Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study

An impaired fibrinolytic function due to elevated plasma levels of plasminogen activator inhibitor (PAI)-1 activity or tissue plasminogen activator (tPA) antigen is correlated with the development of myocardial infarction (MI) in patients with manifest coronary heart disease. Recently, methods for determining the specific tPA/inhibitor complexes constituting tPA antigen in plasma have become available. In the Stockholm Heart Epidemiology Program (SHEEP) study, 86 of 1212 MI patients, subjected to blood sampling in a metabolically stable period, suffered reinfarction before the end of 1996. These individuals have been compared with an approximately equal number of matched MI patients without recurrence and a group of matched healthy control subjects regarding the plasma concentrations of some hemostatic factors. The hemostatic compounds studied (fibrinogen, von Willebrand factor, tPA antigen, PAI-1, and the tPA/PAI-1 complex) were typically higher in the groups (men and women) with recurrence of MI compared with those without. The plasma concentrations were also typically higher in the pooled groups of patients compared with the groups of healthy control subjects. The largest between-group differences were found for the plasma tPA/PAI-1 complex. The crude odds ratio for reinfarction associated with higher concentration (>/=75th percentile among the control subjects) of tPA/PAI-1 was 1.8 (95% CI 1.1 to 3.1); the corresponding crude odds ratio for von Willebrand factor was 2.3 (1. 3 to 4.0). The tPA/PAI-1 complex correlated strongly with PAI-1 and tPA antigen in all groups and with serum triglycerides and body mass index in all groups except for women with reinfarction. An increased plasma level of tPA/PAI-1 complex is a novel risk marker for recurrent MI in men and women. Most likely, increased plasma levels of tPA/PAI-1 complex reflect impaired fibrinolysis, because the correlation with PAI-1 is strong. Further support is obtained indicating that the plasma concentration of von Willebrand factor is also an important risk marker for recurrent MI.     

氯沙坦和依那普利对心肌梗死后纤溶-凝血功能的影响

目的　探讨氯沙坦和依那普利对急性心肌梗死 (AMI)患者纤溶 凝血功能的影响。方法　将 41例AMI患者随机分为氯沙坦组、依那普利组和对照组 ,以发色底物法和ELISA法测定三组患者入院即刻、发病 2周、2个月的血浆PAI 1活性、纤溶酶原激活物 (tPA)抗原水平和血管血友病病因子(vWF)含量。结果　与对照组相比 ,氯沙坦组 2周和 2个月时的PAI 1活性分别减低 2 2 % (P <0 0 1)和 18% (P <0 0 5 ) ,tPA抗原水平分别减低 32 % (P <0 0 1)和 2 5 % (P <0 0 5 ) ;依那普利组相应分别减低 2 8% (P <0 0 1)和 2 1% (P <0 0 5 ) ,tPA抗原水平分别减低 38% (P <0 0 1)和 2 9% (P <0 0 5 ) ;两个治疗组之间差异无显著性。两种药物对vWF含量均无影响。结论　氯沙坦和依那普利可改善心肌梗死后的纤溶功能 ,长期应用这两种药物可能会降低心肌梗死后发生急性心脏事件的危险。     

Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency

Congenital plasminogen activator inhibitor-1 (PAI-1) deficiency is an extremely rare disorder characterized by a bleeding diathesis that begins in childhood due to hyperfibrinolysis as a result of decreased PAI-1 activity. We now present 4 unrelated pediatric cases of congenital PAI-1 deficiency. All 4 patients had a history of recurrent episodes of subcutaneous bleeding beginning in early childhood. These episodes were characterized by abnormal prolonged bleeding after trauma, tooth extraction, and surgical procedures, as well as by rebleeding following initial hemostasis. The 2 female patients both had symptoms compatible with hypermenorrhea. The family history was positive in 2 of the 4 patients. Hemostatic screening studies in all 4 patients revealed no abnormalities. Testing for factor XIII antigen, von Willebrand factor antigen, ristocetin cofactor activity, alpha(2)-plasmin inhibitor (alpha2PI) activity, and plasminogen activity was normal. The euglobulin lysis times were shortened in all cases as compared with those in normal control subjects. None of the patients had elevated tissue plasminogen activator (tPA) antigen levels, but PAI activity was markedly decreased in all cases. Three of the patients also had reduced levels of PAI-1 antigen. There tended to be a reduction in tPA-PAI-1 complex in all cases. In addition, 2 patients had elevated PIC (plasmin-alpha2PI complex). Tourniquet tests were performed in 2 patients, with no appreciable rise in PAI-1 activity or PAI-1 antigen levels. The administration of tranexamic acid clearly improved hemorrhagic symptoms in these patients. We considered PAI-1 deficiency to be the likely etiology of the congenital bleeding diatheses in these 4 cases.     

