The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with ...The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with minimally invasive surgery (MIS) and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS (T1), post-MIS (T2) and day 10-16 (T3) following diagnostic computed tomographic scans (To). Forty-three patients aged 52.8±11.1 years with (n=30) or without rt-PA (n=13) were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 (1) mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls (77.9%±20.4% vs. 64%±15%; P=0.046). From TI to T2, reduction in PHE volume was strongly associ- ated with the percentage of clot evacuation (p=0.34; P=-0.027). In addition, PHE volume was positively correlated with residual ICH volume at the same day (p ranging from 0.39-0.56, P〈0.01). There was no correlation between the cumulative dose of rt-PA and early (T2) PHE volume (p=0.24; P=0.12) or de- layed (T3) PHE volume (p=0.19; P=0.16). The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mor- tality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.展开更多
BACKGROUND:The study aimed to compare the therapeutic effect of recombinant tissue plasminogen activator(rt-PA) on the onset of acute cerebral infarction(ACI) at different time points of the first 6 hours.METHODS:A re...BACKGROUND:The study aimed to compare the therapeutic effect of recombinant tissue plasminogen activator(rt-PA) on the onset of acute cerebral infarction(ACI) at different time points of the first 6 hours.METHODS:A retrospective analysis was conducted in 74 patients who received rt-PA thrombolysis treatment within 4.5 hours after ACI and another 15 patients who received rt-PA thrombolysis treatment between 4.5-6 hours after ACI.RESULTS:National Institute of Health Stroke Scale(NIHSS) scores were statistically decreased in both groups(P>0.05) at 24 hours and 7 days after ACI.There was no significant difference in modified ranking scores and mortality at 90 days after the treatment between the two groups(P>0.05).CONCLUSIONS:The therapeutic effect and mortality of rt-PA treatment in patients with ACI between 4.5-6 hours after the onset of the disease were similar to those in patients who received rtPA within 4.5 hours after the onset of this disease.Therefore,intravenous thrombolytic therapy for ACI within 4.5-6 hours after ACI was effective and safe.展开更多
The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a ...The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly(ethylene glycol)- poly(ε-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4℃. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P〈0.001). RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.展开更多
Objective In order to investigate the pharmacological properties of Ginkgo biloba extract (GBE) on improving blood circulation, the regulating action of GBE and quercetin (a main flavonoid ingredient in GBE) on th...Objective In order to investigate the pharmacological properties of Ginkgo biloba extract (GBE) on improving blood circulation, the regulating action of GBE and quercetin (a main flavonoid ingredient in GBE) on thrombomodulin (TM) expression and tissue-type plasminogen activator (t-PA) secretion was studied. Methods Using flow cytometer and gel image system respectively, we evaluated the TM expression and the t-PA secretion by human umbilical vein endothelial cells (HUVECs) in vitro. Results The increase of TM expression on HUVECs surface was induced by GBE rather than quercetin in a dose- and time-dependent manner. Both GBE and quercetin increased the t-PA release significantly. Conclusion The effect of GBE on improving blood circulation may be partly attributed to its promoting TM expression and t-PA secretion by endothelial ceils, and quercetin participated in the effect of GBE on t-PA secretion. However, the action of GBE on increasing TM expression needs further study.展开更多
The effects of in vivo local expression of recombined human tissue-type plasminogen activator (t-PA) gene on the thrombosis and neointima formation of vein grafts were explored. Jugular vein-to-artery bypass graftin...The effects of in vivo local expression of recombined human tissue-type plasminogen activator (t-PA) gene on the thrombosis and neointima formation of vein grafts were explored. Jugular vein-to-artery bypass grafting was performed on 72 New Zealand white rabbits. The rabbits were divided into 3 groups according to the different processing methods: transfected t-PA gene group (n = 24), vector group (n= 24) and blank control group (n = 24). Samples of vein grafts were harvested at different time points after surgery. The expression of t-PA gene in vein graft was detected by RT-PCR and the synthesis of t-PA protein by Western-Blot assay. The t-PA activity was measured by chromogenic substrate assay. The Cr51 labeled platelets accumulation in vein grafts was counted. The histopathological changes were compared in intima hyperplasia index among the three groups after operation. The results showed that at the 2^nd , 5^th , 14^th and 28^th day after operation, RT-PCR and Western-blot confirmed the expression of t-PA mRNA and protein at the site of gene transfer. The t-PA activity detected on the 2^nd, 5^th, 14^th and 28^th day in experimental group was 370. 63±59. 44, 344. 13±48. 47, 252.87±51.80 and 161.75±68. 94 U/g respectively, and disappeared on the 60^th day and undetected in the control groups. The number of platelets accumulated in the vein grafts in gene group, vector group and blank control group was (85. 04 ± 21.58) 10s, (225.87±85.13) 10^6 and (211.57±78.02) 10^6 respectively. The number of platelets accumulated in gene group was significantly fewer than that in the control groups. Morphometric analysis revealed that intimal hyperplasia was markedly reduced in the t-PA gene group as compared with that in the control groups. It was suggested that the local expression of t-PA gene in vein graft significantly inhibited the accumulation of platelets, thrombosis and concomitant intimal hyperplasia, by which stenosis of bypass graft could be prevented effectively.展开更多
