2 型糖尿病微血管病变患者纤溶系统变化与胰岛素抵抗的关系

目的 探讨2型糖尿病微血管病变患者纤溶活性变化与胰岛素抵抗(IR)之间的关系.方法 采用酶联免疫吸附试验测定53例2型糖尿病惠者(包括无血管并发症组30例和微血管并发症组23例)和25例正常对照者血浆组织型纤溶酶原激活剂(t-PA)、纤溶酶原激活物抑制剂-1(PAI-1)含量,结合临床资料分析其变化趋势及影响因素.结果 2型糖尿病患者血浆t-PA含量明显降低,而PAI-1含量明显升高,t-PA分别是(7.09±2.10)μg/L vs(12.40±2.11)μg/L(P＜0.05),PAI-1分别是(40.38±1.74)μg/L vs(25.28±2.83)μg/L(P＜0.05),合并微血管病变者,此变化更为显著,t-PA分别(6.22±1.23)μg/L vs(12.40±2.11)/μg/L,PAI-1分别是(44.57±2.16)μg/L vs(25.28±2.83)μg/L(均P＜0.01).多元逐步回归分析显示,HOMA模型胰岛素抵抗指教(HOMA-IR)是PAI-1升高的独立危险因素.结论 2型糖尿病患者纤溶活性降低,IR在降低其纤溶活性,并发微血管病变中起了重要作用.     

电针对急性脑梗死大鼠血浆t-PA和PAI-1含量的影响

目的:研究电针对急性脑梗死大鼠血浆组织型纤溶酶原激活物(t-PA)及纤溶酶原激活物抑制物-1(PAI-1)含量的影响。方法:40只SD大鼠随机分为正常组、假手术组、模型组及电针组各10只,模型组及电针组大鼠制成脑梗死模型;假手术组手术步骤同前2组,但不线栓;正常组不作任何处理。造模成功后,4组大鼠均同步喂养,电针组大鼠于造模成功后即刻给予电针百会、水沟穴,每天1次,30min。治疗5d后,4组大鼠均采用ELISA法检测血浆t-PA及PAI-1含量。结果:与正常组及假手术组比较,模型组及电针组大鼠血浆t-PA、PAI-1含量均显著升高(P<0.01),但电针组低于模型组(P<0.05,0.01)。结论:电针能显著降低急性脑梗死大鼠血浆t-PA、PAI-1含量,调节机体纤溶系统活性,改善梗死区域的血液循环,促进功能恢复。     

伴有糖尿病的冠心病患者纤溶系统的变化及罗格列酮的干预研究

目的通过观察伴有糖尿病(DM)的冠心病(CHD)患者纤溶系统的变化,并以罗格列酮进行干预,由此对罗格列酮防止支架术后再狭窄机制作初步探讨。方法试验对象共分为3组:伴有2型DM的CHD患者48例;不伴有2型DM的CHD患者36例;正常对照组:同期我院体检健康成人20例;3组对象均在入院后清晨抽血、分离血浆。检测一氧化氮(NO)、组织型纤溶酶原激活物(t-PA)和纤溶酶原激活物抑制剂(PAI-1)的含量;培养上清中NO采用硝酸还原酶法测定;t-PA和PAI-1采用酶联免疫法(ELISA)测定;另外将合并DM的CHD组48例患者分为两组,一组针对CHD和DM常规治疗,另一组在此基础上加用罗格列酮,4 mg/d,口服。治疗3个月后复查上述指标。结果伴有或不伴有DM的CHD患者NO的浓度分别为(40.83±5.34)μmol/L、(50.31±5.34)μmol/L均低于正常对照组(73.37±6.46)μmol/L(P均<0.01);t-PA的浓度分别为(18.53±7.05)μg/L、(26.72±8.20)μg/L均低于正常对照组(40.17±8.30)μg/L(P均<0.01);PAI-1的浓度分别为(86.04±8.88)μg/L(、78.52±7.34)μg/L均高于正常对照组(48.86±5.41)μg/L(P<0.01);伴有DM的CHD患者NO和t-PA的浓度均低于不伴有DM的CHD患者组(P<0.05),PAI-1的浓度高于不伴有DM的CHD患者组(P<0.05)。伴有DM的CHD患者常规治疗和常规 罗格列酮治疗后NO,t-PA显著高于治疗前:NO治疗前后的变化值分别为(20.97±3.49)μmol/L、(30.32±3.36)μmol/L(P均<0.01);t-PA治疗前后的变化值分别为(11.97±2.07)μg/L、(21.32±2.21)μg/L(P均<0.01);伴有DM的CHD患者常规治疗和常规 罗格列酮治疗后PAI-1的浓度显著低于治疗前,PAI-1治疗前后的变化值分别为(-23.98±5.12)μg/L、(-34.02±5.64)μg/L(P<0.01);和常规组比较,常规 罗格列酮治疗组改善的幅度要高于常规组(P<0.01)。结论伴或不伴DM的CHD患者冠心病患者体内存在不同程度纤溶活性的降低,这种高凝状态会促进血栓形成和再狭窄的发生。对于冠心病患者,在常规冠心病治疗基础上,加用罗格列酮能促进纤溶系统的激活,防止血栓的形成,有效防止支架术后再狭窄,特别是对于伴有糖尿病的CHD患者。     