疏血通注射液对心房颤动患者血栓前状态的影响

目的研究疏血通注射液对心房颤动患者血栓前状态的改善作用。方法将63例心房颤动患者随机分为疏血通组和对照组,疏血通组应用疏血通注射液治疗14d,对照组除不使用疏血通,其他用药与疏血通组相同。治疗前和治疗2周后测量两组血浆纤溶酶原激活物(tPA)及其抑制物(PAI-1)活性,D-二聚体(D-D)和血管性假血友病因子(vWF)水平。结果疏血通组和对照组在治疗前血浆tPA、PAI-1活性、D-D和vWF水平无统计学意义(P>0.05)。疏血通组治疗后血浆tPA活性显著性增高(P<0.05),血浆PAI-1活性、D-D和vWF水平均显著性下降(P<0.05),而对照组无显著性改变(P>0.05)。组间比较发现,疏血通组治疗后血浆PAI-1活性、D-D和vWF水平比对照组更低(P<0.05),而血浆tPA活性无显著增高(P>0.05)。结论短期疏血通静脉输注可以明显改善心房颤动患者的血栓前状态,这可能降低心房颤动患者的血栓栓塞危险。     

Plasminogen activator inhibitor and von Willebrand factor in polymyalgia rheumatica

Summary Endothelial cell products, plasminogen activator inhibitor (PAI) and von Willebrand factor (vWF), were assayed in 25 patients with newly-diagnosed and untreated polymyalgia rheumatica (PMR), before and after three and 12 months of corticosteroid treatment. The mean values of PAI and vWF, and also the levels of acute phase reactants (erythrocyte sedimentation rate, fibrinogen, haptoglobin, orosomucoid, C-reactive protein) and platelet counts, were elevated in the active untreated disease. In contrast to the acute phase proteins, both PAI and vWF remained increased after three and 12 months of glucocorticoid treatment. This suggested an active vasculitis, despite a clinically-inactive disease. Particularly high levels of vWF both before and after glucocorticoid therapy were found in two patients who subsequently developed vascular complications during the follow-up period.     

脓毒症患者血栓调节蛋白和纤溶酶原激活物抑制剂-1及内皮细胞损伤程度的研究初探

研究血栓调节蛋白（TM）和纤溶酶原激活物抑制剂-1（PAI-1）与脓毒症内皮细胞损伤严重程度的相关性。选2017年2月—2019年2月华中科技大学协和江北医院重症医学科脓毒症患者100例,根据疾病严重程度分为感染性休克组50例,脓毒症组50例,另选健康体检者80例为健康对照组。检测3组受试者TM、PAI-1及循环内皮祖...     

持续气道正压通气对OSAHS患者血管内皮细胞及纤溶系统的影响

为探讨经鼻持续气道正压通气（nCPAP)治疗前后阻塞性睡眠呼吸暂停低通气综合征（OSAHS）患者血管内皮细胞及纤溶系统的变化及临床意义，选择年龄，性别，体重指数（BMI）无明显差异的OSAHS患者38例和健康者对照组32例，用多导睡眠呼吸监测仪进行监测，以凝固法测定纤维蛋白原（Fg），发色底物法测组织纤溶酶原激活物活性（tPA：A）、纤溶酶原激活物抑制物－1活性（PAI－1：A），酶联免疫法测vonWillebrand因子（vWF)、组织纤溶酶原激活物抗原（tPA:Ag）、纤溶酶原含量（PLg:Ag)和纤溶酶原激活物抑制物－1含量（PAI－1：Ag）。结果OSAHS组与对照组比较，vWF,Fg,tPA:Ag、PAI－1：A明显升高（P分别＜0．01，0．001，0．001，0．01），PLg:Ag、tPA:A、tPA:Ag、最低血氧饱和度（SaO2low)明显降低（P分别＜0．01，0．001，0．001，0．01).nCPAP治疗后与治疗前比较，vWF,Fg,PAI-1:Ag,PAI-1:A明显降低（P分别＜0．05，0．01，0．01，0．01），PLg:Ag,tPA:A,tPA:Ag，最低SaO2明显升高（P分别＜0．05，0．001，0．001，0．01）。提示OSAHS患者血管内皮细胞损伤，凝血功能增强，纤溶系统功能减弱;nCPAP治疗能部分纠正各指标的异常。     