To detect the presence of endothelial injury in patients with severe acute respiratory syndrome (SARS) via enhanced levels of tissue-type plasminogen activator (t-PA) and soluble thrombomodulin (sTM). Methods Ca...To detect the presence of endothelial injury in patients with severe acute respiratory syndrome (SARS) via enhanced levels of tissue-type plasminogen activator (t-PA) and soluble thrombomodulin (sTM). Methods Case patients were from Xuanwu Hospital (Capital University of Medical Sciences, Beijing, China), and all of them met clinical criteria for SARS. Healthy controls were some of the hospital employees. Endothelial injury bio-markers tPA and sTM were detected by commercial ELISA-methods. Results Classic plasma markers of endothelial injury, tPA and sTM significantly elevated in SARS patients in comparison to controls [t-PA: 1.48±0.16 nmol/L versus 0.25±0.03 nmol/L (P〈0.0001), and sTM: 0.26±0.06 nmol/L versus 0.14±0.02 nmol/L (P〈0.05)]. The only patient who died had extremely high levels of these endothelial injury markers (t-PA: 2.77 nmol/L and sTM: 1.01 nmol/L). The likelihood ratio analysis indicated the excellent discriminating power for SARS at the optimal cut-point of 0.49 nmol/L for tPA and 0.20 nmol/L for sTM, respectively. Significant numerical correlations were found among these endothelial injury markers in SARS patients. The numerical coefficient of correlation Pearson r between t-PA and sTM was 0.5867 (P〈0.05). Conclusion Increased plasma concentrations of tPA and sTM in patients with SARS suggest the possibility of endothelial injury. SARS patients might need anticoagulant therapy or fibrinolytic therapy in order to reverse intraalveolar coagulation, microthrombi formation, alveolar and interstitial fibrin deposition. It may not only provide a useful treatment and prognostic index but also allow a further understanding of the pathological condition of the disease.展开更多
Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator(t PA) from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes t...Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator(t PA) from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density(PSD) that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^(2+)/calmodulin-dependent protein kinase IIα(pCa MKIIα),followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA) receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate(NMDA) receptors and cyclin-dependent kinase 5(Cdk5)-induced phosphorylation of the protein phosphatase 1(PP1) at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.展开更多
It is here reported for the first time that luteal cells are capable of secreting plasminogen activators(PA),(both tissue-type,tPA,and urokinase-type,uPA),and plasminogen activator inhibitor type-1(PAl-1).Using organ ...It is here reported for the first time that luteal cells are capable of secreting plasminogen activators(PA),(both tissue-type,tPA,and urokinase-type,uPA),and plasminogen activator inhibitor type-1(PAl-1).Using organ culture model,we have demonstrated that tPA,but not uPA,showed markedchange during luteolytic period in rat corpus luteum.A great amount oftPA was secreted in corpusluteum on D 14 and D 17 while very low level of tPA activity was detected before D 12.Correspondingly,the progesterone production in the corpus luteum increased gradually in a time-dependent manner from D 1 to D 12 but dropped abruptly to a very low level on D 14.Additionof exogenous tPA to the CL culture caused considerable decrease in progesterone secretion whileinclusion of purified monoclone tPA antibodies in the culture augmented progesterone productionof CL.It is therefore suggested that tPA may play an important role in luteolytic process.展开更多
Objective To observe the changes of the activity of tissue -type plasminogen activa tor(TPA)after asphyxia.Methods As-phyxia was induced in mouse pups by performing a ‘delayed cesarean section’.The experiment was de...Objective To observe the changes of the activity of tissue -type plasminogen activa tor(TPA)after asphyxia.Methods As-phyxia was induced in mouse pups by performing a ‘delayed cesarean section’.The experiment was designed for a co ntrol group and 4asphyctic groups to detect the activity of TPA.Results TPAactivity of brain increased afte r asphyxia(P <0.01).Conclusion TPAincreased after asphyxia might be able to attack the b asement membrane of microvessels,t hen opened the blood -brain barrier a nd induced neuronal damage.展开更多
A number of studies have confirmed the existence of tissue-type plasminogen activator-independent roles of neuroserpin, a member of the serine protease inhibitor superfamily. In this review article, we aim to clarify ...A number of studies have confirmed the existence of tissue-type plasminogen activator-independent roles of neuroserpin, a member of the serine protease inhibitor superfamily. In this review article, we aim to clarify this role. These unique roles of neuroserpin are involved in its neuroprotective effect during ischemic brain injury, its regulation of tumorigenesis, and the mediation of emotion and cognition through the inhibition of urokinase-type plasminogen activator and fibrinolysin, modification of Th cells, reducing plaque formation, promoting process growth and intracellular adhesion, and alterina the expression of cadherin and nuclear factor kaooa B.展开更多