水蛭提取液对凝血酶诱导血管内皮细胞释放凝血因子的影响

目的 观察水蛭提取液对凝血酶诱导人脐静脉内皮细胞(HUVECs)释放血管性血友病因子(vWF)、纤溶酶原激活物抑制剂-1(PAI-1)、组织型纤溶酶原激活物(t-PA)的影响,探讨水蛭抗凝的作用机制.方法 体外培养 HUVECs,将生长良好的2～3代细胞分为对照组、凝血酶刺激组及水蛭提取液高、中、低剂量组5组.将生药浓度600、300、150 mg/L的水蛭提取液加入到10 kU/L凝血酶刺激的HUVECs培养12 h,对照组加等量RPMI 1640培养液.用酶联免疫吸附法(ELISA)检测细胞培养上清液中vWF、PAI-1、t-PA的含量.结果 与对照组比较,凝血酶刺激组细胞培养上清液中vWF、PAI-1(μg/L)含量显著升高[vWF:(11.01±0.54)%比(7.05±0.49)%;PAI-1:72.26±0.85比55.89±1.26,均P<0.01],t-PA(μg/L)含量显著降低(15.15±1.41比34.29±1.22,P<0.01).与凝血酶刺激组比较,水蛭提取液高、中、低剂量组vWF、PAI-1含量[vWF:(9.48±0.64)%、 (8.57±0.50)%、 (7.97±0.44)%;PAI-1:58.30±0.90、 62.69±1.01、 67.47±1.28]显著降低,t-PA含量(32.59±1.46、 26.40±0.82、 21.06±1.13)显著升高(均P<0.01).说明水蛭提取液能显著减弱凝血酶诱导HUVECs释放vWF、PAI-1,增强凝血酶促进HUVECs表达t-PA.结论 水蛭具有明显的抗凝作用,其作用机制可能为参与调节内皮细胞释放vWF,调节纤溶平衡及保护受损的血管内皮细胞.     

冠心病患者行为类型与纤溶激活系统的关系

目的:研究不同行为类型冠心病患者之间纤溶激活系统的变化,为冠心病患者心理干预提供理论依据。方法:用A型行为问卷评定56例冠心病患者和52例健康人群,用发色底物法测定他们血浆中的纤溶激活系统中纤溶酶原激活物抑制剂1(plasminogenactivatorinhibitor1,PAI-1)、组织型纤溶酶原激活物(tissueplasminogenactivator,t-PA)活性。结果:冠心病患者PAI-1活性(AU/mL)高于正常人群(1.04±0.18比0.52±0.07,t=20.42,P<0.001),t-PA活性(IU/mL)低于正常人群(0.35±0.09比0.38±0.04,t=2.81,P<0.01);这种改变在不同行为类型之间比较,与非A型行为类型的冠心病患者比,A型行为类型PAI-1的活性高(1.19±0.19比0.90±0.12,t=5.25,P<0.01),而t-PA活性低(0.30±0.08比0.37±0.09,t=3.53,P<0.01),差异有显著性。结论:冠心病患者随着A型行为的增加,血浆中PAI-1活性上升,t-PA活性下降,导致凝血功能亢进,纤溶功能下降,血液处于高凝状态,促进血栓形成和发展,从而导致各种血管性事件的发生。     

癌症患者血浆PAI-1浓度变化

目的测定多种恶性肿瘤患者血浆中纤溶酶原激活物抑制剂1(Plasminogen activator inhibitor-1,PAI-1)浓度变化情况,探讨PAI-1血浆含量变化作为恶性肿瘤诊断中的作用。方法收集乳腺癌、肺癌、喉癌血液标本各40例,并以正常人血液标本作对照,用ELISA法检测肿瘤患者及正常对照组血浆中PAI-1的含量,并比较其差异。结果与正常对照组(9.84±4.66 ng/ml)相比,乳腺癌(21.49±10.54 ng/ml),肺癌(15.10±8.55 ng/ml),喉癌(14.03±7.14 ng/ml)患者血浆中PAI-1含量均明显升高,其中乳腺癌组与正常组相比差异极为显著(P0.01)。结论血浆中PAI-1的浓度升高可作为肿瘤诊断辅助指标,PAI-1可作为肿瘤治疗潜在靶位。     