Regulation of endothelial tissue plasminogen activator and plasminogen activator inhibitor type 1 synthesis by diacylglycerol,phorbol ester,and thrombin

Summary The influence of diacylglycerols, which are physiological activators of protein kinase C, on the production of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) by human umbilical vein endothelial cells (HUVEC) was studied in order to gain insight into the regulation of fibrinolysis by these cells. 1,2-dioctanoyl-sn-glycerol (diC₈) stimulated tPA production in a dose- and time-dependent manner. The tPA antigen in cell supernatants increased from 0.9 ng/10⁶ cells in unstimulated cells to 12.4 ng (10⁶ cells after incubation with 400µM diC₈ for 24 hours. In contrast, PAI-1 production was not influenced by diC₈, whereas phorbol 12-myristrate 13-acetate (PMA) or thrombin stimulated both, tPA and PAI-1 production by HUVEC. Staurosporine and H7, which are inhibitors of protein kinase C, inhibited tPA synthesis by HUVEC. The degree of inhibition was dependent on the agonist used. While diC₈-induced tPA production was inhibited to more than 80% by H7 (10µM) and staurosporine (10 nM), higher doses of inhibitors were required to inhibit thrombin- and PMA-induced tPA production. Thrombin-induced PAI-1 production was inhibited to more than 80% by H7 (10µM) and to about 50% by staurosporine, whereas PMA-induced PAI-1 production was not inhibited by staurosporine, and only to about 50% by higher doses of H7 (30µM). These data suggest that activation of protein kinase C is a common intracellular trigger mechanism for the induction of tPA synthesis by HUVEC. Protein kinase C is most likely also involved in the regulation of PAI-1 synthesis by HUVEC.     

Levothyroxine (LT4) suppression treatment for benign thyroid nodules alters coagulation

Objective  Endogenous hyperthyroidism is associated with altered coagulation. The aim of the present study is to investigate the effect of levothyroxine (LT₄) suppression treatment for benign thyroid nodules on coagulation system.
Design  Prospective case-control study.
Patients  Thirty consecutive euthyroid pre-menopausal women with nodular goitre disease and 28 healthy controls were included in the study.
Measurements  Plasma fibrinogen, d-dimer, von Willebrand factor (vWF), tissue factor (TF), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) and tissue factor pathway inhibitor (TFPI) levels were measured at baseline and after LT₄ suppression therapy.
Results  Plasma levels of fibrinogen, d-dimer, vWF, TF and PAI-1 increased significantly after treatment with LT₄ for 1 year. Serum FT₄ was a significant predictor of increased fibrinogen, vWF and PAI-1 levels, when the data was controlled for age and BMI.
Conclusions  Our results suggest that LT₄ suppression therapy for benign thyroid nodules is associated with enhanced coagulation.     

Independent relationship between microalbuminuria and plasminogen activator inhibitor-1 activity (PAI-1) activity in clinically healthy 58-year-old men.

The aim of this cross-sectional study was to investigate the relationship between low-grade albuminuria (microalbuminuria) and factors of the coagulation- and fibrinolysis systems in 104 clinically healthy 58-year-old men recruited from the general population. Urinary albumin excretion was significantly associated with body mass index, systolic and diastolic blood pressure, plasminogen activator inhibitor (PAI)-1 activity, tissue plasminogen activator (tPA) antigen, tPA activity (negatively) and protein S (P<0.05). There were no associations between urinary albumin excretion and antithrombin III, fibrinogen, protein C, thrombin/antithrombin factor or von Willebrand factor. In multiple regression analysis urinary albumin excretion was independently and significantly associated with PAI-1 activity and systolic blood pressure (P<0.05). In conclusion we report that urinary albumin excretion was independently and significantly associated with PAI-1 activity in clinically healthy 58-year-old men. This relationship may contribute to the previously reported increased cardiovascular morbidity in subjects with microalbuminuria.     