Background Thrombolysis with recombinant tissue plasminogen activator (rt-PA) has gained international recognition, clinical outcomes following this thrombolytic therapy varied from patient to patient. Factors affec...Background Thrombolysis with recombinant tissue plasminogen activator (rt-PA) has gained international recognition, clinical outcomes following this thrombolytic therapy varied from patient to patient. Factors affecting clinical outcomes have not been well understood yet, so this retrospective case-control study aimed to investigate factors that may influence clinical outcomes of acute ischemic stroke treated with intravenous rt-PA. Methods One hundred and one patients with acute ischemic stroke who received intravenous rt-PA thrombolysis within 4.5 hours from disease onset were included. Patients were divided into good or poor outcome group according to modified Rankin Scale (mRS) score, good outcome group: mRS score of 0-1; poor outcome group: mRS of 2-6. Stroke characteristics were compared between the two groups. Factors for stroke outcomes were analyzed via univariate analysis and Logistic regression. Results Of the 101 patients studied, patients in good outcome group (n=55) were significantly younger than patients in poor outcome group (n=46, (62.82±14.25) vs. (68.81±9.85) years, P=0.029). Good outcome group had fewer patients with diabetic history (9.09% vs. 28.26%, P=0.012), fewer patients with leukoaraiosis (7.27% vs. 28.26%, P=-0.005) and presented with lower blood glucose level ((5.72±1.76) vs. (6.72±1.32) mmol/L, P=0.012), lower systolic blood pressure level ((135.45±19.36) vs. (148.78±19.39) mmHg, P=0.003), lower baseline NIHSS score (12.02±5.26 vs. 15.78±4.98, P=0.002) and shorter onset-to-treatment time (OTT) ((2.38±1.21) vs. (2.57±1.03) hours, P=0.044) than poor outcome group. Logistic regression analysis showed that absence of diabetic history (odds ratio (OR) 0.968 (95% CI 0.941-0.996)), absence of leukoaraiosis (OR 0.835 (95% C/0.712-0.980)), lower baseline NIHSS score (OR 0.885 (95% Cl 0.793- 0.989)), lower pre-thrombolysis systolic blood pressure (OR 0.962 (95% CI 0.929-0.997)), and lower blood glucose level (OR 0.699 (95% Cl 0.491-0.994)) before thrombolysis were significantly associated with better outcome. Conclusion Patients with no history of diabetes, no leukoaraiosis, low blood glucose level, low systolic blood pressure level and low baseline NIHSS score before thrombolvsis have a better outcome.展开更多
Background The association between vulnerability of plaque assessed with intravascular ultrasound (IVUS) and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome (ACS). ...Background The association between vulnerability of plaque assessed with intravascular ultrasound (IVUS) and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome (ACS). However, few data are available on the relationship between the levels of tissue type plasminogen activator (t-PA) and virtual histological intravascular ultrasound (VH-IVUS) signs of plaque instability. Methods Eighty-nine patients with ACS were enrolled in the study. Blood was collected to measure t-PA levels by liquid phase bead flow cytometry. Eighty-nine nonbifurcate lesions (identified by coronary angiography and ECG) were investigated using IVUS before catheterization. IVUS radiofrequency data obtained with a 20 MHz catheter were analyzed with IVUS virtual histological software. The areas of plaque and media were calculated and lesions were classified into two groups: VH-IVUS derived thin cap fibroatheroma (VH-TCFA) and non-VH-TCFA plaque. Results Plasma t-PA level in the patients with TCFA was significantly lower than that with non-TCFA ((1489 ± 715) pg/ml vs (2163 ± 1004) pg/ml). Decreased plasma levels of t-PA were associated with plaque vulnerability. Plasma levels of t-PA correlated negatively with plaque plus media and necrotic core in plaque in patients with ACS. Conclusions t-PA is an independent risk factor and a powerful predictor of vulnerable plaques. Decreased levels of t-PA may reflect instability of atherosclerotic plaques and might therefore serve as noninvasive determinants of those at high risk for consequent adverse events.展开更多
New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (bu...New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (but not uPA) and PAI-1 secretion in the culture are modified by FSH, forskolin, dbcAMP, GnRH, PMA and growth factors (EGF and FGF), but not by hCG and androstenedione (△4); (iii) in vitro secretion of tPA and PA-PAI-1 complexes of Sertoli cells are greatly enhanced by presence of Leydig cells which produce negligible tPA but measurable PAI-1 activity;(iv) combination culture of Sertoli and Leydig cells remarkably increases FSH-induced PAI-1 activity and decreases hCG- and forskolin-induced inhibitor activity as compared with that of two cell types cultured alone. These data suggest that rat Sertoli cells, similar to ovarian granulosa cells, are capable of secreting both tPA and uPA, as well as PAI-1. The interaction of Sertoli cells and Leydig cells is essential for the cells to response展开更多
Two types of plasminogen activators, tissue type (tPA) and urokinase type(uPA),and a plasminogen activator inhibitor (PAI-1) have been identified in ovariangranulosa cells (GC) of both rat and rhesus monkey. Interacti...Two types of plasminogen activators, tissue type (tPA) and urokinase type(uPA),and a plasminogen activator inhibitor (PAI-1) have been identified in ovariangranulosa cells (GC) of both rat and rhesus monkey. Interaction and coordinated expression of tPA and PAI-1 in the same tissue cells are closely related with certain reproductive processes such as ovulation, spermatogenesis and endometrium cycle. In our previous studies on gonadotropin-induced ovulation in rhesus monkeys,we展开更多