慢性心力衰竭患者肾素血管紧张素系统对纤溶功能的影响

目的研究慢性心力衰竭(CHF)患者肾素血管紧张素系统(RAS)和纤溶功能的变化,及RAS对纤溶功能的影响.方法 CHF患者60例.健康体检者20例(正常对照组).用放射免疫法(RIA)测定CHF组和对照组血浆肾素活性(PRA)、血管紧张素Ⅱ(Ang Ⅱ)、醛固酮(ALD)水平,并用酶联免疫吸附法(ELISA)测定血浆组织型纤溶酶原激活物(t-PA)、纤溶酶原激活物抑制物-1(PAI-1)抗原含量.结果 CHF组血浆PRA、AngⅡ、ALD、t-PA和PAI-1平均水平都明显高于对照组(P<0.01).CHF患者血浆PAI-1和AngⅡ水平增高程度随心力衰竭恶化而愈加明显.CHF患者血浆PAI-1抗原含量与AngⅡ水平呈正相关(r=0.994, P<0.01).结论在CHF的发展过程中RAS对纤溶功能具有重要调节作用.     

糖尿病肾病组织纤溶酶原激活剂活性及其抑制物的变化

目的:观察糖尿病肾病纤溶系统功能的变化。方法:100例2型糖尿病肾病病人分成两组,50例早期糖尿病肾病组和50例临床糖尿病肾病组,分别测定血浆组织纤溶酶原激活剂(t-PA)活性和纤溶酶原激活物抑制剂(PAI-1)含量并和正常人组40例进行对照。结果:糖尿病肾病t-PA活性明显低于正常人组(P<0.01),而PAI-1则高于正常人组(P<0.01),临床糖尿病肾病组t-PA活性低于早期糖尿病肾病组(P<0.01),而PAI-1高于早期糖尿病肾病组(P<0.01)。结论:糖尿病肾病病人存在t-PA/PAI-1失衡,t-PA升高,PAI-1降低,失衡程度与肾脏的病变程度呈正相关。     

原发性高血压患者纤溶系统功能的变化

目的观察未经治疗的原发性高血压患者的纤溶指标的变化及临床意义。方法选取36例初次就诊的原发性高血压患者犤男17例,女19例,平均年龄(52±7)岁犦及31例血压正常者犤男16例,女15例,平均年龄(51±7)岁犦。两组受试者的临床特点无明显差别。用发色底物法测定他们的血浆组织型纤溶酶原激活物(t-PA)及其抑制剂(PAI-1)的活性和a2-PI活性。结果原发性高血压患者血浆t-PA和a2-PI活性明显低于对照者,P<0.05,PAI-l,活性明显高于对照组,P<0.05。结论原发性高血压患者存在内源性纤溶功能低下。     

高血压胰岛素抵抗患者血栓前状态变化分析

目的了解高血压胰岛素抵抗患者血清溶栓功能指标变化情况。方法对164例高血压胰岛素抵抗患者血清P选择素(Ps)、组织型纤溶酶原激活物(tPA)、纤溶酶原激活物抑制物(PAI)和遗传性假血友病因子(vWF)水平进行检测,并与130例健康体检者和156例高血压胰岛素正常者比较。结果高血压胰岛素抵抗组和高血压胰岛素正常组均比对照组的血清Ps、PAI和vWF水平升高,tPA水平降低,Ps分别为(39.55±12.64)pg/L、(32.59±12.57)pg/L vs(23.78±10.38)pg/L(P<0.05或<0.01);PAI分别为(1 580±650)U/L、(830±390)U/L vs(650±360)U/L(P<0.05或<0.01);vWF水平分别为(197.4±51.5)%、(129.9±34.4)%vs(96.7±32.9)%(均P<0.01);tPA分别是(0.32±0.36)μg/L、(0.65±0.43)%vs(0.97±0.41)%(均P<0.01)。结论高血压胰岛素抵抗患者其机体纤溶功能受损,表现为纤溶亢进,其受损的程度较高血压胰岛素正常组重。     

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。     

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…     

纤溶酶原激活物抑制剂-1的研究进展

纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor 1,PAI-1)作为体内组织型纤溶酶原激活物(tissue-type plasminogen activator,t-PA)和尿激酶型纤溶酶原激活物(urokinase-type plasminogen activator,u-PA)的主要抑制剂,与动静脉血栓、出血和凝血异常、细胞迁移密切相关,进而引起缺血性脑卒中、冠心病、静脉血栓、肿瘤转移、出血、股骨头坏死、流产等一系列疾病的发生发展。同时,体内血浆PAI-1活性水平又受血脂、血糖等调节,进一步参与肥胖、糖尿病、高脂血症等疾病的进程,又影响着上述相关疾病的预后。     

