与172例健康对照者，同时做PAI-1基因型分析并测定PAI-1，PAI：A。结果 PAI-1基因型分布在冠心病组4G/4G型最多（47.2%)。对照组中以4G/5G型最多（49.4%)；PAI-1与PAI：A在4G/4G，5G/5G，4G/5G3种基因型组间比较差异有显著性意义。其中以4G/4G基因型组PAI-1及PAI：A最高。结论 血浆PAI-1增高，是冠心病发病的危险因素。冠心病组4G/4G基因型频率是PAI-1增高的重要影响因素，PAI-1基因4G/5G多态性可能部分地决定了冠心病发病的倾向性。     

Heparin-triggered release of camouflaged tissue plasminogen activator for targeted thrombolysis

A targetable, heparin-triggered release system for tissue plasminogen activator (tPA) was designed to prevent the excessive ‘lytic’ state associated with the current tPA therapy for acute thrombotic conditions, such as myocardial infarction (MI). The strategy is, upon target accumulation, to trigger tPA release from a prodrug construct by a usual heparin dose. A relatively inactive form of tPA was constructed by conjugating tPA with low-molecular weight heparin followed by complexation with albumin-protamine conjugate, termed ‘camouflage’. The modified tPA was ~ 97% as active as native tPA. The prodrug construct of tPA significantly masked the enzymatic activity, which was fully recovered upon heparin addition. The camouflaged tPA was stable in human blood for at least 30 min and was able to trigger enzyme activation in vitro at heparin level of 0.4 U/mL. In vivo studies on jugular vein rat thrombosis model showed that the clot lysis of the heparin-triggered camouflaged tPA group was equivalent to the tPA + heparin group without prolongation of activated partial thromboplastin time (aPTT) before and after the treatment. This proof-of-principle study suggests that the activity of the tPA prodrug construct can be triggered at the thrombus site at therapeutic heparin concentration conjunctively used for MI with reduced bleeding risk.     

A left MCA territory infarction during intravenous recombinant tissue plasminogen activator therapy for right MCA territory ischaemic stroke

An 81 year old man with a history of hypertension received intravenous recombinant tissue plasminogen activator (tPA) for right middle cerebral artery (MCA) infarction. He had not had stroke or arrhythmia previously. The initial National Institute of Health Stroke Scale (NIHSS) score was 8. However, a left MCA territory infarction developed 2 minutes after the full course of tPA therapy was completed, and 24 hours after tPA infusion, NIHSS score was 17. The subsequent magnetic resonance imaging scan confirmed an extensive left MCA territory infarction and a small right MCA territory infarction. Although the intracerebral haemorrhage after tPA therapy is relatively more common, tPA infusion may result in an ischaemic cerebral stroke in rare cases.     

Lipoprotein(a), tissue plasminogen activator and plasminogen activator inhibitor 1 levels in hyperlipidaemic patients in Kuwait

Plasma levels of lipoprotein(a) [Lp(a)], tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) were assessed in addition to anthropometry and levels of glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and apo A1 and B in 73 patients (36 men and 37 women) with primary hyperlipidaemia (group NDHL) in Kuwait. Lp(a) levels (212 mg L^?1, 8–600 mg L^?1, median and range) were similar to those obtained in a matched group of 32 non-insulin-dependent diabetes mellitus (NIDDM) patients with hyperlipidaemia (218 mg L^?1, 50–610 mg L^?1) and slightly higher, although not significantly so (P = 0.06), than levels seen in 68 healthy normolipidaemic control subjects (182 mg L^?1, 70–488 mg L^?1). tPA levels (8.4 ng mL^?1, 3.8–18.4 ng mL^?1, median and range) in group NDHL were lower than in the diabetic group (11.4 ng mL^?1, 5.2–14.2 ng mL^?1) but higher than in the healthy control subjects (7.4 ng mL^?1, 2.8–12.6 ng mL^?1). PAI-1 levels in group NDHL (40.4 ng mL^?1, 8.6–55 ng mL^?1, median and range) were higher than in the control subjects (32.5 ng mL^?1, 14.6–46.4 ng mL^?1) but lower than in diabetic patients (43.8 ng mL^?1, 15.6–55 ng mL^?1). Hyperlipidaemia phenotype (hypercholesterolaemia or hypertriglyceridaemia) did not influence tPA and PAI-1 levels, but Lp(a) levels were significantly lower with hypertriglyceridaemia. Gender, cigarette smoking and racial origin (Kuwaitis, other Arabs or South Asians) did not affect Lp(a), tPA and PAI-1 levels, but tPA levels were higher in postmenopausal subjects. Low-density lipoprotein (LDL) levels (whether in total cholesterol or as apo B) correlated significantly (P < 0.05) with Lp(a) levels. tPA levels were correlated with age and the plasma levels of glucose and uric acid (P < 0.05); this correlation with glucose may explain the high levels associated with diabetes, whereas the age association might account not only for the differences observed between group NDHL and the younger control group but also for the higher levels in the postmenopausal women. PAI-1 levels correlated with tPA and triglyceride (TG) levels in the groups of subjects (normo- and hyperlipidaemic). In the normolipidaemic control group, the significant associations of tPA and PAI-1 were with body mass, expressed as the body mass index or the waist–hip ratio. These results suggest that different factors influence the plasma levels of the prothrombotic factors Lp(a), tPA and PAI-1 in healthy control subjects and in patients with hyperlipidaemia. In the latter, hyperlipidaemia phenotype, age, glycaemic status and uric acid levels are important determinants of the levels of these prothrombotic variables, whereas in the healthy, young control population, body mass was the single important association with tPA and PAI–1.     

康复训练对脑血栓形成患者血浆组织型纤溶酶原激活物及抑制物活性的影响

以４０例亚急性期、恢复早期脑血栓形成偏瘫患者为研究对象，随机分成康复治疗组和对照组，观察分析康复训练后即刻及３周后纤溶活性的变化。２０例健康老年人作为正常对照。结果为：康复治疗后即刻、康复后３周与康复前相比，组织型纤溶酶原激活物活性分别提高３０％和１２．６％，组织型纤溶酶原抑制物与激活物比值降低，纤溶活性增高（Ｐ＜０．０１），并高于对照组（Ｐ＜０．０１）。康复训练可部分逆转脑血栓形成患者组织型纤溶酶原激活物及抑制物的异常改变，提高纤溶活性。