Background Cigarette smoking has an influence on both arterial-type and venous-type thrombosis. However, little is known about the direct effect of cigarette smoke extract (CSE) on fibrinolytic activity of human umb...Background Cigarette smoking has an influence on both arterial-type and venous-type thrombosis. However, little is known about the direct effect of cigarette smoke extract (CSE) on fibrinolytic activity of human umbilical vein endothelial cells (HUVECs). Most recently, simvastatin has been marked in its effect on endothelial cells protection and anticoagulation. In this study, the effect of CSE on the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-l(PAl-1) in HUVECs was addressed. The role of simvastatin in CSE-induced fibrinolytic activity changes was investigated as well. Methods The fourth to fifth generation of HUVECs were incubated respectively with 0, 5%, 10% and 20% CSE for 6 hours or exposed to 5% CSE for 0, 4, 6, 8, 12, 24 hours to determine the expression changes of t-PA and PAl-1 protein. Meanwhile, cells were also accordingly exposed either to 5% CSE alone or simvastatin pre-treated and 5% CSE for 24 hours to assess the role of simvastatin in CSE-induced t-PA and PAl-1 protein and mRNA expression in HUVECs. RT-PCR and ELISA techniques were used for detecting the t-PA or PAl-1 mRNA and protein. Results After 6-hour exposure to CSE, the expression levels of t-PA protein in 10% and 20% CSE-treated groups reduced significantly ((0.0365±0.0083) ng/ml, (0.0255±0.0087) ng/ml) when compared with that of control group ((0.0660±0.0120) ng/ml) (P 〈0.05). In contrast, the levels of PAl-1 protein in 5%, 10% and 20% CSE-treated groups increased remarkably ((13.3225±0.5680) ng/ml, (14.2675±1.5380) ng/ml, (14.4292±1.6230) ng/ml) when compared with that of control group ((8.5193_±0.7537)ng/ml) (P〈0.05). After stimulation with 5% CSE for 0, 4, 6, 8, 12, 24 hours, the levels of PAl-1 protein increased over time and reached the peak at 24 hours ((14.6400±1.0651) ng/ml), which was significantly higher than that of control group ((12.0656±0.6148) ng/ml) (P 〈0.05). Additionally, CSE could up-regulate PAl-1 expression at both the mRNA and the protein levels. The levels of PAl-1 mRNA and protein increased significantly in 5% CSE-treated group ((8.8030±0.4745) ng/ml, (1.8155±0.0412) ng/ml) compared with those of control groups ((5.0588±0.2315) ng/ml, (1.3030±0.0647) ng/ml) (P 〈0.01), and decreased after 2-hour simvastatin pre-treatment ((5.4875±0.3166) ng/ml, (1.3975-±0.0297) ng/ml) (P 〈0.01). No significant difference was found at the levels of t-PA protein and mRNA (P 〉0.05). Conclusions CSE inhibits the fibrinolytic activity of HUVECs in vitro. Simvastatin plays a protective role in CSE-induced fibrinolytic malfunction.展开更多
In view of the similarity of the charge distribution between fibrin A_α148--161 and Achain 149--157 of urokinase,the latter might compete with fibrin A_α148--161 when singlechain pro-urokinase is converted to double...In view of the similarity of the charge distribution between fibrin A_α148--161 and Achain 149--157 of urokinase,the latter might compete with fibrin A_α148--161 when singlechain pro-urokinase is converted to double chain urokinase.To test this, the stretch of uro-kinase A chain 135--157 was separated from the low molecular weight urokinase, a competi-tive binding between this stretch and fibrin to tPA kringle-2 was shown by radio-bindingassay. The inhibition of the stretch on the fibrin stimulated activation of plasminogen wasdemonstrated in the caseinolytic system. The synthesized novapeptide urokinase A chain 149--157 (R-peptide) showed a significant inhibition on the activation of plasminogen in the pres-ence of fibrin. By contrasting finely with R-peptide, a synthesized novapeptide in which Arg154and Arg156 were replaced by Asp (D-peptide) did not show any inhibition effect on the fi-brin stimulated activation of plasminogen by tPA. These results suggest that the positivelycharged residues in展开更多
INCREASING evidence has demonstrated that the locally controlled proteolytic activity generatedby coordinated expression of tPA and PAI-1 in different tissues may play an important role inmany reproductive events. The...INCREASING evidence has demonstrated that the locally controlled proteolytic activity generatedby coordinated expression of tPA and PAI-1 in different tissues may play an important role inmany reproductive events. These are largely related to fibrinolytic activity. They include folli-cle rupture, luteolysis, spermatogenesis and trophoblast implantation. Parturition, whichis a complex process, may also be associated with tissue destruction. Detachment of placentaldecidua and partial breakdown of fetal membranes are possible examples. It has been展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81171089 and No.30770751)Key Clinical Program of the Ministry of Health of China(2010)the Future Program of New Technology and New Business in Tongji Hospital,China(2012)
文摘The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with minimally invasive surgery (MIS) and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS (T1), post-MIS (T2) and day 10-16 (T3) following diagnostic computed tomographic scans (To). Forty-three patients aged 52.8±11.1 years with (n=30) or without rt-PA (n=13) were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 (1) mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls (77.9%±20.4% vs. 64%±15%; P=0.046). From TI to T2, reduction in PHE volume was strongly associ- ated with the percentage of clot evacuation (p=0.34; P=-0.027). In addition, PHE volume was positively correlated with residual ICH volume at the same day (p ranging from 0.39-0.56, P〈0.01). There was no correlation between the cumulative dose of rt-PA and early (T2) PHE volume (p=0.24; P=0.12) or de- layed (T3) PHE volume (p=0.19; P=0.16). The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mor- tality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.