Influence of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 gene polymorphisms on tissue-type plasminogen activator-induced recanalization in ischemic stroke patients

OBJECTIVE: Endogenous resistance to tissue-type plasminogen activator (t-PA) might decrease the benefit of thrombolysis-induced recanalization. Thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are fibrinolysis inhibitors. TAFI removes residues from partially degraded fibrin that in turn eliminates plasminogen binding sites; PAI-1 directly inhibits the activity of t-PA. We aimed to study whether the presence of two common functional polymorphisms of the TAFI and PAI-1 genes influence rates of recanalization of the middle cerebral artery (MCA) among t-PA-treated stroke patients. METHODS AND RESULTS: TAFI and PAI-1 polymorphism determinations were performed by restriction fragment length polymorphism mapping and conventional sequencing in 139 patients with strokes involving the MCA and who received t-PA within 3 h. Recanalization was diagnosed by means of transcranial Doppler. No association was found between PAI-1 4 G/5 G polymorphism and recanalization rate. Dyslipidemia and TAFI Thr325Ile polymorphism were the main variables associated with recanalization resistance by the end of t-PA infusion: odds ratio (OR) 4.1 [95% confidence interval (95% CI) 1.6-10.8, P = 0.003] and OR 5.6 (95% CI 1.2-20, P = 0.031), respectively. The combination of the two polymorphisms doubled the risk of absence of recanalization: OR 11.1 (95% CI 1.4-89.8, P = 0.025). CONCLUSIONS: Polymorphic fibrinolysis inhibitor genes influence t-PA-induced recanalization resistance in ischemic stroke patients, especially when coexisting in the same patient. Efforts to individualize thrombolytic treatments are required.     

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.     

uPA、uPAR、PAI-1血浆含量与卵巢恶性肿瘤的相关性研究

目的：探讨尿激酶型纤溶酶原激活物（uPA）及其受体（uPAR）和抑制剂（PAI-1）血浆含量与卵巢恶性肿瘤之间的关系。方法：收集52例卵巢恶性肿瘤患者血液标本,以30例健康人作对照,用ELISA法分别检测uPA、uPAR和PAI-1的含量。结果：uPA、uPAR在卵巢恶性肿瘤各期之间均有极显著性差异（P〈0．01）,PAI-1在卵巢恶性肿瘤FIGO Ⅰ～Ⅲ期的含量逐渐升高,但在FIG0Ⅳ期时显著下降（P〈0．05）。患者组uPA、uPAR、PAI-1均较对照组升高,差异极显著（P〈0．01）。结论uPA、uPAR在卵巢恶性肿瘤患者可作为预后的判断指标,PAI-1与卵巢恶性肿瘤的分期有一定的相关性。     

Fibrinolytic shut-down after surgery: impairment of the balance between tissue-type plasminogen activator and its specific inhibitor

In nine patients with non-malignant diseases undergoing major upper abdominal surgery, the mechanism of the postoperative fibrinolytic shut-down was investigated because of its potential significance for postoperative deep vein thrombosis by employing new and specific methods for assessing and stimulating the fibrinolytic system. The shut-down was found to result from an impairment of the balance between tissue-type plasminogen activator, t-PA, and its recently discovered fast-acting inhibitor. In this balance, the t-PA antigen concentrations both in resting conditions and after stimulation evoked by desamino-D-arginine vasopressin (DDAVP) were found to be unchanged by surgery. However, there was a significant postoperative increase in t-PA inhibitor levels. The release of t-PA under the stimulus of DDAVP infusion overcame the postoperative shut-down of t-PA activity. However, DDAVP infusion was associated with potentially unfavourable increases in the Factor VIII/von Willebrand factor complex. The discovery of increased t-PA inhibitor in the postoperative period opens new possibilities for a rational approach to reduce or abolish the postoperative fibrinolytic shut-down.     

重组组织型纤溶酶原激活剂静脉溶栓治疗急性心肌梗死的疗效观察

目的:观察重组组织型纤溶酶原激活剂重组组织型纤溶酶原激活剂,静脉溶栓治疗急性心肌梗死的疗效和安全性.方法:选择15例急性心肌梗死患者应用重组组织型纤溶酶原激活剂静脉溶栓治疗,观察临床症状,心电图、心肌酶谱的变化,判断冠状动脉再通率.结果:根据冠脉再通标准判断,15例急性心肌梗死患者,冠脉再通11例,再通率73.3%,其中10例发病6 h以内溶栓再通8例,再通率80%;5例发病6～24 h溶栓再通3例,再通率60%.两者相比有显著差异(P＜0.01).结论:急性心肌梗死患者选用重组组织型纤溶酶原激活剂静脉溶栓是一种安全、有效的治疗方法.