高血糖合并冠心病患者血管性假性血友病因子、纤溶酶原激活剂抑制物及脂联素水平研究

目的探讨高血糖合并冠心病患者血管性假性血友病因子（vWF）、纤溶酶原激活剂抑制物1（PAI-1）及脂联素水平及其意义。方法163例明确诊断冠心病患者,行口服75g葡萄糖耐量试验确诊冠心病合并2型糖尿病44例（26．99％）,冠心病合并单纯糖耐量低减59例（24．38％）,冠心病合并单纯空腹血糖受损15例（7．46％）,冠心病正常糖代谢40例（24．54％）。应用酶联免疫吸附法检测糖尿病组、糖耐量低减组、空腹血糖受损组及正常糖耐量组的vWF、PAI-1及脂联素水平。结果糖尿病合并冠心病组、糖耐量低减合并冠心病组vWF均明显高于正常血糖组,具有显著统计学意义。糖尿病合并冠心病组PAI-1较正常血糖组明显增高,具有统计学意义,而糖耐量低减组及空腹血糖受损组与正常血糖组无明显差异。糖尿病及糖耐量低减组脂联素较正常血糖组明显降低,具有统计学意义,空腹血糖受损组和正常血糖组未见明显差异。结论高血糖合并冠心病患者血管内皮损伤较血糖正常冠心病患者更加明显,及早发现并积极控制血糖对于防止冠心病的发生发展具有重要意义。     

西拉普利对心房颤动犬内皮细胞功能及纤溶系统的影响

目的研究血管紧张素转换酶抑制剂西拉普利对心房颤动(房颤)犬内皮功能和纤溶系统的影响。方法应用埋藏式高频心脏起搏器快速起搏心房建立房颤犬动物模型。实验分为未起搏组、单纯起搏组和起搏 西拉普利组。采用ISO-NOP3005一氧化氮(NO)敏感电极测定心内膜NO含量;酶联免疫吸附双抗体夹心法测定血浆血管性血友病因子水平;Westernblot定量分析心房心肌纤溶酶原激活剂抑制物-1(PAI-1)和组织型纤溶酶原激活剂(tPA)蛋白表达;同时免疫组化检测蛋白表达位置。血浆PAI-1和tPA含量采用酶联免疫吸附双抗体夹心法测定。结果西拉普利能显增加房颤犬心内膜NO合成,降低血浆血管性血友病因子水平,同时显减少心房肌PAI-1蛋白表达和血浆PAI-1含量,增加心房肌tPA蛋白表达和血浆含量。结论西拉普利能明显改善房颤犬内皮细胞功能,恢复纤溶系统平衡,可能对房颤的血栓前状态有益。     

Quantitative measurement of carotid atherosclerosis in relation to levels of von Willebrand factor and fibrinolytic variables in plasma--a 2-year follow-up study

BACKGROUND: It has been proposed that the mechanism of action of the new risk factors for myocardial infarction and stroke, von Willebrand factor (vWF), tissue plasminogen activator (tPA) and tissue plasminogen activator inhibitor-1 (PAI-1) could possibly be mediated via a primary effect on atherogenesis but there is little data to substantiate this. DESIGN: A prospective single-centre cohort study of progression of atherosclerosis. METHODS: Carotid plaque area was quantitated by two-dimensional (2D) ultrasound in 258 subjects at entry and after 1 and 2 years. Plasma and serum samples were drawn at baseline and serum lipids and plasma levels of haemostatic factors were measured. RESULTS: The traditional risk factors, smoking, total cholesterol, hypertension and male gender explained 51% of the variance in plaque area at baseline and 48% at 1-year follow-up. There were small positive associations of plaque area with vWF, tPA and tPA/PAI-1 complex and a tendency to negative associations with PAI-1 levels, independent from the traditional risk factors. The additional explanatory power of the haemostatic factors did not exceed 3%. CONCLUSION: The data accord with a marginal role in atherogenesis of vWF and tPA, and underline the major impact of smoking, hypertension and cholesterol on carotid plaque area progression.     

Severity of venous insufficiency is related to the density of microvascular deposition of PAI-1, uPA and von Willebrand factor