基金supported by a grant from Shanghai Municipal Health Bureau(GWDTR201219)
文摘BACKGROUND:The study aimed to compare the therapeutic effect of recombinant tissue plasminogen activator(rt-PA) on the onset of acute cerebral infarction(ACI) at different time points of the first 6 hours.METHODS:A retrospective analysis was conducted in 74 patients who received rt-PA thrombolysis treatment within 4.5 hours after ACI and another 15 patients who received rt-PA thrombolysis treatment between 4.5-6 hours after ACI.RESULTS:National Institute of Health Stroke Scale(NIHSS) scores were statistically decreased in both groups(P>0.05) at 24 hours and 7 days after ACI.There was no significant difference in modified ranking scores and mortality at 90 days after the treatment between the two groups(P>0.05).CONCLUSIONS:The therapeutic effect and mortality of rt-PA treatment in patients with ACI between 4.5-6 hours after the onset of the disease were similar to those in patients who received rtPA within 4.5 hours after the onset of this disease.Therefore,intravenous thrombolytic therapy for ACI within 4.5-6 hours after ACI was effective and safe.
基金This work was supported by the National Basic Scientific Research Program of China (973 Program, No. 2007CB935803), the National Natural Science Foundation of China (No. 30825018) and the Key Clinical Program of the Ministry of Health of China (No. 2010439).
文摘The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly(ethylene glycol)- poly(ε-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4℃. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P〈0.001). RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.
文摘Objective In order to investigate the pharmacological properties of Ginkgo biloba extract (GBE) on improving blood circulation, the regulating action of GBE and quercetin (a main flavonoid ingredient in GBE) on thrombomodulin (TM) expression and tissue-type plasminogen activator (t-PA) secretion was studied. Methods Using flow cytometer and gel image system respectively, we evaluated the TM expression and the t-PA secretion by human umbilical vein endothelial cells (HUVECs) in vitro. Results The increase of TM expression on HUVECs surface was induced by GBE rather than quercetin in a dose- and time-dependent manner. Both GBE and quercetin increased the t-PA release significantly. Conclusion The effect of GBE on improving blood circulation may be partly attributed to its promoting TM expression and t-PA secretion by endothelial ceils, and quercetin participated in the effect of GBE on t-PA secretion. However, the action of GBE on increasing TM expression needs further study.
文摘The effects of in vivo local expression of recombined human tissue-type plasminogen activator (t-PA) gene on the thrombosis and neointima formation of vein grafts were explored. Jugular vein-to-artery bypass grafting was performed on 72 New Zealand white rabbits. The rabbits were divided into 3 groups according to the different processing methods: transfected t-PA gene group (n = 24), vector group (n= 24) and blank control group (n = 24). Samples of vein grafts were harvested at different time points after surgery. The expression of t-PA gene in vein graft was detected by RT-PCR and the synthesis of t-PA protein by Western-Blot assay. The t-PA activity was measured by chromogenic substrate assay. The Cr51 labeled platelets accumulation in vein grafts was counted. The histopathological changes were compared in intima hyperplasia index among the three groups after operation. The results showed that at the 2^nd , 5^th , 14^th and 28^th day after operation, RT-PCR and Western-blot confirmed the expression of t-PA mRNA and protein at the site of gene transfer. The t-PA activity detected on the 2^nd, 5^th, 14^th and 28^th day in experimental group was 370. 63±59. 44, 344. 13±48. 47, 252.87±51.80 and 161.75±68. 94 U/g respectively, and disappeared on the 60^th day and undetected in the control groups. The number of platelets accumulated in the vein grafts in gene group, vector group and blank control group was (85. 04 ± 21.58) 10s, (225.87±85.13) 10^6 and (211.57±78.02) 10^6 respectively. The number of platelets accumulated in gene group was significantly fewer than that in the control groups. Morphometric analysis revealed that intimal hyperplasia was markedly reduced in the t-PA gene group as compared with that in the control groups. It was suggested that the local expression of t-PA gene in vein graft significantly inhibited the accumulation of platelets, thrombosis and concomitant intimal hyperplasia, by which stenosis of bypass graft could be prevented effectively.
文摘To detect the presence of endothelial injury in patients with severe acute respiratory syndrome (SARS) via enhanced levels of tissue-type plasminogen activator (t-PA) and soluble thrombomodulin (sTM). Methods Case patients were from Xuanwu Hospital (Capital University of Medical Sciences, Beijing, China), and all of them met clinical criteria for SARS. Healthy controls were some of the hospital employees. Endothelial injury bio-markers tPA and sTM were detected by commercial ELISA-methods. Results Classic plasma markers of endothelial injury, tPA and sTM significantly elevated in SARS patients in comparison to controls [t-PA: 1.48±0.16 nmol/L versus 0.25±0.03 nmol/L (P〈0.0001), and sTM: 0.26±0.06 nmol/L versus 0.14±0.02 nmol/L (P〈0.05)]. The only patient who died had extremely high levels of these endothelial injury markers (t-PA: 2.77 nmol/L and sTM: 1.01 nmol/L). The likelihood ratio analysis indicated the excellent discriminating power for SARS at the optimal cut-point of 0.49 nmol/L for tPA and 0.20 nmol/L for sTM, respectively. Significant numerical correlations were found among these endothelial injury markers in SARS patients. The numerical coefficient of correlation Pearson r between t-PA and sTM was 0.5867 (P〈0.05). Conclusion Increased plasma concentrations of tPA and sTM in patients with SARS suggest the possibility of endothelial injury. SARS patients might need anticoagulant therapy or fibrinolytic therapy in order to reverse intraalveolar coagulation, microthrombi formation, alveolar and interstitial fibrin deposition. It may not only provide a useful treatment and prognostic index but also allow a further understanding of the pathological condition of the disease.
基金supported in part by National Institutes of Health Grants NS-079331(to MY)and NS-091201(to MY)
文摘Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator(t PA) from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density(PSD) that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^(2+)/calmodulin-dependent protein kinase IIα(pCa MKIIα),followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA) receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate(NMDA) receptors and cyclin-dependent kinase 5(Cdk5)-induced phosphorylation of the protein phosphatase 1(PP1) at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.
基金Project supported by HRP,WHO,The State Family Planning commission State Key Laboratory of Reproductive Biology.
文摘It is here reported for the first time that luteal cells are capable of secreting plasminogen activators(PA),(both tissue-type,tPA,and urokinase-type,uPA),and plasminogen activator inhibitor type-1(PAl-1).Using organ culture model,we have demonstrated that tPA,but not uPA,showed markedchange during luteolytic period in rat corpus luteum.A great amount oftPA was secreted in corpusluteum on D 14 and D 17 while very low level of tPA activity was detected before D 12.Correspondingly,the progesterone production in the corpus luteum increased gradually in a time-dependent manner from D 1 to D 12 but dropped abruptly to a very low level on D 14.Additionof exogenous tPA to the CL culture caused considerable decrease in progesterone secretion whileinclusion of purified monoclone tPA antibodies in the culture augmented progesterone productionof CL.It is therefore suggested that tPA may play an important role in luteolytic process.
文摘Objective To observe the changes of the activity of tissue -type plasminogen activa tor(TPA)after asphyxia.Methods As-phyxia was induced in mouse pups by performing a ‘delayed cesarean section’.The experiment was designed for a co ntrol group and 4asphyctic groups to detect the activity of TPA.Results TPAactivity of brain increased afte r asphyxia(P <0.01).Conclusion TPAincreased after asphyxia might be able to attack the b asement membrane of microvessels,t hen opened the blood -brain barrier a nd induced neuronal damage.
基金supported by the National Natural Science Foundation of China, No. 30700908, 30772343 and 30973215
文摘A number of studies have confirmed the existence of tissue-type plasminogen activator-independent roles of neuroserpin, a member of the serine protease inhibitor superfamily. In this review article, we aim to clarify this role. These unique roles of neuroserpin are involved in its neuroprotective effect during ischemic brain injury, its regulation of tumorigenesis, and the mediation of emotion and cognition through the inhibition of urokinase-type plasminogen activator and fibrinolysin, modification of Th cells, reducing plaque formation, promoting process growth and intracellular adhesion, and alterina the expression of cadherin and nuclear factor kaooa B.
文摘Background Thrombolysis with recombinant tissue plasminogen activator (rt-PA) has gained international recognition, clinical outcomes following this thrombolytic therapy varied from patient to patient. Factors affecting clinical outcomes have not been well understood yet, so this retrospective case-control study aimed to investigate factors that may influence clinical outcomes of acute ischemic stroke treated with intravenous rt-PA. Methods One hundred and one patients with acute ischemic stroke who received intravenous rt-PA thrombolysis within 4.5 hours from disease onset were included. Patients were divided into good or poor outcome group according to modified Rankin Scale (mRS) score, good outcome group: mRS score of 0-1; poor outcome group: mRS of 2-6. Stroke characteristics were compared between the two groups. Factors for stroke outcomes were analyzed via univariate analysis and Logistic regression. Results Of the 101 patients studied, patients in good outcome group (n=55) were significantly younger than patients in poor outcome group (n=46, (62.82±14.25) vs. (68.81±9.85) years, P=0.029). Good outcome group had fewer patients with diabetic history (9.09% vs. 28.26%, P=0.012), fewer patients with leukoaraiosis (7.27% vs. 28.26%, P=-0.005) and presented with lower blood glucose level ((5.72±1.76) vs. (6.72±1.32) mmol/L, P=0.012), lower systolic blood pressure level ((135.45±19.36) vs. (148.78±19.39) mmHg, P=0.003), lower baseline NIHSS score (12.02±5.26 vs. 15.78±4.98, P=0.002) and shorter onset-to-treatment time (OTT) ((2.38±1.21) vs. (2.57±1.03) hours, P=0.044) than poor outcome group. Logistic regression analysis showed that absence of diabetic history (odds ratio (OR) 0.968 (95% CI 0.941-0.996)), absence of leukoaraiosis (OR 0.835 (95% C/0.712-0.980)), lower baseline NIHSS score (OR 0.885 (95% Cl 0.793- 0.989)), lower pre-thrombolysis systolic blood pressure (OR 0.962 (95% CI 0.929-0.997)), and lower blood glucose level (OR 0.699 (95% Cl 0.491-0.994)) before thrombolysis were significantly associated with better outcome. Conclusion Patients with no history of diabetes, no leukoaraiosis, low blood glucose level, low systolic blood pressure level and low baseline NIHSS score before thrombolvsis have a better outcome.