BACKGROUND: Impaired microcirculation in chronic venous insufficiency leads to chronic inflammation and dystrophic changes of the skin, and finally to leg ulceration. The purpose of this study was to investigate in more detail coagulation and fibrinolytic protein response of the capillaries in skin biopsies of the lower extremity. PATIENTS AND METHODS: From eighteen ambulant patients with venous leg ulcer(s) (n = 8) and controls (n = 10) with various degrees of venous insufficiency according to the CEAP classification, we obtained 4 mm punch biopsies. Immunohistochemical staining with tissue derived plasminogen activator (tPA), urokinase derived plasminogen activator (uPA), plasminogen activator inhibitor (PAI-1) and von Willebrand Factor (vWF) was performed and analyzed with bright field microscopy. RESULTS: The amount of staining with vWF (p = 0.04) and uPA (p = 0.02) showed statistically significant differences, PAI-1 (p = 0.09) and tPA (p = 0.50) showed no difference between leg ulcer and control groups. A strong proliferation of capillaries with tortuous capillary loops in the papillary dermis was seen, but no statistically significant difference (M-W test, p = 0.10) was found between the groups. Comparison between CEAP classes 0-6 showed a statistically significant increased staining pattern of vWF (p = 0.06), uPA (p = 0.02) and PAI-1 (p = 0.02), but not from tPA (p = 0.30). CONCLUSIONS: In skin biopsies of the lower extremity of patients with severe venous insufficiency increased deposition of vWF, PAI-1 and uPA were found in the capillaries. These findings point to a local imbalance in coagulation and fibrinolytic status, which might contribute to impaired microcirculation and finally to the development of venous leg ulceration.     

Tissue plasminogen activator and plasminogen activator inhibitor gene polymorphisms: possible relation to atherosclerosis and its complications

In the present review the dates about association of genetic variants of a plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) with ischemic heart disease and atherosclerosis of other localization are toted. The singularities of synthesis of PAI-1 and tPA, possible paths of regulation of their activity briefly surveyed. Known polymorphisms of PAI-1 gene and tPA gene, their localization, frequencies in different ethnic groups are circumscribed. In operation the genetic influence of polymorphisms of PAI-1 gene and tPA gene on synthesis and plasma concentration of PAI-1 and tPA, including under an operation of risk factors of atherosclerosis, and as possible clinical consequences of sectional violations is featured. In the review the possible role of polymorphisms of PAI-1 gene and tPA gene in a pathogenesis of atherosclerosis, association with hazard thrombotic complications for different diseases is considered. Many clinical examinations are circumscribed which have confirmed or not confirmed a possible connection of genetic markers with development and current of ischemic heart disease and other vascular diseases. We considered that there are no enough dates to one valued estimation of possible role of polymorphisms of PAI-1 and tPA genes in pathogenesis of atherosclerosis. It is necessary to get new genetic studies in groups of patient with high risk of ischemic heart disease and atherosclerosis.     

氯沙坦和阿替洛尔对高血压患者纤溶系统及血浆血管性血友病因子的作用比较

目的比较血管紧张素受体拮抗剂(ARB)氯沙坦和β受体阻滞剂阿替洛尔对原发性高血压患者纤溶系统及血浆血管性血友病因子(vWF)的影响。方法轻中度原发性高血压患者60例随机分成氯沙坦组和阿替洛尔组(每组30例),分别给予氯沙坦50mg/(次.d)或阿替洛尔50mg/(次.d),共治疗8周。每4周随访1次,4周时血压如不达标(BP<140/90mmHg)则加用双氢克尿噻12.5mg/(次.d)。治疗前后行血浆组织型纤溶酶原激活物(tPA)及纤溶酶原激活物抑制剂1(PAI-1)检测,并计算PAI-1/tPA作为纤溶参数,同时测定血浆vWF的含量。结果两组的基线血压等一般情况具有可比性。治疗4周及8周时两组血压均较治疗前显著下降,组间比较无差异。同治疗前相比,氯沙坦组治疗8周时血浆PAI-1和vWF水平下降(P值分别<0.05及<0.01),PAI-1/tPA也有显著下降(P<0.05),而tPA则无显著变化(P>0.05);阿替洛尔组治疗8周时血浆PAI-1和vWF水平及PAI-1/tPA均无显著变化,而tPA则有所上升(P<0.05)。治疗后血浆vWF两组间比较,差异有非常显著意义。结论氯沙坦治疗能改善原发性高血压患者的纤溶系统并降低血浆vWF,而阿替洛尔则未见有此作用。     

Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with antiphospholipid antibodies

OBJECTIVE: Impaired fibrinolytical outcomes may be one of the pathogenic factors for thrombotic events in patients with antiphospholipid antibodies (aPL). We investigated the consequences of the gene polymorphisms of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in patients positive for aPL. METHODS: Seventy-seven Japanese and 82 British patients with aPL were examined for Alu-repeat insertion (I)/deletion (D) polymorphism of the tPA gene by polymerase chain reaction (PCR), and 4G/5G polymorphism in the PAI-1 promoter gene by site-directed mutagenesis-PCR and restriction fragment length polymorphism analysis. Correlations between these polymorphisms and clinical symptoms of antiphospholipid syndrome (APS) (arterial thrombosis, venous thrombosis, miscarriage) were analyzed. RESULTS: Significant differences in the allele frequencies of these genes did not exist between patients and controls. There was no significant correlation between these gene polymorphisms and clinical symptoms of APS in patients with aPL. CONCLUSION: Polymorphisms of the tPA or PAI-1 genes probably do not significantly influence the risk of anerial thrombosis, venous thrombosis, or pregnancy morbidity in patients with aPL.     

ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension

BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with an increased incidence of myocardial infarction. Recent studies have investigated a potential influence of ACE gene polymorphism on fibrinolysis or endothelial function. It has been previously established that essential hypertension is accompanied by endothelial dysfunction and fibrinolytic balance disorders. The aim of our study was to study the relation between ACE gene polymorphism and fibrinolytic/hemostatic factors as well as endothelial cell damage markers in patients with hypertension. METHODS: The following parameters were evaluated in 104 patients with previously untreated hypertension: plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) antigen, fibrinogen, D-dimer, and von Willebrand factor (vWF). The genotype of the ACE gene was also determined (by the polymerase chain reaction method), and patients were characterized according to the observed alleles as deletion/deletion (DD), insertion/insertion (II), or insertion/deletion (ID). RESULTS: Those with DD genotype (n = 42) had significantly higher plasma levels of PAI-1 antigen (P =. 012), tPA antigen (P =.0001), fibrinogen (P =.0002), D-dimer (P =. 0001) and vWF (P =.0004) compared with ID (n = 30) or II (n = 32) genotypes. The ACE gene genotypes appeared to be significant predictors for plasma PAI-1 antigen, tPA antigen, fibrinogen, D -dimer, and vWF even after adjustment for age, sex, body mass index, triglyceride and cholesterol levels, and blood pressure. CONCLUSIONS: Our findings suggest that the ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial damage in patients with untreated hypertension.     

Protection by α2-macroglobulin of tissue plasminogen activator against inhibition by plasminogen activator inhibitor-1

Tissue plasminogen activator (tPA) is widely used in the treatment of acute myocardial infarction (MI). However, its thrombolytic efficacy does not correlate with the dose administered. The interactions between tPA, α2-macroglobulin (α2-M), and plasminogen activator inhibitor-1 (PAI-1) were investigated both in vitro and in patients undergoing tPA therapy for MI in an attempt to identify variables that might affect the clinical efficacy of tPA.
Purified α2-M (5.4 mg/ml) protected 16.0% or 22.4% of tPA (12.5 IU/ml) activity from inhibition by PAI-1 at 4 or 8 IU/ml in vitro . Of nine patients treated with 5–20 mega IU of tPA for MI, the plasma activity of tPA remained increased for 15–30 min after the cessation of infusion in eight; the patient who failed to exhibit a persistent increase in tPA activity had a low plasma concentration of α2-M. Total tPA activity, derived from the area under the activity-versus-time curve (AUC), showed a significant inverse correlation with the ratio of the plasma PAI-1 activity to the plasma α2-M concentration. Total tPA activity did not correlate with plasma PAI-1 activity or plasma α2-M concentration alone. Results suggest that α2-M, by binding to tPA, protects the latter against inhibition by PAI-1.     

The effect of heparin and other glycosaminoglycans on levels of tissue plasminogen activator and plasminogen activator inhibitor in cultured human umbilical vein endothelial cells

Human umbilical vein endothelial cells (HUVEC) were cultured in the presence of various glycosaminoglycans and the intracellular levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) measured by ELISA. 10 IU/ml heparin (90 micrograms/ml) brought about a significant (20-fold) increase in intracellular tPA levels over the 6-day culture period; intracellular PAI-1 levels were significantly decreased (by 60-70%) and culture growth rate promoted. The final cell density of heparin-containing cultures was 1.7 to 2.3 times greater than that of control cultures. Low molecular weight heparin (First International Standard) had similar effects but was less potent than unfractionated heparin. Chondroitin sulphate and heparan sulphate had no effect on tPA and PAI-1 levels but dermatan sulphate reduced PAI-1 significantly. The changes observed following exposure of HUVEC to heparin are consonant with the view that glycosaminoglycans may affect endothelial production of fibrinolytic components.