文摘Background The association between vulnerability of plaque assessed with intravascular ultrasound (IVUS) and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome (ACS). However, few data are available on the relationship between the levels of tissue type plasminogen activator (t-PA) and virtual histological intravascular ultrasound (VH-IVUS) signs of plaque instability. Methods Eighty-nine patients with ACS were enrolled in the study. Blood was collected to measure t-PA levels by liquid phase bead flow cytometry. Eighty-nine nonbifurcate lesions (identified by coronary angiography and ECG) were investigated using IVUS before catheterization. IVUS radiofrequency data obtained with a 20 MHz catheter were analyzed with IVUS virtual histological software. The areas of plaque and media were calculated and lesions were classified into two groups: VH-IVUS derived thin cap fibroatheroma (VH-TCFA) and non-VH-TCFA plaque. Results Plasma t-PA level in the patients with TCFA was significantly lower than that with non-TCFA ((1489 ± 715) pg/ml vs (2163 ± 1004) pg/ml). Decreased plasma levels of t-PA were associated with plaque vulnerability. Plasma levels of t-PA correlated negatively with plaque plus media and necrotic core in plaque in patients with ACS. Conclusions t-PA is an independent risk factor and a powerful predictor of vulnerable plaques. Decreased levels of t-PA may reflect instability of atherosclerotic plaques and might therefore serve as noninvasive determinants of those at high risk for consequent adverse events.
基金Project supported by the National Natural Science Foundation of China and State Family Planning Commission.
文摘New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (but not uPA) and PAI-1 secretion in the culture are modified by FSH, forskolin, dbcAMP, GnRH, PMA and growth factors (EGF and FGF), but not by hCG and androstenedione (△4); (iii) in vitro secretion of tPA and PA-PAI-1 complexes of Sertoli cells are greatly enhanced by presence of Leydig cells which produce negligible tPA but measurable PAI-1 activity;(iv) combination culture of Sertoli and Leydig cells remarkably increases FSH-induced PAI-1 activity and decreases hCG- and forskolin-induced inhibitor activity as compared with that of two cell types cultured alone. These data suggest that rat Sertoli cells, similar to ovarian granulosa cells, are capable of secreting both tPA and uPA, as well as PAI-1. The interaction of Sertoli cells and Leydig cells is essential for the cells to response
基金Task Foroe for Post-ovulatory Method Special Programme of Research Development+1 种基金Research Training in Human Reproduction of the World Health OrganizationState Family Planning Commission
文摘Two types of plasminogen activators, tissue type (tPA) and urokinase type(uPA),and a plasminogen activator inhibitor (PAI-1) have been identified in ovariangranulosa cells (GC) of both rat and rhesus monkey. Interaction and coordinated expression of tPA and PAI-1 in the same tissue cells are closely related with certain reproductive processes such as ovulation, spermatogenesis and endometrium cycle. In our previous studies on gonadotropin-induced ovulation in rhesus monkeys,we
文摘Background Cigarette smoking has an influence on both arterial-type and venous-type thrombosis. However, little is known about the direct effect of cigarette smoke extract (CSE) on fibrinolytic activity of human umbilical vein endothelial cells (HUVECs). Most recently, simvastatin has been marked in its effect on endothelial cells protection and anticoagulation. In this study, the effect of CSE on the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-l(PAl-1) in HUVECs was addressed. The role of simvastatin in CSE-induced fibrinolytic activity changes was investigated as well. Methods The fourth to fifth generation of HUVECs were incubated respectively with 0, 5%, 10% and 20% CSE for 6 hours or exposed to 5% CSE for 0, 4, 6, 8, 12, 24 hours to determine the expression changes of t-PA and PAl-1 protein. Meanwhile, cells were also accordingly exposed either to 5% CSE alone or simvastatin pre-treated and 5% CSE for 24 hours to assess the role of simvastatin in CSE-induced t-PA and PAl-1 protein and mRNA expression in HUVECs. RT-PCR and ELISA techniques were used for detecting the t-PA or PAl-1 mRNA and protein. Results After 6-hour exposure to CSE, the expression levels of t-PA protein in 10% and 20% CSE-treated groups reduced significantly ((0.0365±0.0083) ng/ml, (0.0255±0.0087) ng/ml) when compared with that of control group ((0.0660±0.0120) ng/ml) (P 〈0.05). In contrast, the levels of PAl-1 protein in 5%, 10% and 20% CSE-treated groups increased remarkably ((13.3225±0.5680) ng/ml, (14.2675±1.5380) ng/ml, (14.4292±1.6230) ng/ml) when compared with that of control group ((8.5193_±0.7537)ng/ml) (P〈0.05). After stimulation with 5% CSE for 0, 4, 6, 8, 12, 24 hours, the levels of PAl-1 protein increased over time and reached the peak at 24 hours ((14.6400±1.0651) ng/ml), which was significantly higher than that of control group ((12.0656±0.6148) ng/ml) (P 〈0.05). Additionally, CSE could up-regulate PAl-1 expression at both the mRNA and the protein levels. The levels of PAl-1 mRNA and protein increased significantly in 5% CSE-treated group ((8.8030±0.4745) ng/ml, (1.8155±0.0412) ng/ml) compared with those of control groups ((5.0588±0.2315) ng/ml, (1.3030±0.0647) ng/ml) (P 〈0.01), and decreased after 2-hour simvastatin pre-treatment ((5.4875±0.3166) ng/ml, (1.3975-±0.0297) ng/ml) (P 〈0.01). No significant difference was found at the levels of t-PA protein and mRNA (P 〉0.05). Conclusions CSE inhibits the fibrinolytic activity of HUVECs in vitro. Simvastatin plays a protective role in CSE-induced fibrinolytic malfunction.
基金Project supported by the National High-Technology Development Plant of China (Grant 863-103-19).
文摘In view of the similarity of the charge distribution between fibrin A_α148--161 and Achain 149--157 of urokinase,the latter might compete with fibrin A_α148--161 when singlechain pro-urokinase is converted to double chain urokinase.To test this, the stretch of uro-kinase A chain 135--157 was separated from the low molecular weight urokinase, a competi-tive binding between this stretch and fibrin to tPA kringle-2 was shown by radio-bindingassay. The inhibition of the stretch on the fibrin stimulated activation of plasminogen wasdemonstrated in the caseinolytic system. The synthesized novapeptide urokinase A chain 149--157 (R-peptide) showed a significant inhibition on the activation of plasminogen in the pres-ence of fibrin. By contrasting finely with R-peptide, a synthesized novapeptide in which Arg154and Arg156 were replaced by Asp (D-peptide) did not show any inhibition effect on the fi-brin stimulated activation of plasminogen by tPA. These results suggest that the positivelycharged residues in
文摘INCREASING evidence has demonstrated that the locally controlled proteolytic activity generatedby coordinated expression of tPA and PAI-1 in different tissues may play an important role inmany reproductive events. These are largely related to fibrinolytic activity. They include folli-cle rupture, luteolysis, spermatogenesis and trophoblast implantation. Parturition, whichis a complex process, may also be associated with tissue destruction. Detachment of placentaldecidua and partial breakdown of fetal membranes are possible examples. It has been
文摘目的探究血管内介入联合重组组织型纤溶酶原激活物(recombinant tissue plasminogen activator,r-TPA)动脉溶栓治疗对急性脑梗死(acute cerebral infarction,ACI)患者血管完全再通率及血管内皮生长因子(vascular endothelial growth factor,VEGF)、D-二聚体(D-Dimer,D-D)水平的影响。方法选取2019-06/2021-07月在作者医院收治的202例ACI患者,采用简单随机分组和随机数表法将纳入的ACI患者分为观察组(n=101例)和对照组(n=101例)。对照组接受r-TPA动脉溶栓治疗,观察组采用r-TPA动脉溶栓与血管内介入联合治疗,均持续治疗2周。比较两组治疗前后血管完全再通率,采用美国国立卫生研究院卒中量表(national institute of health stroke scale,NIHSS)和日常生活能力量表(activity of daily living scale,ADL)对两组神经功能损伤和生活质量进行评分,比较两组ACI患者治疗前后血清VEGF、单核细胞趋化蛋白1(monocyte chemoattractant protein 1,MCP-1)和白细胞介素6(interleukin 6,IL-6)水平变化。观察两组凝血指标的变化,包括D-D、纤维蛋白原(fibrinogen,FIB)和凝血酶原时间(prothrombin time,PT),并记录治疗过程中可能出现的不良反应情况。结果治疗后,观察组临床疗效和血管完全再通率较对照组明显升高(P<0.05)。观察组在治疗后NIHSS评分和ADL评分均优于对照组(P均<0.05)。治疗前两组血清VEGF、MCP-1和IL-1水平差异无统计学意义。治疗后,两组VEGF水平升高,IL-6和MCP-1水平均降低(P均<0.05)。治疗后,两组D-D水平均降低,且观察组低于对照组(P<0.05)。治疗后观察组出血不良事件较对照组明显改善(P<0.05)。结论血管内介入联合r-TPA动脉溶栓治疗ACI可提高血管完全再通率,调节VEGF、MCP-1、IL-6和D-D水平,有利于患者神经功能恢复。